Reduction of inner retinal thickness in patients with autosomal dominant optic atrophy associated with OPA1 mutations.
To determine the morphologic changes in the retina in the macula and around the optic disc in patients with autosomal dominant optic atrophy (ADOA) associated with a mutation in the OPA1 gene. Cross-sectional images of the macular area of the retina were obtained by optical coherence tomography (OCT) in patients with ADOA who had a heterozygous mutation in the OPA1 gene. There were 15 eyes of eight patients from five families: four men and four women. The average age of the patients was 48.1 years. In the OCT images, the cross sections of the sensory retina were divided manually into four areas. The thickness of the overall sensory retina and the divided areas were measured at 1 and 2 mm on the temporal, nasal, superior, and inferior sides of the fovea as well as at the fovea. The thickness of the retinal nerve fiber layer (RNFL) around the optic discs was measured by taking circular scans (3.4 mm in diameter) centered on the optic disc. The results in the patients with ADOA were compared with those from 11 normal control subjects. The overall thickness of the sensory retina in the macular area was significantly thinner in the patients with ADOA than in the control subjects at all points except the fovea (P < 0.0001). The RNFL in the macular area in the patients with ADOA was significantly thinner than that in control subjects at all points (P < 0.0001), especially at 1 mm from the fovea. The circumpapillary RNFL was significantly thinner at the temporal, superior, and inferior areas in patients with ADOA but not in the nasal area. The total cross-sectional area of the circumpapillary RNFL was significantly correlated with visual acuity. The thickness of the combined ganglion cell layer, inner plexiform layer, inner nuclear layer, and outer plexiform layer in the macular area was significantly thinner in the patients (P < 0.0056). The thickness of the outer nuclear layer and the photoreceptor inner segments and the thickness of the photoreceptor outer segments were not significantly different between the patients with ADOA and normal control subjects. The RNFL and the layer including the ganglion cell layer are significantly thinner in patients with ADOA associated with an OPA1 gene mutation, whereas the photoreceptor layers are not affected morphologically. The inner retina is the main area of the retina altered in ADOA.


Oritavancin for acute bacterial skin and skin structure infections.
Inpatient treatment of acute bacterial skin and skin structure infections (ABSSSIs) exerts a significant economic burden on the healthcare system. Oritavancin is a concentration-dependent, rapid bactericidal agent approved for the treatment of ABSSSIs. Its prolonged half-life with one-time intravenous (i.v.) dosing offers a potential solution to this burden. In addition, oritavancin represents an alternative therapy for Streptococci and multidrug-resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Animal models have also shown promising results with oritavancin for other disease states including those that require long courses of i.v. This review covers oritavancin's basic chemistry, spectrum of activity, pharmacodynamics/pharmacokinetics and efficacy in clinical trials, and provides expert opinion on future directions. To compose this review, a search of PubMed was performed, and articles written in the English language were selected based on full text availability. If oritavancin is proven to be a cost-effective strategy for outpatient treatment and prevents complications of prolonged i.v. therapy, it will be sought as an alternative antibiotic therapy for ABSSSIs. In addition, further clinical data demonstrating efficacy in Gram-positive infections requiring prolonged therapy such as endocarditis and osteomyelitis could support oritavancin's success in the current market.


Nonlinear Memory Capacity of Parallel Time-Delay Reservoir Computers in the Processing of Multidimensional Signals.
This letter addresses the reservoir design problem in the context of delay-based reservoir computers for multidimensional input signals, parallel architectures, and real-time multitasking. First, an approximating reservoir model is presented in those frameworks that provides an explicit functional link between the reservoir architecture and its performance in the execution of a specific task. Second, the inference properties of the ridge regression estimator in the multivariate context are used to assess the impact of finite sample training on the decrease of the reservoir capacity. Finally, an empirical study is conducted that shows the adequacy of the theoretical results with the empirical performances exhibited by various reservoir architectures in the execution of several nonlinear tasks with multidimensional inputs. Our results confirm the robustness properties of the parallel reservoir architecture with respect to task misspecification and parameter choice already documented in the literature.


A Low-Cost, Wireless, 3-D-Printed Custom Armband for sEMG Hand Gesture Recognition.
Wearable technology can be employed to elevate the abilities of humans to perform demanding and complex tasks more efficiently. Armbands capable of surface electromyography (sEMG) are attractive and noninvasive devices from which human intent can be derived by leveraging machine learning. However, the sEMG acquisition systems currently available tend to be prohibitively costly for personal use or sacrifice wearability or signal quality to be more affordable. This work introduces the 3DC Armband designed by the Biomedical Microsystems Laboratory in Laval University; a wireless, 10-channel, 1000 sps, dry-electrode, low-cost (∼150 USD) myoelectric armband that also includes a 9-axis inertial measurement unit. The proposed system is compared with the Myo Armband by Thalmic Labs, one of the most popular sEMG acquisition systems. The comparison is made by employing a new offline dataset featuring 22 able-bodied participants performing eleven hand/wrist gestures while wearing the two armbands simultaneously. The 3DC Armband systematically and significantly ( p < 0.05 ) outperforms the Myo Armband, with three different classifiers employing three different input modalities when using ten seconds or more of training data per gesture. This new dataset, alongside the source code, Altium project and 3-D models are made readily available for download within a Github repository.


Phylogenetic analysis of HIV-1 shows frequent cross-country transmission and local population expansions.
Understanding of pandemics depends on the characterization of pathogen collections from well-defined and demographically diverse cohorts. Since its emergence in Congo almost a century ago, Human Immunodeficiency Virus Type 1 (HIV-1) has geographically spread and genetically diversified into distinct viral subtypes. Phylogenetic analysis can be used to reconstruct the ancestry of the virus to better understand the origin and distribution of subtypes. We sequenced two 3.6-kb amplicons of HIV-1 genomes from 3,197 participants in a clinical trial with consistent and uniform sampling at sites across 35 countries and analyzed our data with another 2,632 genomes that comprehensively reflect the HIV-1 genetic diversity. We used maximum likelihood phylogenetic analysis coupled with geographical information to infer the state of ancestors. The majority of our sequenced genomes (n = 2,501) were either pure subtypes (A-D, F, and G) or CRF01_AE. The diversity and distribution of subtypes across geographical regions differed; USA showed the most homogenous subtype population, whereas African samples were most diverse. We delineated transmission of the four most prevalent subtypes in our dataset (A, B, C, and CRF01_AE), and our results suggest both continuous and frequent transmission of HIV-1 over country borders, as well as single transmission events being the seed of endemic population expansions. Overall, we show that coupling of genetic and geographical information of HIV-1 can be used to understand the origin and spread of pandemic pathogens.


A Roadmap for Understanding the Evolutionary Significance of Structural Genomic Variation.
Structural genomic variants (SVs) are ubiquitous and play a major role in adaptation and speciation. Yet, comparative and population genomics have focused predominantly on gene duplications and large-effect inversions. The lack of a common framework for studying all SVs is hampering progress towards a more systematic assessment of their evolutionary significance. Here we (i) review how different types of SVs affect ecological and evolutionary processes; (ii) suggest unifying definitions and recommendations for future studies; and (iii) provide a roadmap for the integration of SVs in ecoevolutionary studies. In doing so, we lay the foundation for population genomics, theoretical, and experimental approaches to understand how the full spectrum of SVs impacts ecological and evolutionary processes.


Renal-cell carcinoma-specific lysis by cytotoxic T-lymphocyte clones isolated from peripheral blood lymphocytes and tumor-infiltrating lymphocytes.
Melanoma and renal-cell carcinoma (RCC) are generally considered to be relatively immunogenic tumor types in humans. In the case of melanoma, many major histocompatibility complex (MHC) class I-restricted tumor-specific cytotoxic T lymphocytes (CTL) have been isolated from either tumor-infiltrating lymphocytes (TIL) or autologous peripheral blood lymphocytes (PBL). In contrast, such CTL have only incidentally been described in the case of RCC. It has often been reported that TIL lines isolated from RCC display non-MHC-restricted and non-specific activity. Here, we report the isolation and characterization of tumor-specific CTL from PBL of one RCC patient and from TIL of another RCC patient. CTL clones 263/17 and 263/45, isolated from the PBL of patient LE-9211, were restricted by HLA-B7. CTL clone 5E, isolated from the TIL of patient LE-8915, was restricted by HLA-B37. The autologous RCC cell lines were efficiently lysed by the CTL clones, whereas normal epithelial cells of the proximal tubuli matched for the restriction element and K562 were not. From a panel of allogeneic RCC cell lines, CTL 5E recognized MZ-1940-RCC. Reactivity to allogeneic RCC sharing HLA-B7 was also observed with CTL 263/17 and 263/45, both of which could lyse the HLA-B7-positive cell line MZ-1851-RCC. Our data provide evidence that common tumor antigens are recognized by CTL on RCC.


Role of physician perception of patient smile on pretest probability assessment for acute pulmonary embolism.
Many clinicians use a global visual interpretation of patient appearance to decide if a patient looks sick or not. For patients with suspected acute pulmonary embolism (PE), we tested the relationship between visual appearance of a happy patient facial affect and probability of PE+ on CT pulmonary angiography (CTPA). Eligible patients were selected by usual care to undergo CTPA, the criterion standard for PE+ or PE-. Prior to CTPA result, trained study personnel obtained physician pretest probability using the gestalt method (visual analogue scale, 0%-100%), the Wells score (0-12) and physicians' impression of whether the patient smiled during the initial examination (smile+). Patients' faces were also video recorded and analysed with an automated neural network-based algorithm (Noldus FaceReader) for happy affect. Of the 208 patients enrolled, 27 were PE+ and smile+ was more frequent in patients with PE+ than PE-, a finding confirmed by the Noldus. The diagnostic sensitivity and specificity of smile was low, and physicians overestimated presence of an alternative diagnosis more likely to PE with smile+ than smile- patients in patients with true PE. As a result, the area under the receiver operating characteristic curve (AUROC) was lower for the Wells score in smile+ patients. However, the physicians' mean gestalt estimate of PE did not differ with smile status, nor did smile status affect the AUROC for gestalt. In patients with suspected PE, physician recollection of patients' smile+ was more common in PE+ patients, and was associated with a less accurate Wells score, primarily because physicians overestimated probability of alternative diagnosis. However, the overall diagnostic accuracy of physicians' gestalt did not differ with perceived smile status. These data suggest that the patients' smile had less effect on the numeric gestalt pretest probability assessment than on the binary decision about an alternative diagnosis.


