Red flags for appropriate referral to the gastroenterologist and the rheumatologist of patients with inflammatory bowel disease and spondyloarthritis.
Collaboration between gastroenterologists and rheumatologists is recommended for the correct management of patients with associated spondyloarthritis (SpA) and inflammatory bowel disease (IBD). We aimed to establish the appropriateness of several red flags for a prompt specialist referral. A systematic review of the literature was performed using the GRADE method to describe the prevalence of co-existing IBD-SpA and the diagnostic accuracy of red flags proposed by a steering committee. Then, a consensus among expert gastroenterologists and rheumatologists (10 in the steering committee and 13 in the expert panel) was obtained using the RAND method to confirm the appropriateness of each red flag as 'major' (one sufficient for patient referral) or 'minor' (at least three needed for patient referral) criteria for specialist referral. The review of the literature confirmed the high prevalence of co-existing IBD-SpA. Positive and negative predictive values of red flags were not calculated, given the lack of available data. A consensus among gastroenterology and rheumatology specialists was used to confirm the appropriateness of each red flag. Major criteria to refer patients with SpA to the gastroenterologist included: rectal bleeding, chronic abdominal pain, perianal fistula or abscess, chronic diarrhoea and nocturnal symptoms. Major criteria to refer patients with IBD to the rheumatologist included: chronic low back pain, dactylitis, enthesitis and pain/swelling of peripheral joints. Several major and minor red flags have been identified for the diagnosis of co-existing IBD-SpA. The use of red flags in routine clinical practice may avoid diagnostic delay and reduce clinic overload.


The emergence of Ug99 races of the stem rust fungus is a threat to world wheat production.
Race Ug99 of the fungus Puccinia graminis tritici that causes stem or black rust disease on wheat was first detected in Uganda in 1998. Seven races belonging to the Ug99 lineage are now known and have spread to various wheat-growing countries in the eastern African highlands, as well as Zimbabwe, South Africa, Sudan, Yemen, and Iran. Because of the susceptibility of 90% of the wheat varieties grown worldwide, the Ug99 group of races was recognized as a major threat to wheat production and food security. Its spread, either wind-mediated or human-aided, to other countries in Africa, Asia, and beyond is evident. Screening in Kenya and Ethiopia has identified a low frequency of resistant wheat varieties and breeding materials. Identification and transfer of new sources of race-specific resistance from various wheat relatives is underway to enhance the diversity of resistance. Although new Ug99-resistant varieties that yield more than current popular varieties are being released and promoted, major efforts are required to displace current Ug99 susceptible varieties with varieties that have diverse race-specific or durable resistance and mitigate the Ug99 threat.


Glucagon-like peptide-1 (GLP-1) increases in plasma and colon tissue prior to estrus and circulating levels change with increasing age in reproductively competent Wistar rats.
There is a well-documented association between cyclic changes to food intake and the changing ovarian hormone levels of the reproductive cycle in female mammals. Limited research on appetite-controlling gastrointestinal peptides has taken place in females, simply because regular reproductive changes in steroid hormones present additional experimental factors to account for. This study focussed directly on the roles that gastrointestinal-secreted peptides may have in these reported, naturally occurring, changes to food intake during the rodent estrous cycle and aimed to determine whether peripheral changes occurred in the anorexigenic (appetite-reducing) hormones peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1) in female Wistar rats (32-44 weeks of age). Total forms of each peptide were measured in matched fed and fasted plasma and descending colon tissue samples for each animal during the dark (feeding) phase. PYY concentrations did not significantly change between defined cycle stages, in either plasma or tissue samples. GLP-1 concentrations in fed plasma and descending colon tissue were significantly increased during proestrus, just prior to a significant reduction in fasted stomach contents at estrus, suggesting increased satiety and reduced food intake at this stage of the cycle. Increased proestrus GLP-1 concentrations could contribute to the reported reduction in food intake during estrus and may also have biological importance in providing the optimal nutritional and metabolic environment for gametes at the potential point of conception. Additional analysis of the findings demonstrated significant interactions of ovarian cycle stage and fed/fasted status with age on GLP-1, but not PYY plasma concentrations. Slightly older females had reduced fed plasma GLP-1 suggesting that a relaxation of regulatory control of this incretin hormone may also take place with increasing age in reproductively competent females.


Identifying anatomical shape difference by regularized discriminative direction.
Identifying the shape difference between two groups of anatomical objects is important for medical image analysis and computer-aided diagnosis. A method called "discriminative direction" in the literature has been proposed to solve this problem. In that method, the shape difference between groups is identified by deforming a shape along the discriminative direction. This paper conducts a thorough study about inferring this discriminative direction in an efficient and accurate way. First, finding the discriminative direction is reformulated as a preimage problem in kernel-based learning. This provides a complementary but conceptually simpler solution than the previous method. More importantly, we find that a shape deforming along the original discriminative direction cannot faithfully maintain its anatomical correctness. This unnecessarily introduces spurious shape differences and leads to inaccurate analysis. To overcome this problem, this paper further proposes a regularized discriminative direction by requiring a shape to conform to its underlying distribution when it deforms. Two different approaches are developed to impose the regularization, one from the perspective of probability distributions and the other from a geometric point of view, and their relationship is discussed. After verifying their superior performance through controlled experiments, we apply the proposed methods to detecting and localizing the hippocampal shape difference between sexes. We get results consistent with other independent research, providing a more compact representation of the shape difference compared with the established discriminative direction method.


AKAP149 binds to HIV-1 reverse transcriptase and is involved in the reverse transcription.
Like all retroviruses, human immunodeficiency virus type 1 (HIV-1) undergoes reverse transcription during its replication cycle. The cellular cofactors potentially involved in this process still remain to be identified. We show here that A-kinase anchoring protein 149 (AKAP149) interacts with HIV-1 reverse transcriptase (RT) in both the yeast two-hybrid system and human cells. The AKAP149 binding site has been mapped to the RNase H domain of HIV-1 RT. AKAP149 silencing by RNA interference in HIV-1-infected cells inhibited viral replication at the reverse transcription step. We selected single-point mutants of RT defective for AKAP149 binding and demonstrated that mutant G462R, despite retaining significant intrinsic RT activity in vitro, failed to carry out HIV-1 reverse transcription correctly in infected cells. This suggests that the interaction between RT and AKAP149 in infected cells may play an important role in HIV-1 reverse transcription.


Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress.
Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare sporadic disorder with an incidence of approximately 1 per 8 million live births. The phenotypic appearance consists of short stature, sculptured nose, alopecia, prominent scalp veins, small face, loss of subcutaneous fat, faint mid-facial cyanosis, and dystrophic nails. HGPS is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. The most common mutation in subjects with HGPS is a de novo single-base pair substitution, G608G (GGC>GGT), within exon 11 of LMNA. This creates an abnormal splice donor site, leading to expression of a truncated protein. We studied a new case of a 5 year-old girl with HGPS and found a heterozygous point mutation, G608G, in LMNA. Complementary DNA sequencing of RNA showed that this mutation resulted in the deletion of 50 amino acids in the carboxyl-terminal tail domain of prelamin A. We characterized a primary dermal fibroblast cell line derived from the subject's skin. These cells expressed the mutant protein and exhibited a normal growth rate at early passage in primary culture but showed alterations in nuclear morphology. Expression levels and overall distributions of nuclear lamins and emerin, an integral protein of the inner nuclear membrane, were not dramatically altered. Ultrastructural analysis of the nuclear envelope using electron microscopy showed that chromatin is in close association to the nuclear lamina, even in areas with abnormal nuclear envelope morphology. The fibroblasts were hypersensitive to heat shock, and demonstrated a delayed response to heat stress. Dermal fibroblasts from a subject with HGPS expressing a mutant truncated lamin A have dysmorphic nuclei, hypersensitivity to heat shock, and delayed response to heat stress. This suggests that the mutant protein, even when expressed at low levels, causes defective cell stability, which may be responsible for phenotypic abnormalities in the disease.


Treatment of antineutrophil cytoplasm autoantibody-associated systemic vasculitis: initiatives of the European Community Systemic Vasculitis Clinical Trials Study Group.
The diagnosis, treatment, and monitoring of the primary systemic vasculitides associated with circulating antineutrophil cytoplasm autoantibodies (ANCA) have formed the focus of a multicenter collaborative study. Consensus has been reached on criteria for classification, clinical subgroupings by extent and severity of disease, and "standard" and "best alternative" therapeutic regimens. Two series of randomized controlled trials have been designed; their aims are (1) to harmonize current approaches to treatment and (2) to test the value of newer therapeutic agents. In support of these trials, semiobjective scoring systems have been created and validated, and previous standardization of ANCA serologic and histologic analysis has been adopted. The systems of classification and clinical management described herein represent the recommendations of a multidisciplinary study group that hopes to improve the outcome of patients with primary systemic vasculitis by wide dissemination of the collective experience from interested centers.


Impact of screening on incidence and mortality of prostate cancer in the United States.
The potential confounding influence of changing treatment patterns and misattribution bias make a definitive conclusion about the link between PSA screening and mortality rates tentative at best. At least some of the mortality decline since 1991 appears likely to be due to screening, but the precise magnitude of the screening effect is difficult to estimate. The possible reduction in mortality due to screening, while uncertain, must be weighed against the substantial decrements in treatment-specific health outcomes (32-34) among men treated for clinically localized tumors typically detected by screening. Population data and ongoing screening trials in the United States and Europe (24, 35) will be complementary in the final determination of the relative contribution of the impact of screening versus other causes on recent mortality trends.


PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21.
Prostate cancer development and progression are associated with alterations in expression and function of elements of cytokine networks, some of which can activate multiple signaling pathways. Protein inhibitor of activated signal transducers and activators of transcription (PIAS)1, a regulator of cytokine signaling, may be implicated in the modulation of cellular events during carcinogenesis. This study was designed to investigate the functional significance of PIAS1 in models of human prostate cancer. We demonstrate for the first time that PIAS1 protein expression is significantly higher in malignant areas of clinical prostate cancer specimens than in normal tissues, thus suggesting a growth-promoting role for PIAS1. Expression of PIAS1 was observed in the majority of tested prostate cancer cell lines. In addition, we investigated the mechanism by which PIAS1 might promote prostate cancer and found that down-regulation of PIAS1 leads to decreased proliferation and colony formation ability of prostate cancer cell lines. This decrease correlates with cell cycle arrest in the G0/G1 phase, which is mediated by increased expression of p21(CIP1/WAF1). Furthermore, PIAS1 overexpression positively influences cell cycle progression and thereby stimulates proliferation, which can be mechanistically explained by a decrease in the levels of cellular p21. Taken together, our data reveal an important new role for PIAS1 in the regulation of cell proliferation in prostate cancer.


Test-retest reliability of the Swedish version of the Life-Space Assessment Questionnaire among community-dwelling older adults.
To examine the test-retest reliability of the Swedish version of the Life-Space Assessment Questionnaire. Test-retest reliability study. A total of 298 community-dwelling subjects between 75 and 90 years of age. The Life-Space Assessment Questionnaire was translated into Swedish. By personal interviews during home visits and two weeks later by telephone interviews the subjects were asked about their life-space mobility during the past four weeks, and how often and whether they were independent or needed assistance from another person or equipment to reach different life-space levels. None of the four scoring methods showed significant difference between test sessions. The mean (SD) total scores were 65 (22) and 65 (23) out of the maximum possible score of 120 at the two sessions. High levels were found for independent, assisted, and maximal life-space at both sessions. Intraclass correlation coefficients and weighted Kappa-values between 0.84-0.94 were found for the total score, the independent, and the assisted life-space levels, indicating good to excellent reliability. A lower Kappa-value was observed for the maximal life-space level, mainly owing to skewed distributions. The method error values showed that a change of 10 in the total score and a change of one level in any of the three life-space levels can be considered to indicate a real change in clinical practice. The Swedish version of the Life-Space Assessment Questionnaire can be reliably used among community-dwelling older adults.


Cross-site evaluation of a comprehensive pediatric asthma project: the Merck Childhood Asthma Network, Inc. (MCAN).
The Merck Childhood Asthma Network, Inc. (MCAN) initiative selected five sites that had high asthma burden and established asthma programs but were ready for greater program integration across schools, health care systems, and communities. MCAN supported a community-based approach that was tailored to the needs of each program site. As a result, each site was unique in its combination of interventions, but all sites served common goals of integration of care, incorporation of evidence-based programs, and improvement in knowledge, self-management, health, and quality of life. This case study of the MCAN cross-site evaluation discusses the challenges associated with evaluating interventions involving multiple stakeholders that have been adjusted to fit the unique needs of specific communities. The evaluation triangulates data from site-specific monitoring and evaluation data; site documents, site visits, and cross-site meetings; qualitative assessments of families, organizational partners, and other stakeholders; and quantitative data from a common instrument on health indicators before and after the intervention. The evaluation employs the RE-AIM framework--reach, effectiveness, adoption, implementation, and maintenance--to assess the barriers and facilitators of translation from theory into practice. Our experience suggests trade-offs between rigor of evaluation and burden of assessment that have applicability for other community-based translational efforts.


The effects of racemization rate for age estimation of pink teeth.
Pink teeth is thought to result from the seepage of hemoglobin caused by dental pulp decomposition. We investigated whether racemization can be applied for age estimation in cases of pink teeth where the whole tooth is used. The pink teeth used were three cases and the normal teeth for control were five mandibular canines of known age. Age of the pink teeth was calculated on the basis of regression formula obtained from the five control teeth. Only a slight error was noted between the actual and estimated ages of the pink teeth (R(2) = 0.980, r = 0.990): Cases 1-3 actually aged 23, 53, and 59 years were estimated to be 26, 52, and 60 years. Based on our results of testing pink teeth of known age, we suggest that racemization techniques allow for the age estimation of pink teeth using the same methods for normally colored teeth.


SubtiList: the reference database for the Bacillus subtilis genome.
SubtiList is the reference database dedicated to the genome of Bacillus subtilis 168, the paradigm of Gram-positive endospore-forming bacteria. Developed in the framework of the B.subtilis genome project, SubtiList provides a curated dataset of DNA and protein sequences, combined with the relevant annotations and functional assignments. Information about gene functions and products is continuously updated by linking relevant bibliographic references. Recently, sequence corrections arising from both systematic verifications and submissions by individual scientists were included in the reference genome sequence. SubtiList is based on a generic relational data schema and a World Wide Web interface developed for the handling of bacterial genomes, called GenoList. The World Wide Web interface was designed to allow users to easily browse through genome data and retrieve information according to common biological queries. SubtiList also provides more elaborate tools, such as pattern searching, which are tightly connected to the overall browsing system. SubtiList is accessible at http://genolist.pasteur.fr/SubtiList/. Similar bacterial databases are accessible at http://genolist.pasteur.fr/.


Anatomical Reconstruction and Functional Imaging Reveal an Ordered Array of Skylight Polarization Detectors in Drosophila.
Many insects exploit skylight polarization as a compass cue for orientation and navigation. In the fruit fly, Drosophila melanogaster, photoreceptors R7 and R8 in the dorsal rim area (DRA) of the compound eye are specialized to detect the electric vector (e-vector) of linearly polarized light. These photoreceptors are arranged in stacked pairs with identical fields of view and spectral sensitivities, but mutually orthogonal microvillar orientations. As in larger flies, we found that the microvillar orientation of the distal photoreceptor R7 changes in a fan-like fashion along the DRA. This anatomical arrangement suggests that the DRA constitutes a detector for skylight polarization, in which different e-vectors maximally excite different positions in the array. To test our hypothesis, we measured responses to polarized light of varying e-vector angles in the terminals of R7/8 cells using genetically encoded calcium indicators. Our data confirm a progression of preferred e-vector angles from anterior to posterior in the DRA, and a strict orthogonality between the e-vector preferences of paired R7/8 cells. We observed decreased activity in photoreceptors in response to flashes of light polarized orthogonally to their preferred e-vector angle, suggesting reciprocal inhibition between photoreceptors in the same medullar column, which may serve to increase polarization contrast. Together, our results indicate that the polarization-vision system relies on a spatial map of preferred e-vector angles at the earliest stage of sensory processing. The fly's visual system is an influential model system for studying neural computation, and much is known about its anatomy, physiology, and development. The circuits underlying motion processing have received the most attention, but researchers are increasingly investigating other functions, such as color perception and object recognition. In this work, we investigate the early neural processing of a somewhat exotic sense, called polarization vision. Because skylight is polarized in an orientation that is rigidly determined by the position of the sun, this cue provides compass information. Behavioral experiments have shown that many species use the polarization pattern in the sky to direct locomotion. Here we describe the input stage of the fly's polarization-vision system.


Oxidation and structural perturbation of redox-sensitive enzymes in injured skeletal muscle.
Molecular events that control skeletal muscle injury and regeneration are poorly understood. However, inflammation associated with oxidative stress is considered a key player in modulating this process. To understand the consequences of oxidative stress associated with muscle injury, inflammation, and regeneration, hind-limb muscles of C57Bl/6J mice were studied after injection of cardiotoxin (CT). Within 1 day post-CT injection, polymorphonuclear neutrophilic leukocyte accumulation was extensive. Compared to baseline, tissue myeloperoxidase (MPO) activity was elevated eight- and fivefold at 1 and 7 days post-CT, respectively. Ubiquitinylated protein was elevated 1 day postinjury and returned to baseline by 21 days. Cysteine residues of creatine kinase (CK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were irreversibly oxidized within 1 day post-CT injection and were associated with protein conformational changes that fully recovered after 21 days. Importantly, protein structural alterations occurred in conjunction with significant decreases in CK activity at 1, 3, and 7 days post-CT injury. Interestingly, elevations in tissue MPO activity paralleled the time course of conformational changes in CK and GAPDH. In combination, these results demonstrate that muscle proteins in vivo are structurally and functionally altered via the generation of reactive oxygen species produced during inflammatory events after muscle injury and preceding muscle regeneration.


