Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis.
Type 2 diabetes (T2D) is a heterogeneous disease for which (1) disease-causing pathways are incompletely understood and (2) subclassification may improve patient management. Unlike other biomarkers, germline genetic markers do not change with disease progression or treatment. In this paper, we test whether a germline genetic approach informed by physiology can be used to deconstruct T2D heterogeneity. First, we aimed to categorize genetic loci into groups representing likely disease mechanistic pathways. Second, we asked whether the novel clusters of genetic loci we identified have any broad clinical consequence, as assessed in four separate subsets of individuals with T2D. In an effort to identify mechanistic pathways driven by established T2D genetic loci, we applied Bayesian nonnegative matrix factorization (bNMF) clustering to genome-wide association study (GWAS) results for 94 independent T2D genetic variants and 47 diabetes-related traits. We identified five robust clusters of T2D loci and traits, each with distinct tissue-specific enhancer enrichment based on analysis of epigenomic data from 28 cell types. Two clusters contained variant-trait associations indicative of reduced beta cell function, differing from each other by high versus low proinsulin levels. The three other clusters displayed features of insulin resistance: obesity mediated (high body mass index [BMI] and waist circumference [WC]), "lipodystrophy-like" fat distribution (low BMI, adiponectin, and high-density lipoprotein [HDL] cholesterol, and high triglycerides), and disrupted liver lipid metabolism (low triglycerides). Increased cluster genetic risk scores were associated with distinct clinical outcomes, including increased blood pressure, coronary artery disease (CAD), and stroke. We evaluated the potential for clinical impact of these clusters in four studies containing individuals with T2D (Metabolic Syndrome in Men Study [METSIM], N = 487; Ashkenazi, N = 509; Partners Biobank, N = 2,065; UK Biobank [UKBB], N = 14,813). Individuals with T2D in the top genetic risk score decile for each cluster reproducibly exhibited the predicted cluster-associated phenotypes, with approximately 30% of all individuals assigned to just one cluster top decile. Limitations of this study include that the genetic variants used in the cluster analysis were restricted to those associated with T2D in populations of European ancestry. Our approach identifies salient T2D genetically anchored and physiologically informed pathways, and supports the use of genetics to deconstruct T2D heterogeneity. Classification of patients by these genetic pathways may offer a step toward genetically informed T2D patient management.


Multiple resolution representation and probabilistic matching of 2-d gray-scale shape.
One approach to pattern classification is to match a structural description of a pattern to models which describe the structural properties of pattern classes. The central problem in structural pattern matching is to determine the correspondence between the symbols which comprise a model and symbols which describe a pattern. The difficulty of determining this correspondence depends critically on the representation that is used to describe patterns. This correspondence presents a probabilistic representation for structural models of pattern classes. Both pattern descriptions and models for pattern classes are based on symbols which represent grayscale information at multiple resolutions. A pattern description is given by a tree of symbols with attribute values. Structural models are represented by a tree of symbols with probabilistic attributes. The position and scale (resolution) of the symbols, as well as other ``features,'' are represented by these attributes. An algorithm is presented for determining the correspondence between symbols in a description of a pattern and symbols in a model of a pattern class. This algorithm uses the connectivity between symbols at different scales to constrain the search for correspondence. An interactive training program for learning models of pattern classes is described, and some conclusions from the work are presented.


Physical activity in children and adolescents with congenital heart disease. Aspects of measurements with an activity monitor.
The aim of the present study was to evaluate different aspects of a device designed to monitor physical activity. Measurements of different axes and placement of the monitor were tested using a treadmill with ranging increments in incline or speed. The monitor was also used to assess the level of physical activity among children and adolescents with congenital heart disease and in healthy controls at the same age. The results indicate that the monitor is a valid and reproducible instrument for measurements of physical activity. The study revealed that the level of activity was higher for healthy boys than healthy girls (p<0.0001). Boys with congenital heart disease also displayed higher values compared to girls with congenital heart disease, although the difference was not significant (p=0.067). Healthy boys revealed a significantly higher level of activity than did boys with congenital heart disease (p=0.003), but no such difference was found in girls (p=0.757). Nor were any differences found between younger and older individuals among patients with congenital heart disease. Young healthy controls, however, showed significantly higher levels of activity than their older counterparts. There were differences in activity monitored during the week, with lower activity in the weekends, but the activity on the same day in different weeks seemed stable. Neither were there any differences between measurements over whole weeks. The results indicate that the Computer Science & Application monitor is a valid instrument for assessing physical activity. The monitor may also be used, therefore, to validate the levels of physical activity level in children with congenital heart disease after medical and surgical treatment.


Mapping clinical pharmacy practice in Swiss hospitals: a cross-sectional study.
Clinical pharmacy activities developed significantly in the last decade. The extent and organisation of these activities in Switzerland remained unknown. To map clinical pharmacy services (CPS) provided in Swiss hospitals and to discuss their development focusing on different cultural regions and healthcare systems. We enrolled all chief hospital pharmacists affiliated with the Swiss Society of Public Health Administration and Hospital Pharmacists (n=47) for an online survey. We asked them to describe the extent and organisation of CPS concerning patient-related, therapy-related or process-related activities, the structural organisation and the available human resources. The survey took place from March to April 2013. It was completed by 44 chief hospital pharmacists (return rate 94%), representing the hospital landscape in Switzerland comprehensively. Thirty-three (75%) hospitals offered regular CPS and seven (16%) planned to do so. Institutions in regions without drug-dispensing physicians rather employed pharmacists assigned with clinical activities (n=20, 22% of 135.3 full-time equivalent (FTE)) than regions with partial (n=8, 7% of 35.8 FTE) or unrestricted drug dispensing by physicians (n=16, 6% of 68.1 FTE, p=0.026). Of hospitals with implemented CPS, 73% had weekly interprofessional ward rounds, and in 9.1%, clinical pharmacists daily reconciled medicines at patient discharge. Our data show regional differences in the implementation and pattern of CPS. A significant correlation to drug dispensing by physicians in ambulatory care and human resources provided for CPS was found. While interprofessional ward rounds were performed periodically, seamless care activities by clinical pharmacists remained insufficiently established.


Inflammatory Bowel Diseases Benefit from Enhanced Recovery After Surgery [ERAS] Protocol: A Systematic Review with Practical Implications.
Enhanced Recovery After Surgery [ERAS] is widely adopted in patients undergoing colorectal surgery, with demonstrated benefits. Few studies have assessed the feasibility, safety, and effectiveness of ERAS in patients with inflammatory bowel diseases [IBD]. The aim of this study was to investigate the current adoption and outcomes of ERAS in IBD. This PRISMA-compliant systematic review of the literature included all articles reporting on adult patients with IBD who underwent colorectal surgery within an ERAS pathway. PubMed/MEDLINE, Cochrane Library, and Web of Science were searched. Endpoints included ERAS adoption, perioperative outcomes, and ERAS items more consistently reported, with associated evidence levels [EL] [PROSPERO CRD42021238653]. Out of 217 studies, 16 totalling 2347 patients were included. The median number of patients treated was 50.5. Malnutrition and anaemia optimisation were only included as ERAS items in six and four articles, respectively. Most of the studies included the following items: drinking clear fluids until 2 h before the surgery, fluid restriction, nausea prophylaxis, early feeding, and early mobilisation. Only two studies included postoperative stoma-team and IBD-team evaluation before discharge. Highest EL were observed for ileocaecal Crohn's disease resection [EL2]. Median in-hospital stay was 5.2 [2.9-10.7] days. Surgical site infections and anastomotic leaks ranged between 3.1-23.5% and 0-3.4%, respectively. Complications occurred in 5.7-48%, and mortality did not exceed 1%. Evidence on ERAS in IBD is lacking, but this group of patients might benefit from consistent adoption of the pathway. Future studies should define if IBD-specific ERAS pathways and selection criteria are needed.


Nosocomial fungemia in a large community teaching hospital.
This report reviews 48 episodes of hospital-acquired fungemia that occurred over a four-year period at a large community teaching hospital. The incidence of hospital-acquired fungemia increased eightfold during the study period. Candida albicans (58%), Candida tropicalis (25%), and Candida parapsilosis (15%) were the most common fungal pathogens isolated from blood cultures. Twenty-one patients (44%) had concomitant bacteremia. Intravascular catheters (100%), antibiotic administration (98%), urinary catheters (81%), surgical procedures (65%), parenteral alimentation (60%), and corticosteroid administration (54%) were the most common predisposing factors. The overall mortality rate was 75%. Hospitalization on the medical service, age greater than 60 years, and hospital stay less than 100 days were associated with a significantly increased mortality rate.


Current methods of controlling post-operative pain.
Until recently, the clinical significance of post-surgical pain and its undertreatment were for the most part unappreciated. Recognition that inadequate analgesia adversely affects the patient's cardiovascular, pulmonary, and emotional status has spurred development of new and highly effective methods of controlling pain. With the introduction of spinal opioid and patient-controlled analgesia (PCA) came the realization that, while such forms of therapy provided superior pain relief, they were not without their own unique and occasionally serious side effects. For this reason, both techniques are more safely provided by highly trained members of a dedicated acute/post-surgical pain service. Although spinal opioid (epidural, intrathecal) techniques are invasive and require patient cooperation, they have a high degree of safety in low-risk populations (ASA 1 and 2). The major therapeutic advantage of spinal opioids is their ability to prevent pain from being perceived. PCA permits patients to titrate intravenous opioids in proportion to their particular level of pain intensity. Although PCA provides effective pain "relief," the technique is incapable of preventing pain from being appreciated. A number of studies have observed that pain scores in patients successfully employing PCA were significantly higher than those noted in individuals treated with epidural opioids. Nevertheless, the control gained by self-administration, uniformity of analgesia, and low level of adverse results associated with PCA provides higher patient satisfaction and decreased sedation when compared with traditional intramuscular dosing. The effectiveness of PCA may be improved by adjusting for patient variables, utilizing opioids having rapid onset, the addition of a basal infusion, and supplementation with non-steroidal anti-inflammatory agents. Interpleural analgesia represents an important therapeutic option in patients sensitive to opioid-induced respiratory depression. The technique is more effective when local anesthetic solutions are continually infused. Analgesic efficacy may be further enhanced by the addition of "low-dose" PCA.