COVID-19: Current understanding of its Pathophysiology, Clinical presentation and Treatment.
The severe acute respiratory syndrome (SARS) coronavirus-2 is a novel coronavirus belonging to the family Coronaviridae and is now known to be responsible for the outbreak of a series of recent acute atypical respiratory infections originating in Wuhan, China. The disease caused by this virus, termed coronavirus disease 19 or simply COVID-19, has rapidly spread throughout the world at an alarming pace and has been declared a pandemic by the WHO on March 11, 2020. In this review, an update on the pathophysiology, clinical presentation and the most recent management strategies for COVID-19 has been described. A search was conducted for literature and various articles/case reports from 1997 to 2020 in PUBMED/MEDLINE for the keywords coronavirus, SARS, Middle East respiratory syndrome and mRNA virus. COVID-19 has now spread globally with increasing morbidity and mortality among all populations. In the absence of a proper and effective antibody test, the diagnosis is presently based on a reverse-transcription PCR of nasopharyngeal and oropharyngeal swab samples. The clinical spectrum of the disease presents in the form of a mild, moderate or severe illness. Most patients are either asymptomatic carriers who despite being without symptoms have the potential to be infectious to others coming in close contact, or have a mild influenza-like illness which cannot be differentiated from a simple upper respiratory tract infection. Moderate and severe cases require hospitalisation as well as intensive therapy which includes non-invasive as well as invasive ventilation, along with antipyretics, antivirals, antibiotics and steroids. Complicated cases may require treatment by immunomodulatory drugs and plasma exchange therapy. The search for an effective vaccine for COVID-19 is presently in full swing, with pharmaceutical corporations having started human trials in many countries.


Interaction of saliva and taste.
In spite of the coexistence of saliva and taste in the oral cavity, an understanding of their interactions is still incomplete. Saliva has modulating effects on sour, salt, and the monosodium-glutamate-induced savory or umami taste. It has a diminishing effect on sour taste as a result of the buffering by salivary bicarbonate. It probably also contributes to the umami taste with endogenous salivary glutamate levels. Salt taste is detected only when above salivary sodium-chloride concentrations; thus saliva influences salt taste threshold levels. It also provides the ionic environment for taste cells, probably critical in signal transduction. Salivary flow rate and composition are influenced by the type of taste stimuli. In general, sour taste, elicited by citric acid or sour food, induces the highest flow rate and Na+ concentrations, while salt gives rise to high protein and Ca2+ concentrations. Stimulation with the four basic taste modalities (sour, sweet, salty, and bitter), however, does not increase the relative proportion of any of the salivary proteins. This review examines the literature on the interactions of saliva with taste, and the effect of taste on salivary composition. The possible role of the von Ebner's salivary glands and the role of saliva as a chemical cue are also discussed.


Model-Based Methods to Translate Adolescent Medicine Trials Network for HIV/AIDS Interventions Findings Into Policy Recommendations: Rationale and Protocol for a Modeling Core (ATN 161).
The United States Centers for Disease Control and Prevention estimates that approximately 60,000 US youth are living with HIV. US youth living with HIV (YLWH) have poorer outcomes compared with adults, including lower rates of diagnosis, engagement, retention, and virologic suppression. With Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) support, new trials of youth-centered interventions to improve retention in care and medication adherence among YLWH are underway. This study aimed to use a computer simulation model, the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Adolescent Model, to evaluate selected ongoing and forthcoming ATN interventions to improve viral load suppression among YLWH and to define the benchmarks for uptake, effectiveness, durability of effect, and cost that will make these interventions clinically beneficial and cost-effective. This protocol, ATN 161, establishes the ATN Modeling Core. The Modeling Core leverages extensive data-already collected by successfully completed National Institutes of Health-supported studies-to develop novel approaches for modeling critical components of HIV disease and care in YLWH. As new data emerge from ongoing ATN trials during the award period about the effectiveness of novel interventions, the CEPAC-Adolescent simulation model will serve as a flexible tool to project their long-term clinical impact and cost-effectiveness. The Modeling Core will derive model input parameters and create a model structure that reflects key aspects of HIV acquisition, progression, and treatment in YLWH. The ATN Modeling Core Steering Committee, with guidance from ATN leadership and scientific experts, will select and prioritize specific model-based analyses as well as provide feedback on derivation of model input parameters and model assumptions. Project-specific teams will help frame research questions for model-based analyses as well as provide feedback regarding project-specific inputs, results, sensitivity analyses, and policy conclusions. This project was funded as of September 2017. The ATN Modeling Core will provide critical information to guide the scale-up of ATN interventions and the translation of ATN data into policy recommendations for YLWH in the United States.


Barriers to occupational heat stress risk adaptation of mining workers in Ghana.
Increasing temperature and climate warming impacts are aggravating the vulnerability of workers to occupational heat stress. Adaptation and social protection strategies have become crucial to enhance workers' health, safety, productive capacity and social lives. However, the effective implementation of work-related heat stress adaptation mechanisms appears to be receiving little attention. This study assessed the barriers to occupational heat stress adaptation and social protection strategies of mining workers in Ghana. Based on a mixed methods approach, focus group discussions and questionnaires were used to elicit data from 320 mining workers. Workers' adaptation strategies (water intake, wearing loose and light-coloured clothing, participating in training programmes, taking regular breaks, use of mechanical equipment, use of cooling systems and housing designs) varied significantly across the type of mining activity (p < .001). Workers' social protection measures were adequate. The disparities in workers' social protection measures significantly differed across the type of mining activity (p < .001). Barriers of workers to the implementation of relevant adaptation strategies (inadequate knowledge of coping and adaptive behaviour, lack of regular training on adaptation measures, lack of specific heat-related policy regulations, lack of management commitment and the lack of access to innovative technology and equipment) also differed across the type of mining activity (p < .001). Adaptation policy options and recommendations centred on overcoming the barriers that constrain the adaptive capacity of workers and employers have the potential to reduce workers' vulnerability to occupational heat stress.


Effects of simvastatin in prevention of pain recurrences after surgery for endometriosis.
To compare efficacy of simvastatin with GnRHa (Decapeptyl 3.75 mg) on endometriosis-related pains following surgery for endometriosis. Sixty women with pelvic endometriosis, after laparoscopic diagnosis and conservative laparoscopic surgery, were treated with either simvastatin (n=30) for 16 weeks or Decapeptyl (n=30) every 4 weeks for 4 doses. Using VAS, the score of dyspareunia, dysmenorrhea, and pelvic pain 6 months after laparoscopic surgery declined significantly in both groups (p=0.001), but the difference between results of the 2 groups was not significant (p>0.05). Both treatment modalities showed comparable effectiveness in the treatment of pains related to endometriosis.


A novel reconfigurable optical interconnect architecture using an Opto-VLSI processor and a 4-f imaging system.
A novel reconfigurable optical interconnect architecture for on-board high-speed data transmission is proposed and experimentally demonstrated. The interconnect architecture is based on the use of an Opto-VLSI processor in conjunction with a 4-f imaging system to achieve reconfigurable chip-to-chip or board-to-board data communications. By reconfiguring the phase hologram of an Opto-VLSI processor, optical data generated by a vertical Cavity Surface Emitting Laser (VCSEL) associated to a chip (or a board) is arbitrarily steered to the photodetector associated to another chip (or another board). Experimental results show that the optical interconnect losses range from 5.8dB to 9.6dB, and that the maximum crosstalk level is below -36dB. The proposed architecture is tested for high-speed data transmission, and measured eye diagrams display good eye opening for data rate of up to 10Gb/s.


Assessing mathematical models of influenza infections using features of the immune response.
The role of the host immune response in determining the severity and duration of an influenza infection is still unclear. In order to identify severity factors and more accurately predict the course of an influenza infection within a human host, an understanding of the impact of host factors on the infection process is required. Despite the lack of sufficiently diverse experimental data describing the time course of the various immune response components, published mathematical models were constructed from limited human or animal data using various strategies and simplifying assumptions. To assess the validity of these models, we assemble previously published experimental data of the dynamics and role of cytotoxic T lymphocytes, antibodies, and interferon and determined qualitative key features of their effect that should be captured by mathematical models. We test these existing models by confronting them with experimental data and find that no single model agrees completely with the variety of influenza viral kinetics responses observed experimentally when various immune response components are suppressed. Our analysis highlights the strong and weak points of each mathematical model and highlights areas where additional experimental data could elucidate specific mechanisms, constrain model design, and complete our understanding of the immune response to influenza.


A genetic analysis of in vivo selenate reduction by Salmonella enterica serovar Typhimurium LT2 and Escherichia coli K12.
The twin-arginine transport (Tat) system is dedicated to the translocation of folded proteins across the bacterial cytoplasmic membrane. Proteins are targeted to the Tat system by signal peptides containing a twin-arginine motif. In Salmonella enterica serovar Typhimurium and Escherichia coli many Tat substrates are known or predicted to bind a molybdenum cofactor in the cytoplasm prior to export. In the case of N- and S-oxide reductases, co-ordination of molybdenum cofactor insertion with protein export involves a 'Tat proofreading' process where chaperones of the TorD family bind the signal peptides, thus preventing premature export. Here, a genetic approach was taken to determine factors required for selenate reductase activity in Salmonella and E. coli. It is reported for both biological systems that an active Tat translocase and a TorD-like chaperone (DmsD) are required for complete in vivo reduction of selenate to elemental red selenium. Further mutagenesis and in vitro biophysical experiments implicate the Salmonella ynfE gene product, and the E. coli YnfE and YnfF proteins, as putative Tat-targeted selenate reductases.


Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states.
The tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel SNS/PN3 and the newly discovered NaN/SNS2 are expressed in sensory neurones, particularly in nociceptors. Using specific antibodies, we have studied, for the first time in humans, the presence of SNS/PN3 and NaN/SNS2 in peripheral nerves, including tissues from patients with chronic neurogenic pain. In brachial plexus injury patients, there was an acute decrease of SNS/PN3- and NaN/SNS2-like immunoreactivity in sensory cell bodies of cervical dorsal root ganglia (DRG) whose central axons had been avulsed from spinal cord, with gradual return of the immunoreactivity to control levels over months. In contrast, there was increased intensity of immunoreactivity to both channels in some peripheral nerve fibers just proximal to the site of injury in brachial plexus trunks, and in neuromas. These findings suggest that the expression of these sodium channels in neuronal cell bodies is reduced after spinal cord root avulsion injury in man, but that pre-synthesized channel proteins may undergo translocation with accumulation at sites of nerve injury, as in animal models of peripheral axotomy. The latter may contribute to positive symptoms, as our patients all showed a positive Tinel's sign. Nerve terminals in distal limb neuromas and skin from patients with chronic local hyperalgesia and allodynia all showed marked increases of SNS/PN3-immunoreactive fibers, but little or no NaN/SNS2-immunoreactivity, suggesting that the former may be related to the persistent hypersensitive state. Axonal immunoreactivity to both channels was similar to control nerves in sural nerve biopsies in a selection of neuropathies, irrespective of nerve inflammation, demyelination or spontaneous pain, including a patient with congenital insensitivity to pain. Our studies suggest that the best target for SNS/PN3 blocking agents is likely to be chronic local hypersensitivity.


Assessment of endothelialization of aneurysm wall over time in a rabbit model through CD31 scoring.
Intracranial aneurysms represent a significant health concern and are poorly understood despite decades of research. Our study focused on understanding temporal patterns of endothelial cell distribution in different spatial locations within the aneurysm early after creation in a rabbit model. Elastase induced saccular aneurysms were created in rabbits and harvested on day 1 (n=3) and after 2 (n=5), 4 (n=4), 8 (n=5), and 12 (n=6) weeks. Sham operated controls (n=3) were harvested on the same day. Aneurysm and control tissue samples were subjected to en face whole mount CD31 staining for endothelial cells. Semiquantitative scoring was performed on the basis of endothelial coverage of the vessel wall (proximal, middle, and distal portions of the aneurysm dome). Mixed effects models were used to assess the effect of time and aneurysm section on endothelial coverage. Aneurysmal segments were near completely de-endothelialized at 4 and 8 weeks but had re-endothelialized by 12 weeks. Compared with controls, aneurysms at all time points showed decreased endothelialization, but the difference was only significant compared with the 4 and 8 week groups. Both time (P=0.03) and aneurysm section (P=0.07) were significantly associated with the degree of endothelialization. Proximal locations showed increased endothelialization compared with distal locations (P=0.03). In experimental aneurysms of rabbits, endothelial cells regress during the first month after creation, followed by ascending re-endothelialization that stays incomplete. These findings suggest that re-population of endothelial cells comes from resident cells in the adjacent parent artery and that deranged hemodynamics may affect full reconstitution of endothelial cells long term.


Cryogenic optical testing of an 800 mm lightweight C/SiC composite mirror mounted on a C/SiC optical bench.
We tested the optical performance at cryogenic temperatures of an 800 mm diameter lightweight mirror, consisting of carbon-fiber reinforced silicon carbide and with a mass of 11.2 kg. The ceramic composite of the mirror was HB-Cesic, developed by ECM, Germany, and Mitsubishi Electric Corporation, Japan. The test was carried out while the mirror was mounted, via Invar stress relief supports, on a lightweight optical bench also made of HB-Cesic. During the test, both the mirror and the optical bench were cooled to 18 K in a liquid-helium chamber. The test consisted of measuring the mirror's change of surface figure with an interferometer installed outside the cryo-chamber. The cryogenic deformation of the mirror was 110 nm RMS with no significant residual deformation after cooling, which is very promising for the applicability of the HB-Cesic composite to large lightweight cryogenic space optics.


A major DNA binding protein encoded by BALF2 open reading frame of Epstein-Barr virus (EBV) forms a complex with other EBV DNA-binding proteins: DNAase, EA-D, and DNA polymerase.
A major 135-kDa DNA binding protein (mDBP) encoded by the BALF2 open reading frame of Epstein-Barr Virus (EBV) is known to be an essential protein for the induction of the lytic cycle. The present investigation was carried out to know whether this protein forms a complex in vivo with other viral DNA binding proteins (DBP) involved in DNA replication: DNA polymerase, EA-D (diffused early antigen), and DNAase. Immunoprecipitation assays followed by mono- and two-dimensional electrophoresis showed that mDBP forms a complex with these three DBP. Other complexes were also found such as EA-D/DNAase, DNA polymerase/DNAase, and DNA polymerase/EA-D. The complexed forms already exist in the early stage of EBV cycle before DNA synthesis is induced in the EBV producer P3HR-1 cell line. The exonuclease activity encoded by DNAase was found to be inhibited when this enzyme complexed with mDBP, while the EBV DNA polymerase retained its activity in the complexed form with mDBP. Our results suggest that these complexes already present before DNA synthesis are necessary for EBV DNA synthesis.


Factors predicting the recurrence of spontaneous bacterial peritonitis in patients with cirrhosis.
To evaluate the frequency of recurrence of spontaneous bacterial peritonitis (SBP) in patients with end stage liver disease and the factors responsible for it. Descriptive study. The Aga Khan University Hospital, Karachi, from November 2008 till November 2009. Patients with cirrhosis who were admitted at AKUH with diagnosis of SBP during the study period were included. Any episode of SBP after resolution of the first index case of SBP within one year was considered as recurrence. Out of 238 cirrhotic patients, 157 (66%) had single, while 81 (34%) had recurrent episodes of SBP. History of using proton pump inhibitors (PPI) and diuretics was found in 113 (47.5%) and 139 (58.4%) patients respectively. Only 58 24.4%) patients were on prophylactic antibiotic therapy. Univariate analysis revealed that the female gender (52%), and presence of porto-systemic encephalopathy (PSE, 31%) were statistically significant (p=0.03) among those who had recurrent SBP. On multivariate analysis bilirubin level of > 1.0 mg (OR=7.03; 95%CI=1.55-32), protective factor of hepatitis B (OR 0.31; 95%CI=0.13-0.70) and presence of urinary tract infection (UTI) (OR=2.24; 95%CI=0.99-5.09) were significant in patients with recurrent SBP. Recurrent SBP was noticed in 34% patients. Serum bilirubin level of > 1.0 mg, protective factor of HBV and presence of UTI were significant factors present in patients with recurrent SBP.


The Contribution of Germline Predisposition Gene Mutations to Clinical Subtypes of Invasive Breast Cancer From a Clinical Genetic Testing Cohort.
The germline cancer predisposition genes associated with increased risk of each clinical subtype of breast cancer, defined by estrogen receptor (ER), progesterone receptor (PR), and HER2, are not well defined. A total of 54 555 invasive breast cancer patients with 56 480 breast tumors were subjected to clinical hereditary cancer multigene panel testing. Heterogeneity for predisposition genes across clinical breast cancer subtypes was assessed by comparing mutation frequencies by gene among tumor subtypes and by association studies between each tumor subtype and reference controls. Mutations in 15 cancer predisposition genes were detected in 8.6% of patients with ER+/HER2-; 8.9% with ER+/HER2+; 7.7% with ER-/HER2+; and 14.4% of ER-/PR-/HER2- tumors. BRCA1, BRCA2, BARD1, and PALB2 mutations were enriched in ER- and HER2- tumors; RAD51C and RAD51D mutations were enriched in ER- tumors only; TP53 mutations were enriched in HER2+ tumors, and ATM and CHEK2 mutations were enriched in both ER+ and/or HER2+ tumors. All genes were associated with moderate (odds ratio > 2.00) or strong (odds ratio > 5.00) risks of at least one subtype of breast cancer in case-control analyses. Mutations in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53 had predicted lifetime absolute risks of at least 20.0% for breast cancer. Germline mutations in hereditary cancer panel genes confer subtype-specific risks of breast cancer. Combined tumor subtype, age at breast cancer diagnosis, and family history of breast and/or ovarian cancer information provides refined categorical estimates of mutation prevalence for women considering genetic testing.


Relationships among biomechanical ergonomic factors, handwriting product quality, handwriting efficiency, and computerized handwriting process measures in children with and without handwriting difficulties.
Handwriting is a work activity for children, hence it may be evaluated based on ergonomic factors. This study investigated whether nonproficient handwriters could be distinguished by biomechanical ergonomic factors during handwriting, as well as by measures of handwriting efficiency. Furthermore, the relationships among ergonomic factors, handwriting quality, efficiency, and measures of the handwriting process were examined. Fifty proficient and 50 nonproficient third-grade handwriters performed a handwriting task on an electronic tablet. Biomechanical ergonomic factors, measures of handwriting quality, and efficiency were rated using the Hebrew Handwriting Evaluation. Handwriting process measures were obtained from a computerized system. Biomechanical ergonomic factors and handwriting efficiency measures significantly differentiated between the study groups. Significant correlations were found among ergonomic factors and handwriting quality, efficiency, and process measures. Nonproficient handwriting is a work activity that is often characterized by inferior biomechanical ergonomics, handwriting quality, efficiency, and significantly different handwriting process measures. Results provide insights that can assist in planning intervention.


