Epidermal growth factor receptor and notch signaling in non-small-cell lung cancer.
Lung cancer is the most common reason of cancer deaths and about 85% of these are non-small-cell lung cancer. Currently, lung cancer therapy is mainly based on the tumor node metastasis (TNM) disease staging and tumor histological classification. Despite therapeutic innovations, the prognosis for lung cancer patients has not significantly changed in the last years. Therefore, a proper understanding of cell signaling pathways involved in cancer pathogenesis seems to be essential for improvement in cancer therapy field. The knowledge of crosstalk between epidermal growth factor receptor (EGFR) and Notch pathway can lead to enhanced screening for the expression of these genes allowing patients to optimize treatment options and predict potential treatment resistance. This review focuses on recent advances related to the mechanisms of EGFR and Notch signaling in non-small-cell lung cancer and the effectiveness of current Notch- and EGFR-targeted therapies.


Effects of different vibration frequencies, amplitudes and contraction levels on lower limb muscles during graded isometric contractions superimposed on whole body vibration stimulation.
Indirect vibration stimulation, i.e., whole body vibration or upper limb vibration, has been investigated increasingly as an exercise intervention for rehabilitation applications. However, there is a lack of evidence regarding the effects of graded isometric contractions superimposed on whole body vibration stimulation. Hence, the objective of this study was to quantify and analyse the effects of variations in the vibration parameters and contraction levels on the neuromuscular responses to isometric exercise superimposed on whole body vibration stimulation. In this study, we assessed the 'neuromuscular effects' of graded isometric contractions, of 20%, 40%, 60%, 80% and 100% of maximum voluntary contraction, superimposed on whole body vibration stimulation (V) and control (C), i.e., no-vibration in 12 healthy volunteers. Vibration stimuli tested were 30 Hz and 50 Hz frequencies and 0.5 mm and 1.5 mm amplitude. Surface electromyographic activity of the vastus lateralis, vastus medialis and biceps femoris were measured during V and C conditions with electromyographic root mean square and electromyographic mean frequency values used to quantify muscle activity and their fatigue levels, respectively. Both the prime mover (vastus lateralis) and the antagonist (biceps femoris) displayed significantly higher (P < 0.05) electromyographic activity with the V than the C condition with varying percentage increases in EMG root-mean-square (EMGrms) values ranging from 20% to 200%. For both the vastus lateralis and biceps femoris, the increase in mean EMGrms values depended on the frequency, amplitude and muscle contraction level with 50 Hz-0.5 mm stimulation inducing the largest neuromuscular activity. These results show that the isometric contraction superimposed on vibration stimulation leads to higher neuromuscular activity compared to isometric contraction alone in the lower limbs. The combination of the vibration frequency with the amplitude and the muscle tension together grades the final neuromuscular output.


Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells.
Natural killer (NK) cells destroy virus-infected and tumour cells, apparently without the need for previous antigen stimulation. In part, target cells are recognized by their diminished expression of major histocompatibility complex (MHC) class I molecules, which normally interact with inhibitory receptors on the NK cell surface. NK cells also express triggering receptors that are specific for non-MHC ligands; but the nature of the ligands recognized on target cells is undefined. NKp46 is thought to be the main activating receptor for human NK cells. Here we show that a soluble NKp46-immunoglobulin fusion protein binds to both the haemagglutinin of influenza virus and the haemagglutinin-neuraminidase of parainfluenza virus. In a substantial subset of NK cells, recognition by NKp46 is required to lyse cells expressing the corresponding viral glycoproteins. The binding requires the sialylation of NKp46 oligosaccharides, which is consistent with the known sialic binding capacity of the viral glycoproteins. These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein.


Efficacy of the Incredible Years group parent program with families in Head Start who self-reported a history of child maltreatment.
A prevention form of the Incredible Years (IY) parenting program was offered to parents who had children enrolled in Head Start, regardless of whether they reported having a history of child maltreatment. This study compared whether parenting practices and child behavioral outcomes differed in families who self reported a history of child maltreatment relative to families who did not. A site-randomized controlled trial of the IY parenting program was conducted in 64 classrooms in seven Head Start centers in Seattle, Washington. Families of 481 children took part in the study, with 335 in the IY condition and 146 in the control condition. Parenting practices and child behavior were measured by blinded raters through in-home observations and self-report questionnaires prior to the start of the IY program, in the spring after the IY program had concluded, and 12-18 months after study enrollment when children were in kindergarten. Analyses examine the impact of the IY program on parenting practices and children's behavior, exploring whether the program had differential impacts for parents with and without a self-reported history of child maltreatment. The IY program resulted in improvements along many parenting dimensions and on characteristics of observed child behavior. Program impacts were similar for parents who did and did not report a history of child maltreatment. However, parents with a reported history of prior maltreatment had greater initial room for improvement in areas such as harsh/critical parenting, nurturing/supportive parenting, and discipline competence than parents without such a history. The IY parenting program has positive impacts for parents who self-reported a history of child maltreatment. While similar benefits were observed for both groups of parents in this study, results support delivering evidence-based parenting programs of longer duration and higher intensity than often used by agencies serving parents in contact with child welfare. Agencies serving parents referred for child maltreatment should carefully examine the characteristics of the parenting programs they deliver. Use of a parenting program that has a sound base of empirical support, such as IY, and sufficient intensity and duration, is likely to make substantial changes in parents' child-rearing practices.


RNA specificity and regulation of catalysis in the eukaryotic polynucleotide kinase Clp1.
RNA-specific polynucleotide kinases of the Clp1 subfamily are key components of various RNA maturation pathways. However, the structural basis explaining their substrate specificity and the enzymatic mechanism is elusive. Here, we report crystal structures of Clp1 from Caenorhabditis elegans (ceClp1) in a number of nucleotide- and RNA-bound states along the reaction pathway. The combined structural and biochemical analysis of ceClp1 elucidates the RNA specificity and lets us derive a general model for enzyme catalysis of RNA-specific polynucleotide kinases. We identified an RNA binding motif referred to as "clasp" as well as a conformational switch that involves the essential Walker A lysine (Lys127) and regulates the enzymatic activity of ceClp1. Structural comparison with other P loop proteins, such as kinases, adenosine triphosphatases (ATPases), and guanosine triphosphatases (GTPases), suggests that the observed conformational switch of the Walker A lysine is a broadly relevant mechanistic feature.


Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California.
Pandemic influenza A(H1N1) emerged rapidly in California in April 2009. Preliminary comparisons with seasonal influenza suggest that pandemic 2009 influenza A(H1N1) disproportionately affects younger ages and causes generally mild disease. To describe the clinical and epidemiologic features of pandemic 2009 influenza A(H1N1) cases that led to hospitalization or death. Statewide enhanced public health surveillance of California residents who were hospitalized or died with laboratory evidence of pandemic 2009 influenza A(H1N1) infection reported to the California Department of Public Health between April 23 and August 11, 2009. Characteristics of hospitalized and fatal cases. During the study period there were 1088 cases of hospitalization or death due to pandemic 2009 influenza A(H1N1) infection reported in California. The median age was 27 years (range, <1-92 years) and 68% (741/1088) had risk factors for seasonal influenza complications. Sixty-six percent (547/833) of those with chest radiographs performed had infiltrates and 31% (340/1088) required intensive care. Rapid antigen tests were falsely negative in 34% (208/618) of cases evaluated. Secondary bacterial infection was identified in 4% (46/1088). Twenty-one percent (183/884) received no antiviral treatment. Overall fatality was 11% (118/1088) and was highest (18%-20%) in persons aged 50 years or older. The most common causes of death were viral pneumonia and acute respiratory distress syndrome. In the first 16 weeks of the current pandemic, the median age of hospitalized infected cases was younger than is common with seasonal influenza. Infants had the highest hospitalization rates and persons aged 50 years or older had the highest mortality rates once hospitalized. Most cases had established risk factors for complications of seasonal influenza.


Ultrasound-Guided Laparoscopic Ovarian Wedge Resection in Recurrent Serous Borderline Ovarian Tumours.
The aim of this study was to demonstrate the use of intraoperative ultrasound-guided ovarian wedge resection in the treatment of recurrent serous borderline ovarian tumors (sBOTs) that are too small to be visualized laparoscopically. This was a prospective analysis of all women with recurrent sBOTs that were not visible laparoscopically, who underwent intraoperative ultrasound-guided ovarian wedge resection between January 2015 and December 2016 at the West London Gynaecological Cancer Centre, Imperial College NHS Trust, London, United Kingdom. We evaluated 7 patients, with a median age of 35 years (range, 28-39 years). Six women were nulliparous, whereas 1 woman had a single child. Previous surgical intervention left 5 women with a single ovary, whereas the remaining 2 had previous ovarian-sparing surgery. The median size of recurrence was 18 mm (range, 12-37 mm). All women underwent uncomplicated intraoperative guided ovarian wedge resections. Histological assessment confirmed sBOT in all 7 cases. Six of the women remain disease-free. One woman recurred postoperatively with her third recurrence, who previously had bilateral disease and noninvasive implants with microinvasive disease and micropapillary pattern. No cases progressed to invasive disease. The median follow-up time was 12 months (range, 1-20 months). One pregnancy has been achieved postoperatively but resulted in miscarriage. Continuous intraoperative ultrasound can be used to facilitate complete tumor excision in recurrent sBOT while minimizing the removal of ovarian tissue in women with recurrent sBOT. It is essential that surgical techniques evolve simultaneously with diagnostic imaging modalities to enable surgeons to treat such pathology.