Isolation and quantification of microRNAs from urinary exosomes/microvesicles for biomarker discovery.
Recent studies indicate that microRNA (miRNA) is contained within exosome. Here we sought to optimize the methodologies for the isolation and quantification of urinary exosomal microRNA as a prelude to biomarker discovery studies. Exosomes were isolated through ultracentrifugation and characterized by immunoelectron microscopy. To determine the RNA was confined inside exosomes, the pellet was treated with RNase before RNA isolation. The minimum urine volume, storage conditions for exosomes and exosomal miRNA was evaluated. The presence of miRNAs in patients with various kidney diseases was validated with real-time PCR. The result shows that miRNAs extracted from the exosomal fraction were resistant to RNase digestion and with high quality confirmed by agarose electrophoresis. 16 ml of urine was sufficient for miRNA isolation by absolute quantification with 4.15×10(5) copies/ul for miR-200c. Exosomes was stable at 4℃ 24h for shipping before stored at -80℃ and was stable in urine when stored at -80°C for 12 months. Exosomal miRNA was detectable despite 5 repeat freeze-thaw cycles. The detection of miRNA by quantitative PCR showed high reproducibility (>94% for intra-assay and >76% for inter-assay), high sensitivity (positive call 100% for CKD patients), broad dynamic range (8-log wide) and good linearity for quantification (R(2)>0.99). miR-29c and miR-200c showed different expression in different types of kidney disease. In summary, the presence of urinary exosomal miRNA was confirmed for patients with a diversity of chronic kidney disease. The conditions of urine collection, storage and miRNA detection determined in this study may be useful for future biomarker discovery efforts.


Intraretinal proliferation induced by retinal detachment.
Cellular proliferation after retinal detachment was studied by 3H-thymidine light microscopic autoradiography in cats that had experimental detachments of 0.5-180 days duration. The animals underwent labeling 2 hr before death with an intraocular injection of 200 microCi of 3H-thymidine. The number of labeled nuclei were counted in 1-micron thick tissue sections in regions of detachment, in regions of the experimental eyes that remained attached, and in control eyes that had no detachments. In the normal eye, in one that had only the lens and vitreous removed, and in the eyes with 0.5- and 1-day detachments, the number of labeled nuclei ranged from 0/mm (0.5-day detachment) to 0.38/mm (lens and vitreous removed only). By 2 days postdetachment, the number of labeled nuclei increased to 2.09/mm. The highest levels of labeling occurred in two animals with detachments of 3 (7.86/mm) and 4 (7.09/mm) days. Thereafter, the numbers declined steadily until near-baseline counts were obtained at 14 days. The number of labeled nuclei was slightly elevated in the attached regions of two animals with 3-day detachments. Labeled cell types included: Müller cells, astrocytes, pericytes, and endothelial cells of the retinal vasculature, and both resident (microglial cells) and invading macrophages. In an earlier study RPE cells were also shown to proliferate in response to detachment. Thus, these data show that proliferation is a rapid response to detachment, reaching a maximum within 4 days, and that virtually every nonneuronal cell type in the retina can participate in this response. The data suggest that events leading to such clinical manifestations as proliferative vitreoretinopathy and subretinal fibrosis may have their beginnings in this very early proliferative response.


Crystal structure of E. coli Hsp100 ClpB nucleotide-binding domain 1 (NBD1) and mechanistic studies on ClpB ATPase activity.
E. coli Hsp100 ClpB was recently identified as a critical part in a multi-chaperone system to play important roles in protein folding, protein transport and degradation in cell physiology. ClpB contains two nucleotide-binding domains (NBD1 and NBD2) within their primary sequences. NBD1 and NBD2 of ClpB can be classified as members of the large ATPase family known as ATPases associated with various cellular activities (AAA). To investigate how ClpB performs its ATPase activities for its chaperone activity, we have determined the crystal structure of ClpB nucleotide-binding domain 1 (NBD1) by MAD method to 1.80 A resolution. The NBD1 monomer structure contains one domain that comprises 11 alpha-helices and six beta-strands. When compared with the typical AAA structures, the crystal structure of ClpB NBD1 reveals a novel AAA topology with six-stranded beta-sheet as its core. The N-terminal portion of NBD1 structure has an extra beta-strand flanked by two extra alpha-helices that are not present in other AAA structures. Moreover, the NBD1 structure does not have a C-terminal helical domain as other AAA proteins do. No nucleotide molecule is bound with ClpB NBD1 in the crystal structure probably due to lack of the C-terminal helix domain in the structure. Isothermal titration calorimetry (ITC) studies of ClpB NBD1 and other ClpB deletion mutations showed that either ClpB NBD1 or NBD2 alone does not bind to nucleotides. However, ClpB NBD2 combined with ClpB C-terminal fragment can interact with one ADP or ATP molecule. ITC data also indicated that full-length ClpB could bind two ADP molecules or one ATP analogue ATPgammaS molecule. Further ATPase activity studies of ClpB and ClpB deletion mutants showed that only wild-type ClpB have ATPase activity. None of ClpB NBD1 domain, NBD2 domain and NBD2 with C-terminal fragment has detectable ATPase activities. On the basis of our structural and mutagenesis data, we proposed a "see-saw" model to illustrate the mechanisms by which ClpB performs its ATPase activities for chaperone functions.


Two decades after BRCA: setting paradigms in personalized cancer care and prevention.
The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.


Coordination of upper and lower body during balance recovery following a support translation.
Strategies for recovery of posture were studied after lateral mechanical perturbations. 11 participants standing in tandem stance were unexpectedly submitted to lateral support translations with the eyes open or closed at two translation amplitudes. The trajectories of the center of mass of the upper and lower body and muscle activities allowed identification of three strategies, involving either the ankle or the hip only, or both. Hip use increased with vision and with amplitude of perturbation. Short-to-medium latency electromyographic activities were observed in leg and trunk muscles, and long-latency responses in the back leg muscles. Vision increased the activity of both leg and trunk muscles but did not influence the onset of the muscular responses. These data suggest a hierarchy in the selection of these different strategies: the hip is mobilized when the perturbation is more destabilizing but this strategy has a cost and needs specific sensory information supplied by vision.


Managing biological invasions in urban environments with the acceptance sampling approach.
Detections of invasive species outbreaks are often followed by the removal of susceptible host organisms in order to slow the spread of the invading pest population. We propose the acceptance sampling approach for detection and optional removal of susceptible host trees to manage an outbreak of the emerald ash borer (EAB), a highly destructive forest pest, in Winnipeg, Canada. We compare the strategy with two common delimiting survey techniques that do not consider follow-up management actions such as host removal. Our results show that the management objective influences the survey strategy. The survey-only strategies maximized the capacity to detect new infestations and prioritized sites with high likelihood of being invaded. Comparatively, the surveys with subsequent host removal actions allocated most of the budget to sites where complete host removal would minimize the pest's ability to spread to uninvaded locations. Uncertainty about the pest's spread causes the host removal measures to cover a larger area in a uniform spatial pattern and extend to farther distances from already infested sites. If a decision maker is ambiguity-averse and strives to avoid the worst-case damages from the invasion, the optimal strategy is to survey more sites with high host densities and remove trees from sites at farther distances, where EAB arrivals may be uncertain, but could cause significant damage if not detected quickly. Accounting for the uncertainty about spread helps develop a more robust pest management strategy. The approach is generalizable and can support management programs for new pest incursions.


A boy with a submicroscopic 22qter deletion, general overgrowth and features suggestive of FG syndrome.
Over recent years, submicroscopic subtelomeric rearrangements have been shown to be a significant cause of mental retardation and, therefore, such abnormalities should be considered in every child with moderate to severe retardation with additional features suggestive of a chromosomal abnormality. The FG syndrome is an X-linked recessive mental retardation syndrome with congenital hypotonia, relative macrocephaly, a characteristic facies and constipation. We describe a severely mentally retarded boy with a history of severe constipation, truncal hypotonia, facial dysmorphism, fetal pads, and joint laxity, leading to an initial diagnosis of FG syndrome at the age of 3 years. Clinical re-evaluation at the age of 6 years, when he showed signs of general overgrowth, initiated a telomere screen, and a submicroscopic 22q13.3 telomere deletion was detected. The features suggestive of FG syndrome in this boy with a 22q13.3--> qter deletion may indicate testing for submicroscopic 22qter deletions in patients with atypical features of FG syndrome without a definite X-linked family history.


Electromyographic activity of the cervical flexor muscles in patients with temporomandibular disorders while performing the craniocervical flexion test: a cross-sectional study.
Most patients with temporomandibular disorders (TMD) have been shown to have cervical spine dysfunction. However, this cervical dysfunction has been evaluated only qualitatively through a general clinical examination of the cervical spine. The purpose of this study was to determine whether patients with TMD had increased activity of the superficial cervical muscles when performing the craniocervical flexion test (CCFT) compared with a control group of individuals who were healthy. A cross-sectional study was conducted. One hundred fifty individuals participated in this study: 47 were healthy, 54 had myogenous TMD, and 49 had mixed TMD. All participants performed the CCFT. Data for electromyographic activity of the sternocleidomastoid (SCM) and anterior scalene (AS) muscles were collected during the CCFT for all participants. A 3-way mixed-design analysis of variance for repeated measures was used to evaluate the differences in EMG activity for selected muscles while performing the CCFT under 5 incremental levels. Effect size values were calculated to evaluate the clinical relevance of the results. Although there were no statistically significant differences in electromyographic activity in the SCM or AS muscles during the CCFT in patients with mixed and myogenous TMD compared with the control group, those with TMD tended to have increased activity of the superficial cervical muscles. The results obtained in this research are applicable for the group of individuals who participated in this study under the protocols used. They could potentially be applied to people with TMD having characteristics similar to those of the participants of this study. This information may give clinicians insight into the importance of evaluation and possible treatment of the deep neck flexors in patients with TMD. However, future research should test the effectiveness of this type of program through a randomized controlled trial in people with TMD in order to determine the real value of treating this type of impairment in this population.