Effect of caffeic acid phenethyl ester on myringosclerosis development in the tympanic membrane of rat.
Myringosclerosis is hyalinization and calcification of certain areas of the tympanic membrane, especially the fibrous lamina propria layer and appears as white sclerotic lesions. Ventilation tube insertion is one of the most performed operations in the pediatric otorhinolaryngology practice to treat chronic otitis media with effusion. Myringosclerosis is a very common sequela of ventilation tube insertion. In this experimental study, our aim was to show the histopathological effects of caffeic acid phenethyl ester on myringosclerosis development in rat tympanic membrane after myringotomy. The rats were randomly categorized into four experimental groups including the comparison group (n = 4), non-treated group (n = 7), the saline (control) group (n = 7), the caffeic acid phenethyl ester group (n = 7). Non-treated group did not receive any treatment for 15 days. Saline (2.5 mL/kg, intraperitoneal) was administered to the third group once a day for 15 days. Fourth group received caffeic acid phenethyl ester intraperitoneally once a day at a dose of 10 μmol/kg for 15 days. Myringotomy was performed on the right tympanic membrane of all rats except comparison group using a sterile pick with the help of an operating microscope. Histopathological examination of myringosclerosis formation was done by a pathologist under light microscope. In histopathological analysis of groups, the severity of inflammation was milder in caffeic acid phenethyl ester group compared to non-treated and saline groups (p < 0.05). There was less myringosclerotic plaques in caffeic acid phenethyl ester group than in non-treated and saline groups (p < 0.05). TM thickness measurements were very close to each other in non-treated and saline groups. The tympanic membrane thickness of caffeic acid phenethyl ester group was much thinner than the other two groups (p < 0.05). Caffeic acid phenethyl ester decreases inflammation severity and the formation of myringosclerotic plaques. These two effects resulted in thinner tympanic membranes of rats which were treated with caffeic acid phenethyl ester. As a result, caffeic acid phenethyl ester has potential preventive effects on myringosclerosis development after myringotomy and ventilation tube insertion.


Reliability of an injury scoring system for horses.
The risk of injuries is of major concern when keeping horses in groups and there is a need for a system to record external injuries in a standardised and simple way. The objective of this study, therefore, was to develop and validate a system for injury recording in horses and to test its reliability and feasibility under field conditions. Injuries were classified into five categories according to severity. The scoring system was tested for intra- and inter-observer agreement as well as agreement with a 'golden standard' (diagnosis established by a veterinarian). The scoring was done by 43 agricultural students who classified 40 photographs presented to them twice in a random order, 10 days apart. Attribute agreement analysis was performed using Kendall's coefficient of concordance (Kendall's W), Kendall's correlation coefficient (Kendall's τ) and Fleiss' kappa. The system was also tested on a sample of 100 horses kept in groups where injury location was recorded as well. Intra-observer agreement showed Kendall's W ranging from 0.94 to 0.99 and 86% of observers had kappa values above 0.66 (substantial agreement). Inter-observer agreement had an overall Kendall's W of 0.91 and the mean kappa value was 0.59 (moderate). Agreement for all observers versus the 'golden standard' had Kendall's τ of 0.88 and the mean kappa value was 0.66 (substantial). The system was easy to use for trained persons under field conditions. Injuries of the more serious categories were not found in the field trial. The proposed injury scoring system is easy to learn and use also for people without a veterinary education, it shows high reliability, and it is clinically useful. The injury scoring system could be a valuable tool in future clinical and epidemiological studies.


Associations between seasonal influenza and meteorological parameters in Costa Rica, Honduras and Nicaragua.
Seasonal influenza affects a considerable proportion of the global population each year. We assessed the association between subnational influenza activity and temperature, specific humidity and rainfall in three Central America countries, i.e. Costa Rica, Honduras and Nicaragua. Using virologic data from each country's national influenza centre, rainfall from the Tropical Rainfall Measuring Mission and air temperature and specific humidity data from the Global Land Data Assimilation System, we applied logistic regression methods for each of the five sub-national locations studied. Influenza activity was represented by the weekly proportion of respiratory specimens that tested positive for influenza. The models were adjusted for the potentially confounding co-circulating respiratory viruses, seasonality and previous weeks' influenza activity. We found that influenza activity was proportionally associated (P<0.05) with specific humidity in all locations [odds ratio (OR) 1.21-1.56 per g/kg], while associations with temperature (OR 0.69-0.81 per °C) and rainfall (OR 1.01-1.06 per mm/day) were location-dependent. Among the meteorological parameters, specific humidity had the highest contribution (~3-15%) to the model in all but one location. As model validation, we estimated influenza activity for periods, in which the data was not used in training the models. The correlation coefficients between the estimates and the observed were ≤0.1 in 2 locations and between 0.6-0.86 in three others. In conclusion, our study revealed a proportional association between influenza activity and specific humidity in selected areas from the three Central America countries.


Effects of lithium and valproate on serum and hippocampal neurotrophin-3 levels in an animal model of mania.
It has been demonstrated that lithium (Li) and valproate (VPT), first line mood stabilizers, increase BDNF content in rat hippocampus and frontal cortex, which suggests that the regulation of neurotrophic factors might be associated with their pharmacological effects. In sight of the scarcity of studies with other neurotrophins, and the possible relevance of multiple neurotrophic signaling systems in bipolar disorder we investigated the effects of Li and VPT on NT-3 levels in rat serum and hippocampus, using an animal model of mania induced by amphetamine (AMPH). In the reversal model, adult male Wistar rats received AMPH or saline for 14 days, and between the 8th and 14th days, animals were treated with Li, VPT or saline. In the prevention model, rats were pretreated with Li, VPT or saline, and between the 8th and 14th days, the animals received AMPH or saline. Li increased serum and hippocampal NT-3 levels in all conditions, whereas VPT increased hippocampal NT-3 in the prevention model only. Li reversed AMPH changes in NT-3 in the reversal model, and VPT prevented AMPH changes in NT-3 in the prevention model. These results suggest that both Li and VPT modulate serum and central (hippocampal) NT-3 levels, and further support that the regulation of neurotrophic signaling systems may be related to the mechanisms of action of mood stabilizers.


Inclusion of molecular biotherapies with radical radiotherapy: modeling of combined modality treatment schedules.
The use of molecular biology based therapies concurrently with radical radiotherapy is likely to offer potential benefits, but there is relatively little use of classical radiobiology in the rationale for such applications. The biological mechanisms that govern the outcomes of radiotherapy need to be completely understood before rational application and optimization of such adjuvant biotherapies with radiotherapy. Existing biomathematical models of radiotherapy can be used to explore the possible impact of biotherapies that modify tumor proliferation rates and/or radiosensitivity parameters during radiotherapy. Equations that show how to incorporate biotherapies with the linear-quadratic model of radiation cell kill are presented. Also considered are changes in tumor physiology, such as improved blood flow with enhanced delivery of biotherapy to the tumor cells and accelerated clonogen repopulation during radiotherapy. Monte Carlo random sampling methods are used to simulate these effects in heterogenous tumor populations with variation in radiosensitivities, clonogen numbers, and doubling times, as well as variations in repopulation onset rates and in vascular perfusion rates with time. The time onset and duration of exposure of each type of biotherapy during radical radiotherapy can influence the predicted tumor cure probabilities in subtle ways. In general, the efficacy of biotherapies that radiosensitize will depend upon the number of radiotherapy fractions that are sensitized and the change in blood flow with time during radiotherapy. Biotherapies that control repopulation will depend not only on the duration of exposure but also, where accelerated repopulation occurs, on the time at which biotherapy is initiated during radiotherapy. From the ranges of radiobiological parameters and biotherapy efficacies assumed for exploratory examples, large changes of tumor control probability (TCP) are encountered in individual tumors from the application of cytostatic therapy. There are predictions of smaller increments in TCP in heterogenous tumor populations from the application of cytostatic and radiosensitizing biotherapies in combination. The exercises show how the scheduling of biotherapies may critically influence tumor cure probabilities in subtle ways and give considerable insight into the interacting biological mechanisms that influence these changes. Future therapeutic developments should be guided by these principles.


Breaking the waves: modelling the potential impact of public health measures to defer the epidemic peak of novel influenza A/H1N1.
On June 11, 2009, the World Health Organization declared phase 6 of the novel influenza A/H1N1 pandemic. Although by the end of September 2009, the novel virus had been reported from all continents, the impact in most countries of the northern hemisphere has been limited. The return of the virus in a second wave would encounter populations that are still nonimmune and not vaccinated yet. We modelled the effect of control strategies to reduce the spread with the goal to defer the epidemic wave in a country where it is detected in a very early stage. We constructed a deterministic SEIR model using the age distribution and size of the population of Germany based on the observed number of imported cases and the early findings for the epidemiologic characteristics described by Fraser (Science, 2009). We propose a two-step control strategy with an initial effort to trace, quarantine, and selectively give prophylactic treatment to contacts of the first 100 to 500 cases. In the second step, the same measures are focused on the households of the next 5,000 to 10,000 cases. As a result, the peak of the epidemic could be delayed up to 7.6 weeks if up to 30% of cases are detected. However, the cumulative attack rates would not change. Necessary doses of antivirals would be less than the number of treatment courses for 0.1% of the population. In a sensitivity analysis, both case detection rate and the variation of R0 have major effects on the resulting delay. Control strategies that reduce the spread of the disease during the early phase of a pandemic wave may lead to a substantial delay of the epidemic. Since prophylactic treatment is only offered to the contacts of the first 10,000 cases, the amount of antivirals needed is still very limited.


Nursing students' perspectives on the patient and the impact of the nursing culture: a meta-synthesis.
To explore and interpret how nursing students develop their understanding of the patient as a human being. Understanding the patient is the main characteristic of good, caring performance. In addition, nurse leaders play an active role in creating a culture in which nursing students can flourish and improve. This meta-synthesis was based on Noblit and Hare's meta-ethnography. The overarching metaphor was interpreted as the nursing students' capacity for compassion. Two central metaphors were revealed, based on how nursing students developed their understanding of the patient as a human being. These central metaphors were labelled 'The open door', comprising seven key metaphors and 'The closed door' based on two key metaphors. During practical training, the students observed both virtuous and unkind nurses. Virtue is a skill that can be taught, but not all students were able to learn it. Some students acquired the ability to reflect on ethical issues, while others did not. Therefore, good role models are of major importance. The nurse leader should function as a facilitator in the students' efforts to gain the capacity to face the suffering patient and to develop an understanding of the patient's situation.