[Intra-articular oxygen partial pressure measurements under functional conditions].
Oxygen partial pressure is directly related to the vascularisation of different tissues. Different investigations in tissue (muscle, kidney, brain, heart, bone etc.) proved this correlation. The development of a special flexible microcatheter named Licox enables us to do measurements of intraarticular oxygen partial pressure under physiological and pathological conditions for the first time. The aim of this study was to examine the influence of different knee joint stresses on the intraarticular oxygen partial pressure under normal conditions and in osteoarthritis. The results showed that the different exercise patterns influence the intraarticular oxygen partial pressure. Patients with osteoarthritis showed a lower increase of the intraarticular oxygen partial pressure compared to the control group. This phenomenon is directly correlated to degree velocity of the isokinetic exercises. The same findings occur under ergometric conditions. The method permits functional, intraarticular in vivo measurements under different exercise patterns. For the very first time we were able to measure the influence of the joint movement on the intraarticular process of nutrition under physiological and pathological conditions. Different therapy concepts in osteoarthritis can be evaluated directly in vivo for the first time.


Gene therapy with secretory leukoprotease inhibitor promoter-controlled replication-competent adenovirus for non-small cell lung cancer.
Secretory leukoprotease inhibitor (SLPI) is highly expressed in almost all non-small cell lung cancers (NSCLCs), but not in the majority of other tumor types. In an attempt to create a specific gene therapy for NSCLC, we constructed AdSLPI.E1AdB, an adenovirus vector with a double expression cassette consisting of E1A driven by the SLPI promoter gene followed by E1B-19K under the control of the cytomegalovirus (CMV) promoter that can selectively replicate only in NSCLC cells. Infection with AdSLPI.E1AdB yielded E1A protein expression and adenovirus replication resulting in a >100-fold increase of the virus titers only in SLPI-producing NSCLC cells (A549, H358, and HS24 cells). In contrast, neither E1A protein nor replication was detected in non-SLPI-producing HepG2 cells. Treatment with AdSLPI.E1AdB significantly inhibited the proliferation of NSCLC cells in vitro in a dose-dependent manner, whereas the cell growth of HepG2 or normal human bronchial epithelial cells was not affected by AdSLPI.E1AdB infection. Direct injection of AdSLPI.E1AdB into A549 and H358 tumors in nude mice resulted in a marked reduction in tumor growth compared with controls (A549, 57%, P < 0.02; H358, 67%, P < 0.03). Histological examination revealed the replication of AdSLPI.E1AdB and strong induction of necrosis and apoptosis. In addition, we evaluated the combination of AdSLPI.E1AdB and AdCMV.NK4 encoding NK4 protein, which has strong antiangiogenic activity. E1A expressed by AdSLPI.E1AdB trans-acts on the replication of AdCMV.NK4 and thus increases the expression of NK4. Injection of these two vectors into H358 tumors resulted in a more striking reduction of tumor growth compared with single injection of each vector. These results suggest that AdSLPI.E1AdB could provide a selective therapeutic modality for NSCLC and that the combination of AdSLPI.E1AdB and AdCMV.NK4 may be a more effective gene therapy for NSCLC.


Camptothecinoids from the seeds of Taiwanese Nothapodytes foetida.
Two new alkaloids, 9-methoxy-18,19-dehydrocamptothecin (1) and 5- hydroxymappicine-20-O-beta-glucopyranoside (2a/2b as a racemic mixture), together with nine known compounds: camptothecin (3), 9-methoxy-camptothecin (4), 5-hydroxycamptothecin (5a/5b racemic mixture), 5-hydroxy-9-methoxycamptothecin (6a/6b racemic mixture), diosmetin (7), apigenin (8), apigenin-7-O-glucopyranoside (9), rosin (cinnamyl-O-beta-D-glucopyranoside) (10) and amarantholidoside IV (11) were isolated from the immature seeds of Nothapodytes foetida (Wight) Sleumer. The structures were elucidated by spectroscopic analyses. In the present research, compounds 1, 3, 4, 5a/5b and 6a/6b, also showed in vitro cytotoxicity against six cancer cell lines (HepG2, Hep3B, MDA-MB- 231, MCF-7, A549, and Ca9-22). Among them, compound 1 exhibited significant cytotoxicity against these cancer cell lines, with IC(50) of 0.24-6.57 microM. Furthermore, HPLC profiles were developed for qualitative and quantitative analysis of these active constituents in different parts of this plant, including mature and immature seeds, leaves, stems and roots. The results revealed that compounds 3 and 4 have the highest concentrations, which are found in the roots part of the plant.


Sputum issues as defined by patients with cystic fibrosis: a qualitative investigation.
Patients with cystic fibrosis (CF) are asked to provide a sputum sample at clinic to test for potentially harmful pathogens. However, some appear to struggle with this request. Research into the difficulties experienced by these patients is lacking. This study set out to explore this issue in depth, using a qualitative research approach. Semi-structured interviews were conducted with 18 patients identified as having difficulties with sputum by the physiotherapists involved in their care. Framework analysis was applied to collected data. An overarching concept derived from the interview material was a concern about sputum coming to be a defining feature of identity. This was reflected in the following four themes: (1) being seen as dirty because sputum is socially vilified as thus; (2) sputum exposing an invisible condition; (3) sputum acting as a reminder of having CF; (4) being seen as sputum producers by practitioners. Patients' difficulties with expectorating sputum were multifaceted and included psychosocial and physical factors. Practitioners need to appreciate that for some people, a request for sputum can cause significant discomfort. Individualized interventions to assist these patients may prove helpful.


Misrepresentation of authorship by applicants to pediatrics training programs.
To determine whether applicants to pediatrics residency and fellowship programs misrepresented authorship of publications. The authors sampled 1995 applications to the University of Washington School of Medicine's pediatrics residency program and pediatrics pulmonary fellowship program. They submitted all publications claimed in the submitted applications to extensive efforts to authenticate both their existence and authorship. Among the 404 pediatrics residency program applications studied, 147 claimed authorship of publications; 29 (19.7%) of these contained at least one unverifiable publication. Of the 401 publications claimed in the 147 applications, 41 (10.2%) could not be confirmed. Among 31 fellowship applications, 14 claimed publications. At least one citation was unverifiable for each of the 14 applications. Of the total 77 publications claimed, 31 (40%) could not be confirmed. Misrepresentation occurs on graduate medical education applications; solutions are needed to address this problem.


"I'm a different kind of nurse": advice from nurses in rural and remote Canada.
The sustainability of the rural and remote nursing workforce in Canada is increasingly at issue as the country becomes more urbanized and the nursing workforce ages. In order to support the retention of nurses in rural and remote communities and the recruitment of nurses to these communities, we require a better understanding of what is important to rural and remote nurses themselves. As part of the in-depth interviews conducted within The Nature of Nursing Practice in Rural and Remote Canada, a national research project, registered nurses (RNs) were asked what advice they would have for new nurses, educators, administrators and policy makers. This is the first of two papers describing that advice. It focuses on RNs in acute care, long-term care, home care, community health/public health and primary care roles in rural and remote communities across the country. The RNs were generous with their advice and gave many rich examples. While they were enthusiastic about their nursing practice and encouraging of other nurses to work in rural settings, they were intent that improvements be made in several key areas: education available to new practitioners and themselves, working conditions for rural and remote nurses, leadership, organizational supports and policies that better support rural and remote practice and communities.


Prevalence of Attention Deficit Hyperactivity Disorder in primary school children.
There is a lacuna of studies on Attention Deficit Hyperactivity Disorder (ADHD) in the Indian context. (i) To identify the prevalence of ADHD in primary school children, (ii) To identify the gender difference in the prevalence of ADHD, (iii) To compare the distribution of ADHD among different socioeconomic status, (iv) To identify the presence of any co-morbid factors associated with ADHD. This is a cross sectional study of school aged children selected from four different schools in Coimbatore district. Seven hundred seventy children aged between 6 and 11 years were selected from four schools in Coimbatore district after obtaining informed consent from their parents. The presence of ADHD was assessed by using Conner's Abbreviated Rating Scale (CARS) given to parents and teachers. The children identified as having ADHD were assessed for the presence of any co-morbid factors by administering Children's Behavioural Questionnaire (CBQ) to the teachers and Personal Information Questionnaire to the parents. Statistical Product and Service Solutions (SPSS) 10 software, Mean and Standard Deviation, and student's t test were used for statistical analysis. The prevalence of ADHD among primary school children was found to be 11.32%. Prevalence was found to be higher among the males (66.7%) as compared to that of females (33.3%). The prevalence among lower socio-economic group was found to be 16.33% and that among middle socio-economic group was 6.84%. The prevalence was highest in the age group 9 and 10 years. The present study shows a high prevalence of ADHD among primary school children with a higher prevalence among the males than the females.


Cardiovascular and psychological reactivity and recovery from harassment in a biracial sample of high and low hostile men and women.
This study emphasizes the importance of studying the emotional, motivational, and cognitive characteristics accompanying and the potential hemodynamic mechanisms underlying cardiovascular reactivity to and recovery from interpersonal conflict. The relation of dispositional hostility to cardiovascular reactivity during a frustrating anagram task and post-task recovery was investigated. The sample was composed of 99 healthy participants (age, 18-30 years; 53% women; 51% Caucasian; 49% African American)-half randomly assigned to a harassment condition. High and low hostility groups were created by a median split specific to sex and race subgroup score distributions on the Cook-Medley Hostility Scale. It was hypothesized that hostility would interact with harassment such that harassed, high hostile individuals would display the greatest cardiovascular and emotional reactivity and slowest recovery of the four groups. Participants completed a 10-min baseline, a 6-min anagram task, and a 5-min recovery period with blood pressure, heart rate, pre-ejection period, stroke index, cardiac index, and total peripheral resistance index measured. Harassed participants displayed significantly greater cardiovascular responses and lower positive affect to the task and slower systolic blood pressure (SBP) recovery than did nonharassed participants. The high hostile group, irrespective of harassment, showed blunted cardiovascular responses during the task and delayed SBP recovery than the low hostile group. Although the predicted interaction between hostility and harassment was not supported in the context of cardiovascular responses, such an interaction was observed in the context of blame attributions, whereby harassed hostile participants were found to blame others for their task performance than the other subgroups.