A tyrosine-phosphorylated protein that binds to an important regulatory region on the cool family of p21-activated kinase-binding proteins.
The p21-activated kinases (Pak) are major targets of the small GTPases Cdc42 and Rac. We, and others, recently identified a family of proteins termed Cool/Pix, which interact with Pak3. In cells, p50(Cool-1) suppresses Pak activation by upstream activators; p85(Cool-1) has a permissive effect on Pak activation, and we now show that the closely related Cool-2 stimulates Pak kinase activity. To understand the differential regulation of Pak by Cool proteins, we screened for Cool-interacting proteins by affinity purification and microsequencing. This has led to the identification of two closely related proteins called Cat (Cool-associated, tyrosine phosphorylated), which contain a zinc finger followed by three ankyrin repeats. Cat-1 is identical to the recently identified binding partner for the beta-adrenergic receptor kinase (betaARK or GRK-2), which was shown to have Arf-GAP activity. Cat-1 and Cat-2 both bind to the COOH-terminal region of p85(Cool-1) and p85(Cool-2) but do not bind to p50(Cool-1). Cat-1 is tyrosine-phosphorylated in growing NIH 3T3 fibroblasts, and its tyrosine phosphorylation is increased following cell spreading on fibronectin, decreased in cells arrested in mitosis, and increased in the ensuing G(1) phase. Cat proteins are tyrosine-phosphorylated when co-expressed in cells with the focal adhesion kinase Fak and Src. These findings suggest that in addition to playing a role in Cool/Pak interactions, Cat proteins may serve as points of convergence between G protein-coupled receptors, integrins, Arf GTPases, cell cycle regulators, and Cdc42/Rac/Pak signaling pathways.


Wnt signaling mediates regional specification in the vertebrate face.
At early stages of development, the faces of vertebrate embryos look remarkably similar, yet within a very short timeframe they adopt species-specific facial characteristics. What are the mechanisms underlying this regional specification of the vertebrate face? Using transgenic Wnt reporter embryos we found a highly conserved pattern of Wnt responsiveness in the developing mouse face that later corresponded to derivatives of the frontonasal and maxillary prominences. We explored the consequences of disrupting Wnt signaling, first using a genetic approach. Mice carrying compound null mutations in the nuclear mediators Lef1 and Tcf4 exhibited radically altered facial features that culminated in a hyperteloric appearance and a foreshortened midface. We also used a biochemical approach to perturb Wnt signaling and found that in utero delivery of a Wnt antagonist, Dkk1, produced similar midfacial malformations. We tested the hypothesis that Wnt signaling is an evolutionarily conserved mechanism controlling facial morphogenesis by determining the pattern of Wnt responsiveness in avian faces, and then by evaluating the consequences of Wnt inhibition in the chick face. Collectively, these data elucidate a new role for Wnt signaling in regional specification of the vertebrate face, and suggest possible mechanisms whereby species-specific facial features are generated.


Frequency and quality of first aid offered by older adolescents: a cluster randomised crossover trial of school-based first aid courses.
Research indicates that school-based first aid programmes appear to improve students' knowledge and skills. However, evidence for their effectiveness is limited by a lack of rigorously designed studies. This research used a cluster randomised crossover trial to assess the effects of two different types of first aid training on the frequency and appropriateness of older adolescents' first aid behaviours towards their peers 12 months after training. Schools eligible to participate were government funded and able to accommodate first aid training and survey time for two consecutive Year 10 student cohorts. Four Australian public schools were matched in two pairs and randomly assigned to receive either physical first aid (PFA) or teen mental health first aid (tMHFA) training for their Year 10 student cohort (mean age 16 years). In the second year, the new Year 10 cohort received the other intervention. Four cohorts were randomised to receive PFA and four were randomised to receive tMHFA. Online surveys were administered at baseline and 12 months after training, measuring whether students had encountered a peer needing PFA, whether they had provided PFA, what actions they performed and, if applicable, why they had been unable to help the person. Only research staff analysing the data could be blinded to measurement occasion, school identity and condition. Four cohorts received PFA and four received tMHFA. The results indicated that there were no differences between groups regarding the frequency of appropriate first aid actions performed 12 months after training. The most common types of PFA provided to a peer were sending for help and wound care. Students most commonly mentioned someone else attending to their peer or lacking skills or experience as reasons for not performing PFA actions. More research that examines first aid behaviours using rigorous, longitudinal study designs is needed to establish the effectiveness of school-based first aid training for older adolescents.


Accurate prediction of enthalpies of formation of organic azides by combining G4 theory calculations with an isodesmic reaction scheme.
Accurate gas-phase enthalpies of formation (ΔfH298°) of 29 azides are recommended by combining G4 theory calculations with an isodesmic reaction approach. The internal consistency over a set of ΔfH298° values was achieved by sequential adjustment of their values through the isodesmic reactions. The HN₃ was chosen as a key reference compound. Of the experimental data available for 16 compounds, our predictive values agree well with 9 of them, while the deviations from 25 to 55 kJ/mol are observed for 7 compounds; possible systematic errors in the experimental data for phenyl azide, 2-azidoethanol, azidocyclopentane, azidocyclohexane, 3-azido-3-ethylpentane, 2-azido-2-phenylpropane, and 1-azidoadamantane are discussed. The recommended enthalpies of formation of organic azides were used as reference values to estimate the enthalpy of formation of four nitrogen-rich carbon nitrides. The calculations do not support the high value of the solid-state enthalpy of formation of TAAT (4,4',6,6'-tetra(azido)azo-1,3,5-triazine); its value is estimated to be 300-400 kJ/mol lower than that measured experimentally.


Trends in influenza vaccination uptake among people aged over 74 years, 1997-2000: survey of 73 general practices in Britain.
Influenza vaccination policy for elderly people in Britain has changed twice since 1997 to increase protection against influenza but there is no information available on how this has affected vaccine uptake, and socioeconomic variation therein, among people aged over 74 years. Vaccination information for 1997-2000 was collected directly from general practices taking part in a MRC-funded Trial of the Assessment and Management of Older People in the Community. This was linked to information collected during assessments carried out as part of the Trial. Regression modelling was used to assess relative probabilities (as relative risks, RR) of having vaccination according to year, gender, age, area and individual socioeconomic characteristics. Out of 106 potential practices, 73 provided sufficient information to be included in the analysis. Uptake was 48% (95% CI 45%, 55%) in 1997 and did not increase substantially until 2000 when the uptake was a third higher at 63% (50%, 66%). Vaccination uptake was lower among women than men (RR 0.9), people aged 85 or more compared to people aged under 80 (RR 0.9), those in the most deprived areas (RR 0.8) compared to the least deprived, and was relatively high for those in owner-occupied homes with central heating compared to other non-supported housing (RR for remainder = 0.9). This pattern did not change over the years studied. Increased uptake in 2000 may have resulted from the additional financial resources given to practices; it was not at the expense of more disadvantaged socioeconomic groups but nor did they benefit disproportionately.


Online ranking by projecting.
We discuss the problem of ranking instances. In our framework, each instance is associated with a rank or a rating, which is an integer in 1 to k. Our goal is to find a rank-prediction rule that assigns each instance a rank that is as close as possible to the instance's true rank. We discuss a group of closely related online algorithms, analyze their performance in the mistake-bound model, and prove their correctness. We describe two sets of experiments, with synthetic data and with the EachMovie data set for collaborative filtering. In the experiments we performed, our algorithms outperform online algorithms for regression and classification applied to ranking.


[Lymphoproliferative disorders after renal transplantation in a child].
Post transplant lymphoproliferative disorder (PTLD) is the commonest form of post transplant malignancy in children. The incidence in renal transplant recipients varies between 2%-4%. They are characterized by uncontrolled B lymphocyte proliferation, in most cases driven by Epstein Barr virus (EBV). They are more common in younger children, EBV seronegative patients and those who receive aggressive immunosuppression. PTLD commonly presents in an unspecific form and it requires high suspicion rate for its diagnosis, especially in children with risk factors. We report a twelve year-old girl who developed fever, sore throat and lymph node enlargement, six months after receiving a renal allograft. Laboratory assessment and imaging studies were compatible with PTLD, which was confirmed by biopsy. Treatment was reduction of immunosuppression and surveillance. The patient had a favorable evolution.


Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix.
The conjunctive presence of mechanical stress and active transforming growth factor beta1 (TGF-beta1) is essential to convert fibroblasts into contractile myofibroblasts, which cause tissue contractures in fibrotic diseases. Using cultured myofibroblasts and conditions that permit tension modulation on the extracellular matrix (ECM), we establish that myofibroblast contraction functions as a mechanism to directly activate TGF-beta1 from self-generated stores in the ECM. Contraction of myofibroblasts and myofibroblast cytoskeletons prepared with Triton X-100 releases active TGF-beta1 from the ECM. This process is inhibited either by antagonizing integrins or reducing ECM compliance and is independent from protease activity. Stretching myofibroblast-derived ECM in the presence of mechanically apposing stress fibers immediately activates latent TGF-beta1. In myofibroblast-populated wounds, activation of the downstream targets of TGF-beta1 signaling Smad2/3 is higher in stressed compared to relaxed tissues despite similar levels of total TGF-beta1 and its receptor. We propose activation of TGF-beta1 via integrin-mediated myofibroblast contraction as a potential checkpoint in the progression of fibrosis, restricting autocrine generation of myofibroblasts to a stiffened ECM.