Strengthening primary level health service delivery: lessons from a state in India.
The main aim of the study was to assess primary health centers (PHCs) in terms of availability of assured services, facility of primary management of selected cases, surgeries, maternal and newborn health care services, and child health care services with respect to Indian Public Health Standards (IPHS). Data were collected from service providers (medical officerin-charge) at PHCs through well-structured questionnaire developed by referring the IPHS for PHCs prescribed by the Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. The study was conducted at five districts (i.e. Bundi, SawaiMadhopur, Kota, Tonk, and Karauli) of Rajasthan state of India. All 148 PHCs of these five districts were included in the study. Findings depict that more than 90% of the study PHCs showed availability of services such as outpatient department (OPD), antenatal check up (ANC), postnatal check up (PNC), management of reproductive tract infections/sexual transmitted infection (RTI/STI), immunization, and treatment of diarrhea. However, services such as emergency services (24 h), primary management of fractures, surgery of cataract, medical termination of pregnancy (MTP) services, management of low-birth-weight babies, facility for tubectomy and vasectomy, and facility for internal examination for gynecological conditions were poor at PHCs of the study districts, which need to be addressed for further strengthening of primary health centers.


Induction of apoptosis by Drosophila Myc.
Myc proteins are essential regulators of cellular growth and proliferation during normal development. Activating mutations in myc genes result in excessive growth and are frequently associated with human cancers. At the same time, forced expression of Myc sensitizes vertebrate cells towards different pro-apoptotic stimuli. Recently, the ability of overexpressed Myc to induce cell-autonomous apoptosis has been shown to be evolutionarily conserved in Drosophila Myc (dMyc). Here, we show that dMyc induced apoptosis is accompanied by the induction of Drosophila p53 mRNA, but that dp53 activity is not essential for dMyc's ability to induce apoptosis. Conversely, larvae carrying a hypomorphic dmyc mutation are more resistant to the apoptosis-promoting effects of X-irradiation. These data suggest that the control of apoptosis is a physiological function of Myc and that dMyc might play a role in the response to DNA damage.


Implementing national guidelines for person-centered care of people with dementia in residential aged care: effects on perceived person-centeredness, staff strain, and stress of conscience.
Person-centeredness has had substantial uptake in the academic literature on care of older people and people with dementia. However, challenges exist in interpreting and synthesizing the evidence on effects of providing person-centered care, as the person-centered components of some intervention studies are unclear - targeting very different and highly specific aspects of person-centeredness, as well as not providing empirical data to indicate the extent to which care practice was actually perceived to become more person-centered post-intervention. The study employed a quasi-experimental, one-group pre-test-post-test design with a 12-month follow-up to explore intervention effects on person-centeredness of care and the environment (primary endpoints), and on staff strain and stress of conscience (secondary endpoints). The intervention resulted in significantly higher scores on person-centeredness of care at follow-up, and the facility was rated as being significantly more hospitable at follow-up. A significant reduction of staff stress of conscience was also found at follow-up, which suggests that, to a larger extent, staff could provide the care and activities they wanted to provide after the intervention. The results indicated that an interactive and step-wise action-research intervention consisting of knowledge translation, generation, and dissemination, based on national guidelines for care of people with dementia, increased the staff self-reported person-centeredness of care practice, perceived hospitality of the setting, and reduced staff stress of conscience by enabling staff to provide the care and activities they want to provide.


ASimulatoR: splice-aware RNA-Seq data simulation.
A plethora of tools exist for RNA-Seq data analysis with a focus on alternative splicing (AS). However, appropriate data for their comparative evaluation is missing. The R package ASimulatoR simulates gold standard RNA-Seq datasets with fine-grained control over the distribution of AS events, which allow for evaluating alternative splicing tools, e.g. to study the effect of sequencing depth on the performance of AS event detection. ASimulatoR is freely available at https://github.com/biomedbigdata/ASimulatoR as an R package under GPL-3 license.


Clinical effectiveness of non-invasive selective cryolipolysis.
Excess subcutaneous fat causes not only cosmetic issues, but also substantial systemic health problems. Cryolipolysis has been reported to provide non-invasive fat reduction that significantly reduces subcutaneous fat cells with controlled, localized cooling. This study is intended to determine whether a cryolipolysis device can effectively reduce subcutaneous fat without damaging the overlying skin or causing significant side effects and ultimately produce improved cosmetic results. A total of 15 patients participated in this study and they were treated unilaterally in a split-body trial manner with a non-invasive cryolipolysis device (Micool(™), Hironic Co., Seongnam, Korea). The degree of improvement was assessed by both objective and subjective assessments. Complications and side effects were recorded at every visit. The results of both objective and subjective assessments showed significant improvements in subcutaneous fat reduction without any meaningful complications. Non-invasive selective cryolipolysis has been reported to be a safe and effective treatment modality for the reduction of excess adipose tissue. Therefore, cryolipolysis is a promising technology that could be an appropriate and safe therapeutic option for subcutaneous fat reduction.


Fabrication of anti-reflective micro-structure at terahertz frequency by using Chinese acupuncture needles.
A terahertz (THz) anti-reflective structure on a polystyrene layer was fabricated by using a handmade metallic mold comprising a bunch of Chinese acupuncture needles. Polystyrene was spin-coated onto a silicon substrate and then deformed by the mold via a hot-embossing process. The deformed layer yielded gradient refractive index profiles on the substrate. Compared with a common single antireflective layer, we observed an increase of ∼20% in the transmittance. We also observed broader bandwidth properties compared with the single layer structure. The process imposes no substrate limiting, i.e., it can be applied onto various THz device surfaces for antireflection purpose.


Combined effects of double mutations on catalytic activity and structural stability contribute to clinical manifestations of glucose-6-phosphate dehydrogenase deficiency.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans, affecting ~ 500 million worldwide. A detailed study of the structural stability and catalytic activity of G6PD variants is required to understand how different mutations cause varying degrees of enzyme deficiency, reflecting the response of G6PD variants to oxidative stress. Furthermore, for G6PD double variants, investigating how two mutations jointly cause severe enzyme deficiency is important. Here, we characterized the functional and structural properties of nine G6PD variants: G6PD Gaohe, G6PD Mahidol, G6PD Shoklo, G6PD Canton, G6PD Kaiping, G6PD Gaohe + Kaiping, G6PD Mahidol + Canton, G6PD Mahidol + Kaiping and G6PD Canton + Kaiping. All variants were less catalytically active and structurally stable than the wild type enzyme, with G6PD double mutations having a greater impact than single mutations. G6PD Shoklo and G6PD Canton + Kaiping were the least catalytically active single and double variants, respectively. The combined effects of two mutations were observed, with the Canton mutation reducing structural stability and the Kaiping mutation increasing it in the double mutations. Severe enzyme deficiency in the double mutants was mainly determined by the trade-off between protein stability and catalytic activity. Additionally, it was demonstrated that AG1, a G6PD activator, only marginally increased G6PD enzymatic activity and stability.


Lattice cleaving: a multimaterial tetrahedral meshing algorithm with guarantees.
We introduce a new algorithm for generating tetrahedral meshes that conform to physical boundaries in volumetric domains consisting of multiple materials. The proposed method allows for an arbitrary number of materials, produces high-quality tetrahedral meshes with upper and lower bounds on dihedral angles, and guarantees geometric fidelity. Moreover, the method is combinatoric so its implementation enables rapid mesh construction. These meshes are structured in a way that also allows grading, to reduce element counts in regions of homogeneity. Additionally, we provide proofs showing that both element quality and geometric fidelity are bounded using this approach.


Influence of the X-chromosome on neuroanatomy: evidence from Turner and Klinefelter syndromes.
Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an additional X-chromosome (47XXY). As these disorders essentially represent copy number variants of the sex chromosomes, investigation of brain structure across these disorders allows us to determine whether sex chromosome gene dosage effects exist. We used voxel-based morphometry to investigate this hypothesis in a large sample of children in early puberty, to compare regional gray matter volumes among individuals with one (45X), two (typically developing 46XX females and 46XY males), and three (47XXY) sex chromosomes. Between-group contrasts of TS and KS groups relative to respective sex-matched controls demonstrated highly convergent patterns of volumetric differences with the presence of an additional sex chromosome being associated with relatively decreased parieto-occipital gray matter volume and relatively increased temporo-insular gray matter volumes. Furthermore, z-score map comparisons between TS and KS cohorts also suggested that this effect occurs in a linear dose-dependent fashion. We infer that sex chromosome gene expression directly influences brain structure in children during early stages of puberty, extending our understanding of genotype-phenotype mechanisms underlying sex differences in the brain.


Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: A Multi-Center Experience of 154 Consecutive Embolizations.
Middle meningeal artery (MMA) embolization has emerged as a promising treatment for chronic subdural hematoma (cSDH). To determine the safety and efficacy of MMA embolization. Consecutive patients who underwent MMA embolization for cSDH (primary treatment or recurrence after conventional surgery) at 15 centers were included. Clinical details and follow-up were collected prospectively. Primary clinical and radiographic outcomes were the proportion of patients requiring additional surgical treatment within 90 d after index treatment and proportion with > 50% cSDH thickness reduction on follow-up computed tomography imaging within 90 d. National Institute of Health Stroke Scale and modified Rankin Scale were also clinical outcomes. A total of 138 patients were included (mean age: 69.8, 29% female). A total of 15 patients underwent bilateral interventions for 154 total embolizations (66.7% primary treatment). At presentation, 30.4% and 23.9% of patients were on antiplatelet and anticoagulation therapy, respectively. Median admission cSDH thickness was 14 mm. A total of 46.1% of embolizations were performed under general anesthesia, and 97.4% of procedures were successfully completed. A total of 70.2% of embolizations used particles, and 25.3% used liquid embolics with no significant outcome difference between embolization materials (P > .05). On last follow-up (mean 94.9 d), median cSDH thickness was 4 mm (71% median thickness reduction). A total of 70.8% of patients had >50% improvement on imaging (31.9% improved clinically), and 9 patients (6.5%) required further cSDH treatment. There were 16 complications with 9 (6.5%) because of continued hematoma expansion. Mortality rate was 4.4%, mostly unrelated to the index procedure but because of underlying comorbidities. MMA embolization may provide a safe and efficacious minimally invasive alternative to conventional surgical techniques.