Diverse GABAergic neurons organize into subtype-specific sublaminae in the ventral lateral geniculate nucleus.
In the visual system, retinal axons convey visual information from the outside world to dozens of distinct retinorecipient brain regions and organize that information at several levels, including either at the level of retinal afferents, cytoarchitecture of intrinsic retinorecipient neurons, or a combination of the two. Two major retinorecipient nuclei which are densely innervated by retinal axons are the dorsal lateral geniculate nucleus, which is important for classical image-forming vision, and ventral LGN (vLGN), which is associated with non-image-forming vision. The neurochemistry, cytoarchitecture, and retinothalamic connectivity in vLGN remain unresolved, raising fundamental questions of how it receives and processes visual information. To shed light on these important questions, used in situ hybridization, immunohistochemistry, and genetic reporter lines to identify and characterize novel neuronal cell types in mouse vLGN. Not only were a high percentage of these cells GABAergic, we discovered transcriptomically distinct GABAergic cell types reside in the two major laminae of vLGN, the retinorecipient, external vLGN (vLGNe) and the non-retinorecipient, internal vLGN (vLGNi). Furthermore, within vLGNe, we identified transcriptionally distinct subtypes of GABAergic cells that are distributed into four adjacent sublaminae. Using trans-synaptic viral tracing and in vitro electrophysiology, we found cells in each these vLGNe sublaminae receive monosynaptic inputs from retina. These results not only identify novel subtypes of GABAergic cells in vLGN, they suggest the subtype-specific laminar distribution of retinorecipient cells in vLGNe may be important for receiving, processing, and transmitting light-derived signals in parallel channels of the subcortical visual system.


Some pharmacological properties of o-methyl-alpha-propylaminopropioananilide, a new local anaesthetic.
The anaesthetic action of o-methyl-alpha-propylaminopropionanilide (L 67, Astra) has been studied and compared with lignocaine in different in vitro and in vivo tests. Procaine and amethocaine (tetracaine) were also included in several of the comparisons. In nerve block on the isolated frog sciatic nerve L 67 is somewhat less effective than lignocaine. In all in vivo conditions, however, L 67 is quite comparable to lignocaine as to duration, latency and frequency of anaesthesia. As a spinal anaesthetic in rabbits 2 to 4% solutions of L 67 give a longer duration of anaesthesia than lignocaine. Toxicity in mice and rabbits and respiratory and circulatory effects in cats have also been evaluated. L 67 is almost twice as well tolerated as lignocaine. It is concluded that L 67 may prove to be a useful anaesthetic in certain clinical applications.


Environmental Response and Genomic Regions Correlated with Rice Root Growth and Yield under Drought in the OryzaSNP Panel across Multiple Study Systems.
The rapid progress in rice genotyping must be matched by advances in phenotyping. A better understanding of genetic variation in rice for drought response, root traits, and practical methods for studying them are needed. In this study, the OryzaSNP set (20 diverse genotypes that have been genotyped for SNP markers) was phenotyped in a range of field and container studies to study the diversity of rice root growth and response to drought. Of the root traits measured across more than 20 root experiments, root dry weight showed the most stable genotypic performance across studies. The environment (E) component had the strongest effect on yield and root traits. We identified genomic regions correlated with root dry weight, percent deep roots, maximum root depth, and grain yield based on a correlation analysis with the phenotypes and aus, indica, or japonica introgression regions using the SNP data. Two genomic regions were identified as hot spots in which root traits and grain yield were co-located; on chromosome 1 (39.7-40.7 Mb) and on chromosome 8 (20.3-21.9 Mb). Across experiments, the soil type/ growth medium showed more correlations with plant growth than the container dimensions. Although the correlations among studies and genetic co-location of root traits from a range of study systems points to their potential utility to represent responses in field studies, the best correlations were observed when the two setups had some similar properties. Due to the co-location of the identified genomic regions (from introgression block analysis) with QTL for a number of previously reported root and drought traits, these regions are good candidates for detailed characterization to contribute to understanding rice improvement for response to drought. This study also highlights the utility of characterizing a small set of 20 genotypes for root growth, drought response, and related genomic regions.


Environmental DNA assays for the sister taxa sauger (Sander canadensis) and walleye (Sander vitreus).
Sauger (Sander canadensis) and walleye (S. vitreus) are percid fishes that naturally co-occur throughout much of the eastern United States. The native range of sauger extends into the upper Missouri River drainage where walleye did not historically occur, but have been stocked as a sport fish. Sauger populations have been declining due to habitat loss, fragmentation, and competition with non-native species, such as walleye. To effectively manage sauger populations, it is necessary to identify areas where sauger occur, and particularly where they co-occur with walleye. We developed quantitative PCR assays that can detect sauger and walleye DNA in filtered water samples. Each assay efficiently detected low quantities of target DNA and failed to detect DNA of non-target species with which they commonly co-occur.


Surface plasmon resonance sensor interrogation with a double-clad fiber coupler and cladding modes excited by a tilted fiber Bragg grating.
We present a novel optical fiber surface plasmon resonance (SPR) sensor scheme using reflected guided cladding modes captured by a double-clad fiber coupler and excited in a gold-coated fiber with a tilted Bragg grating. This new interrogation approach, based on the reflection spectrum, provides an improvement in the operating range of the device over previous techniques. The device allows detection of SPR in the reflected guided cladding modes and also in the transmitted spectrum, allowing comparison with standard techniques. The sensor has a large operating range from 1.335 to 1.432 RIU, and a sensitivity of 510.5 nm/RIU. The device shows strong dependence on the polarization state of the guided core mode which can be used to turn the SPR on or off.


Characterization of the periplasmic region of PomB, a Na+-driven flagellar stator protein in Vibrio alginolyticus.
The stator proteins PomA and PomB form a complex that couples Na(+) influx to torque generation in the polar flagellar motor of Vibrio alginolyticus. This stator complex is anchored to an appropriate place around the rotor through a putative peptidoglycan-binding (PGB) domain in the periplasmic region of PomB (PomB(C)). To investigate the function of PomB(C), a series of N-terminally-truncated and in-frame mutants with deletions between the transmembrane (TM) segment and the PGB domain of PomB was constructed. A PomB(C) fragment consisting of residues 135 to 315 (PomB(C₅) formed a stable homodimer and significantly inhibited the motility of wild-type cells when overexpressed in the periplasm. A fragment with an in-frame deletion (PomB(ΔL)) of up to 80 residues retained function, and its overexpression with PomA impaired cell growth. This inhibitory effect was suppressed by a mutation at the functionally critical Asp (D24N) in the TM segment of PomB, suggesting that a high level of Na(+) influx through the mutant stator causes the growth impairment. The overproduction of functional PomA/PomB(ΔL) stators also reduced the motile fractions of the cells. That effect could be slightly relieved by a mutation (L168P) in the putative N-terminal α-helix that connects to the PGB domain without affecting the growth inhibition, suggesting that a conformational change of the region including the PGB domain affects stator assembly. Our results reveal common features of the periplasmic region of PomB/MotB and demonstrate that a flexible linker that contains a "plug" segment is important for the control of Na(+) influx through the stator complex as well as for stator assembly.


The J. Robert Gladden Orthopaedic Society: Past, Present, and Future.
Officially chartered in 1998, the J. Robert Gladden Orthopaedic Society (JRGOS) is a multicultural society dedicated to improving the diversity of the orthopaedic surgeon workforce and ending disparities in musculoskeletal health care. The purpose of this article is to discuss why an organization such as the JRGOS was needed within the American Academy of Orthopaedic Surgeons and highlight the key figures in orthopaedic history who supported the formation of the JRGOS. It also highlights the present efforts of the JRGOS, which include mentorship of Black, indigenous people of color medical students, residents and fellows in training, and support of research related to disparities in musculoskeletal care. As the JRGOS enters its third decade of existence, additional partnerships with the American Academy of Orthopaedic Surgeons, American Orthopaedic Association, AALOS, Orthopaedic Diversity Leadership Consortium, RJOS, Nth Dimensions, BWOS, and industry will help to realize the dream of making the orthopaedic workforce as diverse as the United States.


Generation and properties of the new asphalt binder model using molecular dynamics (MD).
Asphalt binder is the main material for road pavement and building construction. It is a complex mixture composed of a large number of hydrocarbons with different molecular weights. The study of asphalt binders and asphalt concretes from a molecular perspective is an important means to understand the intricate properties of asphalt. Molecular dynamics simulation is based on Newton's law and predicts the microscopic performance of materials by calculating the intra- and intermolecular interactions. The asphalt binder can be divided into four components: saturates, aromatics, resins, and asphaltenes (SARA). A new molecular model of asphalt was proposed and verified in this study. Eight molecules selected from the literature were used to represent the four components of asphalt. The AMBER Cornell Extension Force Field was applied in this study to model building and the calculation of properties. The density of the asphalt model was calculated and compared with experimental results for validity verifications. The results show that the purposed model can be used to calculate the microscopic properties of the asphalt binder because the density of the model is close to the real value in the field. Besides, the proportions of different molecules in the model were adjusted to predict the relationship between the asphalt binder density and the hydrocarbon ratios and heteroatom contents of the molecular model. Moreover, the glass transition temperature of the asphalt binder model is predicted by the simulation of the heating process. The range of the glass transition temperature is determined by calculating the relationship between specific volume and temperature, and the calculated range is close to the experimental value.