Gender Differences in the Clinical Features of Sleep Apnea Syndrome.
Objective Sleep apnea syndrome is more prevalent among men than women and is frequently accompanied by metabolic syndrome (MetS). However, gender differences in the effect of sleep-disordered breathing (SDB) leading to the risk of MetS remain unclear. The aim of our study was to investigate the clinical characteristics of SDB in women and the differential influence of SDB on MetS between genders. Methods In a single-center retrospective study, we compared the data of 1,809 consecutive SDB patients by gender to clarify the characteristics of sleep disorders in women. We also compared the prevalence of MetS and its related abnormalities by gender. A logistic regression analysis was used to determine the contributory factors for MetS. Results The mean age and proportion of patients over 50 years of age were higher in women than in men. SDB was milder in women than in men according to polysomnography findings. Elevated Hemoglobin A1c levels and hyperlipidemia were less frequent in women than in men. The MetS prevalence was similar in women and men (30.0% vs. 35.2%). A logistic regression analysis showed that the apnea-hypopnea index (AHI) was an independent risk factor for MetS in both genders, but that female gender was independently associated with a decreased prevalence of MetS and its related abnormalities. Conclusion Female SDB patients tend to be older with milder apnea and sleepiness than male SDB patients. A higher AHI is a significant risk factor for MetS in both genders, although female gender is an independent inhibitory factor for developing MetS in SDB patients.


Redesigning Residency Training: Summary Findings From the Preparing the Personal Physician for Practice (P4) Project.
The Preparing the Personal Physician for Practice (P4) project (2007 to 2014) involved a comparative case study of experiments conducted by 14 selected family medicine programs designed to evaluate new models of residency education that aligned with the patient-centered medical home (PCMH). Changes in length, structure, content, and location of training were studied. We conducted both a critical review of P4 published Evaluation Center and site-specific papers and a qualitative narrative analysis of process reports compiled throughout the project. We mapped key findings from P4 to results obtained from a survey of program directors on their top 10 "need to know" areas in family medicine education. Collectively, 830 unique residents took part in P4, which explored 80 hypotheses regarding 44 innovations. To date, 39 papers have resulted from P4 work, with the P4 Evaluation Center producing 17 manuscripts and faculty at individual sites producing 22 manuscripts. P4 investigators delivered 21 presentations and faculty from P4 participating programs delivered 133 presentations at national meetings. For brevity, we present findings derived from the analyses of project findings according to the following categories: (1) how residency training aligned with PCMH; (2) educational redesign and assessment; (3) methods of financing new residency experiences; (4) length of training; (5) scope of practice; and (6) setting standards for conducting multisite educational research. The P4 project was a successful model for multisite graduate medical education research. Insights gained from the P4 project could help family medicine educators with future residency program redesign.


Predicting the chances of having a baby with or without treatment at different time points in couples with unexplained subfertility.
Can we develop a prediction model that can estimate the chances of conception leading to live birth with and without treatment at different points in time in couples with unexplained subfertility? Yes, a dynamic model was developed that predicted the probability of conceiving under expectant management and following active treatments (in vitro fertilisation (IVF), intrauterine insemination with ovarian stimulation (IUI + SO), clomiphene) at different points in time since diagnosis. Couples with no identified cause for their subfertility continue to have a realistic chance of conceiving naturally, which makes it difficult for clinicians to decide when to intervene. Previous fertility prediction models have attempted to address this by separately estimating either the chances of natural conception or the chances of conception following certain treatments. These models only make predictions at a single point in time and are therefore inadequate for informing continued decision-making at subsequent consultations. A population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011. A dynamic prediction model was developed that estimates the chances of conception within 6 months from the point when a diagnosis of unexplained subfertility was made. These predictions were recomputed each month to provide a dynamic assessment of the individualised chances of conception while taking account of treatment status in each month. Conception must have led to live birth and treatments included clomiphene, IUI + SO, and IVF. Predictions for natural conception were externally validated using a prospective cohort from The Netherlands. A total of 554 (42%) couples started fertility treatment within 2 years of their first fertility consultation. The natural conception leading to live birth rate was 0.24 natural conceptions per couple per year. Active treatment had a higher chance of conception compared to those who remained under expectant management. This association ranged from weak with clomiphene to strong with IVF [clomiphene, hazard ratio (HR) = 1.42 (95% confidence interval, 1.05 to 1.91); IUI + SO, HR = 2.90 (2.06 to 4.08); IVF, HR = 5.09 (4.04 to 6.40)]. Female age and duration of subfertility were significant predictors, without clear interaction with the relative effect of treatment. We were unable to adjust for other potentially important predictors, e.g. measures of ovarian reserve, which were not available in the linked Grampian dataset that may have made predictions more specific. This study was conducted using single centre data meaning that it may not be generalizable to other centres. However, the model performed as well as previous models in reproductive medicine when externally validated using the Dutch cohort. For the first time, it is possible to estimate the chances of conception following expectant management and different fertility treatments over time in couples with unexplained subfertility. This information will help inform couples and their clinicians of their likely chances of success, which may help manage expectations, not only at diagnostic workup completion but also throughout their fertility journey. This work was supported by a Chief Scientist Office postdoctoral training fellowship in health services research and health of the public research (ref PDF/12/06). B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck, and Guerbet. None of the other authors declare any conflicts of interest.


Improved generation of rat gene knockouts by target-selected mutagenesis in mismatch repair-deficient animals.
The laboratory rat (Rattus norvegicus) is one of the preferred model organisms in physiological and pharmacological research, although the availability of specific genetic models, especially gene knockouts, is limited. N-ethyl-N-nitrosourea (ENU)-driven target-selected mutagenesis is currently the most successful method in rats, although it is still very laborious and expensive. As ENU-induced DNA damage is normally recognized by the mismatch repair (MMR) system, we hypothesized that the effectiveness of the target-selected mutagenesis approach could be improved by using a MMR-deficient genetic background. Indeed, Msh6 knockout rats were found to be more sensitive to ENU treatment and the germ line mutation rate was boosted more than two-fold to 1 mutation per 585 kb. In addition, the molecular mutation spectrum was found to be changed in favor of generating knockout-type alleles by approximately 20%, resulting in an overall increase in efficiency of approximately 2.5 fold. The improved effectiveness was demonstrated by high throughput mutation discovery in 70 Mb of sequence in a set of only 310 mutant F1 rats. This resulted in the identification of 89 mutations of which four introduced a premature stopcodon and 64 resulted in amino acid changes. Taken together, we show that the use of a MMR-deficient background considerably improves ENU-driven target-selected mutagenesis in the rat, thereby reducing animal use as well as screening costs. The use of a mismatch repair-deficient genetic background for improving mutagenesis and target-selected knockout efficiency is in principle applicable to any organism of interest.


Neuron loss and dysfunctionality in hippocampus explain aircraft noise induced working memory impairment: a resting-state fMRI study on military pilots.
Long-term aircraft noise exposure may cast a detrimental effect upon the working memory of military pilots, and the brain structural and functional bases of noise related cognitive impairment remains unclear. In this study, we enrolled 30 fighter jet pilots and 30 matched controls. The working memory performance of the subjects was measured with a neurobehavioral test battery including immediate verbal/visual memory and delayed verbal/visual memory tests. Structural MRI and resting-state functional magnetic resonance imaging (rs-fMRI) were utilized to quantify brain grey matter volumes (GMV), regional homogeneity (ReHo), amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) differences between the two groups. Furthermore, correlation analyses were performed to find the association between the neural imaging changes with individual neurobehavioral performance. The military pilots showed significantly lower accuracy in delayed verbal and visual memory tests in comparison to the controls, indicating a potential working memory deficit in this population. Structural MRI data and rs-fMRI data showed that the pilots displayed markedly decreased GMVs, ReHo and ALFF signals in the left hippocampus, suggesting neuron dysfunction of the hippocampus. Besides, ReHo and ALFF/fALFF analysis also revealed reduced ReHo in the left amygdala, left thalamus, left superior temporal gyrus and right superior/middle frontal gyrus, indicating disrupted local neural activity under chronic noise exposure. Furthermore, Spearman correlation analysis proved that the GMV and ReHo of left hippocampus were significantly associated with working memory accuracy. This study provided direct evidence of dysfunctional hippocampus serving as the structural and functional bases for neuropsychological impairment under aircraft noise exposure.


Health care outcomes and advance care planning in older adults who receive home-based palliative care: a pilot cohort study.
Approximately 20% of seniors live with five or more chronic medical illnesses. Terminal stages of their lives are often characterized by repeated burdensome hospitalizations and advance care directives are insufficiently addressed. This study reports on the preliminary results of a Palliative Care Homebound Program (PCHP) at the Mayo Clinic in Rochester, Minnesota to service these vulnerable populations. The study objective was to evaluate inpatient hospital utilization and the adequacy of advance care planning in patients who receive home-based palliative care. This is a retrospective pilot cohort study of patients enrolled in the PCHP between September 2012 and March 2013. Two control patients were matched to each intervention patient by propensity scoring methods that factor in risk and prognosis. Primary outcomes were six-month hospital utilization including ER visits. Secondary outcomes evaluated advance care directive completion and overall mortality. Patients enrolled in the PCHP group (n = 54) were matched to 108 controls with an average age of 87 years. Ninety-two percent of controls and 33% of PCHP patients were admitted to the hospital at least once. The average number of hospital admissions was 1.36 per patient for controls versus 0.35 in the PCHP (p < 0.001). Total hospital days were reduced by 5.13 days. There was no difference between rates of ER visits. Advanced care directive were completed more often in the intervention group (98%) as compared to controls (31%), with p < 0.001. Goals of care discussions were held at least once for all patients in the PCHP group, compared to 41% in the controls.