Sigma54 enhancer binding proteins and Myxococcus xanthus fruiting body development.
A search of the M1genome sequence, which includes 97% of the Myxococcus xanthus genes, identified 53 sequence homologs of sigma54-dependent enhancer binding proteins (EBPs). A DNA microarray was constructed from the M1genome that includes those homologs and 318 other M. xanthus genes for comparison. To screen the developmental program with this array, an RNA extract from growing cells was compared with one prepared from developing cells at 12 h. Previous reporter studies had shown that M. xanthus has initiated development and has begun to express many developmentally regulated genes by 12 h. The comparison revealed substantial increases in the expression levels of 11 transcription factors that may respond to environmental stimuli. Six of the 53 EBP homologs were expressed at significantly higher levels at 12 h of development than during growth. Three were previously unknown genes, and they were inactivated to look for effects on fruiting body development. One knockout mutant produced fruiting bodies of abnormal shape that depended on the composition of the medium.


Retinal microglia are critical for subretinal neovascular formation.
Abnormal subretinal neovascularization is a characteristic of vision-threatening retinal diseases, including macular telangiectasia (MacTel) and retinal angiomatous proliferation (RAP). Subretinal neovascular tufts and photoreceptor dysfunction are observed in very-low-density lipoprotein receptor (Vldlr-/-) mutant mice. These changes mirror those observed in patients with MacTel and RAP, but the pathogenesis is largely unknown. In this study, we show that retinal microglia were closely associated with retinal neovascular tufts in Vldlr-/- mice and retinal tissue from patients with MacTel; ablation of microglia/macrophages dramatically prevented formation of retinal neovascular tufts and improved neuronal function, as assessed by electroretinography. Vldlr-/- mice with retinal pigmented epithelium-specific (RPE-specific) Vegfa had greatly reduced subretinal infiltration of microglia/macrophages, subsequently reducing neovascular tufts. These findings highlight the contribution of microglia/macrophages to the pathogenesis of neovascularization, provide valuable clues regarding potential causative cellular mechanisms for subretinal neovascularization in patients with MacTel and RAP and suggest that targeting microglia activation may be a therapeutic option in these diseases.


The role of alexithymia in reduced eye-fixation in Autism Spectrum Conditions.
Eye-tracking studies have demonstrated mixed support for reduced eye fixation when looking at social scenes in individuals with Autism Spectrum Conditions (ASC). We present evidence that these mixed findings are due to a separate condition-alexithymia-that is frequently comorbid with ASC. We find that in adults with ASC, autism symptom severity correlated negatively with attention to faces when watching video clips. However, only the degree of alexithymia, and not autism symptom severity, predicted eye fixation. As well as potentially resolving the contradictory evidence in this area, these findings suggest that individuals with ASC and alexithymia may form a sub-group of individuals with ASC, with emotional impairments in addition to the social impairments characteristic of ASC.


One membrane protein, two structures and six environments: a comparative molecular dynamics simulation study of the bacterial outer membrane protein PagP.
PagP is a bacterial outer membrane protein consisting of an 8 stranded transmembrane beta-barrel and an N-terminal alpha-helix. It is an enzyme which catalyses transfer of a palmitoyl chain from a phospholipid to lipid A. Molecular dynamics simulations have been used to compare the dynamic behaviour in simulations starting from two different structures (X-ray vs. NMR) and in six different environments (detergent micelles formed by dodecyl phosphocholine and by octyl glucoside, vs. four species of phospholipid bilayer). Analysis of interactions between the protein and its environment reveals the role played by the N-terminal alpha-helix, which interacts with the lipid headgroups to lock the PagP molecule into the bilayer. The PagP beta-barrel adopts a tilted orientation in lipid bilayers, facilitating access of lipid tails into the mouth of the central binding pocket. In simulations starting from the X-ray structure in lipid bilayer, the L1 and L2 loops move towards one another, leading to the formation of a putative active site by residues H33, D76 and S77 coming closer together.


Behavioral and Cognitive Impacts of Mindfulness-Based Interventions on Adults with Attention-Deficit Hyperactivity Disorder: A Systematic Review.
Mindfulness-based interventions (MBIs) are becoming increasingly popular as treatments for physical and psychological problems. Recently, several studies have suggested that MBIs may also be effective in reducing symptoms of attention-deficit hyperactivity disorder (ADHD). Most studies have examined the effectiveness in children, but there are now a sufficient number of individual treatment trials to consider a systematic review in adults. Majority of existing systematic reviews and meta-analyses only consider ADHD symptoms as an outcome, and most of them do not fully report potential biases of included studies, thus limiting considerably their conclusions. This is an important facet because some studies could be found ineligible to be included in future analysis due to their low quality. In this systematic review, we followed the PRISMA/PICO criteria and we thoroughly assessed the risks of bias for each of the selected studies according to Cochrane guidelines. We searched the available literature concerning MBIs in adult participants with ADHD using PsycINFO, PubMed, Scopus, and ERIC databases. In total, 13 studies conducted with 753 adults (mean age of 35.1 years) were identified as eligible. Potential moderators such as participants' age, ADHD subtypes, medication status, comorbidity, intervention length, mindfulness techniques, homework amount, and training of therapists were carefully described. Aside from measuring the symptoms of ADHD, outcome measures were categorized into executive/cognitive functioning, emotional disturbances, quality of life, mindfulness, and grade point average at school. According to presented descriptive results, all the studies (100%) showed improvement of ADHD symptoms. In addition, mindfulness meditation training improves some aspects of executive function and emotion dysregulation. Although these are promising findings to support treatment efficacy of MBIs for ADHD, various biases such as absence of randomization and lack of a control group may affect the actual clinical value and implications of the studies. Moreover, the relatively low quality of selection and performance criteria in several studies, as well as relatively high attrition bias across studies, call for caution before considering conducting further analysis.


In vivo and in vitro replication consequences of stereoisomeric benzo[a]pyrene-7,8-dihydrodiol 9,10-epoxide adducts on adenine N6 at the second position of N-ras codon 61.
Benzo[a]pyrene-7,8-dihydrodiol 9,10-epoxide (BPDE), a metabolite of the widespread environmental pollutant benzo[a]pyrene, is a mutagenic in both bacterial and mammalian systems. Toward understanding the mutagenic effects of different stereoisomers of BPDE at specific sites in DNA, six stereochemically defined BPDE adducts were constructed on adenine N6 at position 2 of the human N-ras 61 codon within an 11-base oligonucleotide fragment. Both the nonadducted and BPDE-adducted N-ras 61 11-mers were inserted into a unique EcoRI site in single-stranded M13mp7L2 DNA and utilized for in vivo studies. The ligation efficiencies of BPDE-adducted 11-mers into the single-stranded vector were determined by Southern hybridization and confirmed by electron microscopy. Repair-deficient AB2480 E. coli cells were transformed with adducted and non-adducted DNA samples. The resultant plaque-forming abilities were used to evaluate the replication competence of the various BPDE adducts with respect to the nonadducted 11-mer. Point mutations due to aberrant replication at the adducted site were identified by the technique of differential DNA hybridization. All of the six BPDE adducts examined were mutagenic in vivo, generating exclusively A-->G mutations at frequencies ranging from 0.26 to 1.20%. In vitro replication studies using these BPDE-adducted 11-mers involved primer extension assays with Klenow fragment. All of the BPDE-modified templates demonstrated distinct blockage at the adducted site and/or 1 base 3' to the adducted site, allowing essentially no translesion synthesis to form fully extended polymerization products in vitro.


Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer.
Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor-like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B-sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.


Targeted disruption of NeuroD, a proneural basic helix-loop-helix factor, impairs distal lung formation and neuroendocrine morphology in the neonatal lung.
Despite the importance of airspace integrity in vertebrate gas exchange, the molecular pathways that instruct distal lung formation are poorly understood. Recently, we found that fibrillin-1 deficiency in mice impairs alveolar formation and recapitulates the pulmonary features of human Marfan syndrome. To further elucidate effectors involved in distal lung formation, we performed expression profiling analysis comparing the fibrillin-1-deficient and wild-type developing lung. NeuroD, a basic helix-loop-helix transcription factor, fulfilled the expression criteria for a candidate mediator of distal lung development. We investigated its role in murine lung development using genetically targeted NeuroD-deficient mice. We found that NeuroD deficiency results in both impaired alveolar septation and altered morphology of the pulmonary neuroendocrine cells. NeuroD-deficient mice had enlarged alveoli associated with reduced epithelial proliferation in the airway and airspace compartments during development. Additionally, the neuroendocrine compartment in these mice manifested an increased number of neuroepithelial bodies but a reduced number of solitary pulmonary neuroendocrine cells in the neonatal lung. Overexpression of NeuroD in a murine lung epithelial cell line conferred a neuroendocrine phenotype characterized by the induction of neuroendocrine markers as well as increased proliferation. These results support an unanticipated role for NeuroD in the regulation of pulmonary neuroendocrine and alveolar morphogenesis and suggest an intimate connection between the neuroendocrine compartment and distal lung development.