Clinical features and outcomes of posterior reversible encephalopathy syndrome following bevacizumab treatment.
Posterior reversible encephalopathy syndrome (PRES) is a potentially devastating complication of bevacizumab treatment. We examined the clinical features, treatment and outcomes of patients who developed PRES following bevacizumab treatment at our institution and those reported in the literature. Retrospective audit and systematic review. Patients were identified from the Mayo Clinic database and the published literature using 'PubMed' and 'OVID' databases, from January 2006 to June 2010, who developed PRES features within 3 weeks of bevacizumab treatment, who had brain imaging findings of focal vasogenic edema and radiologic proof of reversibility. Two patients with definite PRES were identified from our institution and a further 10 cases were identified from the published literature (total, n=12). The mean age of these patients was 52 years (range 4-68 years), four of whom were men and eight women. Headaches (n=7), seizures (n=6), visual disturbances (n=5) and nausea and vomiting (n=3) were the common presenting symptoms. In a majority of patients (n=10), an increase in blood pressure from their baseline values was observed during their acute presentation. PRES resolved following withdrawal of bevacizumab and blood pressure control in all patients. PRES is a catastrophic neurological complication of bevacizumab treatment, which responds favorably to prompt bevacizumab withdrawal and blood pressure control.


Coexpression of HSP47 gene and type I and type III collagen genes in LPS-induced pulmonary fibrosis in rats.
Diffuse alveolar damage is the histopathologic hallmark of acute respiratory distress syndrome (ARDS). A significant proportion of ARDS survivors have residual pulmonary fibrosis and compromised pulmonary function. On the other hand, heat shock protein 47 (HSP47) is a collagen-binding stress protein that is assumed to act as a collagen-specific molecular chaperone during the biosynthesis and secretion of procollagen in living cells. The synthesis of HSP47 has been reported to correlate with that of collagen in several cell lines. We examined the expression of HSP47 mRNA and protein during the progression of lipopolysaccharide (LPS)-induced ARDS in rat lung. Male Wistar rats were randomly divided into two groups: a control group with instillation of 0.9% NaCl solution alone, and a LPS group with instillation of LPS dissolved in 0.9% NaCl solution (10 mg/kg). Histologic changes thereafter appeared in the LPS-treated rats. Northern blot analysis revealed the expression of HSP47 mRNA to be markedly induced during the progression of lung damage in parallel with type I and type III collagen mRNA. These results suggest that the upregulation of HSP47 and collagen may play an important role in the fibrotic process of LPS-induced ARDS lung.


Mononuclear odontoclast participation in tooth resorption: the distribution of nuclei in human odontoclasts.
Osteoclasts and odontoclasts have been considered multinucleated giant cells which resorb hard tissue by ruffled borders. Recently, the authors reported the presence of a mononuclear osteoclast and odontoclast with a ruffled border. However, the relative frequency of such cells and the distribution of the number of nuclei including mononuclear cells in them have not been elucidated. Six human deciduous teeth were used in this study. After fixation and decalcification, tartrate-resistant acid phosphatase (TRAP) activity was detected with the azo dye method, and then TRAP-positive cells were observed on resorbing areas of teeth by light microscopy. The cells for investigation were serially sectioned by semithin sections to observe the presence of resorptive lacuna and the number of nuclei. The TRAP activity was detected in both multinucleated and mononuclear odontoclasts from serial semithin sections, and 242 TRAP-positive cells which formed lacunae on dentin were investigated to determine the frequency distribution of the number of nuclei. The mean number of nuclei per cell was 5.3, and median was 4. Only 2.9% of odontoclasts were mononucleus and 93.8% had 10 or fewer nuclei. The majority of odontoclasts forming lacunae on the dentin were cells with 10 or fewer nuclei, and mononuclear odontoclasts participated in human deciduous tooth resorption together with multinucleated ones.


Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection.
Human Endogenous Retroviruses (HERVs) comprise about 8% of the human genome and have lost their ability to replicate or to produce infectious particles after having accumulated mutations over time. We assessed the kinetics of expression of HERV-K (HML-2) Envelope mRNA transcript and surface unit (SU) and transmembrane (TM) subunit proteins during HIV-1 infection. We also mapped the specificity of the humoral response to HERV-K (HML-2) Envelope protein in HIV-1 infected subjects at different stages of disease, and correlated the response with plasma viral load. We found that HIV-1 modified HERV-K (HML-2) Env mRNA expression, resulting in the expression of a fully N-glycosylated HERV-K (HML-2) envelope protein on the cell surface. Serological mapping of HERV-K (HML-2) envelope protein linear epitopes revealed two major immunogenic domains, one on SU and another on the ectodomain of TM. The titers of HERV-K (HML-2) TM antibodies were dramatically increased in HIV-1 infected subjects (p < 0.0001). HIV-1 infected adults who control HIV-1 in the absence of therapy ("elite" controllers) had a higher titer response against TM compared to antiretroviral-treated adults (p < 0.0001) and uninfected adults (p < 0.0001). These data collectively suggest that HIV-1 infection induces fully glycosylated HERV-K (HML-2) envelope TM protein to which antibodies are induced. These anti-HERV-K (HML-2) TM antibodies are a potential marker of HIV-1 infection, and are at higher titer in elite controllers. HERV-K (HML-2) envelope TM protein may be a new therapeutic target in HIV-1 infection.


The Endophthalmitis Population Study of Western Australia (EPSWA): first report.
Over the period of 19 years to 1999, cataract surgery numbers increased 6% per annum in Western Australia (WA), promoted by the convenience, efficacy, and general safety of outpatient phacoemulsification surgery. Although endophthalmitis is an uncommon complication, it is a major cause of post-cataract surgery blindness. The present population study investigates not only the prevalence of endophthalmitis but provides an accurate incidence of endophthalmitis in WA over the same period. Using the hospital morbidity data system (HMDS) of the WA Record Linkage Project, and cross validating against three independent databases (anaesthetic and microbiological databases and surgeons' logbooks) the authors examined 698 case notes that were potentially cases of endophthalmitis for the period 1980 to June 1999. As the database linkage was incomplete for 1999, only the 188 confirmed cases to 1998 were included in the present study. Additional case note validation was performed to confirm the correct codes for the cataract surgical procedure. Despite changes in surgical technique and prophylaxis over the study period of 19 years, the incidence of endophthalmitis remained largely unchanged, averaging one in 500 surgical cases overall. However, the incidence fluctuated over time and varied with the location of surgery ranging from 0.65 per 1000 operations to 16.4 per 1000 operations. These data highlight previously undescribed temporal and geographic variations in the incidence of endophthalmitis. It is uncertain whether the wide variation in prophylactic practices throughout the ophthalmic community has any bearing on the incidence of endophthalmitis.


A cis-regulatory logic simulator.
A major goal of computational studies of gene regulation is to accurately predict the expression of genes based on the cis-regulatory content of their promoters. The development of computational methods to decode the interactions among cis-regulatory elements has been slow, in part, because it is difficult to know, without extensive experimental validation, whether a particular method identifies the correct cis-regulatory interactions that underlie a given set of expression data. There is an urgent need for test expression data in which the interactions among cis-regulatory sites that produce the data are known. The ability to rapidly generate such data sets would facilitate the development and comparison of computational methods that predict gene expression patterns from promoter sequence. We developed a gene expression simulator which generates expression data using user-defined interactions between cis-regulatory sites. The simulator can incorporate additive, cooperative, competitive, and synergistic interactions between regulatory elements. Constraints on the spacing, distance, and orientation of regulatory elements and their interactions may also be defined and Gaussian noise can be added to the expression values. The simulator allows for a data transformation that simulates the sigmoid shape of expression levels from real promoters. We found good agreement between sets of simulated promoters and predicted regulatory modules from real expression data. We present several data sets that may be useful for testing new methodologies for predicting gene expression from promoter sequence. We developed a flexible gene expression simulator that rapidly generates large numbers of simulated promoters and their corresponding transcriptional output based on specified interactions between cis-regulatory sites. When appropriate rule sets are used, the data generated by our simulator faithfully reproduces experimentally derived data sets. We anticipate that using simulated gene expression data sets will facilitate the direct comparison of computational strategies to predict gene expression from promoter sequence. The source code is available online and as additional material. The test sets are available as additional material.


Intensive intermittent physical therapy in infants with cerebral palsy: a randomized controlled pilot study.
The effectiveness of intensive versus standard physical therapy for motor progress in children with cerebral palsy is controversial. Sitting acquisition is considered an important developmental milestone. To assess the acquisition of sitting and gross motor progress in infants with cerebral palsy treated with intermittent intensive physical therapy as compared to a matched group treated with a standard physical therapy regimen. We conducted a randomized controlled crossover study in 10 infants aged 12-22 months with cerebral palsy; 5 were assigned to the intensive intermittent therapy group and 5 to the control group. After 4 weeks of baseline intervention, the intervention program was administered to the experimental group for8 weeks and the regularly scheduled weekly program to the comparison group, targeting sitting as the treatment goal. Thereafter the comparison group crossed over. The Gross Motor Function Measure 66 and 88 (GMFM 66 and 88) were used at 4 week intervals. The intermittent intensive regimen yielded a mean improvement of 7.8% as compared to 1.2% with the standard treatment. However, these results were attributed to infants with a low functional level only (P < 0.01). Goal-directed intensive intermittent regimen could possibly be beneficial in infants with a low functional level.