The science of sex verification and athletic performance.
The division of athletes into male and female categories for competition is a widely accepted practice and is ordinarily straightforward, requiring no intervention from authorities. However, for reasons ranging from deliberate cheating to complex medical conditions resulting in ambiguous development of sex organs, the controversy of sex verification in athletic events has existed for 70 years. Testing procedures, initially implemented to prevent cheating by men masquerading as women, have produced humiliating outcomes for women athletes who were often for the first time confronted with the possibility that they have one of the disorders of sex development. Sporting authorities have and continue to formulate position stands for the management of such cases. An important missing component in this debate is the sound scientific evidence to determine (a) whether a performance advantage actually exists and (b) how large it might be. The division of competition into separate categories and the large difference in sporting performance between male and female necessitate that sport-governing bodies define the boundaries between the sexes in a just and fair manner for all participating athletes. This review will therefore provide the historical context of the debate and aim to discuss relevant physiological and performance aspects of the sex verification process.


Joining together to combat poverty.
The International Poverty and Health Network (IPHN) was created in December 1997 following a series of conferences organized by the World Health Organization, with the aim of integrating health into plans to eradicate poverty. Around 1.3 billion people live on less than US$1 per day. Of the 4.4 billion people in developing countries nearly 60% lack access to sanitation, 30% do not have clean water, 20% have no health care, and 20% do not have enough dietary energy and protein. Even among rich nations there are gross socioeconomic inequalities. Many children are robbed of their physical and mental potential through poverty. Expressed in constant 1963 US dollars, an average Croatian family needed the annual income of US$894 to meet the poverty line in 1960 and US$9,027 in 1995. Accordingly, 9-25% of Croatian households were below the poverty line between 1960 and 1995. The increase in the poverty rate after 1991 was compounded by the war that destroyed almost a third of industrial capacity and infrastructure. Dissipation of the communist economy and inadequate privatization have contributed to the increase in unemployment rate, corruption, and other social ills. IPHN invited Croatian Medical Journal to publish this editorial to help push the issue of poverty up political and medical agendas on a global level. We argue that a factor contributing to the failure of most large-scale programs against poverty to date is the excessive emphasis on material and infrastructure assistance at the expense of spiritual, moral, and intellectual development.


A prospective cohort study of insomnia and chronic kidney disease in Japanese workers.
The role of insomnia in chronic kidney disease (CKD) is controversial. To date, there have been no prospective studies investigating insomnia, CKD and the effect of shift work. We assessed insomnia and CKD risk in a prospective, occupational cohort study. A total of 3600 participants with normal kidney function were followed for an average of 4.4 years. Insomnia was assessed using the Athens Insomnia Scale (AIS). CKD was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 at the first health examination. Cox proportional hazard regression models were used to estimate hazard ratios with 95% confidence intervals of insomnia for CKD development. A total of 182 CKD cases were identified. After adjustment for potential confounders, we did not observe an association between insomnia (AIS score ≥6) and CKD. However, the AIS item of awakening during the night was associated with a significantly increased CKD risk (hazard ratio = 3.10, 95% confidence interval 1.68-5.30). In further analyses, having difficulty with sleep induction was associated with an increased CKD risk among shift workers (hazard ratio = 3.34, 95% confidence interval 1.22-8.31). This association was not present among non-shift workers. Awakening during the night is associated with a moderately increased CKD risk.


Autosomal dominant polycystic kidney disease: the changing face of clinical management.
Autosomal dominant polycystic kidney disease is the most common inherited kidney disease and accounts for 7-10% of all patients on renal replacement therapy worldwide. Although first reported 500 years ago, this disorder is still regarded as untreatable and its pathogenesis is poorly understood despite much study. During the past 40 years, however, remarkable advances have transformed our understanding of how the disease develops and have led to rapid changes in diagnosis, prognosis, and treatment, especially during the past decade. This Review will summarise the key findings, highlight recent developments, and look ahead to the changes in clinical practice that will likely arise from the adoption of a new management framework for this major kidney disease.


Effects of a Short Video-Based Resident-as-Teacher Training Toolkit on Resident Teaching.
To pilot a short video-based resident-as-teacher training toolkit and assess its effect on resident teaching skills in clinical settings. A video-based resident-as-teacher training toolkit was previously developed by educational experts at Beth Israel Deaconess Medical Center, Harvard Medical School. Residents were recruited from two academic hospitals, watched two videos from the toolkit ("Clinical Teaching Skills" and "Effective Clinical Supervision"), and completed an accompanying self-study guide. A novel assessment instrument for evaluating the effect of the toolkit on teaching was created through a modified Delphi process. Before and after the intervention, residents were observed leading a clinical teaching encounter and scored using the 15-item assessment instrument. The primary outcome of interest was the change in number of skills exhibited, which was assessed using the Wilcoxon signed-rank test. Twenty-eight residents from two academic hospitals were enrolled, and 20 (71%) completed all phases of the study. More than one third of residents who volunteered to participate reported no prior formal teacher training. After completing two training modules, residents demonstrated a significant increase in the median number of teaching skills exhibited in a clinical teaching encounter, from 7.5 (interquartile range 6.5-9.5) to 10.0 (interquartile range 9.0-11.5; P<.001). Of the 15 teaching skills assessed, there were significant improvements in asking for the learner's perspective (P=.01), providing feedback (P=.005), and encouraging questions (P=.046). Using a resident-as-teacher video-based toolkit was associated with improvements in teaching skills in residents from multiple specialties.


Deep Neural Network for Structural Prediction and Lane Detection in Traffic Scene.
Hierarchical neural networks have been shown to be effective in learning representative image features and recognizing object classes. However, most existing networks combine the low/middle level cues for classification without accounting for any spatial structures. For applications such as understanding a scene, how the visual cues are spatially distributed in an image becomes essential for successful analysis. This paper extends the framework of deep neural networks by accounting for the structural cues in the visual signals. In particular, two kinds of neural networks have been proposed. First, we develop a multitask deep convolutional network, which simultaneously detects the presence of the target and the geometric attributes (location and orientation) of the target with respect to the region of interest. Second, a recurrent neuron layer is adopted for structured visual detection. The recurrent neurons can deal with the spatial distribution of visible cues belonging to an object whose shape or structure is difficult to explicitly define. Both the networks are demonstrated by the practical task of detecting lane boundaries in traffic scenes. The multitask convolutional neural network provides auxiliary geometric information to help the subsequent modeling of the given lane structures. The recurrent neural network automatically detects lane boundaries, including those areas containing no marks, without any explicit prior knowledge or secondary modeling.


[How does Hinduism analyze an ethical clinical dilemma].
It is indispensable for physicians to understand and recognize the fusion of different cultures, to deliver the best possible service to patients with different cultural backgrounds, especially when ethical-medical problems are involved. The Hindu community in Chile differs in significant ways with the western culture. This is especially true for some issues such as the belief in reincarnation or gender inequality, among others. These discrepancies can be relevant for the analysis of several bioethical problems. Therefore, it is necessary to understand the different beliefs, traditions and Hindu visions. We hereby present a review of Hinduism, its relation with medical practice and, as an example, a case of abortion in a Hindu family. Reviewing the traditions, beliefs and methods will help to understand and respect the beliefs of different cultures in contemporary and globalized bioethics.


In-vitro activity of polymyxin B, rifampicin, tigecycline alone and in combination against carbapenem-resistant Acinetobacter baumannii in Singapore.
Carbapenem-resistant Acinetobacter baumannii (CR-AB) is an emerging cause of nosocomial infections worldwide. Combination therapy may be the only viable option until new antibiotics become available. The objective of this study is to identify potential antimicrobial combinations against CR-AB isolated from our local hospitals. AB isolates from all public hospitals in Singapore were systematically collected between 2006 and 2007. MICs were determined according to CLSI guidelines. All CR-AB isolates were genotyped using a PCR-based method. Clonal relationship was elucidated. Time-kill studies (TKS) were conducted with polymyxin B, rifampicin and tigecycline alone and in combination using clinically relevant (achievable) unbound concentrations. 31 CR AB isolates were identified. They are multidrug-resistant, but are susceptible to polymyxin B. From clonal typing, 8 clonal groups were identified and 11 isolates exhibited clonal diversity. In single TKS, polymyxin B, rifampicin and tigecycline alone did not exhibit bactericidal activity at 24 hours. In combination TKS, polymyxin plus rifampicin, polymyxin B plus tigecycline and tigecycline plus rifampicin exhibited bactericidal killing in 13/31, 9/31 and 7/31 isolates respectively at 24 hours. Within a clonal group, there may be no consensus with the types of antibiotics combinations that could still kill effectively. Monotherapy with polymyxin B may not be adequate against polymyxin B susceptible AB isolates. These findings demonstrate that in-vitro synergy of antibiotic combinations in CR AB may be strain dependant. It may guide us in choosing a pre-emptive therapy for CR AB infections and warrants further investigations.