Sweat electrolyte loss during exercise in the heat: effects of gender and maturation.
Humans may lose large amounts of water and electrolytes from sweat during prolonged exercise in a hot climate. Gender and maturational differences for the total sweat electrolyte losses have not been reported. The purpose of this study was to compare sweat electrolyte losses of prepubescent (PP), pubescent (P) and young adult (YA) males and females, under the same environmental conditions and relative exercise intensities. Twenty-five females (8 PP, 9 P, 8 YA) and 26 males (10 PP, 8 P, 8 YA) cycled for two 20-min bouts at 50% of their peak VO2 in a climatic chamber (42 degrees C, 18% relative humidity). Sweat was collected from a plastic bag attached to the lower back. Total body sweat loss was calculated from the differences in nude body weight corrected for fluid intake, urine, and respiratory water loss. Sweat [Na+] and [Cl-] tended to increase with maturation while sweat [K+] was lower in YA compared with that of PP. Children had a lower sweating rate than YA, even when corrected for body surface area. As a result, total Na+ and Cl- losses per kg body weight from sweat (mEq.kg-1.h-1) were higher in YA compared with those of PP and P; however, no maturational difference was found in K+ losses. Within the same maturational group, there were no gender differences in any of the electrolyte losses. These results may be useful in recommending "optimal" fluid-electrolyte drinks for children exercising in the heat.


Cell loss factors and the linear-quadratic model.
A method is described for incorporating a variable cell loss factor (phi) within the linear-quadratic (LQ) model. By allowing for a progressive reduction in phi as treatment progresses, the revised model behaves in a way which is consistent with the apparent presence of accelerated tumour repopulation during fractionated radiotherapy. Predictions based on a slowing of the cell loss process, rather than a true increase in clonogen proliferation rate, are consistent with the phenomenon of 'unmasking' of potential doubling time described by Fowler (Fowler, J.F. Rapid repopulation in radiotherapy: a debate on mechanism. Radiother Oncol 24: 125, 1992). An optional time delay factor may be included, to allow for the fact that progressive reduction in cell loss may not begin until part of the treatment has been delivered. The model provides a description of the manner in which tumour control doses are likely to increase as overall treatment time is increased.


Seasonal impoundment management reduces nitrogen cycling but not resilience to surface fire in a tidal wetland.
Hydrology and salinity regimes of many impounded wetlands are manipulated to provide seasonal habitats for migratory waterfowl, with little-known consequences for ecosystem structure and function. Managed hydrology can alter ecosystems by directly changing soil properties and processes and by influencing plant community dynamics. Additionally, management history may influence ecosystem response to disturbance, including fires. To better understand how wetland management regime influences ecosystem response to disturbance, we quantified elevation, soil nitrogen concentrations and process rates, and plant community structure and diversity in a natural experiment following the 2018 Branscombe Fire. We measured paired burned-unburned patches in both tidally-influenced and managed, seasonally-impounded wetlands in Suisun Marsh, California, USA. Unburned ecosystem structure and nutrient cycling differed by wetland management history; unburned impounded wetlands were ∼1 m lower in elevation and plant community composition was dominated by succulents whereas the unburned tidal wetland was dominated by graminoids. Unburned impounded wetland soil nitrogen cycling (potential nitrification and denitrification) rates were <28% of those measured in unburned tidal wetland soils and soil extractable nitrate, ammonium, and dissolved inorganic phosphorus concentrations were also substantially lower in unburned impounded than unburned tidal wetlands. Despite these differences in pre-disturbance (i.e., unburned) conditions, all soil processes recovered to baseline levels within 6 months after surface fire, and we found no evidence of plant community change 1 year after fire in either wetland management type. Overall, water management history exerted stronger control on ecosystem processes and structure than surface fire disturbance. Low extractable soil nitrate and potential denitrification rates may indicate limitation of soil nitrogen removal in impounded wetlands, with implications for downstream environmental quality and eutrophication across managed landscapes.


Conducting perception research over the internet: a tutorial review.
This article provides an overview of the recent literature on the use of internet-based testing to address important questions in perception research. Our goal is to provide a starting point for the perception researcher who is keen on assessing this tool for their own research goals. Internet-based testing has several advantages over in-lab research, including the ability to reach a relatively broad set of participants and to quickly and inexpensively collect large amounts of empirical data, via services such as Amazon's Mechanical Turk or Prolific Academic. In many cases, the quality of online data appears to match that collected in lab research. Generally-speaking, online participants tend to be more representative of the population at large than those recruited for lab based research. There are, though, some important caveats, when it comes to collecting data online. It is obviously much more difficult to control the exact parameters of stimulus presentation (such as display characteristics) with online research. There are also some thorny ethical elements that need to be considered by experimenters. Strengths and weaknesses of the online approach, relative to others, are highlighted, and recommendations made for those researchers who might be thinking about conducting their own studies using this increasingly-popular approach to research in the psychological sciences.


Metabolic syndrome and risk of death from cancers of the digestive system.
We tested the hypothesis that risk of early mortality from cancers of the digestive system will be greater in men with, compared with men without, the metabolic syndrome (MetS). Participants were 33,230 men who were seen at the Cooper Clinic in Dallas, TX, and followed for 14.4 (SD = 7.0) years. Metabolic syndrome was defined as having at least 3 of the following risk factors: abdominal obesity, fasting hypertriglyceridemia, low high-density lipoprotein cholesterol, high blood pressure, or high fasting glucose level or diabetes. Metabolic syndrome was associated with higher mortality (hazard ratio [HR] = 1.90 [95% confidence interval = 1.42-2.55]), and there was a graded positive association for the addition of more syndrome components (P < .01). Adjustment for cardiorespiratory fitness attenuated the risk estimates by 20% to 30%, but they remained significant after this adjustment. Evaluation of the independent contribution of each of the syndrome components revealed that both abdominal obesity (HR = 1.89 [1.36-2.62]) and high glucose (HR = 1.38 [1.02-1.87]) were independently associated with cancer mortality. Our results support the hypothesis that metabolic syndrome is positively associated with mortality from cancers of the digestive system. Interventions that reduce abnormalities associated with the syndrome could reduce risk of premature death from these cancers.


Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain.
Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase-2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2*2), which is also present in human ALDH2 of ~540 million East Asians. The ALDH2*1/*2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R(2) = 0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde- and formalin-induced nociceptive behavior was greater in the ALDH2*1/*2 mice than in the wild-type mice. Finally, Alda-1 treatment was even beneficial when given after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic, cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians' apparent lower pain tolerance.


Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial.
Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0-2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov, NCT03182634; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96-99% (n=800, kappa 0·89-0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83-98) overall and 98% (87-100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0-23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9-49]) of 20 patients in cohort B and four (22% [6-48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3-17]) of 74 in cohort A and two (11% [1-33]) of 19 patients in cohort D having a response. The most common grade 3-4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C). ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment. Cancer Research UK, AstraZeneca, and Puma Biotechnology.


CDK2 regulates nuclear envelope protein dynamics and telomere attachment in mouse meiotic prophase.
In most organisms, telomeres attach to the nuclear envelope at the onset of meiosis to promote the crucial processes of pairing, recombination and synapsis during prophase I. This attachment of meiotic telomeres is mediated by the specific distribution of several nuclear envelope components that interact with the attachment plates of the synaptonemal complex. We have determined by immunofluorescence and electron microscopy that the ablation of the kinase CDK2 alters the nuclear envelope in mouse spermatocytes, and that the proteins SUN1, KASH5 (also known as CCDC155) and lamin C2 show an abnormal cap-like distribution facing the centrosome. Strikingly, some telomeres are not attached to the nuclear envelope but remain at the nuclear interior where they are associated with SUN1 and with nuclear-envelope-detached vesicles. We also demonstrate that mouse testis CDK2 phosphorylates SUN1 in vitro. We propose that during mammalian prophase I the kinase CDK2 is a key factor governing the structure of the nuclear envelope and the telomere-led chromosome movements essential for homolog pairing.


Inflammation-driven brain and gut barrier dysfunction in stress and mood disorders.
Regulation of emotions is generally associated exclusively with the brain. However, there is evidence that peripheral systems are also involved in mood, stress vulnerability vs. resilience, and emotion-related memory encoding. Prevalence of stress and mood disorders such as major depression, bipolar disorder, and post-traumatic stress disorder is increasing in our modern societies. Unfortunately, 30%-50% of individuals respond poorly to currently available treatments highlighting the need to further investigate emotion-related biology to gain mechanistic insights that could lead to innovative therapies. Here, we provide an overview of inflammation-related mechanisms involved in mood regulation and stress responses discovered using animal models. If clinical studies are available, we discuss translational value of these findings including limitations. Neuroimmune mechanisms of depression and maladaptive stress responses have been receiving increasing attention, and thus, the first part is centered on inflammation and dysregulation of brain and circulating cytokines in stress and mood disorders. Next, recent studies supporting a role for inflammation-driven leakiness of the blood-brain and gut barriers in emotion regulation and mood are highlighted. Stress-induced exacerbated inflammation fragilizes these barriers which become hyperpermeable through loss of integrity and altered biology. At the gut level, this could be associated with dysbiosis, an imbalance in microbial communities, and alteration of the gut-brain axis which is central to production of mood-related neurotransmitter serotonin. Novel therapeutic approaches such as anti-inflammatory drugs, the fast-acting antidepressant ketamine, and probiotics could directly act on the mechanisms described here improving mood disorder-associated symptomatology. Discovery of biomarkers has been a challenging quest in psychiatry, and we end by listing promising targets worth further investigation.