Framework for validation and implementation of in vitro toxicity tests.
The development and application of in vitro alternatives designed to reduce or replace the use of animals, or to lessen the distress and discomfort of laboratory animals, is a rapidly developing trend in toxicology. However, at present there is no formal administrative process to organize, coordinate, or evaluate validation activities. A framework capable of fostering the validation of new methods is essential for the effective transfer of new technologic developments from the research laboratory into practical use. This committee has identified four essential validation resources: chemical bank(s), cell and tissue banks, a data bank, and reference laboratories. The creation of a Scientific Advisory Board composed of experts in the various aspects and endpoints of toxicity testing, and representing the academic, industrial, and regulatory communities, is recommended. Test validation acceptance is contingent on broad buy-in by disparate groups in the scientific community--academics, industry, and government. This is best achieved by early and frequent communication among parties and agreement on common goals. It is hoped that the creation of a validation infrastructure composed of the elements described in this report will facilitate scientific acceptance and utilization of alternative methodologies and speed implementation of replacement, reduction, and refinement alternatives in toxicity testing.


Door-to-needle time for administration of fibrinolytics in acute myocardial infarction in Cape Town.
To determine the current door-to-needle time for the administration of fibrinolytics for acute myocardial infarction (AMI) in emergency centres (ECs) at three hospitals in Cape Town, and to compare it with the American Heart Association/American College of Cardiology (AHA/ACC) recommendation of 30 minutes as a marker of quality of care. A retrospective review of case notes from January 2008 to July 2010 of all patients receiving thrombolytics for AMI in the ECs of three Cape Town hospitals. The total door-to-needle time was calculated and patient demographics and presentation, physician qualification, clinical symptomology and reasons for delays in thromobolytic administration were analysed. A total of 372 patients with acute ST elevation myocardial infarction (STEMI) were identified; 161 patients were eligible for the study. The median door-to-needle time achieved was 54 minutes (range 13 - 553 mins). A door-to-needle time of 30 minutes or less was achieved in 33 (20.5%) patients; 51.3% of the patients arrived by ambulance; 34% of patients had a pre-hospital 12-lead ECG; and 88.8% had typical symptoms of myocardial infarction. Medical officers administered thrombolytics to 44.7% of the patients. The predominant infarct location on ECG was inferior (55.9%). A significant number of patients were not thrombolysed within 30 minutes of presentation. The lack of senior doctors, difficulty interpreting ECGs, atypical presentations and EC system delays prolonged the door-to-needle time in this study.


Topoisomerase IIα promotes activation of RNA polymerase I transcription by facilitating pre-initiation complex formation.
Type II DNA topoisomerases catalyse DNA double-strand cleavage, passage and re-ligation to effect topological changes. There is considerable interest in elucidating topoisomerase II roles, particularly as these proteins are targets for anti-cancer drugs. Here we uncover a role for topoisomerase IIα in RNA polymerase I-directed ribosomal RNA gene transcription, which drives cell growth and proliferation and is upregulated in cancer cells. Our data suggest that topoisomerase IIα is a component of the initiation-competent RNA polymerase Iβ complex and interacts directly with RNA polymerase I-associated transcription factor RRN3, which targets the polymerase to promoter-bound SL1 in pre-initiation complex formation. In cells, activation of rDNA transcription is reduced by inhibition or depletion of topoisomerase II, and this is accompanied by reduced transient double-strand DNA cleavage in the rDNA-promoter region and reduced pre-initiation complex formation. We propose that topoisomerase IIα functions in RNA polymerase I transcription to produce topological changes at the rDNA promoter that facilitate efficient de novo pre-initiation complex formation.


An expression map for Anopheles gambiae.
Quantitative transcriptome data for the malaria-transmitting mosquito Anopheles gambiae covers a broad range of biological and experimental conditions, including development, blood feeding and infection. Web-based summaries of differential expression for individual genes with respect to these conditions are a useful tool for the biologist, but they lack the context that a visualisation of all genes with respect to all conditions would give. For most organisms, including A. gambiae, such a systems-level view of gene expression is not yet available. We have clustered microarray-based gene-averaged expression values, available from VectorBase, for 10194 genes over 93 experimental conditions using a self-organizing map. Map regions corresponding to known biological events, such as egg production, are revealed. Many individual gene clusters (nodes) on the map are highly enriched in biological and molecular functions, such as protein synthesis, protein degradation and DNA replication. Gene families, such as odorant binding proteins, can be classified into distinct functional groups based on their expression and evolutionary history. Immunity-related genes are non-randomly distributed in several distinct regions on the map, and are generally distant from genes with house-keeping roles. Each immunity-rich region appears to represent a distinct biological context for pathogen recognition and clearance (e.g. the humoral and gut epithelial responses). Several immunity gene families, such as peptidoglycan recognition proteins (PGRPs) and defensins, appear to be specialised for these distinct roles, while three genes with physically interacting protein products (LRIM1/APL1C/TEP1) are found in close proximity. The map provides the first genome-scale, multi-experiment overview of gene expression in A. gambiae and should also be useful at the gene-level for investigating potential interactions. A web interface is available through the VectorBase website http://www.vectorbase.org/. It is regularly updated as new experimental data becomes available.


Effect of tirzepatide on glycaemic control and weight loss compared with other glucagon-like peptide-1 receptor agonists in Japanese patients with type 2 diabetes mellitus.
To compare the therapeutic effects of glucose-dependent insulinotropic polypeptide (GIP)/ glucagon-like peptide-1 receptor agonists (GLP-1RAs) or GLP-1RAs in Japanese patients with type 2 diabetes (T2D). We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library up to July 2023. Randomized controlled trials (RCTs) that compared GLP-1RAs or GIP/GLP-1RAs in Japanese patients with T2D were selected. A network meta-analysis was conducted to indirectly compare the treatments, focusing on efficacy in reducing glycated haemoglobin (HbA1c) levels and body weight (BW). A total of 18 RCTs were included in this analysis. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and BW compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference [95% confidence interval] -0.52 [-0.96; -0.08] and - 1.23 [-1.64; -0.81]; BW: -5.07 [-8.28; -1.86] and -6.84 [-8.97; -4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP-1RAs, such as dulaglutide, liraglutide and lixisenatide. Among Japanese patients with T2D, tirzepatide showed the greatest effectiveness in reducing HbA1c levels and inducing weight loss. The study provides evidence to guide GLP-1RA treatment strategies in Japanese patients with T2D.


Health worker transfer processes within the public health sector in Ghana: a study of three districts in the Eastern Region.
The lack of appropriate policies and procedures to ensure transparent transfer practices is an important source of dissatisfaction among health workers in low- and middle-income countries. In order to alter and improve current practices, a more in-depth and context-specific understanding is needed. This study aims to (1) identify rationales behind transfer decisions in Ghana and (2) examine how transfers are managed in practice versus in policies. The study took place in 2014 in three districts in Eastern Ghana. The study population included (1) national, regional, and district health administrators with decision-making authority in terms of transfer decisions and (2) health workers who had transferred between 2011 and 2014. Data was collected through semi-structured and structured face-to-face interviews focusing on rationales behind transfer decisions, health administrators' role in managing transfers, and health workers' experience of transfers. A data triangulation approach was applied to compare identified practices with national policies and procedures. A total of 44 health workers and 21 administrators participated in the study. Transfers initiated by health workers were mostly based on family conditions and preferences to move away from rural areas, while transfers initiated by administrators were based on service requirements, productivity, and performance. The management of transfers was not guided by clear and explicit procedures and thus often depended on the discretion of decision-makers. Moreover, health workers frequently reported not being involved in transfer decision-making processes. We found existing staff perceptions of a non-transparent system. Our findings suggest a need to foster incentives to attract and retain health workers in rural areas. Moreover, health worker-centered procedures and systems that effectively guide and monitor transfer practices must be developed to ensure that transfers are carried out in a timely, fair, and transparent way.


Understanding Inequalities in Ride-Hailing Services Through Simulations.
Despite the potential of ride-hailing services to democratize the labor market, they are often accused of fostering unfair working conditions and low wages. This paper investigates the effect of algorithm design decisions on wage inequality in ride-hailing platforms. We create a simplified city environment where taxis serve passengers to emulate a working week in a worker's life. Our simulation approach overcomes the difficulties stemming from both the complexity of transportation systems and the lack of data and algorithmic transparency. We calibrate the model based on empirical data, including conditions about locations of drivers and passengers, traffic, the layout of the city, and the algorithm that matches requests with drivers. Our results show that small changes in the system parameters can cause large deviations in the income distributions of drivers, leading to an unpredictable system that often distributes vastly different incomes to identically performing drivers. As suggested by recent studies about feedback loops in algorithmic systems, these short-term income differences may result in enforced and long-term wage gaps.


Interest groups or the public interest--why do we regulate health occupations?
State regulation of occupations has become more prevalent even while its negative consequences are becoming understood. This raises questions about the source of such regulation and the extent to which the interests of the public are being represented. In my study of the regulation of health occupations, I explore the influence of organized interest groups, of the general public interest, and the structure of the legislature and the political environment. I analyze six health occupations (dietician, nurse-midwife, occupational therapist, physician assistant, psychologist, and social worker) and find that although organized interest groups do influence how these occupations are regulated, the public interest also plays an important role.


Routine Use of Probiotics in Preterm Infants: Longitudinal Impact on the Microbiome and Metabolome.
Probiotics are live microbial supplements that colonize the gut and potentially exert health benefit to the host. We aimed to determine the impact of a probiotic (Infloran®: Lactobacillus acidophilus-NCIMB701748 and Bifidobacterium bifidum-ATCC15696) on the bacterial and metabolic function of the preterm gut while in the neonatal intensive care unit (NICU) and following discharge. Stool samples (n = 88) were collected before, during, and after probiotic intake from 7 patients, along with time-matched controls from 3 patients. Samples were also collected following discharge home from the NICU. Samples underwent bacterial profiling analysis by 16S rRNA gene sequencing and quantitative PCR (qPCR), as well as metabolomic profiling using liquid chromatography mass spectrometry. Bacterial profiling showed greater Bifidobacterium (15.1%) and Lactobacillus (4.2%) during supplementation compared to the control group (4.0% and 0%, respectively). While Lactobacillus became reduced after the probiotic had been stopped, Bifidobacterium remained high following discharge, suggestive of successful colonisation. qPCR analysis showed a significant increase (p ≤ 0.01) in B. bifidum in infants who received probiotic treatment compared to controls, but no significant increase was observed for L. acidophilus (p = 0.153). Metabolite profiling showed clustering based on receiving probiotic or matched controls, with distinct metabolites associated with probiotic administration. Probiotic species successfully colonise the preterm gut, reducing the relative abundance of potentially pathogenic bacteria, and effecting gut functioning. Bifidobacterium (but not Lactobacillus) colonised the gut in the long term, suggesting the possibility that therapeutically administered probiotics may continue to exert important functional effects on gut microbial communities in early infancy.