The sugarcane mitochondrial genome: assembly, phylogenetics and transcriptomics.
Chloroplast genomes provide insufficient phylogenetic information to distinguish between closely related sugarcane cultivars, due to the recent origin of many cultivars and the conserved sequence of the chloroplast. In comparison, the mitochondrial genome of plants is much larger and more plastic and could contain increased phylogenetic signals. We assembled a consensus reference mitochondrion with Illumina TruSeq synthetic long reads and Oxford Nanopore Technologies MinION long reads. Based on this assembly we also analyzed the mitochondrial transcriptomes of sugarcane and sorghum and improved the annotation of the sugarcane mitochondrion as compared with other species. Mitochondrial genomes were assembled from genomic read pools using a bait and assemble methodology. The mitogenome was exhaustively annotated using BLAST and transcript datasets were mapped with HISAT2 prior to analysis with the Integrated Genome Viewer. The sugarcane mitochondrion is comprised of two independent chromosomes, for which there is no evidence of recombination. Based on the reference assembly from the sugarcane cultivar SP80-3280 the mitogenomes of four additional cultivars (R570, LCP85-384, RB72343 and SP70-1143) were assembled (with the SP70-1143 assembly utilizing both genomic and transcriptomic data). We demonstrate that the sugarcane plastome is completely transcribed and we assembled the chloroplast genome of SP80-3280 using transcriptomic data only. Phylogenomic analysis using mitogenomes allow closely related sugarcane cultivars to be distinguished and supports the discrimination between Saccharum officinarum and Saccharum cultum as modern sugarcane's female parent. From whole chloroplast comparisons, we demonstrate that modern sugarcane arose from a limited number of Saccharum cultum female founders. Transcriptomic and spliceosomal analyses reveal that the two chromosomes of the sugarcane mitochondrion are combined at the transcript level and that splice sites occur more frequently within gene coding regions than without. We reveal one confirmed and one potential cytoplasmic male sterility (CMS) factor in the sugarcane mitochondrion, both of which are transcribed. Transcript processing in the sugarcane mitochondrion is highly complex with diverse splice events, the majority of which span the two chromosomes. PolyA baited transcripts are consistent with the use of polyadenylation for transcript degradation. For the first time we annotate two CMS factors within the sugarcane mitochondrion and demonstrate that sugarcane possesses all the molecular machinery required for CMS and rescue. A mechanism of cross-chromosomal splicing based on guide RNAs is proposed. We also demonstrate that mitogenomes can be used to perform phylogenomic studies on sugarcane cultivars.


Beyond the Nuclear Family: Children's Social Networks and Depressive Symptomology.
This study identified social network profiles among children, determined whether profiles vary across sociodemographic characteristics, and investigated links between childhood profiles and depressive symptomology using three waves of data spanning 23 years (Wave 1, 1992 Metro-Detroit representative sample: n = 193, ages 8-12). Latent profile analysis revealed three profiles: Close Family (22%), Varied Family (57%), Friend and Family (21%). White children were more likely than Black children to be in the Friend and Family profile. Children in the Close Family profile reported the lowest levels of depressive symptomology in childhood, but exhibited the steepest increase over time. Findings suggest that close, family centric networks are protective in childhood, but less so as children develop into adulthood, highlighting the importance of considering developmental perspectives.


Prevalence of thermotolerant Campylobacter in pheasants (Phasianus colchicus).
The present study was undertaken with the aim to evaluate the prevalence of thermotolerant Campylobacter spp. in living pheasants in Italy. To achieve this goal, a total of 240 living pheasants, equally shared between female and male birds, were examined. Thermotolerant Campylobacter spp. was isolated in 104 out of 204 (43.3%) living pheasants analysed. Campylobacter coli (100%) and Campylobacter jejuni (13.5%) were identified by polymerase chain reaction. Adult pheasants showed a significantly higher prevalence value (P < 0.05) than younger pheasants.


Monitoring the development and diffusion of EHR systems in Denmark.
The Danish EHR Observatory has monitored Danish EHR projects for several years with respect to a number of parameters such as diffusion, diffusion rate, barriers and limitations, and experience gained. The results of the 2002 monitoring reveal that investment in IT is relatively low and the diffusion rate is below the estimated level. The EHR projects gain a lot of valuable experience, but the coordination of evaluation results should be improved.


Long-term outcomes of percutaneous radiofrequency thermocoagulation of gasserian ganglion for 2nd- and multiple-division trigeminal neuralgia.
The objective of this study was to examine the long-term outcome of percutaneous radiofrequency thermocoagulation (PRT) of the Gasserian ganglion for the 2nd division and multiple division trigeminal neuralgia (TN), compared to the isolated 3rd division TN. One hundred and forty-eight procedures performed in 89 patients with typical TN between April 2004 and September 2011 in a single pain center were retrospectively analyzed. Baseline characteristics of these patients, immediate outcome, duration pain-free, and complications were obtained from their medical records and questionnaires sent in June 2012. Duration pain-free was assessed by Kaplan-Meier analysis. Of the 148 PRT of the Gasserian ganglion, 37 procedures were performed for isolated 2nd-division TN (V2 TN), 67 procedures were for both 2nd- and 3rd-division TN (V2 + V3 TN), and 38 procedures were for isolated 3rd-division TN (V3 TN). The remaining 6 procedures were performed for V1 + V2 TN and V1 + V2 + V3 TN. Immediate success rates of PRT for V2 TN, V2 + V3 TN, and V3 TN were 100%, 86.6%, and 100%, respectively, whereas the durations pain-free for V2 TN and V2 + V3 TN were significantly shorter than that for V3 TN (9, 12, and 36 months, respectively: P = 0.012). For 2nd-division TN and multiple-division TN, less long-term pain relief after PRT of the Gasserian ganglion can be expected compared with that for isolated trigeminal 3rd-division neuralgia, even if immediate pain relief is achieved.


Evidence-Based Strategies for the Treatment of Peritoneal Malignancies during Health Care Resource Restriction: The COVID-19 Pandemic.
Background: The COVID-19 pandemic has put enormous pressure on hospital resources, and has affected all aspects of patient care. As operative volumes decrease, cancer surgeries must be triaged and prioritized with careful thought and attention to ensure maximal benefit for the maximum number of patients. Peritoneal malignancies present a unique challenge, as surgical management can be resource intensive, but patients have limited non-surgical treatment options. This review summarizes current data on outcomes and resource utilization to help inform decision-making and case prioritization in times of constrained health care resources. Methods: A rapid literature review was performed, examining surgical and non-surgical outcomes data for peritoneal malignancies. Narrative data synthesis was cross-referenced with relevant societal guidelines. Peritoneal malignancy surgeons and medical oncologists reviewed recommendations to establish a national perspective on case triage and mitigating treatment strategies. Results and Conclusions: Triage of peritoneal malignancies during this time of restricted health care resource is nuanced and requires multidisciplinary discussion with consideration of individual patient factors. Prioritization should be given to patients where delay may compromise resectability of disease, and where alternative treatment options are lacking. Mitigating strategies such as systemic chemotherapy and/or surgical deferral may be utilized with close surveillance for disease stability or progression, which may affect surgical urgency. Unique hospital capacity, and ability to manage the complex post-operative course for these patients must also be considered to ensure patient and system needs are aligned.


How lead exposure relates to temporal changes in IQ, violent crime, and unwed pregnancy.
This study compares changes in children's blood lead levels in the United States with subsequent changes in IQ, based on norm comparisons for the Cognitive Abilities Test (CogAT) given to representative national samples of children in 1984 and 1992. The CogAT norm comparisons indicate shifts in IQ levels consistent with the blood lead to IQ relationship reported by an earlier study and population shifts in average blood lead for children under age 6 between 1976 and 1991. The CogAT norm comparisons also support studies indicating that the IQ to blood lead slope may increase at lower blood lead levels. Furthermore, long-term trends in population exposure to gasoline lead were found to be remarkably consistent with subsequent changes in violent crime and unwed pregnancy. Long-term trends in paint and gasoline lead exposure are also strongly associated with subsequent trends in murder rates going back to 1900. The findings on violent crime and unwed pregnancy are consistent with published data describing the relationship between IQ and social behavior. The findings with respect to violent crime are also consistent with studies indicating that children with higher bone lead tend to display more aggressive and delinquent behavior. This analysis demonstrates that widespread exposure to lead is likely to have profound implications for a wide array of socially undesirable outcomes.


Orbital Selectivity Enhanced by Nematic Order in FeSe.
Motivated by the recent low-temperature experiments on bulk FeSe, we study the electron correlation effects in a multiorbital model for this compound in the nematic phase using the U(1) slave-spin theory. We find that a finite nematic order helps to stabilize an orbital selective Mott phase. Moreover, we propose that when the d- and s-wave bond nematic orders are combined with the ferro-orbital order, there exists a surprisingly large orbital selectivity between the xz and yz orbitals even though the associated band splitting is relatively small. Our results explain the seemingly unusual observation of strong orbital selectivity in the nematic phase of FeSe, uncover new clues on the nature of the nematic order, and set the stage to elucidate the interplay between superconductivity and nematicity in iron-based superconductors.


Targeted early childhood programming. The promise half fulfilled.
A group of 169 children was followed up from birth to second grade in a community-based early identification and early intervention project. Periodic assessments of health and function yielded profiles of concerns. Over the first five years of life, 39% of the children had health concerns, 20% had cognitive concerns, 25% had motor concerns, 15% had social adjustment problems, and 12% had early attentional problems. Children at the highest risk of having reading and behavioral problems in second grade were those with early attentional disability. At the second-grade level, 31% of the children with early attention concerns were one full grade behind in reading and 38% had behavioral problems; among the youngsters without early attentional concerns, 6% demonstrated a reading delay and 8% had behavioral problems. In addition, children of highly educated mothers were more likely to benefit from the multidisciplinary program than were children of less educated mothers, for whom the intervention effected only a modest improvement when contrasted with randomly selected comparison children. For instance, among children with early cognitive problems and whose mothers had little education, 31% of these children had reading problems in second grade as opposed to 10% of those whose mothers had high educational attainment. Similarly, 39% of children with the combined risks of low maternal education and early attentional problems had reading problems in second grade compared with none of the attention-problem children of highly educated mothers. This study shows that while early identification of health and developmental problems can be carried out in a community-based project, strategies for the early intervention of developmental concerns among children of low socioeconomic status remain less than completely effective.


Fast-electron-relaxation measurement for laser-solid interaction at relativistic laser intensities.
We present measurements of the fast-electron-relaxation time in short-pulse (0.5 ps) laser-solid interactions for laser intensities of 10(17), 10(18), and 10(19) Wcm2, using a picosecond time-resolved x-ray spectrometer and a time-integrated electron spectrometer. We find that the laser coupling to hot electrons increases as the laser intensity becomes relativistic, and that the thermalization of fast electrons occurs over time scales on the order of 10 ps at all laser intensities. The experimental data are analyzed using a combination of models that include Kalpha generation, collisional coupling, and plasma expansion.


