Risk of total knee arthroplasty after operatively treated tibial plateau fracture: a matched-population-based cohort study.
The aims of operative treatment of displaced tibial plateau fractures are to stabilize the injured knee to restore optimal function and to minimize the risk of posttraumatic arthritis and the eventual need for total knee arthroplasty. The purpose of our study was to define the rate of subsequent total knee arthroplasty after tibial plateau fractures in a large cohort and to compare that rate with the rate in the general population. All patients sixteen years of age or older who had undergone surgical treatment of a tibial plateau fracture from 1996 to 2009 in the province of Ontario, Canada, were identified from administrative health databases with use of surgeon fee codes. Each member of the tibial plateau fracture cohort was matched to four individuals from the general population according to age, sex, income, and urban/rural residence. The rates of total knee arthroplasty at two, five, and ten years were compared by using time-to-event analysis. A separate Cox proportional hazards model was used to explore the influence of patient, provider, and surgical factors on the time to total knee arthroplasty. We identified 8426 patients (48.5% female; median age, 48.9 years) who had undergone fixation of a tibial plateau fracture and matched them to 33,698 controls. The two, five, and ten-year rates of total knee arthroplasty in the plateau fracture and control cohorts were 0.32% versus 0.29%, 5.3% versus 0.82%, and 7.3% versus 1.8%, respectively (p < 0.0001). After adjustment for comorbidity, plateau fracture surgery was found to significantly increase the likelihood of total knee arthroplasty (hazard ratio [HR], 5.29 [95% confidence interval, 4.58, 6.11]; p < 0.0001). Higher rates of total knee arthroplasty were also associated with increasing age (HR, 1.03 [1.03, 1.04] per year over the age of forty-eight; p < 0.0001), bicondylar fracture (HR, 1.53 [1.26, 1.84]; p < 0.0001), and greater comorbidity (HR, 2.17 [1.70, 2.77]; p < 0.001). Ten years after tibial plateau fracture surgery, 7.3% of the patients had had a total knee arthroplasty. This corresponds to a 5.3 times increase in likelihood compared with a matched group from the general population. Older patients and those with more severe fractures are also more likely to need total knee arthroplasty after repair of a tibial plateau fracture.


AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System.
AMPK is a central regulator of metabolism and autophagy. Here we show how lysosomal damage activates AMPK. This occurs via a hitherto unrecognized signal transduction system whereby cytoplasmic sentinel lectins detect membrane damage leading to ubiquitination responses. Absence of Galectin 9 (Gal9) or loss of its capacity to recognize lumenal glycans exposed during lysosomal membrane damage abrogate such ubiquitination responses. Proteomic analyses with APEX2-Gal9 have revealed global changes within the Gal9 interactome during lysosomal damage. Gal9 association with lysosomal glycoproteins increases whereas interactions with a newly identified Gal9 partner, deubiquitinase USP9X, diminishes upon lysosomal injury. In response to damage, Gal9 displaces USP9X from complexes with TAK1 and promotes K63 ubiquitination of TAK1 thus activating AMPK on damaged lysosomes. This triggers autophagy and contributes to autophagic control of membrane-damaging microbe Mycobacterium tuberculosis. Thus, galectin and ubiquitin systems converge to activate AMPK and autophagy during endomembrane homeostasis.


Control processes in verbal working memory: an event-related potential study.
Event-related potentials (ERPs) were recorded using a large electrode array while subjects engaged in tasks designed to dissociate control from storage/maintenance processes in verbal working memory (WM). Increased ERP negativity (450-900 ms post-stimulus onset) over left frontal regions emerged only when required dynamic updating/revision of WM stores was initiated, with augmentation of right frontal negativity in the same epoch relative to more general overall task demands. Increased ERP positivity in a similar time window over parietal regions reflected initiation of required rehearsal/maintenance of memory set contents, with progressive amplitude increases with repeated dynamic updating/revision of memory stores, suggesting increased effortful activity to resist proactive interference effects. These findings are consistent with a left frontal-parietal network for process control in verbal working memory.