Assessment of Palliative Care in Lung Cancer in Turkey.
To investigate the symptoms of lung cancer in Turkey and to evaluate approaches to alleviate these symptoms. This study included 1,245 lung cancer patients from 26 centers in Turkey. Demographic characteristics as well as information regarding the disease and treatments were obtained from medical records and patient interviews. Symptoms were evaluated using the Edmonton Symptom Assessment Scale (ESAS) and were graded on a scale between 0 and 10 points. Data were compared using the χ2, Student t, and Mann-Whitney U tests. Potential predictors of symptoms were analyzed using logistic regression analysis. The most common symptom was tiredness (n = 1,002; 82.1%), followed by dyspnea (n = 845; 69.3%), appetite loss (n = 801; 65.7%), pain (n = 798; 65.4%), drowsiness (n = 742; 60.8%), anxiety (n = 704; 57.7%), depression (n = 623; 51.1%), and nausea (n = 557; 45.5%). Of the 1,245 patients, 590 (48.4%) had difficulty in initiating or maintaining sleep. The symptoms were more severe in stages III and IV. Logistic regression analysis indicated a clear association between demographic characteristics and symptom distress, as well as between symptom distress (except nausea) and well-being. Overall, 804 (65.4%) patients used analgesics, 630 (51.5%) received treatment for dyspnea, 242 (19.8%) used enteral/parenteral nutrition, 132 (10.8%) used appetite stimulants, and 129 (10.6%) used anxiolytics/antidepressants. Of the 799 patients who received analgesics, 173 (21.7%) reported that their symptoms were under control, and also those on other various treatment modalities (dyspnea: 78/627 [12.4%], appetite stimulant: 25/132 [18.9%], and anxiolytics/antidepressants: 25/129 [19.4%]) reported that their symptoms were controlled. In this study, the symptoms progressed and became more severe in the advanced stages of lung cancer, and palliative treatment was insufficient in most of the patients in Turkey.


The Full Scope of Family Physicians' Work Is Not Reflected by Current Procedural Terminology Codes.
The purpose of this study was to characterize the content of family physician (FP) clinic encounters, and to count the number of visits in which the FPs addressed issues not explicitly reportable by 99211 to 99215 and 99354 Current Procedural Terminology (CPT) codes with current reimbursement methods and based on examples provided in the CPT manual. The data collection instrument was modeled on the National Ambulatory Medical Care Survey. Trained assistants directly observed every other FP-patient encounter and recorded every patient concern, issue addressed by the physician (including care barriers related to health care systems and social determinants), and treatment ordered in clinics affiliated with 10 residencies of the Residency Research Network of Texas. A visit was deemed to include physician work that was not explicitly reportable if the number or nature of issues addressed exceeded the definitions or examples for 99205/99215 or 99214 + 99354 or a preventive service code, included the physician addressing health care system or social determinant issues, or included the care of a family member. In 982 physician-patient encounters, patients raised 517 different reasons for visit (total, 5278; mean, 5.4 per visit; range, 1 to 16) and the FPs addressed 509 different issues (total issues, 3587; mean, 3.7 per visit; range, 1 to 10). FPs managed 425 different medications, 18 supplements, and 11 devices. A mean of 3.9 chronic medications were continued per visit (range, 0 to 21) and 4.6 total medications were managed (range, 0 to 22). In 592 (60.3%) of the visits the FPs did work that was not explicitly reportable with available CPT codes: 582 (59.3%) addressed more numerous issues than explicitly reportable, 64 (6.5%) addressed system barriers, and 13 (1.3%) addressed concerns for other family members. FPs perform cognitive work in a majority of their patient encounters that are not explicitly reportable, either by being higher than the CPT example number of diagnoses per code or the type of problems addressed, which has implications for the care of complex multi-morbid patients and the growth of the primary care workforce. To address these limitations, either the CPT codes and their associated rules should be updated to reflect the realities of family physicians' practices or new billing and coding approaches should be developed.


Alterations in integrin expression modulates invasion of pancreatic cancer cells.
Factors mediating the invasion of pancreatic cancer cells through the extracellular matrix (ECM) are not fully understood. In this study, sub-populations of the human pancreatic cancer cell line, MiaPaCa-2 were established which displayed differences in invasion, adhesion, anoikis, anchorage-independent growth and integrin expression. Clone #3 displayed higher invasion with less adhesion, while Clone #8 was less invasive with increased adhesion to ECM proteins compared to MiaPaCa-2. Clone #8 was more sensitive to anoikis than Clone #3 and MiaPaCa-2, and displayed low colony-forming efficiency in an anchorage-independent growth assay. Integrins beta 1, alpha 5 and alpha 6 were over-expressed in Clone #8. Using small interfering RNA (siRNA), integrin beta1 knockdown in Clone #8 cells increased invasion through matrigel and fibronectin, increased motility, decreased adhesion and anoikis. Integrin alpha 5 and alpha 6 knockdown also resulted in increased motility, invasion through matrigel and decreased adhesion. Our results suggest that altered expression of integrins interacting with different extracellular matrixes may play a significant role in suppressing the aggressive invasive phenotype. Analysis of these clonal populations of MiaPaCa-2 provides a model for investigations into the invasive properties of pancreatic carcinoma.


c-axis preferential orientation of hydroxyapatite accounts for the high wear resistance of the teeth of black carp (Mylopharyngodon piceus).
Biological armors such as mollusk shells have long been recognized and studied for their values in inspiring novel designs of engineering materials with higher toughness and strength. However, no material is invincible and biological armors also have their rivals. In this paper, our attention is focused on the teeth of black carp (Mylopharyngodon piceus) which is a predator of shelled mollusks like snails and mussels. Nanoscratching test on the enameloid, the outermost layer of the teeth, indicates that the natural occlusal surface (OS) has much higher wear resistance compared to the other sections. Subsequent X-ray diffraction analysis reveals that the hydroxyapatite (HAp) crystallites in the vicinity of OS possess c-axis preferential orientation. The superior wear resistance of black carp teeth is attributed to the c-axis preferential orientation of HAp near the OS since the (001) surface of HAp crystal, which is perpendicular to the c-axis, exhibits much better wear resistance compared to the other surfaces as demonstrated by the molecular dynamics simulation. Our results not only shed light on the origin of the good wear resistance exhibited by the black carp teeth but are of great value to the design of engineering materials with better abrasion resistance.


The Effects of Psycho-Emotional and Socio-Economic Support for Tuberculosis Patients on Treatment Adherence and Treatment Outcomes - A Systematic Review and Meta-Analysis.
There is uncertainty about the contribution that social support interventions (SSI) can have in mitigating the personal, social and economic costs of tuberculosis (TB) treatment on patients, and improving treatment outcomes. To identify psycho-emotional (PE) and socio-economic (SE) interventions provided to TB patients and to assess the effects of these interventions on treatment adherence and treatment outcomes. We searched PubMed and Embase from 1 January 1990-15 March 2015 and abstracts of the Union World Conference on Lung Health from 2010-2014 for studies reporting TB treatment adherence and treatment outcomes following SSI. Studies measuring the effects of PE or SE interventions on TB treatment adherence, treatment outcomes, and/or financial burden. Two reviewers independently assessed titles and abstracts for inclusion of articles. One reviewer reviewed full text articles and the reference list of selected studies. A second reviewer double checked all extracted information against the articles. Twenty-five studies were included in the qualitative analysis; of which eighteen were included in the meta-analysis. Effects were pooled from 11 Randomized Controlled Trials (RCTs), including 9,655 participants with active TB. Meta-analysis showed that PE support (RR 1.37; CI 1.08-1.73), SE support (RR 1.08; CI 1.03-1.13) and combined PE and SE support (RR 1.17; CI 1.12-1.22) were associated with a significant improvement of successful treatment outcomes. Also PE support, SE support and a combination of these types of support were associated with reductions in unsuccessful treatment outcomes (PE: RR 0.46; CI 0.22-0.96, SE: RR 0.78; CI 0.69-0.88 and Combined PE and SE: RR 0.42; CI 0.23-0.75). Evidence on the effect of PE and SE interventions on treatment adherence were not meta-analysed because the interventions were too heterogeneous to pool. No evidence was found to show whether SE reduced the financial burden for TB patients. Our review and meta-analysis concluded that PE and SE interventions are associated with beneficial effects on TB treatment outcomes. However, the quality of evidence is very low and future well-designed evaluation studies are needed.


Relationships between the Survey of Organizational Research Climate (SORC) and self-reported research practices.
The Survey of Organizational Research Climate (SORC) is a validated tool to facilitate promotion of research integrity and research best practices. This work uses the SORC to assess shared and individual perceptions of the research climate in universities and academic departments and relate these perceptions to desirable and undesirable research practices. An anonymous web- and mail-based survey was administered to randomly selected biomedical and social science faculty and postdoctoral fellows in the United States. Respondents reported their perceptions of the research climates at their universities and primary departments, and the frequency with which they engaged in desirable and undesirable research practices. More positive individual perceptions of the research climate in one's university or department were associated with higher likelihoods of desirable, and lower likelihoods of undesirable, research practices. Shared perceptions of the research climate tended to be similarly predictive of both desirable and undesirable research practices as individuals' deviations from these shared perceptions. Study results supported the central prediction that more positive SORC-measured perceptions of the research climate were associated with more positive reports of research practices. There were differences with respect to whether shared or individual climate perceptions were related to desirable or undesirable practices but the general pattern of results provide empirical evidence that the SORC is predictive of self-reported research behavior.