Repetitive hyperthermia attenuates progression of left ventricular hypertrophy and increases telomerase activity in hypertensive rats.
We investigated the hypothesis that repetitive hyperthermia (RHT) attenuates the progression of cardiac hypertrophy and delays the transition from hypertensive cardiomyopathy to heart failure in Dahl salt-sensitive (DS) hypertensive rats. Six-week-old DS rats were divided into the following five groups: a normal-salt diet (0.4% NaCl) (NS group), a normal-salt diet plus RHT by daily immersion for 10 min in 40°C water (NS+RHT group), a high-salt diet (8% NaCl) (HS group), a high-salt diet (8% NaCl) plus RHT (HS+RHT group), and high-salt diet (8% NaCl) plus RHT with 17-DMAG (HSP90 inhibitor) administration (HS+RHT+17-DMAG group). All rats were killed at 10 wk. Cardiac hypertrophy and fibrosis were noted in the HS group, whereas RHT attenuated salt-induced cardiac hypertrophy, myocardial and perivascular fibrosis, and blood pressure elevation. The phosphorylated endothelial nitric oxide synthase (eNOS) and Akt were decreased in the HS group compared with the NS group, but these changes were not observed in the HS+RHT group. The levels of HSP60, 70, and 90 were elevated by RHT. Moreover, the increased levels of iNOS, nitrotyrosine, Toll-like receptor-4, BNP, PTX3, and TBARS in the HS group were inhibited by RHT. Telomeric DNA length, telomerase activity, and telomere reverse transcriptase (TERT) were reduced in the HS group; however, these changes were partially prevented by hyperthermia. In conclusion, RHT attenuates the development of cardiac hypertrophy and fibrosis and preserves telomerase, TERT activity and the length of telomere DNA in salt-induced hypertensive rats through activation of eNOS and induction of HSPs.


Cytomegalovirus strain AD169 binds beta 2 microglobulin in vitro after release from cells.
We previously reported that a host protein, beta 2 microglobulin (beta 2m) inhibited the detection of human cytomegalovirus (CMV) in urine specimens by enzyme immunoassay and postulated that beta 2m bound to the virus particle and masked the viral antigenic determinants. We report here that CMV strain AD169 grown in cell culture bound human beta 2m when this protein was added to cell culture fluids or when the virus was added to urine. Such binding was not seen with herpes simplex virus. CMV could also bind bovine beta 2m from foetal calf serum in cell culture fluids. The use of radiolabelled beta 2m in other experiments showed that CMV bound beta 2m after release from cells and that the bound beta 2m did not represent acquisition of class I HLA molecules during budding from host cell membranes. Immunoprecipitation studies showed that beta 2m was bound by two viral envelope proteins beta 2m BP1 (beta 2m-binding protein 1) and beta 2m BP2 of molecular masses 36,000 and 65,000 daltons respectively. beta 2m could not bind to separated viral proteins under reducing or non-reducing conditions. We propose that interaction of these two proteins on the viral surface is required to enable CMV to bind beta 2m.


Female university students' preferences for different types of sexual relationships: implications for gender-based violence prevention programs and policies.
Gender-based violence among young women is a growing problem worldwide. The consequences of this victimization have been well reported in the scientific literature, among which negative health outcomes stand out. The factors influencing this problem are many; one highlighted by research is socialization into a dominant coercive discourse that associates sexual-affective attraction to males with violent attitudes and behaviors, while in turn, such discourse empties males with egalitarian behaviors from sexual attractiveness. This coercive discourse may be shaping the sexual preferences of female youth. The current paper explores young women's preferences for different types of sexual relationships and, more particularly, for what type of sexual affective relationships they coercively preferred men with violent attitudes and behavior. A quantitative, mixed-design vignette study was conducted with 191 college females in Spain. We focused the analysis only on responses about vignettes including narratives of men with violent attitudes and behaviors. In addition, we examined whether participants would report higher coerced preferences for violent men when asked about the coerced preferences of their female friends than when asked about their own preferences. Only 28.95% of participants responded that their female friends would prefer a young man with violent behavior for a stable relationship, meanwhile 58.42% would do it for hooking up. When reporting about themselves, the difference was greater: 28.42% would prefer a young man with violent behavior for hooking up and just 5.78% for a stable relationship. The dominant coercive discourse that links attractiveness to people with violent attitudes and behaviors may be explaining the results obtained in this study. The findings can help eliminate the stereotype largely adopted by some intervention and prevention programs which assume that gender-based violence occurs mainly in stable relationships, considering that falling in love is the reason that lead women to suffer from violence. Our results can also support health professionals and others serving young women to enhance their identification of gender violence victimization, as well as our findings point to the need to include the evidence of gender violence in sporadic relationships in prevention programs and campaigns addressed to young women.


Efficacy of the radial approach for the performance of primary PCI for STEMI.
Primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is associated with increased bleeding complications, impacting clinical outcome. Transradial PPCI could decrease the risk of bleeding, but concerns about technical difficulties and longer reperfusion times limit its adoption. This was a retrospective comparison of reperfusion times and bleeding complications in a large cohort of STEMI patients treated by PPCI through the transradial (TR; n = 244) or transfemoral approach (TF; n = 364) from January 2005 to December 2009. Endpoints were door-to-balloon time, access-site and non-access site bleeding, as well 1-month and 1-year mortality rates. Patients treated with TR-PPCI were younger than those having TF-PPCI, (57 ± 13 years vs 62 ± 13 years, respectively; P<.01), more frequently males (84% vs 73%, respectively; P<.01), and had less renal failure (9% vs 16%, respectively; P<.01) or hemodynamic compromise, ie, pulmonary edema or cardiogenic shock (1% vs 4%, respectively; P=.01). Angiographic and angioplasty characteristics, including the angiographic success rate, were similar, with the exception of a higher use of aspiration devices in the TR-PPCI group (31% vs 15%, respectively; P<.01). The door-to-balloon time was similar in both groups (76 ± 40 minutes vs 74 ± 41 minutes; P=NS). Significant lower rates of overall bleeding (6% vs 31%; P<.01), access-site bleeding (4% vs 27%; P<.01), non-access site bleeding (1% vs 3%; P=.01) and need for blood transfusion (0% vs 3%; P=.01) were observed in the TR-PPCI group. One-month (3% vs 7%; P<.05) and 1-year mortality rates (4% vs 11%; P<.05) were lower in the TR-PPCI group. Radial PCI was an independent predictor of 1-year mortality. TR-PPCI is feasible in STEMI patients and can be performed efficiently within the time limits recommended. This approach provides advantages in terms of reduction of bleeding that could translate into an improved clinical outcome.


Impact of the Medicare prescription drug benefit on home- and community-based services waiver programs.
"Dual eligibles" is the term for the 6.4 million low-income, elderly, and disabled Americans who are enrolled in both Medicare and Medicaid. With home-and community-based services waivers allowed under Section 1915(c) of the Social Security Act, many of these individuals are able to live in a home or community setting, thereby avoiding institutionalization. Surveying Maryland's 3,180 dual eligibles who are enrolled in home-and community-based waiver programs, the author finds that the end-of-2005 transfer of prescription drug coverage from Medicaid to Medicare under the Medicare Modernization Act of 2003 could put these beneficiaries in jeopardy. Maryland's experience is likely to be typical of what other states will face. The author recommends a number of federal policy remedies, among them allowing 90-day prescriptions, using open or shared formularies, and lengthening the enrollment period.


Evolution of high-molecular-mass hyaluronic acid is associated with subterranean lifestyle.
Hyaluronic acid is a major component of extracellular matrix which plays an important role in development, cellular response to injury and inflammation, cell migration, and cancer. The naked mole-rat (Heterocephalus glaber) contains abundant high-molecular-mass hyaluronic acid in its tissues, which contributes to this species' cancer resistance and possibly to its longevity. Here we report that abundant high-molecular-mass hyaluronic acid is found in a wide range of subterranean mammalian species, but not in phylogenetically related aboveground species. These subterranean mammalian species accumulate abundant high-molecular-mass hyaluronic acid by regulating the expression of genes involved in hyaluronic acid degradation and synthesis and contain unique mutations in these genes. The abundant high-molecular-mass hyaluronic acid may benefit the adaptation to subterranean environment by increasing skin elasticity and protecting from oxidative stress due to hypoxic conditions. Our work suggests that high-molecular-mass hyaluronic acid has evolved with subterranean lifestyle.


ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52).
The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD19, CD20 and CD52 and to suggest preventive recommendations. Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. Although CD19-targeted agents (blinatumomab or inebilizumab) are not associated with an increased risk of infection, they may cause IgG hypogammaglobulinaemia and neutropenia. The requirement for prolonged intravenous infusion of blinatumomab may increase the risk of catheter-associated bloodstream infections. Infection remains the most common non-haematological adverse effect of anti-CD20 monoclonal antibodies, including severe respiratory tract infection, hepatitis B virus (HBV) reactivation and varicella-zoster virus infection. Screening for chronic or resolved HBV infection is recommended for patients receiving anti-CD20 monoclonal antibodies. Antiviral prophylaxis should be offered for 12-18 months to hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/anti-hepatitis B core antibody (HBc)-positive patients. Anti-Pneumocystis prophylaxis should be considered in patients receiving concomitant chemotherapy, particularly steroids. Alemtuzumab (anti-CD52) increases the risk of infections, in particular among leukaemia and solid organ transplant patients. These populations benefit from anti-Pneumocystis prophylaxis, prevention strategies for cytomegalovirus infection, and screening for HBV, hepatitis C virus and tuberculosis. Antiviral prophylaxis for at least 6-12 months should be provided for HBsAg-positive patients. As there are limited clinical data for many of the reviewed agents, special attention must be given to promptly detect and report emerging infectious complications.