Specialty and full-service hospitals: a comparative cost analysis.
To compare the costs of physician-owned cardiac, orthopedic, and surgical single specialty hospitals with those of full-service hospital competitors. The primary data sources are the Medicare Cost Reports for 1998-2004 and hospital inpatient discharge data for three of the states where single specialty hospitals are most prevalent, Texas, California, and Arizona. The latter were obtained from the Texas Department of State Health Services, the California Office of Statewide Health Planning and Development, and the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project. Additional data comes from the American Hospital Association Annual Survey Database. We identified all physician-owned cardiac, orthopedic, and surgical specialty hospitals in these three states as well as all full-service acute care hospitals serving the same market areas, defined using Dartmouth Hospital Referral Regions. We estimated a hospital cost function using stochastic frontier regression analysis, and generated hospital specific inefficiency measures. Application of t-tests of significance compared the inefficiency measures of specialty hospitals with those of full-service hospitals to make general comparisons between these classes of hospitals. Results do not provide evidence that specialty hospitals are more efficient than the full-service hospitals with whom they compete. In particular, orthopedic and surgical specialty hospitals appear to have significantly higher levels of cost inefficiency. Cardiac hospitals, however, do not appear to be different from competitors in this respect. Policymakers should not embrace the assumption that physician-owned specialty hospitals produce patient care more efficiently than their full-service hospital competitors.


Identification and Validation of Hematoma Volume Cutoffs in Spontaneous, Supratentorial Deep Intracerebral Hemorrhage.
Background and Purpose- Clinical trials in spontaneous intracerebral hemorrhage (ICH) have used volume cutoffs as inclusion criteria to select populations in which the effects of interventions are likely to be the greatest. However, optimal volume cutoffs for predicting poor outcome in deep locations (thalamus versus basal ganglia) are unknown. Methods- We conducted a 2-phase study to determine ICH volume cutoffs for poor outcome (modified Rankin Scale score of 4-6) in the thalamus and basal ganglia. Cutoffs with optimal sensitivity and specificity for poor outcome were identified in the ERICH ([Ethnic/Racial Variations of ICH] study; derivation cohort) using receiver operating characteristic curves. The cutoffs were then validated in the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) by comparing the c-statistic of regression models for outcome (including dichotomized volume) in the validation cohort. Results- Of the 3000 patients enrolled in ERICH, 1564 (52%) had deep ICH, of whom 1305 (84%) had complete neuroimaging and outcome data (660 thalamic and 645 basal ganglia hemorrhages). Receiver operating characteristic curve analysis identified 8 mL in thalamic (area under the curve, 0.79; sensitivity, 73%; specificity, 78%) and 18 mL in basal ganglia ICH (area under the curve, 0.79; sensitivity, 70%; specificity, 83%) as optimal cutoffs for predicting poor outcome. The validation cohort included 834 (84%) patients with deep ICH and complete neuroimaging data enrolled in ATACH-2 (353 thalamic and 431 basal ganglia hemorrhages). In thalamic ICH, the c-statistic of the multivariable outcome model including dichotomized ICH volume was 0.80 (95% CI, 0.75-0.85) in the validation cohort. For basal ganglia ICH, the c-statistic was 0.81 (95% CI, 0.76-0.85) in the validation cohort. Conclusions- Optimal hematoma volume cutoffs for predicting poor outcome in deep ICH vary by the specific deep brain nucleus involved. Utilization of location-specific volume cutoffs may improve clinical trial design by targeting deep ICH patients that will obtain maximal benefit from candidate therapies.


ATP antagonizes thrombin-induced signal transduction through 12(S)-HETE and cAMP.
In this study we have investigated the role of extracellular ATP on thrombin induced-platelet aggregation (TIPA) in washed human platelets. ATP inhibited TIPA in a dose-dependent manner and this inhibition was abolished by apyrase but not by adenosine deaminase (ADA) and it was reversed by extracellular magnesium. Antagonists of P2Y1 and P2Y12 receptors had no effect on this inhibition suggesting that a P2X receptor controlled ATP-mediated TIPA inhibition. ATP also blocked inositol phosphates (IP1, IP2, IP3) generation and [Ca(2+)]i mobilization induced by thrombin. Thrombin reduced cAMP levels which were restored in the presence of ATP. SQ-22536, an adenylate cyclase (AC) inhibitor, partially reduced the inhibition exerted by ATP on TIPA. 12-lipoxygenase (12-LO) inhibitors, nordihidroguaretic acid (NDGA) and 15(S)-hydroxy-5,8,11,13-eicosatetraenoic acid (15(S)-HETE), strongly prevented ATP-mediated TIPA inhibition. Additionally, ATP inhibited the increase of 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(S)-HETE) induced by thrombin. Pretreatment with both SQ-22536 and NDGA almost completely abolished ATP-mediated TIPA inhibition. Our results describe for the first time that ATP implicates both AC and 12-LO pathways in the inhibition of human platelets aggregation in response to agonists.


Evaluation of species identification and rabies virus characterization among bat rabies cases in the United States.
To evaluate species identification and rabies virus (RABV) characterization among samples from bats submitted for rabies testing in the United States and assess whether a standardized approach to specimen selection for RABV characterization could enhance detection of a sentinel event in virus dissemination among bats. United States public health rabies surveillance system data collected in January 2010 through December 2015. The number of rabies-tested bats for which species was reported and the number of RABV-positive samples for which virus characterization would likely provide information regarding introduction of novel RABV variants and translocation and host-shift events were calculated. These specimens were designated as specimens of epizootiological importance (SEIs). Additionally, the estimated test load that public health laboratories could expect if all SEIs underwent RABV characterization was determined. Species was reported for 74,928 of 160,017 (47%) bats submitted for rabies testing. Identified SEIs were grouped in 3 subcategories, namely nonindigenous bats; bats in southern border states, Florida, Puerto Rico, and the US Virgin Islands; and bats of species that are not commonly found to be inflected with RABV. Annually, 692 (95% CI, 600 to 784) SEIs were identified, of which only 295 (95% CI, 148 to 442) underwent virus characterization. Virus characterization of all SEIs would be expected to increase public health laboratories' overall test load by 397 (95% CI, 287 to 506) samples each year. Species identification and RABV characterization may aid detection of a sentinel event in bat RABV dissemination. With additional resources, RABV characterization of all SEIs as a standardized approach to testing could contribute to knowledge of circulating bat RABV variants.


Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000.
Between 1981 and 2000, 6609 children (<18 years of age) were treated in five consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria and Switzerland. Probability of 10-year event-free survival (EFS) (survival) improved from 65% (77%) in study ALL-BFM 81 to 78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: (1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk (HR) ALL patients, and eliminated in non- HR non-T-ALL patients, if it was replaced by high-dose and intrathecal (IT) MTX; (2) omission of delayed re-intensification severely impaired outcome of low-risk patients; (3) 6-month-less maintenance therapy caused an increase in systemic relapses; (4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; (5) condensed induction therapy resulted in significant improvement of outcome; (6) the daunorubicin dose in induction could be safely reduced in low-risk patients and (7) intensification of consolidation/re-intensification treatment led to considerable improvement of outcome in HR patients.


Long-Term Tocolysis With Magnesium Sulfate as a Risk Factor for Low Bone Mass: A Case Series.
Pregnancy and lactation-associated osteoporosis (PLO) is a disease caused by vertebral compression fracture, and it is characterized by low back pain during pregnancy or the postpartum period. However, it is difficult to predict and prevent PLO prepartum in high-risk groups. Recently, long-term tocolysis with magnesium sulfate (MgSO4) has been reported to be associated with PLO. The purpose of this case series was to assess postpartum bone mass after long-term tocolysis with MgSO4 and accumulated doses of MgSO4. We report the case of a pregnant woman with vertebral compression fractures during pregnancy following long-term tocolysis with MgSO4. We investigated whether long-term tocolysis with MgSO4 was a high risk factor for PLO. Therefore, we retrospectively evaluated bone mineral density after delivery in nine women who had long-term tocolysis with MgSO4 (more than 8 days) for treatment of threatened preterm birth at our hospital from January 2020 to December 2020. The age of the women was between 20 and 41 years (mean age, 30 years). The body mass index of the women was between 18.1 and 25.4 kg/m2 (mean 20.0 kg/m2). Three women had a positive smoking history, and none had a family history of osteoporosis. The average duration of tocolysis with MgSO4 was 11 - 97 days. The accumulated doses of MgSO4 were between 168 and 3,756 g. Four of nine cases were diagnosed with low bone mass of young adult mean (YAM) value ≤ 80%. Of them, one case (accumulated doses of MgSO4: 1,260 g) was diagnosed with PLO of YAM value ≤ 70%, and one case (accumulated doses of MgSO4: 3,756 g) was diagnosed with bone fracture with a YAM value of ≤ 70%. Long-term tocolysis with MgSO4 may be suggested as one of the risk factors of PLO. Nutritional guidance and rehabilitation are important interventions for target patients.


BMP15 regulates the inhibin/activin system independently of ovulation rate control in sheep.
Polymorphisms in the gene encoding bone morphogenetic protein 15 (BMP15) have been associated with multiple ovulations in sheep. As BMP15 regulates inhibin expression in rodents, we assumed that the ovarian inhibin/activin system could mediate part of the effect of BMP15 mutations in the regulation of ovulation rate in sheep. To answer this question, we have studied the effects of two natural loss-of-function mutations of BMP15 on the expression of components of this system. The FecXR and the FecXGr mutations, when present respectively in Rasa Aragonesa ewes at the heterozygous state and in Grivette ewes at the homozygous state, were associated with a twofold increase in ovulation rate. There were only small differences between mutant and wild-type ewes for mRNA expression of INHA, INHBA, ACVR1B, ACVR2A, FST or TGFBR3 in granulosa cells and inhibin A or activin A concentrations in follicular fluid. Moreover, the effects of mutations differed between breeds. In cultures of granulosa cells from wild-type ewes, BMP15, acting alone or in synergy with GDF9, stimulated INHA, INHBA and FST expression, but inhibited the expression of TGFBR3 Activin A did not affect INHBA expression, but inhibited the expression of ACVR2A also. The complexity of the inhibin/activin system, including positive and antagonistic elements, and the differential regulation of these elements by BMP15 and activin can explain that the effects of BMP15 mutations differ when present in different genetic backgrounds. In conclusion, the ovarian inhibin/activin system is unlikely to participate in the increase of ovulation rate associated with BMP15 mutations in sheep.