Caffeine and cardiovascular health.
This report evaluates the scientific literature on caffeine with respect to potential cardiovascular outcomes, specifically relative risks of total cardiovascular disease (CVD), coronary heart disease (CHD) and acute myocardial infarction (AMI), effects on arrhythmia, heart failure, sudden cardiac arrest, stroke, blood pressure, hypertension, and other biomarkers of effect, including heart rate, cerebral blood flow, cardiac output, plasma homocysteine levels, serum cholesterol levels, electrocardiogram (EKG) parameters, heart rate variability, endothelial/platelet function and plasma/urine catecholamine levels. Caffeine intake has been associated with a range of reversible and transient physiological effects broadly and cardiovascular effects specifically. This report attempts to understand where the delineations exist in caffeine intake and corresponding cardiovascular effects among various subpopulations. The available literature suggests that cardiovascular effects experienced by caffeine consumers at levels up to 600 mg/day are in most cases mild, transient, and reversible, with no lasting adverse effect. The point at which caffeine intake may cause harm to the cardiovascular system is not readily identifiable in part because data on the effects of daily intakes greater than 600 mg is limited. However, the evidence considered within this review suggests that typical moderate caffeine intake is not associated with increased risks of total cardiovascular disease; arrhythmia; heart failure; blood pressure changes among regular coffee drinkers; or hypertension in baseline populations.


Public Preferences for New Information on Opioids.
Educating the public through information campaigns is a commonly used policy approach to public health problems. Yet, experimental methods that assess the impact of information campaigns may misestimate their effects by failing to account for respondents' willingness to receive new information. This article uses a doubly randomized survey experiment conducted on a nationally representative sample, where some subjects are randomly assigned to an informational treatment about opioids while other subjects are given the choice of whether to receive treatment or not, to examine how public willingness to seek new information shapes the way they update their preferences about policies related to the opioid epidemic. Among those likely to receive information, treatment has a large positive effect on increasing support for policies that address the opioid epidemic by about one half of a standard deviation. Among those who would avoid this information, preferences appear to be unmoved by treatment. These effects would be missed by standard experimental designs. While redressing information asymmetries is only one part of a public health strategy for addressing the opioid epidemic, our findings highlight the importance of access to and receptiveness toward new information.


Expanded breadth of the T-cell response to mosaic human immunodeficiency virus type 1 envelope DNA vaccination.
An effective AIDS vaccine must control highly diverse circulating strains of human immunodeficiency virus type 1 (HIV-1). Among HIV-1 gene products, the envelope (Env) protein contains variable as well as conserved regions. In this report, an informatic approach to the design of T-cell vaccines directed to HIV-1 Env M group global sequences was tested. Synthetic Env antigens were designed to express mosaics that maximize the inclusion of common potential T-cell epitope (PTE) 9-mers and minimize the inclusion of rare epitopes likely to elicit strain-specific responses. DNA vaccines were evaluated using intracellular cytokine staining in inbred mice with a standardized panel of highly conserved 15-mer PTE peptides. One-, two-, and three-mosaic sets that increased theoretical epitope coverage were developed. The breadth and magnitude of T-cell immunity stimulated by these vaccines were compared to those for natural strain Envs; additional comparisons were performed on mutant Envs, including gp160 or gp145 with or without V regions and gp41 deletions. Among them, the two- or three-mosaic Env sets elicited the optimal CD4 and CD8 responses. These responses were most evident in CD8 T cells; the three-mosaic set elicited responses to an average of eight peptide pools, compared to two pools for a set of three natural Envs. Synthetic mosaic HIV-1 antigens can therefore induce T-cell responses with expanded breadth and may facilitate the development of effective T-cell-based HIV-1 vaccines.


Novel Pharmacologic Approaches to Treating Cannabis Use Disorder.
With large and increasing numbers of people using cannabis, the development of cannabis use disorder (CUD) is a growing public health concern. Despite the success of evidence-based psychosocial therapies, low rates of initial abstinence and high rates of relapse during and following treatment for CUD suggest a need for adjunct pharmacotherapies. Here we review the literature on medication development for the treatment of CUD, with a particular focus on studies published within the last three years (2010-2013). Studies in both the human laboratory and in the clinic have tested medications with a wide variety of mechanisms. In the laboratory, the following medication strategies have been shown to decrease cannabis withdrawal and self-administration following a period of abstinence (a model of relapse): the cannabinoid receptor agonist, nabilone, and the adrenergic agonist, lofexidine, alone and in combination with dronabinol (synthetic THC), supporting clinical testing of these medication strategies. Antidepressant, anxiolytic and antipsychotic drugs targeting monoamines (norepinephrine, dopamine, and serotonin) have generally failed to decrease withdrawal symptoms or laboratory measures of relapse. In terms of clinical trials, dronabinol and multiple antidepressants (fluoxetine, venlafaxine and buspirone) have failed to decrease cannabis use. Preliminary results from controlled clinical trials with gabapentin and N-acetylcysteine (NAC) support further research on these medication strategies. Data from open label and laboratory studies suggest lithium and oxytocin also warrant further testing. Overall, it is likely that different medications will be needed to target distinct aspects of problematic cannabis use: craving, ongoing use, withdrawal and relapse. Continued research is needed in preclinical, laboratory and clinical settings.


Cloning and expression of the Erwinia carotovora subsp. carotovora gene encoding the low-molecular-weight bacteriocin carocin S1.
The purpose of this study was to clone the carocin S1 gene and express it in a non-carocin-producing strain of Erwinia carotovora. A mutant, TH22-10, which produced a high-molecular-weight bacteriocin but not a low-molecular-weight bacteriocin, was obtained by Tn5 insertional mutagenesis using H-rif-8-2 (a spontaneous rifampin-resistant mutant of Erwinia carotovora subsp. carotovora 89-H-4). Using thermal asymmetric interlaced PCR, the DNA sequence from the Tn5 insertion site and the DNA sequence of the contiguous 2,280-bp region were determined. Two complete open reading frames (ORF), designated ORF2 and ORF3, were identified within the sequence fragment. ORF2 and ORF3 were identified with the carocin S1 genes, caroS1K (ORF2) and caroS1I (ORF3), which, respectively, encode a killing protein (CaroS1K) and an immunity protein (CaroS1I). These genes were homologous to the pyocin S3 gene and the pyocin AP41 gene. Carocin S1 was expressed in E. carotovora subsp. carotovora Ea1068 and replicated in TH22-10 but could not be expressed in Escherichia coli (JM101) because a consensus sequence resembling an SOS box was absent. A putative sequence similar to the consensus sequence for the E. coli cyclic AMP receptor protein binding site (-312 bp) was found upstream of the start codon. Production of this bacteriocin was also induced by glucose and lactose. The homology search results indicated that the carocin S1 gene (between bp 1078 and bp 1704) was homologous to the pyocin S3 and pyocin AP41 genes in Pseudomonas aeruginosa. These genes encode proteins with nuclease activity (domain 4). This study found that carocin S1 also has nuclease activity.


Comprehensive evaluation of methods to assess overall and cell-specific immune infiltrates in breast cancer.
Breast cancer (BC) immune infiltrates play a critical role in tumor progression and response to treatment. Besides stromal tumor infiltrating lymphocytes (sTILs) which have recently reached level 1B evidence as a prognostic marker in triple negative BC, a plethora of methods to assess immune infiltration exists, and it is unclear how these compare to each other and if they can be used interchangeably. Two experienced pathologists scored sTIL, intra-tumoral TIL (itTIL), and 6 immune cell types (CD3+, CD4+, CD8+, CD20+, CD68+, FOXP3+) in the International Cancer Genomics Consortium breast cancer cohort using hematoxylin and eosin-stained (n = 243) and immunohistochemistry-stained tissue microarrays (n = 254) and whole slides (n = 82). The same traits were evaluated using transcriptomic- and methylomic-based deconvolution methods or signatures. The concordance correlation coefficient (CCC) between pathologists for sTIL was very good (0.84) and for cell-specific immune infiltrates slightly lower (0.63-0.66). Comparison between tissue microarray and whole slide pathology scores revealed systematically higher values in whole slides (ratio 2.60-5.98). The Spearman correlations between microscopic sTIL and transcriptomic- or methylomic-based assessment of immune infiltrates were highly variable (r = 0.01-0.56). Similar observations were made for cell type-specific quantifications (r = 0.001-0.54). We observed a strong inter-method variability between the omics-derived estimations, which is further cell type dependent. Finally, we demonstrated that most methods more accurately identify highly infiltrated (sTIL ≥ 60%; area under the curve, AUC, 0.64-0.99) as compared to lowly infiltrated tumors (sTIL ≤ 10%; AUC 0.52-0.82). There is a lower inter-pathologist concordance for cell-specific quantification as compared to overall infiltration quantification. Microscopic assessments are underestimated when considering small cores (tissue microarray) instead of whole slides. Results further highlight considerable differences between the microscopic-, transcriptomic-, and methylomic-based methods in the assessment of overall and cell-specific immune infiltration in BC. We therefore call for extreme caution when assessing immune infiltrates using current methods and emphasize the need for standardized immune characterization beyond TIL.


Body Mass Index Is Associated With Mucosal Disease in Crohn's: Results of a Case-Control Study.
Recent studies have suggested that increased body mass index (BMI) may have an adverse effect on treatment outcomes and natural history in Crohn's disease (CD). We aimed to test the hypothesis that CD patients with higher BMI would be more likely than those with lower BMI to have persistent active mucosal disease. We designed a case-control study. Sample population comprised CD patients with active disease at the beginning of observation. At the end of observation, cases had persistent active mucosal disease and controls had entered remission. With multivariable logistic regression models, we evaluated the effect of baseline BMI as a continuous variable and a categorical variable on persistent active mucosal disease. We analyzed data from 104 patients (36 cases and 68 controls). In a model containing BMI as a continuous variable, higher BMI was significantly associated with persistent active mucosal disease (odds ratio (OR) = 1.09 per unit increase; 95% confidence interval (CI), 1.02 - 1.17; P = 0.012). In a model containing BMI as a categorical variable, obese patients were 2.7 times more likely to have persistent active mucosal disease compared to non-obese patients (OR = 2.72; 95% CI, 1.00 - 7.35; P = 0.049). Excessive weight measured both quantitatively as BMI and categorically as obesity in CD patients is associated with persistent active mucosal disease.