Facial clefts among epileptic patients.
Anticonvulsants have been suspected of teratogenicity, with facial clefts being the malformation most frequently associated with maternal anticonvulsant therapy. Paternal epilepsy has also been suggested as a factor in the genesis of birth defects, including facial clefts. An association between epilepsy per se and facial clefts would be reflected in a higher facial cleft prevalence among epileptics, and consequently result in an increase of such malformations among their children. The prevalence of facial clefts was determined in an unselected group of 3,203 epileptic probands: their personal data were cross-matched with a complete file of Danish facial cleft patients born between 1934 and 1977. Eleven epileptic probands had a facial cleft, which is twice the expected number. The increased prevalence of cleft defects among epileptics could partly explain why more of their children have facial clefts.


Effect of glucose infusion on glucose and insulin metabolism in early- and mid-lactation ewes and goats fed diets differing in starch and highly digestible fiber concentration.
This study aimed to test possible metabolic differences between ewes and goats in response to an intravenous glucose infusion. Thirty-six animals, 18 mature Sarda dairy ewes and 18 mature Saanen goats (from 15 to 150 ± 11 d in milk [DIM], mean ± SD; body weight: 49.8 ± 6.8 kg for ewes, 60.6 ± 7.3 kg for goats) were compared simultaneously. In early lactation, both species received the same high-starch diet (HS: 20.4% starch, 35.4% neutral detergent fiber [NDF], on dry matter [DM] basis), whereas from 92 ± 11 DIM both species were randomly allocated to 2 dietary treatments: HS (20.0% starch, 36.7% NDF, on DM basis) and low-starch (LS: 7.8% starch, 48.8% NDF, on DM basis) diets. At 50 and 150 ± 11 DIM, ewes and goats were challenged with an intravenous glucose tolerance test and peripheral concentrations of glucose and insulin were determined 15 min before and 5, 10, 15, 30, 45, 90, and 180 min after glucose infusion. In early lactation, baseline plasma glucose and insulin concentrations tended to be higher in ewes than in goats (glucose: 55.8 vs. 42.9 ± 7.3 mg/dL; insulin: 0.13 vs. 0.05 ± 0.04 µg/L). After glucose infusion, glucose and insulin concentrations were higher in ewes than in goats (278.6 vs. 247.6 ± 13.1 mg/dL; 0.82 vs. 0.46 ± 0.12 µg/L). In mid lactation, the dietary treatment (HS vs. LS) did not affect glucose and insulin metabolism. Baseline plasma glucose was numerically highest in ewes, while baseline insulin was higher in ewes than in goats (0.39 vs. 0.12 ± 0.099 µg/L). After glucose infusion, glucose concentration did not differ between ewes and goats, while insulin concentration was highest in ewes. Compared with goats, ewes showed in both periods a higher peak insulin, insulin increment, linear insulin area under the curve, insulin resistance index, and lower insulin sensitivity indices. In conclusion, despite the limitations associated with the use of intravenous glucose tolerance test to assess glucose regulation mechanisms, this study indicated large species differences in both early and mid lactation and a more evident anabolic status in the ewes compared with the goats.


MRI quantification of splenic iron concentration in mouse.
To quantify hepatic and splenic iron load, which is a critical issue for iron overload disease diagnosis. MRI is useful to noninvasively determine liver iron concentration, but not proven to be adequate for robust evaluation of splenic iron load. We evaluated the usefulness of MRI-derived parameters to determine splenic iron concentration in mice. A mouse model of experimental iron load was used. Multi-echo spin-echo images of liver and spleen were acquired at 4.7 Tesla. The parameters were tested at all echoes with and without an external reference. Splenic and hepatic iron concentrations were determined using biochemical assay as the gold standard. Our results show that (i) use of an internal or external reference is essential; (ii) optimal echo times were TE = 19.5 ms and TE = 32.5 ms for the liver and spleen, respectively; (iii) in the liver, the relationship between biochemical and MRI iron concentration determinations is logarithmic; (iv) in the spleen, the best relationship is an inverse function. A single spin-echo sequence allows robust estimation of hepatic and splenic iron content. Parameters classically used for hepatic iron concentration cannot be applied to splenic iron determination, which requires both the specific sequence and the adapted fitting function.


Targeting Fluorescent Nanodiamonds to Vascular Endothelial Growth Factor Receptors in Tumor.
The increased expression of vascular endothelial growth factor (VEGF) and its receptors is associated with angiogenesis in a growing tumor, presenting potential targets for tumor-selective imaging by way of targeted tracers. Though fluorescent tracers are used for targeted in vivo imaging, the lack of photostability and biocompatibility of many current fluorophores hinder their use in several applications involving long-term, continuous imaging. To address these problems, fluorescent nanodiamonds (FNDs), which exhibit infinite photostability and excellent biocompatibility, were explored as fluorophores in tracers for targeting VEGF receptors in growing tumors. To explore FND utility for imaging tumor VEGF receptors, we used click-chemistry to conjugate multiple copies of an engineered single-chain version of VEGF site-specifically derivatized with trans-cyclooctene (scVEGF-TCO) to 140 nm FND. The resulting targeting conjugates, FND-scVEGF, were then tested for functional activity of the scVEGF moieties through biochemical and tissue culture experiments and for selective tumor uptake in Balb/c mice with induced 4T1 carcinoma. We found that FND-scVEGF conjugates retain high affinity to VEGF receptors in cell culture experiments and observed preferential accumulation of FND-scVEGF in tumors relative to untargeted FND. Microspectroscopy provided unambiguous determination of FND within tissue by way of the unique spectral shape of nitrogen-vacancy induced fluorescence. These results validate and invite the use of targeted FND for diagnostic imaging and encourage further optimization of FND for fluorescence brightness.


[Occupational asthma and reactive airway dysfunction syndrome].
Occupational asthma could be defined as a reversible lung disorder characterized by attacks of breathing difficulty, wheezing, and cough, which are caused by various agents found in the workplace. Incidence varies from 2 to 15% in adult work population; actually there is no data for the child population. Allergic occupational asthma is due to allergic sensitization to a specific substance or material present at the workplace; non-allergic occupational asthma occurs because of the high exposure to an irritant also at the workplace. Over the past few years, more people have been diagnosed as having asthma because of some workplace exposure. The identification of occupational asthma in workers is important because early detection may lead to the control of the worker's symptoms and control of the chemicals in the workplace. In Latin America there is no data about occupational asthma, maybe for the scarce information about it or for its difficult diagnosis.


The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2.
The present outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2. In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS-CoV-2/host/location/isolate/date. While the full spectrum of clinical manifestations associated with SARS-CoV-2 infections in humans remains to be determined, the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus–host interactions in an ever-changing environment and enhance our preparedness for future outbreaks.


The effect of dietary alterations during rearing on feather condition in broiler breeder females.
In commercial production, broiler breeders are severely feed restricted to maintain healthy BW. This restriction can induce stereotypic behavior, including feather pecking, which has negative welfare implications for both the victim and performer. It has been suggested that the problem may be symptomatic of chronic hunger or the frustration of feeding motivation. In this study, we determined whether feather condition, as an indirect measure of feather pecking, could be improved via dietary manipulation. Six dietary treatments were tested, each with 5 replicate pens of 9 to 12 birds. Control diets (C) were fed on a daily or skip-a-day (SAD) basis. Alternative diets included soybean hulls as a bulking ingredient and calcium propionate (CaP) as an appetite suppressant of either a feed grade (F) or purified (P) quality. Both alternative diets were fed on either a daily or SAD basis. Five or 6 birds were randomly chosen from each pen and feather scored at 10, 14, 20, 26, and 36 wk of age. Six body parts (neck, back, wings, legs, vent area, tail) were given a score from 0 to 5 (0 = no feather damage, and 5 ≥ 50% feather loss with tissue damage). Scores were summed for each bird and averaged for each pen. Data were analyzed with room and feeding frequency as main factors and diet as the subfactor with repeated measures. There was an interaction between diet and time (P < 0.01) with the feather condition of the C birds worsening more quickly in comparison with the F and P birds. There was an interaction between feeding frequency and time (P = 0.015), with SAD-fed birds scoring better than daily-fed birds at 20, 26, and 36 wk. This interaction could indicate that SAD feeding increased satiety after the birds became accustomed to the schedule. Because feather condition was better with the alternative diets, this may indicate a reduction in stereotyped feather pecking with these diets. This suggests that the alternative diets increase satiety compared with the control diets.


The clinical significance of dupilumab-induced blood eosinophil elevation in Japanese patients with atopic dermatitis.
This study aims to clarify the clinical significance of dupilumab-induced elevation of blood eosinophil in Japanese patients with atopic dermatitis (AD). Eosinophil elevation was defined as ≥ 5% increase of eosinophil percentage within one year after dupilumab initiation. Seven patients (15.7%) were shown to have eosinophil elevation, six of whom developed dupilumab-associated conjunctivitis (DAC) and were accompanied with DAC more frequently than those without eosinophil elevation, with statistically significant difference. Eosinophil percentage resolved spontaneously in all seven patients, including the one without DAC, despite the continuation of dupilumab treatment. None of the patients with eosinophil elevation had cardiac or pulmonary complications attributable to the hypereosinophilia. The patients with eosinophil elevation were all male. Furthermore, none of four patients in whom efficacy of dupilumab was < 25% showed eosinophil elevation. Childhood onset tended to be more common in patients with the elevation of eosinophil. This study suggests that most eosinophil elevation is associated with DAC, and that the eosinophil ratio is a biomarker for DAC.