The FRUITFULL MADS-box gene mediates cell differentiation during Arabidopsis fruit development.
Fruit morphogenesis is a process unique to flowering plants, and yet little is known about its developmental control. Following fertilization, fruits typically undergo a dramatic enlargement that is accompanied by differentiation of numerous distinct cell types. We have identified a mutation in Arabidopsis called fruitfull (ful-1), which abolishes elongation of the silique after fertilization. The ful-1 mutation is caused by the insertion of a DsE transposable enhancer trap element into the 5' untranslated leader of the AGL8 MADS-box gene. beta-glucuronidase (GUS) reporter gene expression in the enhancer trap line is observed specifically in all cell layers of the valve tissue, but not in the replum, the septum or the seeds, and faithfully mimics RNA in situ hybridization data reported previously. The lack of coordinated growth of the fruit tissues leads to crowded seeds, a failure of dehiscence and, frequently, the premature rupture of the carpel valves. The primary defect of ful-1 fruits is within the valves, whose cells fail to elongate and differentiate. Stomata, which are frequent along the epidermis of wild-type valves, are completely eliminated in the ful mutant valves. In addition to the effect on fruit development, ful cauline leaves are broader than those of wild type and show a reduction in the number of internal cell layers. These data suggest that AGL8/FUL regulates the transcription of genes required for cellular differentiation during fruit and leaf development.


Multiscale classification using nearest neighbor density estimates.
Density estimates based on k-nearest neighbors have useful applications in nonparametric discriminant analysis. In classification problems, optimal values of k are usually estimated by minimizing the cross-validated misclassification rates. However, these cross-validation techniques allow only one value of k for each population density estimate, while in a classification problem, the optimum value of k for a class may also depend on its competing population densities. Further, it is computationally difficult to minimize the cross-validated error rate when there are several competing populations. Moreover, in addition to depending on the entire training data set, a good choice of k should also depend on the specific observation to be classified. Therefore, instead of using a single value of k for each population density estimate, it is more useful in practice to consider the results for multiple values of k to arrive at the final decision. This paper presents one such approach along with a graphical device, which gives more information about classification results for various choices of k and the related statistical uncertainties present there. The utility of this proposed methodology has been illustrated using some benchmark data sets.


Ginger (Zingiber officinale) phytochemicals-gingerenone-A and shogaol inhibit SaHPPK: molecular docking, molecular dynamics simulations and in vitro approaches.
Antibiotic resistance is a defense mechanism, harbored by pathogens to survive under unfavorable conditions. Among several antibiotic resistant microbial consortium, Staphylococcus aureus is one of the most havoc microorganisms. Staphylococcus aureus encodes a unique enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), against which, none of existing antibiotics have been reported. Computational approaches have been instrumental in designing and discovering new drugs for several diseases. The present study highlights the impact of ginger phytochemicals on Staphylococcus aureus SaHPPK. Herein, we have retrieved eight ginger phytochemicals from published literature and investigated their inhibitory interactions with SaHPPK. To authenticate our work, the investigation proceeds considering the known antibiotics alongside the phytochemicals. Molecular docking was performed employing GOLD and CDOCKER. The compounds with the highest dock score from both the docking programmes were tested for their inhibitory capability in vitro. The binding conformations that were seated within the binding pocket showing strong interactions with the active sites residues rendered by highest dock score were forwarded towards the molecular dynamic (MD) simulation analysis. Based on molecular dock scores, molecular interaction with catalytic active residues and MD simulations studies, two ginger phytochemicals, gingerenone-A and shogaol have been proposed as candidate inhibitors against Staphylococcus aureus. They have demonstrated higher dock scores than the known antibiotics and have represented interactions with the key residues within the active site. Furthermore, these compounds have rendered considerable inhibitory activity when tested in vitro. Additionally, their superiority was corroborated by stable MD results conducted for 100 ns employing GROMACS package. Finally, we suggest that gingerenone-A and shogaol may either be potential SaHPPK inhibitors or can be used as fundamental platforms for novel SaHPPK inhibitor development.


Is caffeine consumption a risk factor for osteoporosis?
High caffeine consumption has been proposed as a risk factor for osteoporotic fracture, but the evidence associating high caffeine intake with low bone density is inconsistent. We therefore examined the influence of caffeine consumption on bone mineral at six skeletal sites in an age-stratified random sample of white women residing in Rochester, Minnesota. After age adjustment, there was no association between overall caffeine consumption and bone mineral at five of the six sites. In the femoral shaft, however, there was a statistically significant interaction between age and caffeine consumption so that high caffeine intake was associated with slight reductions in bone mineral among elderly subjects but with modestly increased bone mineral at younger ages. When caffeine intake was categorized by source, no consistent influence of coffee, tea, or other caffeinated beverage consumption could be detected on bone mineral. Caffeine intake was, however, positively associated with cigarette smoking and alcohol consumption. After adjusting for age, caffeine consumption was not correlated with biochemical indices of bone turnover, circulating concentrations of estradiol and estrone, or other dietary and musculoskeletal variables. These data suggest that caffeine intake in the range consumed by a representative sample of white women is not an important risk factor for osteoporosis. Among elderly women, however, in whom calcium balance performance is impaired, high caffeine intake may predispose to cortical bone loss from the proximal femur.


Life course exposures continually shape antibody profiles and risk of seroconversion to influenza.
Complex exposure histories and immune mediated interactions between influenza strains contribute to the life course of human immunity to influenza. Antibody profiles can be generated by characterizing immune responses to multiple antigenically variant strains, but how these profiles vary across individuals and determine future responses is unclear. We used hemagglutination inhibition titers from 21 H3N2 strains to construct 777 paired antibody profiles from people aged 2 to 86, and developed novel metrics to capture features of these profiles. Total antibody titer per potential influenza exposure increases in early life, then decreases in middle age. Increased titers to one or more strains were seen in 97.8% of participants during a roughly four-year interval, suggesting widespread influenza exposure. While titer changes were seen to all strains, recently circulating strains exhibited the greatest titer rise. Higher pre-existing, homologous titers at baseline reduced the risk of seroconversion to recent strains. After adjusting for homologous titer, we also found an increased frequency of seroconversion against recent strains among those with higher immunity to older previously exposed strains. Including immunity to previously exposures also improved the deviance explained by the models. Our results suggest that a comprehensive quantitative description of immunity encompassing past exposures could lead to improved correlates of risk of influenza infection.


Microscopic model of quasiparticle wave packets in superfluids, superconductors, and paired Hall states.
We study the structure of Bogoliubov quasiparticles, bogolons, the fermionic excitations of paired superfluids that arise from fermion (BCS) pairing, including neutral superfluids, superconductors, and paired quantum Hall states. The naive construction of a stationary quasiparticle in which the deformation of the pair field is neglected leads to a contradiction: it carries a net electrical current even though it does not move. However, treating the pair field self-consistently resolves this problem: in a neutral superfluid, a dipolar current pattern is associated with the quasiparticle for which the total current vanishes. When Maxwell electrodynamics is included, as appropriate to a superconductor, this pattern is confined over a penetration depth. For paired quantum Hall states of composite fermions, the Maxwell term is replaced by a Chern-Simons term, which leads to a dipolar charge distribution and consequently to a dipolar current pattern.


Oral L-cysteine ethyl ester (LCEE) reduces amoebic gill disease (AGD) in Atlantic salmon Salmo salar.
There is a need for the development of alternative therapeutic treatments for amoebic gill disease (AGD) in Atlantic salmon Salmo salar L. to maintain the sustainability of the Tasmanian Atlantic salmon aquaculture industry. This study aimed to assess the effects of the mucolytic drug L-cysteine ethyl ester (LCEE) on marine Atlantic salmon mucus and whether or not it may have a therapeutic advantage for the alleviation of AGD when administered orally. We also aimed to document any physiological consequences of LCEE. Results showed that LCEE significantly decreased the viscosity of marine Atlantic salmon mucus both in vitro, where LCEE concentration showed a negative relationship to mucus viscosity (R2 = 0.95 at 11.5 s(-1)), and in vivo. Oral administration of LCEE at 52.7 mg LCEE kg(-1) fish d(-1) over 2 wk significantly delayed the progression of AGD-associated pathology during an aggressive, cohabitation induced, laboratory infection. Medicated fish had approximately 50% less gill filaments affected by AGD than control fed fish at 3 d post-infection when assessed using histology. Palatability of medicated feed was shown to be approximately 65% of control feed. No osmoregulatory disturbance was seen in medicated fish, although blood and whole body flux data indicated a slight acidosis coinciding with an increased plasma total ammonia concentration. However, both variables were within a tolerable physiological range and returned to control levels 3 d post-cessation of medicated feed. LCEE holds potential as an in-feed additive when administered over 2 wk prior to infection to delay the progression of AGD associated pathology. From the parameters measured, LCEE seems to have minimal physiological consequences after 2 wk of administration.


The elusive importance effect: more failure for the Jamesian perspective on the importance of importance in shaping self-esteem.
Following William James (1890/1963), many leading self-esteem researchers continue to support the Individual-importance hypothesis-that the relation between specific facets of self-concept and global self-esteem depends on the importance an individual places on each specific facet. However, empirical support for the hypothesis is surprisingly elusive, whether evaluated in terms of an importance-weighted average model, a generalized multiple regression approach for testing self-concept-by-importance interactions, or idiographic approaches. How can actual empirical support for such an intuitively appealing and widely cited psychological principle be so elusive? Hardy and Moriarty (2006), acknowledging this previous failure of the Individual-importance hypothesis, claim to have solved the conundrum, demonstrating an innovative idiographic approach that provides clear support for it. However, a critical evaluation of their new approach, coupled with a reanalysis of their data, undermines their claims. Indeed, their data provide compelling support against the Individual-importance hypothesis, which remains as elusive as ever.