Cognitive and system factors contributing to diagnostic errors in radiology.
In this article, we describe some of the cognitive and system-based sources of detection and interpretation errors in diagnostic radiology and discuss potential approaches to help reduce misdiagnoses. Every radiologist worries about missing a diagnosis or giving a false-positive reading. The retrospective error rate among radiologic examinations is approximately 30%, with real-time errors in daily radiology practice averaging 3-5%. Nearly 75% of all medical malpractice claims against radiologists are related to diagnostic errors. As medical reimbursement trends downward, radiologists attempt to compensate by undertaking additional responsibilities to increase productivity. The increased workload, rising quality expectations, cognitive biases, and poor system factors all contribute to diagnostic errors in radiology. Diagnostic errors are underrecognized and underappreciated in radiology practice. This is due to the inability to obtain reliable national estimates of the impact, the difficulty in evaluating effectiveness of potential interventions, and the poor response to systemwide solutions. Most of our clinical work is executed through type 1 processes to minimize cost, anxiety, and delay; however, type 1 processes are also vulnerable to errors. Instead of trying to completely eliminate cognitive shortcuts that serve us well most of the time, becoming aware of common biases and using metacognitive strategies to mitigate the effects have the potential to create sustainable improvement in diagnostic errors.


A review of characteristics and outcomes of Australia's undergraduate medical education rural immersion programs.
A key strategy for increasing the supply of rural doctors is rurally located medical education. In 2000, Australia introduced a national policy to increase rural immersion for undergraduate medical students. This study aims to describe the characteristics and outcomes of the rural immersion programs that were implemented in Australian medical schools. Information about 19 immersion programs was sourced in 2016 via the grey and published literature. A scoping review of the published peer-reviewed studies via Ovid MEDLINE and Informit (2000-2016) and direct journal searching included studies that focused on outcomes of undergraduate rural immersion in Australian medical schools from 2000 to 2016. Programs varied widely by selection criteria and program design, offering between 1- and 6-year immersion. Based on 26 studies from 10 medical schools, rural immersion was positively associated with rural practice in the first postgraduate year (internship) and early career (first 10 years post-qualifying). Having a rural background increased the effects of rural immersion. Evidence suggested that longer duration of immersion also increases the uptake of rural work, including by metropolitan-background students, though overall there was limited evidence about the influence of different program designs. Most evidence was based on relatively weak, predominantly cross-sectional research designs and single-institution studies. Many had flaws including small sample sizes, studying internship outcomes only, inadequately controlling for confounding variables, not using metropolitan-trained controls and providing limited justification as to the postgraduate stage at which rural practice outcomes were measured. Australia's immersion programs are moderately associated with an increased rural supply of early career doctors although metropolitan-trained students contribute equal numbers to overall rural workforce capacity. More research is needed about the influence of student interest in rural practice and the duration and setting of immersion on rural work uptake and working more remotely. Research needs to be more nationally balanced and scaled-up to inform national policy development. Critically, the quality of research could be strengthened through longer-term follow-up studies, adjusting for known confounders, accounting for postgraduate stages and using appropriate controls to test the relative effects of student characteristics and program designs.


Cryogenian evolution of stigmasteroid biosynthesis.
Sedimentary hydrocarbon remnants of eukaryotic C26-C30 sterols can be used to reconstruct early algal evolution. Enhanced C29 sterol abundances provide algal cell membranes a density advantage in large temperature fluctuations. Here, we combined a literature review with new analyses to generate a comprehensive inventory of unambiguously syngenetic steranes in Neoproterozoic rocks. Our results show that the capacity for C29 24-ethyl-sterol biosynthesis emerged in the Cryogenian, that is, between 720 and 635 million years ago during the Neoproterozoic Snowball Earth glaciations, which were an evolutionary stimulant, not a bottleneck. This biochemical innovation heralded the rise of green algae to global dominance of marine ecosystems and highlights the environmental drivers for the evolution of sterol biosynthesis. The Cryogenian emergence of C29 sterol biosynthesis places a benchmark for verifying older sterane signatures and sets a new framework for our understanding of early algal evolution.


Neocortical synchronization.
Neuronal synchronization occurs when two or more neuronal events are coordinated across time. Local synchronization produces field potentials. Long-range synchronization between distant brain sites contributes to the electroencephalogram. Neuronal synchronization depends on synaptic (chemical/electrical), ephaptic, and extracellular interactions. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at www.ncbi.nlm.nih.gov/books).


An imported case of canine rabies in Aquitaine: Investigation and management of the contacts at risk, August 2004-March 2005.
In August 2004, a case of rabies was diagnosed in a puppy that had been illegally imported from Morocco to Bordeaux (France). Because a great number of people and animals were thought to have come into contact with the puppy, extensive tracing measures were implemented, and an international alert was launched to trace and treat the contacts at risk. One hundred and eighty seven people received post-exposure treatment, eight of whom also received serovaccination, and 57 animals known to have been exposed to the puppy were tested. Six months after the death of the rabid animal, none of the people treated showed any signs of rabies, nor was any secondary animal case reported. The management of this crisis highlights the importance of the role of a rapid alert system at European level. Strict application of sanitary control regulations is essential for animals introduced into EU countries, and all necessary information must be made available to EU residents travelling to rabies enzootic areas.


Association of a bitter taste receptor mutation with Balkan Endemic Nephropathy (BEN).
Balkan Endemic Nephropathy (BEN) is late-onset kidney disease thought to arise from chronic exposure to aristolochic acid, a phytotoxin that contaminates wheat supplies in rural areas of Eastern Europe. It has recently been demonstrated that humans are capable of perceiving aristolochic acid at concentrations below 40 nM as the result of high-affinity interactions with the TAS2R43 bitter taste receptor. Further, TAS2R43 harbors high-frequency loss-of-function mutations resulting in 50-fold variability in perception. This suggests that genetic variation in TAS2R43 might affect susceptibility to BEN, with individuals carrying functional forms of the receptor being protected by an ability to detect tainted foods. To determine whether genetic variation in TAS2R43 predicts BEN susceptibility, we examined genotype-phenotype associations in a case-control study. A cohort of 88 affected and 99 control subjects from western Bulgaria were genotyped with respect to two key missense variants and a polymorphic whole-gene deletion of TAS2R43 (W35S, H212R, and wt/Δ), which are known to affect taste sensitivity to aristolochic acid. Tests for association between haplotypes and BEN status were then performed. Three major TAS2R43 haplotypes observed in previous studies (TAS2R43-W35/H212, -S35/R212 and -Δ) were present at high frequencies (0.17, 0.36, and 0.47 respectively) in our sample, and a significant association between genotype and BEN status was present (P = 0.020; odds ratio 1.18). However, contrary to expectation, BEN was positively associated with TAS2R43-W35/H212, a highly responsive allele previously shown to confer elevated bitter sensitivity to aristolochic acid, which should drive aversion but might also affect absorption, altering toxin activation. Our findings are at strong odds with the prediction that carriers of functional alleles of TAS2R43 are protected from BEN by an ability to detect and avoid aristolochic acid exposure. Evidence for a positive association between high-sensitivity alleles and BEN status suggests instead that possession of toxin-responsive receptor variants may paradoxically increase vulnerability, possibly by shifting attractive responses associated with low-intensity bitter sensations. The broad-spectrum tuning of the ~25-member TAS2R family as a whole toward xenobiotics points to a potentially far-reaching relevance of bitter responses to exposure-related disease in both individuals and populations.


Evidence Supports Tradition: The in Vitro Effects of Roman Chamomile on Smooth Muscles.
The dried flowers of Chamaemelum nobile (L.) All. have been used in traditional medicine for different conditions related to the spasm of the gastrointestinal system. However, there have been no experimental studies to support the smooth muscle relaxant effect of this plant. The aim of our research was to assess the effects of the hydroethanolic extract of Roman chamomile, its fractions, four of its flavonoids (apigenin, luteolin, hispidulin, and eupafolin), and its essential oil on smooth muscles. The phytochemical compositions of the extract and its fractions were characterized and quantified by HPLC-DAD, the essential oil was characterized by GC and GC-MS. Neuronally mediated and smooth muscle effects were tested in isolated organ bath experiments on guinea pig, rat, and human smooth muscle preparations. The crude herbal extract induced an immediate, moderate, and transient contraction of guinea pig ileum via the activation of cholinergic neurons of the gut wall. Purinoceptor and serotonin receptor antagonists did not influence this effect. The more sustained relaxant effect of the extract, measured after pre-contraction of the preparations, was remarkable and was not affected by an adrenergic beta receptor antagonist. The smooth muscle-relaxant activity was found to be associated with the flavonoid content of the fractions. The essential oil showed only the relaxant effect, but no contracting activity. The smooth muscle-relaxant effect was also detected on rat gastrointestinal tissues, as well as on strip preparations of human small intestine. These results suggest that Roman chamomile extract has a direct and prolonged smooth muscle-relaxant effect on guinea pig ileum which is related to its flavonoid content. In some preparations, a transient stimulation of enteric cholinergic motoneurons was also detected. The essential oil also had a remarkable smooth muscle relaxant effect in this setting. Similar relaxant effects were also detected on other visceral preparations, including human jejunum. This is the first report on the activity of Roman chamomile on smooth muscles that may reassure the rationale of the traditional use of this plant in spasmodic gastrointestinal disorders.