Engineering plant oils as high-value industrial feedstocks for biorefining: the need for underpinning cell biology research.
Plant oils represent renewable sources of long-chain hydrocarbons that can be used as both fuel and chemical feedstocks, and genetic engineering offers an opportunity to create further high-value specialty oils for specific industrial uses. While many genes have been identified for the production of industrially important fatty acids, expression of these genes in transgenic plants has routinely resulted in a low accumulation of the desired fatty acids, indicating that significantly more knowledge of seed oil production is required before any future rational engineering designs are attempted. Here, we provide an overview of the cellular features of fatty acid desaturases, the so-called diverged desaturases, and diacylglycerol acyltransferases, three sets of enzymes that play a central role in determining the types and amounts of fatty acids that are present in seed oil, and as such, the final application and value of the oil. Recent studies of the intracellular trafficking, assembly and regulation of these enzymes have provided new insights to the mechanisms of storage oil production, and suggest that the compartmentalization of enzyme activities within specific regions or subdomains of the ER may be essential for both the synthesis of novel fatty acid structures and the channeling of these important fatty acids into seed storage oils.


Naringenin neutralises oxidative stress and nerve growth factor discrepancy in experimental diabetic neuropathy.
Present study aims to investigate the ameliorative effects of naringenin (NG) on experimentally induced diabetic neuropathy (DN) in rats. Diabetes was induced by single intraperitoneal injection of streptozotocin (STZ, 60 g/kg). Naringenin (25 and 50 mg/kg/day) treatment was started 2 weeks after the diabetes induction and continued for five consecutive weeks. Pain threshold behaviour tests were performed at the end of the treatment. Serum levels of glucose, insulin and pro-inflammatory cytokines were assessed. In sciatic tissues, markers oxidative stress, cytokines and neurotrophic factors were measured. NG treatments showed significant decrease in paw-withdrawal (P < 0.01) and tail-flick latency (P < 0.01). The drug attenuated the diabetic-induced changes in serum glucose, insulin and pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). In sciatic nerve, the diabetic-induced alterations in interleukins and oxidative stress biomarkers were significantly attenuated by NG. Decreased sciatic expressions of insulin growth factor (IGF) and nerve growth factor (NGF) in diabetic rats were also ameliorated by NG. Diabetes-induced dysregulated levels of nitric oxide (NO), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were ameliorated by NG. Histological analysis showed that NG corrected the altered sciatic changes in diabetic animals. We suggest that neuro-protective effect of NG molecules in sciatic nerve of diabetic rats, through its anti-diabetic as well as antioxidant and anti-inflammatory properties.


Identification of an Amino Acid Motif in HLA-DRβ1 That Distinguishes Uveitis in Patients With Juvenile Idiopathic Arthritis.
Uveitis is a visually debilitating disorder that affects up to 30% of children with the most common forms of juvenile idiopathic arthritis (JIA). The disease mechanisms predisposing only a subgroup of children to uveitis are unknown. This study was undertaken to identify genetic susceptibility loci for uveitis in JIA, using a genome-wide association study in 522 children with JIA. Two cohorts of JIA patients with ophthalmologic follow-up data were genotyped. Data were then imputed using a genome-wide imputation reference panel, and an HLA-specific reference panel was used for imputing amino acids and HLA types in the major histocompatibility complex (MHC). After imputation, genome-wide and MHC-specific analyses were performed, and a reverse immunology approach was utilized to model antigen presentation at 13 common HLA-DRβ1 alleles. Presence of the amino acid serine at position 11 (serine 11) in HLA-DRβ1 was associated with an increased risk of uveitis in JIA patients (odds ratio [OR] 2.60, P = 5.43 × 10-10 ) and was specific to girls (Pfemales = 7.61 × 10-10 versus Pmales = 0.18). Serine 11 resides in the YST motif in the peptide-binding groove of HLA-DRβ1; all 3 amino acids in this motif are in perfect linkage disequilibrium and show identical association with disease. Quantitative prediction of binding affinity revealed that HLA-DRβ1 alleles with the YST motif could be distinguished on the basis of discernable peptide-binding preferences. These findings highlight a genetically distinct, sexually dimorphic feature of JIA with uveitis as compared to JIA without uveitis. The association could be indicative of the potential involvement of antigen presentation by HLA-DRβ1 in the development of uveitis in JIA. The results of this study may advance our progress toward improved treatments for, and possible prevention of, the sight-threatening complications of uveitis in children with JIA.


To "vape" or smoke? Experimental evidence on adult smokers.
A growing share of the United States population uses e-cigarettes but the optimal regulation of these controversial products remains an open question. We conduct a discrete choice experiment to investigate how adult tobacco cigarette smokers' demand for e-cigarettes and tobacco cigarettes varies by four attributes: (i) whether e-cigarettes are considered healthier than tobacco cigarettes, (ii) the effectiveness of e-cigarettes as a cessation device, (iii) bans on use in public places, and (iv) price. We find that adult smokers' demand for e-cigarettes is motivated more by health concerns than by the desire to avoid smoking bans or higher prices.


Epidemiological characterization of influenza A(H1N1)pdm09 cases from 2009 to 2010 in Baguio City, the Philippines.
Baguio City, Philippines experienced its first influenza A(H1N1)pdm09 [A(H1)pdm09] case in May 2009. In spite of numerous reports describing the epidemiological and clinical features of A(H1)pdm09 cases, there are no studies about A(H1)pdm09 epidemiology in the Philippines, where year-round influenza activity was observed. We aimed to investigate the epidemiological and clinical features of A(H1)pdm09 in pandemic and post-pandemic periods. Data were collected under enhanced surveillance of influenza-like illness (ILI) and severe acute respiratory infection (SARI) from January 2009 to December 2010. RT-PCR was used to detect A(H1)pdm09, following the protocol of the United States Centers for Disease Control and Prevention. The reproduction number was computed as a simple exponential growth rate. Differences in proportional and categorical data were examined using chi-square test or Fishers' exact test. The outbreak was observed from week 25 to 35 in 2009 and from week 24 to 37 in 2010. The highest proportion of cases was among children aged 5-14 years. The number of ILI outpatients was 2.3-fold higher in 2009 than in 2010, while the number of inpatients was 1.8-fold higher in 2009. No significant difference in gender was observed during the two periods. The clinical condition of all patients was generally mild and self-limiting, with only 2 mortalities among inpatients in 2009. The basic reproduction number was estimated as 1.16 in 2009 and 1.05 in 2010 in the assumption of mean generation time as 2.6 days. School children played a significant role in facilitating influenza transmission.


Pharmacometabolomics of trabectedin in metastatic soft tissue sarcoma patients.
Objective: Trabectedin is an anti-cancer drug commonly used for the treatment of patients with metastatic soft tissue sarcoma (mSTS). Despite its recognized efficacy, significant variability in pharmacological response has been observed among mSTS patients. To address this issue, this pharmacometabolomics study aimed to identify pre-dose plasma metabolomics signatures that can explain individual variations in trabectedin pharmacokinetics and overall clinical response to treatment. Methods: In this study, 40 mSTS patients treated with trabectedin administered by 24 h-intravenous infusion at a dose of 1.5 mg/m2 were enrolled. The patients' baseline plasma metabolomics profiles, which included derivatives of amino acids and bile acids, were analyzed using multiple reaction monitoring LC-MS/MS together with their pharmacokinetics profile of trabectedin. Multivariate Partial least squares regression and univariate statistical analyses were utilized to identify correlations between baseline metabolite concentrations and trabectedin pharmacokinetics, while Partial Least Squares-Discriminant Analysis was employed to evaluate associations with clinical response. Results: The multiple regression model, derived from the correlation between the AUC of trabectedin and pre-dose metabolomics, exhibited the best performance by incorporating cystathionine, hemoglobin, taurocholic acid, citrulline, and the phenylalanine/tyrosine ratio. This model demonstrated a bias of 4.6% and a precision of 17.4% in predicting drug AUC, effectively accounting for up to 70% of the inter-individual pharmacokinetic variability. Through the use of Partial least squares-Discriminant Analysis, cystathionine and hemoglobin were identified as specific metabolic signatures that effectively distinguish patients with stable disease from those with progressive disease. Conclusions: The findings from this study provide compelling evidence to support the utilization of pre-dose metabolomics in uncovering the underlying causes of pharmacokinetic variability of trabectedin, as well as facilitating the identification of patients who are most likely to benefit from this treatment.


Identification of epitopes of the β subunit of soybean β-conglycinin that are antigenic in pigs, dogs, rabbits and fish.
β-Conglycinin (conglycinin) is one of the major seed storage proteins of soybean. Conglycinin is a 7S trimer composed of different combinations of β, α and α' subunits. All subunits of conglycinin have been reported to be allergenic in humans. The goal of this research is to identify epitopes of the β subunit of conglycinin that are antigenic in multiple animal species. Sera from pigs, dogs, rabbits and hybrid striped bass that had antibodies against soybean conglycinin were identified by ELISA. Most of these sera recognized peptides that represent the β subunit of conglycinin. One antigenic region of the β subunit of conglycinin had considerable overlap among all species tested. One region that was similar to a peanut allergenic epitope in humans overlapped with a region that binds IgE from dogs. One region was antigenic in multiple rabbits and pigs, suggesting it may play a role in the response of pigs to soybean in the diet. One region of the β subunit of conglycinin is an important antigen across species and abuts a region similar to the peanut allergen ARA h 1. A second region is particularly antigenic in pigs and rabbits. Variants of these antigenic regions of the β subunit of conglycinin may be useful in determining the role these regions play in the health of animals fed soybean. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.


Development of the Proximal-Anterior Skeletal Elements in the Mouse Hindlimb Is Regulated by a Transcriptional and Signaling Network Controlled by Sall4.
The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated Sall4 using Hoxb6Cre and Plzf in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in hindlimbs. The Sall4; Plzf double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of Sall4; Plzf We found that Sall4 regulates Plzf expression prior to hindlimb outgrowth. Further expression analysis indicated that Hox10 genes and GLI3 are severely downregulated in the Sall4; Plzf double knockout hindlimb bud. In contrast, PLZF expression is reduced but detectable in Sall4; Gli3 double knockout limb buds, and SALL4 is expressed in the Plzf; Gli3 double knockout limb buds. These results indicate that Plzf, Gli3, and Hox10 genes downstream of Sall4, regulate femur and tibia development. In the autopod, we show that Sall4 negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in hindlimbs.