[Determination of anthropometric measurements in obstructive sleep apnea syndrome in Turkish population].
In this study, we aimed to determine the values of anthropometric measurements and rates used in the evaluation of obstructive sleep apnea syndrome (OSAS) in our country. Twenty accredited sleep centers in thirteen provinces participated in this multicenter prospective study. OSAS symptoms and polysomnographic examination and apnea-hypopnea index (AHI) ≥ 5 cases OSAS study group; patients with AHI < 5 and STOP-Bang < 2 were included as control group. Demographic characteristics (age, sex, body mass index-BMI) and anthropometric measurements (neck, waist and hip circumference, waist/hip ratio) of the subjects were recorded. The study included 2684 patients (81.3% OSAS) with a mean age of 50.50 ± 0.21 years from 20 centers. The cases were taken from six geographical regions of the country (Mediterranean, Eastern Anatolia, Aegean, Central Anatolia, Black Sea and Marmara Region). Demographic characteristics and anthropometric measurements; age, neck, waist, hip circumference and waist/ hip ratios and BMI characteristics when compared with the control group; when compared according to regions, age, neck, waist, hip circumference and waist/hip ratios were found to be statistically different (p< 0.001, p< 0.001, p< 0.05, respectively). When compared by sex, age, neck and hip circumference, waist/hip ratio, height, weight and BMI characteristics were statistically different (p< 0.001, respectively). Neck circumference and waist/hip ratio were respectively 42.58 ± 0.10 cm, 0.99 ± 0.002, 39.24 ± 0.16 cm, 0.93 ± 0.004 were found in women. The neck circumference was lower than the standard value in men, but higher in women. The waist/hip ratio was above the ideal measurements in both men and women. In this context, the determination of the country values will allow the identification of patients with the possibility of OSAS and referral to sleep centers for polysomnography.


Joint fractional Fourier analysis of wavefront-coding systems.
The analysis of wavefront-coding systems is explored via the joint fractional Fourier signal representation (JFF) of the pupil function. The properties of the JFF of the pupil function are presented and are shown to be revealing with regard to the system response to defocus. Numerical examples that illustrate the properties are given.


Novel neuroanatomical integration and scaling define avian brain shape evolution and development.
How do large and unique brains evolve? Historically, comparative neuroanatomical studies have attributed the evolutionary genesis of highly encephalized brains to deviations along, as well as from, conserved scaling relationships among brain regions. However, the relative contributions of these concerted (integrated) and mosaic (modular) processes as drivers of brain evolution remain unclear, especially in non-mammalian groups. While proportional brain sizes have been the predominant metric used to characterize brain morphology to date, we perform a high-density geometric morphometric analysis on the encephalized brains of crown birds (Neornithes or Aves) compared to their stem taxa-the non-avialan coelurosaurian dinosaurs and Archaeopteryx. When analyzed together with developmental neuroanatomical data of model archosaurs (Gallus, Alligator), crown birds exhibit a distinct allometric relationship that dictates their brain evolution and development. Furthermore, analyses by neuroanatomical regions reveal that the acquisition of this derived shape-to-size scaling relationship occurred in a mosaic pattern, where the avian-grade optic lobe and cerebellum evolved first among non-avialan dinosaurs, followed by major changes to the evolutionary and developmental dynamics of cerebrum shape after the origin of Avialae. Notably, the brain of crown birds is a more integrated structure than non-avialan archosaurs, implying that diversification of brain morphologies within Neornithes proceeded in a more coordinated manner, perhaps due to spatial constraints and abbreviated growth period. Collectively, these patterns demonstrate a plurality in evolutionary processes that generate encephalized brains in archosaurs and across vertebrates.


A comparison of mindfulness, nonjudgmental, and cognitive dissonance-based approaches to mirror exposure.
This study compares different versions of mirror exposure (ME), a body image intervention with research support. ME protocols were adapted to maximize control and comparability, and scripted for delivery by research assistants. Female undergraduates (N=168) were randomly assigned to receive mindfulness-based (MB; n=58), nonjudgmental (NJ; n=55), or cognitive dissonance-based (CD, n=55) ME. Participants completed the Body Image Avoidance Questionnaire (BIAQ), Body Checking Questionnaire (BCQ), Satisfaction with Body Parts Scale (SBPS), Beck Depression Inventory-II (BDI-II), and Eating Disorders Examination Questionnaire (EDE-Q) at pre-treatment, post-treatment, and 1-month follow-up. Mixed models ANOVAs revealed a significant main effect of time on all measures, and no significant time by condition interaction for any measures except the SBPS. Post-hoc analysis revealed that only CD ME significantly improved SBPS outcome. Results suggest that all versions of ME reduce eating disorder risk factors, but only CD ME improves body satisfaction.