Evaluation of a school-based education program to promote bicycle safety.
Of the 500,000 children in the United States who are injured in bicycle crashes annually, 252 die--97% of whom were not wearing a helmet. Although many intervention programs promote the use of helmets by children, a paucity of school-based evaluation studies exist that report students' knowledge retention or behavioral changes. The purposes of this study were to identify associations between student-reported knowledge of safety-related behaviors, reports of current safety-related practices, and students' participation in the Safety Central program while in the 4th grade. The sample consisted of 284 students currently enrolled in 5th and 6th grades. Findings showed a statistically significant association between participation in the Safety Central program and retention of knowledge and enactment of safety messages after a 1- and 2-year period. Motivators and barriers for helmet use were also identified. Implications for modifications to the content and delivery of the program and future evaluations are addressed.


Changes in surface electromyography signals and kinetics associated with progression of fatigue at two speeds during wheelchair propulsion.
The purpose of this study was to determine whether muscle balance is influenced by fatigue in a recordable way, toward creating novel defensive activity strategies for manual wheelchair users (MWUs). Wheelchair propulsion to a point of mild fatigue, level 15 on the Rating of Perceived Exertion scale, was investigated at two different speeds. Surface electromyographic (EMG) activity of 7 muscles was recorded on 14 nondisabled participants. Kinetic variables were measured using a SmartWheel. No significant effect was found of percentage endurance time on kinetic variables for the two propulsion speeds. Fatigue-related changes in the EMG spectra were identified as an increase of EMG intensity and a decrease of mean power frequency as a function of percent endurance time for the tested muscles under both fast and slow speed conditions. The greater increases in activity for propulsive muscles compared with recovery muscles during fast speed wheelchair propulsion indicated muscle imbalance associated with fatiguing wheelchair propulsion. This study shows how kinetic and EMG information might be used as feedback to MWUs to ensure that they conduct activity in ways that do not precipitate injury.


Acute diarrhoea induces rectal sensitivity in women but not men.
Some patients with diarrhoea predominant irritable bowel syndrome have increased rectal sensitivity. It is uncertain, however, whether the diarrhoea is a consequence of the rectal sensitivity or if it is sensitising the rectum in some way. The aim of this study was to assess whether inducing diarrhoea in normal healthy volunteers can sensitise the rectum and therefore be a potential or partial cause of the sensitive rectum seen in some patients with diarrhoea predominant irritable bowel syndrome. The anorectal responses to balloon distension were measured in 20 healthy volunteers (aged 20-43 years, 10 female) eight hours after laxative induced diarrhoea or under control conditions. Ingestion of an isoosmotic laxative increased stool output from 1.1 (0.7-2.3) (median (range)) to 8 (5-19) bowel movements per day with no significant differences between men and women. In women rectal sensitivity was significantly increased after diarrhoea compared with control conditions (vol to induce discomfort (ml): 116 (96, 136) v 153 (137, 168), mean (95% CI); p < 0.001). This was associated with a reduction in the volume to induce internal anal sphincter relaxation (16 (12, 20) v 28 (21, 36); p < 0.005), and volume to induce sustained internal anal sphincter relaxation (70 (56, 84) v 90 (67, 113); p < 0.03), but no significant change in rectal compliance (ml/cm H2O at 100 ml) 4.8 (3.5, 6.1) v 4.1 (3.0, 5.1) or distension induced motility (motility index) 994 (341, 1647) v 735 (46, 1424). Conversely, in men diarrhoea had no significant effect on anorectal physiology and their control values were not significantly different from those of the women. In conclusion, the results of this study taken with the finding that irritable bowel syndrome is more common in women, suggests that the male or female sex hormonal environment may be an important factor in allowing the gut to be sensitised to noxious stimuli.


Reversible Structural Swell-Shrink and Recoverable Optical Properties in Hybrid Inorganic-Organic Perovskite.
Ion migration in hybrid organic-inorganic perovskites has been suggested to be an important factor for many unusual behaviors in perovskite-based optoelectronics, such as current-voltage hysteresis, low-frequency giant dielectric response, and the switchable photovoltaic effect. However, the role played by ion migration in the photoelectric conversion process of perovskites is still unclear. In this work, we provide microscale insights into the influence of ion migration on the microstructure, stability, and light-matter interaction in perovskite micro/nanowires by using spatially resolved optical characterization techniques. We observed that ion migration, especially the migration of MA(+) ions, will induce a reversible structural swell-shrink in perovskites and recoverably affect the reflective index, quantum efficiency, light-harvesting, and photoelectric properties. The maximum ion migration quantity in perovskites was as high as approximately 30%, resulting in lattice swell or shrink of approximately 4.4%. Meanwhile, the evidence shows that ion migration in perovskites could gradually accelerate the aging of perovskites because of lattice distortion in the reversible structural swell-shrink process. Knowledge regarding reversible structural swell-shrink and recoverable optical properties may shed light on the development of optoelectronic and converse piezoelectric devices based on perovskites.


Single mutations at many sites within the DNA polymerase locus of herpes simplex viruses can confer hypersensitivity to aphidicolin and resistance to phosphonoacetic acid.
Aphidicolin, a tetracyclic diterpenoid which inhibits the DNA polymerase-alpha activities of many eukaryotic cells, inhibited herpes simplex virus growth and DNA synthesis in infected cultures and the activity of the virus DNA polymerase in vitro. A wide range of stable aphidicolin sensitivities was represented amongst a collection of virus strains with no prior exposure to this drug, but viruses with polymerase mutations selected for resistance to phosphonoacetic acid (PAA) or to acycloguanosine typically showed increased sensitivity to aphidicolin. Of 16 unrelated PAA-resistant variants, 7 were hypersensitive to aphidicolin. A number of mutants with temperature-sensitive (ts) lesions in the polymerase gene also showed increased aphidicolin sensitivity (e.g. HSV-1[mP17]tsH) or aphidicolin hypersensitivity (e.g. HSV-1[KOS]tsD9, tsC4). Resistance or hypersensitivity of virus growth and DNA synthesis in vivo were correlated with resistance or hypersensitivity of virus DNA polymerase reactions in vitro. Resistance phenotypes were closely linked to the polymerase gene during recombination with outside markers. Moreover, the selection of aphidicolin-resistant mutants from hypersensitive variants with independent PAA resistance or ts mutations in the polymerase gene could result in co-selection for PAA-sensitive and ts+ phenotypes. Confirmation that multiple independent mutations could determine aphidicolin hypersensitivity was obtained by studies of recombination between independent hypersensitive variants. Aphidicolin-resistant recombinant progeny were formed with recombination frequencies (0.4 to 2.6%) compatible with intragenic events. With parental hypersensitive variants which were products of limited PAA selection, or with the ts polymerase mutations, aphidicolin-resistant recombinants were PAA-sensitive and/or ts+. The segregation of other markers (ts, plaque morphology) amongst recombinant progeny permitted the orientation of multiple determinants of PAA resistance and aphidicolin hypersensitivity with respect to other markers in the polymerase gene and in other genes. The nature of residues determined at any one of a constellation of separate sites within the polymerase locus can determine resistance or sensitivity to antiviral drugs and aphidicolin hypersensitivity associated with changes at the polymerase locus facilitates high resolution genetic analysis of this locus.


Health effects of job insecurity among employees in the Swiss general population.
This study looks at the health consequences of the social distress caused by perceived levels of job insecurity. Through interviews with full- and part-time employees drawn from a random sample (N = 2,024) of the Swiss general population, the authors measured prevalence rates of ten self-reported indicators of health and health-related behavior according to three levels of perceived job insecurity (low, middle, high), and estimated odds ratios using logistic regression adjusted for relevant respondent characteristics. The results show that the psychosocial stress induced by job insecurity (fear of unemployment) has a negative effect on these health indicators. Fear of unemployment had a stronger unfavorable effect on health for highly educated employees than for the less educated. The authors make some recommendations for raising awareness about the health effects of job insecurity and taking these effects into account in policies and legislation affecting the labor market and work environment.


Zinc ions bind to and inhibit activated protein C.
Zn2+ ions were found to efficiently inhibit activated protein C (APC), suggesting a potential regulatory function for such inhibition. APC activity assays employing a chromogenic peptide substrate demonstrated that the inhibition was reversible and the apparent K I was 13 +/- 2 microM. k cat was seven fold decreased whereas K M was unaffected in the presence of 10 microM Zn2+. The inhibitory effect of Zn2+ on APC activity was also observed when factor Va was used as a substrate in an assay coupled to a prothrombinase assay. The interaction of Zn2+ with APC was accompanied by a reversible approximately 40% decrease in tryptophan fluorescence, consistent with the ion inducing a conformational change in the protein. The apparent K D was 7.4 +/- 1.5 microM and thus correlated well with the apparent K I. In the presence of physiological Ca2+ concentration the K I and K D values were three to four fold enhanced, presumably due to the Ca2+-induced conformational change affecting the conformation of the Zn2+-binding site. The inhibition mechanism was non-competitive both in the absence and presence of Ca2+. Comparisons of sequences and structures suggested several possible sites for zinc binding. The magnitude of the apparent KI in relation to the blood and platelet concentrations of Zn2+ supports a physiological role for this ion in the regulation of anticoagulant activity of APC. These findings broaden the understanding of this versatile serine protease and enable the future development of potentially more efficient anticoagulant APC variants for treatments of thrombotic diseases.