Management of Anemia in Patients with Inflammatory Bowel Disease (IBD).
Anemia is the most common complication as well as an extra intestinal manifestation of inflammatory bowel disease (IBD). It is associated with a significant impact on patient's quality of life (QoL); as well it represents a common cause of frequent hospitalization, delay of hospital inpatient discharge and overall increased healthcare burden. In spite of all these, anemia is still often underdiagnosed and undertreated. Our aim in this review is to provide a pathway for physicians to help them achieve early diagnosis as well as timely and appropriate treatment of anemia which in turn would hopefully reduce the prevalence and subsequent complications of this condition among IBD patients. The etiology of anemia among IBD patients is most commonly due to iron deficiency anemia (IDA) followed by anemia of chronic disease. Despite this, more than a third of anemic ulcerative colitis (UC) patients are not tested for IDA and among those tested and diagnosed with IDA, a quarter are not treated with iron replacement therapy. A new algorithm has been validated to predict who will develop moderate to severe anemia at the time of UC diagnosis. While oral iron is effective for the treatment of mild iron deficiency-related anemia, the absorption of iron is influenced by chronic inflammatory states as a consequence of the presence of elevated levels of hepcidin. Also, it is important to recognize that ferritin is elevated in chronic inflammatory states and among patients with active IBD, ferritin levels less than 100 are considered to be diagnostic of iron deficiency. Newer formulations of intra-venous (IV) iron have a good safety profile and can be used for replenishment of iron stores and prevention of iron deficiency in the future. Routine screening for anemia is important among patients with IBD. The cornerstone for the accurate management of anemia in IBD patients lies in accurately diagnosing the type of anemia. All IBD patients with IDA should be considered appropriate for therapy with iron supplementation whereas IV administration of iron is recommended in patients with clinically active IBD, or for patients who are previously intolerant to oral iron, with hemoglobin levels below 10 g/dL, and in patients who need erythropoiesis-stimulating agents (ESAs). As the recurrence of anemia is common after resolution, the monitoring for recurrent anemia is equally important during the course of therapy.


Treatment recommendations in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.
This presentation represents consensus recommendations for the treatment of patients with Waldenstrom's macroglobulinemia (WM), which were prepared in conjunction with the second International Workshop held in Athens, Greece during September 2002. The faculty adopted the following statements for the management of patients with Waldenstrom's macroglobulinemia: (1) Alkylating agents, nucleoside analogues, and rituximab are reasonable choices for first line therapy of WM. (2) Both cladribine and fludarabine are reasonable choices for the therapy of WM. (3) Combinations of alkylating agents, nucleoside analogues, or rituximab should at this time be encouraged in the context of a clinical trial. (4) In WM, rituximab can cause a sudden rise in serum IgM and viscosity levels in certain patients, which may lead to complications, therefore close monitoring of these parameters and symptoms of hyperviscosity is recommended for WM patients undergoing rituximab therapy. (5) For relapsed disease, it is reasonable to use an alternate first line agent or re-use of the same agent; however, since autologous stem cell transplantation may have a role in treating patients with relapsed disease it is recommended that for patients in whom autologous transplantation is seriously being considered, exposure to alkylator or nucleoside analogue drugs should be limited. (6) Combination chemotherapy for patients who can tolerate myelotoxic therapy, thalidomide alone or with dexamethasone, can reasonably be considered to have relapsed. (7) Autologous stem cell transplantation may be considered for patients with refractory or relapsing disease. (8) Allogeneic transplantation should only be undertaken in the context of a clinical trial. (9) Plasmapheresis should be considered as interim therapy until definitive therapy can be initiated. (10) Rituximab should be considered for patients with IgM-related neuropathies. (11) Corticosteroids may be useful in the treatment of symptomatic mixed cryoglobulinemia. (12) Splenectomy is rarely indicated but has been used to manage painful splenomegaly and hypersplenism.


Breast cancer risk assessment across the risk continuum: genetic and nongenetic risk factors contributing to differential model performance.
Clinicians use different breast cancer risk models for patients considered at average and above-average risk, based largely on their family histories and genetic factors. We used longitudinal cohort data from women whose breast cancer risks span the full spectrum to determine the genetic and nongenetic covariates that differentiate the performance of two commonly used models that include nongenetic factors - BCRAT, also called Gail model, generally used for patients with average risk and IBIS, also called Tyrer Cuzick model, generally used for patients with above-average risk. We evaluated the performance of the BCRAT and IBIS models as currently applied in clinical settings for 10-year absolute risk of breast cancer, using prospective data from 1,857 women over a mean follow-up length of 8.1 years, of whom 83 developed cancer. This cohort spans the continuum of breast cancer risk, with some subjects at lower than average population risk. Therefore, the wide variation in individual risk makes it an interesting population to examine model performance across subgroups of women. For model calibration, we divided the cohort into quartiles of model-assigned risk and compared differences between assigned and observed risks using the Hosmer-Lemeshow (HL) chi-squared statistic. For model discrimination, we computed the area under the receiver operator curve (AUC) and the case risk percentiles (CRPs). The 10-year risks assigned by BCRAT and IBIS differed (range of difference 0.001 to 79.5). The mean BCRAT- and IBIS-assigned risks of 3.18% and 5.49%, respectively, were lower than the cohort's 10-year cumulative probability of developing breast cancer (6.25%; 95% confidence interval (CI) = 5.0 to 7.8%). Agreement between assigned and observed risks was better for IBIS (HL X4(2) = 7.2, P value 0.13) than BCRAT (HL X4(2) = 22.0, P value <0.001). The IBIS model also showed better discrimination (AUC = 69.5%, CI = 63.8% to 75.2%) than did the BCRAT model (AUC = 63.2%, CI = 57.6% to 68.9%). In almost all covariate-specific subgroups, BCRAT mean risks were significantly lower than the observed risks, while IBIS risks showed generally good agreement with observed risks, even in the subgroups of women considered at average risk (for example, no family history of breast cancer, BRCA1/2 mutation negative). Models developed using extended family history and genetic data, such as the IBIS model, also perform well in women considered at average risk (for example, no family history of breast cancer, BRCA1/2 mutation negative). Extending such models to include additional nongenetic information may improve performance in women across the breast cancer risk continuum.


Achieving care: promoting alternatives to industrial healthcare.
We march toward industrial healthcare. With different intensities and speeds depending on the nature of each healthcare system, most countries exhibit features of industrialisation. Perhaps this is the case because industrial healthcare may represent the final common pathway for any system that becomes underfunded as a result of austerity or profit extraction. Industrial healthcare is cruel to those at the frontline. It displaces the language of care, which in turn affects how we think and decide. It is time to reframe the conversation, change the language and draw from the traditions of the caring sciences. By focusing on care, developing models for caring and learning based on the actions of people rather than on data, and developing data based on the problems of care rather than on the advancement of decontextualised knowledge, we can advance toward careful and kind care for all.


Activity-dependent phosphorylation of neuronal Kv2.1 potassium channels by CDK5.
Dynamic modulation of ion channel expression, localization, and/or function drives plasticity in intrinsic neuronal excitability. Voltage-gated Kv2.1 potassium channels are constitutively maintained in a highly phosphorylated state in neurons. Increased neuronal activity triggers rapid calcineurin-dependent dephosphorylation, loss of channel clustering, and hyperpolarizing shifts in voltage-dependent activation that homeostatically suppress neuronal excitability. These changes are reversible, such that rephosphorylation occurs after removal of excitatory stimuli. Here, we show that cyclin-dependent kinase 5 (CDK5), a Pro-directed Ser/Thr protein kinase, directly phosphorylates Kv2.1, and determines the constitutive level of Kv2.1 phosphorylation, the rapid increase in Kv2.1 phosphorylation upon acute blockade of neuronal activity, and the recovery of Kv2.1 phosphorylation after stimulus-induced dephosphorylation. We also demonstrate that although the phosphorylation state of Kv2.1 is also shaped by the activity of the PP1 protein phosphatase, the regulation of Kv2.1 phosphorylation by CDK5 is not mediated through the previously described regulation of PP1 activity by CDK5. Together, these studies support a novel role for CDK5 in regulating Kv2.1 channels through direct phosphorylation.


Treatment of Midline Deviation with Miniscrews: A Case Report.
A 15-year-old female presented with the chief complaint of crowding. Extraoral examination revealed little facial asymmetry, which was related with mandibular deviation caused by constriction of the maxilla. Upon intraoral examination, Class III molar and Class II canine relationships were seen on the right side, and Class III molar and Class III canine relationships were seen on the left side. A morphological lower midline shift was detected (4 mm to the right). After the start of treatment with rapid maxillary expansion, miniscrews were inserted into the buccal shelf and canine-premolar areas in order to solve the morphological deviation without extractions. Because there was a need to shift the lower midline to the right side, miniscrews were inserted into the left buccal shelf at the right canine-premolar area. The miniscrews were placed vertically so that the angle between the long axes of the teeth and the long axes of the screws were approximately 20 degrees. Acceptable correction of the midline deviation lasted for four months. At the end of the treatment, a good occlusal relationship was obtained.


High-level diversity of tailed phages, eukaryote-associated viruses, and virophage-like elements in the metaviromes of antarctic soils.
The metaviromes of two distinct Antarctic hyperarid desert soil communities have been characterized. Hypolithic communities, cyanobacterium-dominated assemblages situated on the ventral surfaces of quartz pebbles embedded in the desert pavement, showed higher virus diversity than surface soils, which correlated with previous bacterial community studies. Prokaryotic viruses (i.e., phages) represented the largest viral component (particularly Mycobacterium phages) in both habitats, with an identical hierarchical sequence abundance of families of tailed phages (Siphoviridae > Myoviridae > Podoviridae). No archaeal viruses were found. Unexpectedly, cyanophages were poorly represented in both metaviromes and were phylogenetically distant from currently characterized cyanophages. Putative phage genomes were assembled and showed a high level of unaffiliated genes, mostly from hypolithic viruses. Moreover, unusual gene arrangements in which eukaryotic and prokaryotic virus-derived genes were found within identical genome segments were observed. Phycodnaviridae and Mimiviridae viruses were the second-most-abundant taxa and more numerous within open soil. Novel virophage-like sequences (within the Sputnik clade) were identified. These findings highlight high-level virus diversity and novel species discovery potential within Antarctic hyperarid soils and may serve as a starting point for future studies targeting specific viral groups.