Jamming graphs: a local approach to global mechanical rigidity.
We revisit the concept of minimal rigidity as applied to frictionless, repulsive soft sphere packings in two dimensions with the introduction of the jamming graph. Minimal rigidity is a purely combinatorial property encoded via Laman's theorem in two dimensions. It constrains the global, average coordination number of the graph, for example. However, minimal rigidity does not address the geometry of local mechanical stability. The jamming graph contains both properties of global mechanical stability at the onset of jamming and local mechanical stability. We demonstrate how jamming graphs can be constructed using local moves via the Henneberg construction such that these graphs fall under the jurisdiction of correlated percolation. We then probe how jamming graphs destabilize, or become unjammed, by deleting a bond and computing the resulting rigid cluster distribution. We also study how the system restabilizes with the addition of new contacts and how a jamming graph with extra (redundant) contacts destabilizes. The latter endeavor allows us to probe a disk packing in the rigid phase and uncover a potentially new diverging length scale associated with the random deletion of contacts as compared to the study of cut-out (or frozen-in) subsystems.


Expert by Experience Involvement in Mental Health Nursing Education: Nursing Students' Perspectives on Potential Improvements.
Expert by experience involvement in mental health education for health professional programmes has increased in recent decades. The related literature has articulated the benefits, and changes in attitudes have been measured in some studies. Less attention has been devoted to ways this learning approach could be improved. The aim of this paper is to present the nursing students perspectives on how Expert by Experience input into nursing curricula could be enhanced. Qualitative exploratory research was undertaken, involving focus groups with students who had completed a mental health learning module co-produced by Experts by Experience and nurse academics. Results show two main themes: getting the structure right, and changes to content and approach. Some student responses could directly influence changes to the learning module. In other instances, responses indicate the need to better prepare students of the value of lived experience knowledge in its own right, rather than adjunct to more traditional methods of education. These findings are important in encouraging reflection on how future learning modules co-produced by Experts by Experience and Mental Health Nursing academics can be refined and better articulated.


Thermoreversible magnetic nanochains.
The reversible organization of nanomagnets into highly anisotropic assemblies is of considerable interest for many applications, including theragnostic strategies in vivo. The current preparation strategies lead to structures that are not stable without the permanent presence of an applied magnetic field (MF); otherwise, irreversible assemblies are produced with moderate shape anisotropy at nanoscales. Here, we present a new approach based on the thermoreversible Diels-Alder reaction in the presence of an external MF that enables the assembly of single-domain nanomagnets into narrow chains with lengths of several micrometers. The MF-assisted click chemistry approach included (i) the synthesis of nanoparticles through a modified hydrothermal method, (ii) their functionalization via ligand exchange, (iii) the MF-assisted formation of chains, and (iv) the linkage of the nanomagnets in the presence of the magnetic field. Moreover, the chains can be again disassembled at elevated temperatures through a retro-Diels-Alder reaction. We thus demonstrated for the first time that MF-assisted click chemistry is a convenient method for large-scale preparation of highly anisotropic assemblies of nanosized magnets that can be reversibly decomposed by thermal treatment.


Dethroning the Fano Factor: A Flexible, Model-Based Approach to Partitioning Neural Variability.
Neurons in many brain areas exhibit high trial-to-trial variability, with spike counts that are overdispersed relative to a Poisson distribution. Recent work (Goris, Movshon, & Simoncelli, 2014 ) has proposed to explain this variability in terms of a multiplicative interaction between a stochastic gain variable and a stimulus-dependent Poisson firing rate, which produces quadratic relationships between spike count mean and variance. Here we examine this quadratic assumption and propose a more flexible family of models that can account for a more diverse set of mean-variance relationships. Our model contains additive gaussian noise that is transformed nonlinearly to produce a Poisson spike rate. Different choices of the nonlinear function can give rise to qualitatively different mean-variance relationships, ranging from sublinear to linear to quadratic. Intriguingly, a rectified squaring nonlinearity produces a linear mean-variance function, corresponding to responses with a constant Fano factor. We describe a computationally efficient method for fitting this model to data and demonstrate that a majority of neurons in a V1 population are better described by a model with a nonquadratic relationship between mean and variance. Finally, we demonstrate a practical use of our model via an application to Bayesian adaptive stimulus selection in closed-loop neurophysiology experiments, which shows that accounting for overdispersion can lead to dramatic improvements in adaptive tuning curve estimation.


Extensive spreading of interstitial telomeric sites on the chromosomes of Characidium (Teleostei, Characiformes).
Characidium comprises several species of small freshwater fish that display conserved diploid chromosome numbers and karyotypic formulae. In this study, a comparative cytogenetic analysis using telomeric DNA probes was carried out in nine species of Characidium; a molecular phylogenetic analysis with mitochondrial DNA was also performed in order to investigate the direction of the evolutionary chromosome changes observed here. Our results showed the existence of species with several and variable interstitial telomeric sites (ITSs), with other species showing only terminal signals in their chromosomes. Molecular phylogenetic data suggested that these ITSs emerged once in the evolutionary history of Characidium and were later differentially spread in distinct species/populations of this clade. Additionally, the origin of an exclusive acrocentric pair found in C. pterostictum, C. serrano and C. timbuiense was also investigated, revealing that this pair possibly had a common origin to these species. These results evidence the occurrence of intense and continuous genomic changes among species of Characidium.


Preference for equity as a framing effect.
In previous studies, the authors found that most people, given a fixed budget, would rather offer a less effective screening test to 100% of a Medicaid population than a more effective test to 50% of the population. In a subsequent study, the authors found that the number of people preferring the less effective screening test was dramatically reduced when the percentage of Medicaid enrollees receiving it was less than 100. In this article, 2 new studies are reported that explore whether people's preferences for equity versus efficiency are susceptible to a framing effect. In 2 studies, the authors presented subjects with multiple scenarios involving screening tests that vary in the proportion of people who could receive the tests within a budget constraint and the number of people whose lives each test would save. Across scenarios, the proportion of Medicaid enrollees who could receive each test was varied, as was the question of whether scenarios involved Medicaid enrollees from the same or a different state. In addition, the authors varied the order in which subjects received the scenarios. In the 1st study, people's preferences for equity over efficiency varied significantly depending on the way situations were framed. Preference for equity was stronger when the more widely distributed choice covered the entire population than when it covered only half the population (P < 0.001). In addition, people's preferences were susceptible to order effects, with preference for equity being significantly stronger when the 1st scenario received by subjects involved 1 screening test that could be offered to the entire population (P < 0.001). In the 2nd study, preferences for equity over efficiency diminished even when the different framings were descriptions of identical circumstances--preference for equity was significantly reduced when the population to be screened was framed broadly, in terms of the percentage of patients across 2 states who could receive testing rather than narrowly, in terms of the percentages of patients in 1 state who could receive testing (P = 0.04). Policy planners should be careful about accepting public preferences for equity over efficiency at face value, because such preferences can be dramatically influenced by framing effects and order effects.


Biologic solutions for degenerative disk disease.
Literature review. Review the potential use of biologic therapies for the treatment of degenerative disk disease. Degeneration of the intervertebral disk is a common occurrence which, although asymptomatic in most instances, may result in axial skeletal pain, radiculopathy, and myelopathy. Significant progress has been made in understanding the pathophysiology of degenerative disk disease and as a result, new biologic therapies, including molecular, gene, and cell-based strategies, are being investigated to halt and reverse disk degeneration. Growth factors, inflammatory inhibitors, proteinase inhibitors, and intracellular regulatory proteins are among the molecular therapies that have been studied with encouraging results in both in vitro and in vivo experiments. However, the utility of these therapies in humans may be limited because of the limited therapeutic duration. Gene therapies have the potential to overcome the limited therapeutic duration of molecular treatments by transferring genes to the cells within the disk to encode for therapeutic proteins with potential long-term local production. Gene therapy for disk regeneration has been successful in a number of animal studies, but significant concerns exist with the safety of the many vectors used for gene transfer. Cell-based therapies, including reimplantation of nucleus pulposus cells expanded in culture and stem cell therapies, have also been studied extensively in animal models with good results. The EuroDisc clinical trial is currently underway in Europe exploring the reimplantation of disk cells that are removed at the time of diskectomy and expanded ex vivo. Mesenchymal stem cells, which are readily available without ethical concerns, are being studied extensively for disk regeneration. Mesenchymal stem cells can differentiate into a phenotype similar to native nucleus pulposus cells and have shown the potential for disk regeneration in animal studies. Biologic therapies for intervertebral disk regeneration have produced very encouraging results in both in vitro and in vivo studies. Despite successful experimental results, these therapies face a number of hurdles before acceptance for human use including safety concerns, efficacy in high-order animal and human studies, and issues with the role and timing of these treatments.


Institutional screening for the fragile X syndrome.
Cytogenetic screening of mentally retarded patients for the fragile X (fra[X]) chromosome is helpful in identifying individuals who could benefit from genetic counseling and treatment. Previous studies have demonstrated a prevalence of the fra(X) syndrome as high as 6% in institutionalized retarded males. The physical and behavioral predictors of positive findings from cytogenetic testing have not been clarified, since many features of the fra(X) syndrome are found in other retarded populations. We performed physical and cytogenetic examinations on 440 patients at the Wheat Ridge (Colo) Regional Center. Twenty-eight (6.3%) demonstrated abnormal karyotypes. Seventeen of these were autosomal abnormalities or sex chromosome aneuploidies and 11 demonstrated the fra(X) chromosome (seven males, four females). In males, the physical features that were predictive of the fra(X) syndrome included the combination of ear lengths of 7.0 cm or greater, macroorchidism of 30 mL or greater, and the presence of hand calluses or lesions secondary to hand biting. The fra(X) chromosome was not seen in spastic quadriplegic patients. All seven males with the fra(X) syndrome were detected among the 141 ambulatory males who resided in the highest functioning units at this institution.