Affects of ionizing radiation on T-cell population lymphocyte: a risk factor of irritable bowel syndrome.
Irritable bowel syndrome is observed mostly in Ukrainian children and may be related to adverse health effects as a result of the Chernobyl disaster. The aim of this study was to determine status of T-cell population lymphocytes in children with clinical symptom of irritable bowel syndrome. The test population consisted of 95 participants: 75 rural patients aged 4 to 18 who lived in a contaminated area exposed to natural environmental radiation with clinical symptom of irritable bowel syndrome (categorized in three groups) and 20 healthy urban participants from Kiev aged 5 to 15 as control group. Internal radiation activity has been measured by gamma-ray spectrometry. Peripheral blood leukocytes were analyzed for T-lymphocytes subset such as T-lymphocytes (CD3(+)), T-helper (CD4(+)) and T-cytotoxic (CD8(+)) and then CD4/CD8 ratio was calculated. Percentage of CD3(+) and CD4(+) in all study groups decreased significantly in comparison to control group (p < 0.001). Percentage of CD8(+) increased significantly in all study groups in comparison to control group (p < 0.05). The CD4/CD8 ratio decreased significantly all study groups in comparison to control group (p < 0.001). Cellular immune status of study groups that are residing in a contaminated area has changed. Our data have demonstrated that this change may be related to a higher incidence of children with irritable bowel syndrome.


Binary Set Embedding for Cross-Modal Retrieval.
Cross-modal retrieval is such a challenging topic that traditional global representations would fail to bridge the semantic gap between images and texts to a satisfactory level. Using local features from images and words from documents directly can be more robust for the scenario with large intraclass variations and small interclass discrepancies. In this paper, we propose a novel unsupervised binary coding algorithm called binary set embedding (BSE) to obtain meaningful hash codes for local features from the image domain and words from text domain. Understanding image features with the word vectors learned from the human language instead of the provided documents from data sets, BSE can map samples into a common Hamming space effectively and efficiently where each sample is represented by the sets of local feature descriptors from image and text domains. In particular, BSE explores relationship among local features in both feature level and image (text) level, which can balance the sensitivity of each other. Furthermore, a recursive orthogonalization procedure is applied to reduce the redundancy of codes. Extensive experiments demonstrate the superior performance of BSE compared with state-of-the-art cross-modal hashing methods using either image or text queries.


A Flexible Open-Source Decision Model for Value Assessment of Biologic Treatment for Rheumatoid Arthritis.
The nature of model-based cost-effectiveness analysis can lead to disputes in the scientific community. We propose an iterative and collaborative approach to model development by presenting a flexible open-source simulation model for rheumatoid arthritis (RA), accessible to both technical and non-technical end-users. The RA model is a discrete-time individual patient simulation with 6-month cycles. Model input parameters were estimated based on currently available evidence and treatment effects were obtained with Bayesian network meta-analysis techniques. The model contains 384 possible model structures informed by previously published models. The model consists of the following components: (i) modifiable R and C++ source code available in a GitHub repository; (ii) an R package to run the model for custom analyses; (iii) detailed model documentation; (iv) a web-based user interface for full control over the model without the need to be well-versed in the programming languages; and (v) a general audience web-application allowing those who are not experts in modeling or health economics to interact with the model and contribute to value assessment discussions. A primary function of the initial version of RA model is to help understand and quantify the impact of parameter uncertainty (with probabilistic sensitivity analysis), structural uncertainty (with multiple competing model structures), the decision framework (cost-effectiveness analysis or multi-criteria decision analysis), and perspective (healthcare or limited societal) on estimates of value. In order for a decision model to remain relevant over time it needs to evolve along with its supporting body of clinical evidence and scientific insight. Multiple clinical and methodological experts can modify or contribute to the RA model at any time due to its open-source nature.


Insurers negotiate lower hospital prices for HIX than for commercial groups.
This study investigates a sample of the pricing data released by hospitals under the price transparency law effective January 2021 to better understand the prices paid by health insurance exchange (HIX) plans relative to commercial group and Medicare Advantage plans. Cross-sectional analysis of hospital pricing data. We compared allowed amounts for 25 common inpatient services and 56 common outpatient services across 22 hospital-insurer dyads, selected by the availability of plan-specific pricing data from the top 100 hospitals by bed counts and the top 100 hospitals by gross revenue based on 2017 CMS data. Insurers in our sample generally negotiated allowed amounts for their HIX plans that were lower than their commercial group rates and well above their Medicare Advantage contracts within the same hospital. Allowed amounts for HIX plans were generally lower than commercial group rates and higher than Medicare Advantage rates. Better information on HIX pricing is needed as the federal government and states consider additional ways to expand health care coverage, such as public options or expanded Medicaid or Medicare eligibility.


Magic truffles or Philosopher's stones: a legal way to sell psilocybin?
"Magic mushrooms" is the most common name given to hallucinogenic fungi containing the psychoactive alkaloids psilocybin and psilocin. In recent years, fungis' sclerotia, commonly called "magic truffles" have become a form of supply of psychoactive Psilocybe alkaloids since Psilocybe sclerotia are not specifically included in the laws banning the sale, the purchase and the use of such substances and mushrooms containing them. A liquid chromatography -tandem mass spectrometry (LC-MS/MS) method was developed for the rapid determination of psilocybin and psilocin in Psilocybe sclerotia. Following a simple step extraction with methanol, the alkaloids were separated on a reversed-phase column using a gradient of 0.1% formic acid - acetonitrile s a mobile phase at a flow rate of 0.2 mL/min.. Separated analytes were detected by electrospray ionization tandem mass spectrometry in the positive ion mode using multiple reaction monitoring. The developed method was linear over the calibration range for all two substances under investigation, with a r(2) > 0.99. The detection and quantification limits were 0.3 µg and 1 µg per 100 mg truffles, for both psilocin and psilocybin and the intra- and inter-day coefficients of variation were always better than 15%. Using this method, the presence of only psilocybin was demonstrated in examined Psilocybe sclerotia. The content of psilocybin was found to vary over a concentration range of 59.3 to 167.8 µg per 100 mg of fresh sclerotia.


Geographic Expansion of Lyme Disease in Michigan, 2000-2014.
Most Lyme disease cases in the Midwestern United States are reported in Minnesota and Wisconsin. In recent years, however, a widening geographic extent of Lyme disease has been noted with evidence of expansion eastwards into Michigan and neighboring states with historically low incidence rates. We collected confirmed and probable cases of Lyme disease from 2000 through 2014 from the Michigan Department of Health and Human Services, entering them in a geographic information system. We performed spatial focal cluster analyses to characterize Lyme disease expansion. We compared the distribution of human cases with recent Ixodes scapularis tick distribution studies. Lyme disease cases in both the Upper and Lower Peninsulas of Michigan expanded more than 5-fold over the study period. Although increases were seen throughout the Upper Peninsula, the Lower Peninsula particularly expanded along the Indiana border north along the eastern shore of Lake Michigan. Human cases corresponded to a simultaneous expansion in established I scapularis tick populations. The geographic distribution of Lyme disease cases significantly expanded in Michigan between 2000 and 2014, particularly northward along the Lake Michigan shore. If such dynamic trends continue, Michigan-and possibly neighboring areas of Indiana, Ohio, and Ontario, Canada-can expect a continued increase in Lyme disease cases.


A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis.
To validate the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) scoring system in patients with severe sepsis, we conducted a multicenter, prospective study at 15 critical care centers in tertiary care hospitals. This study included 624 severe sepsis patients. JAAM DIC was scored on the day of diagnosis of severe sepsis (day 1) and day 4. Scores for disease severity and organ dysfunction were also evaluated. The prevalence of JAAM DIC was 46.8% (292/624), and 21% of the DIC patients were scored according to the reduction rate of platelets. The JAAM DIC patients were more seriously ill and exhibited more severe systemic inflammation, a higher prevalence of multiple organ dysfunction syndrome (MODS) and worse outcomes than the non-DIC patients. Disease severity, systemic inflammation, MODS and the mortality rate worsened in accordance with an increased JAAM DIC score on day 1. The Kaplan-Meier curves demonstrated lower 1-year survival in the JAAM DIC patients than in those without DIC (log-rank test P<0.001). The JAAM DIC score on day 1 (odds ratio=1.282, P<0.001) and the Delta JAAM DIC score (odds ratio=0.770, P<0.001) were independent predictors of 28-day death. Dynamic changes in the JAAM DIC score from days 1 to 4 also affected prognoses. The JAAM DIC scoring system included all patients who met the International Society on Thrombosis and Haemostasis overt DIC criteria on day 1. The International Society on Thrombosis and Haemostasis scoring system missed a large number of nonsurvivors recognized by the JAAM scoring system. The JAAM DIC scoring system exhibits good prognostic value in predicting MODS and poor prognosis in patients with severe sepsis and can detect more patients requiring treatment. Conducting repeated daily JAAM scoring increases the ability to predict the patient's prognosis.