A comparison of acetyl- and methoxycarbonylnitrenes by computational methods and a laser flash photolysis study of benzoylnitrene.
Density functional theory (DFT), CCSD(T), and CBS-QB3 calculations were performed to understand the chemical and reactivity differences between acetylnitrene (CH(3)C(=O)N) and methoxycarbonylnitrene (CH(3)OC(=O)N) and related compounds. CBS-QB3 theory alone correctly predicts that acetylnitrene has a singlet ground state. We agree with previous studies that there is a substantial N-O interaction in singlet acetylnitrene and find a corresponding but weaker interaction in methoxycarbonylnitrene. Methoxycarbonylnitrene has a triplet ground state because the oxygen atom stabilizes the triplet state of the carbonyl nitrene more than the corresponding singlet state. The oxygen atom also stabilizes the transition state of the Curtius rearrangement and accelerates the isomerization of methoxycarbonylnitrene relative to acetylnitrene. Acetyl azide is calculated to decompose by concerted migration of the methyl group along with nitrogen extrusion; the free energy of activation for this concerted process is only 27 kcal/mol, and a free nitrene is not produced upon pyrolysis of acetyl azide. Methoxycarbonyl azide, on the other hand, does have a preference for stepwise Curtius rearrangement via the free nitrene. The bimolecular reactions of acetylnitrene and methoxycarbonylnitrene with propane, ethylene, and methanol were calculated and found to have enthalpic barriers that are near zero and free energy barriers that are controlled by entropy. These predictions were tested by laser flash photolysis studies of benzoyl azide. The absolute bimolecular reaction rate constants of benzoylnitrene were measured with the following substrates: acetonitrile (k = 3.4 x 10(5) M(-1) (s-1)), methanol (6.5 x 10(6) M(-1) s(-1)), water (4.0 x 10(6) M(-1) s(-1)), cyclohexane (1.8 x 10(5) M(-1) s(-1)), and several representative alkenes. The activation energy for the reaction of benzoylnitrene with 1-hexene is -0.06 +/- 0.001 kcal/mol. The activation energy for the decay of benzoylnitrene in pentane is -3.20 +/- 0.02 kcal/mol. The latter results indicate that the rates of reactions of benzoylnitrene are controlled by entropic factors in a manner reminiscent of singlet carbene processes.


Flexible intuitions of Euclidean geometry in an Amazonian indigene group.
Kant argued that Euclidean geometry is synthesized on the basis of an a priori intuition of space. This proposal inspired much behavioral research probing whether spatial navigation in humans and animals conforms to the predictions of Euclidean geometry. However, Euclidean geometry also includes concepts that transcend the perceptible, such as objects that are infinitely small or infinitely large, or statements of necessity and impossibility. We tested the hypothesis that certain aspects of nonperceptible Euclidian geometry map onto intuitions of space that are present in all humans, even in the absence of formal mathematical education. Our tests probed intuitions of points, lines, and surfaces in participants from an indigene group in the Amazon, the Mundurucu, as well as adults and age-matched children controls from the United States and France and younger US children without education in geometry. The responses of Mundurucu adults and children converged with that of mathematically educated adults and children and revealed an intuitive understanding of essential properties of Euclidean geometry. For instance, on a surface described to them as perfectly planar, the Mundurucu's estimations of the internal angles of triangles added up to ~180 degrees, and when asked explicitly, they stated that there exists one single parallel line to any given line through a given point. These intuitions were also partially in place in the group of younger US participants. We conclude that, during childhood, humans develop geometrical intuitions that spontaneously accord with the principles of Euclidean geometry, even in the absence of training in mathematics.


The relationship between photometric and spectroscopic oscillation amplitudes from 3D stellar atmosphere simulations.
We establish a quantitative relationship between photometric and spectroscopic detections of solar-like oscillations using ab initio, 3D, hydrodynamical numerical simulations of stellar atmospheres. We present a theoretical derivation as a proof of concept for our method. We perform realistic spectral line formation calculations to quantify the ratio between luminosity and radial velocity amplitude for two case studies: the Sun and the red giant ϵ Tau. Luminosity amplitudes are computed based on the bolometric flux predicted by 3D simulations with granulation background modelled the same way as asteroseismic observations. Radial velocity amplitudes are determined from the wavelength shift of synthesized spectral lines with methods closely resembling those used in Birmingham Solar Oscillations Network (BiSON) and Stellar Oscillations Network Group (SONG) observations. Consequently, the theoretical luminosity to radial velocity amplitude ratios are directly comparable with corresponding observations. For the Sun, we predict theoretical ratios of 21.0 and 23.7 ppm [m s-1]-1 from BiSON and SONG, respectively, in good agreement with observations 19.1 and 21.6 ppm [m s-1]-1. For ϵ Tau, we predict K2 and SONG ratios of 48.4 ppm [m s-1]-1, again in good agreement with observations 42.2 ppm [m s-1]-1, and much improved over the result from conventional empirical scaling relations that give 23.2 ppm [m s-1]-1. This study thus opens the path towards a quantitative understanding of solar-like oscillations, via detailed modelling of 3D stellar atmospheres.


Access to Healthy Wheat and Maize Processed Foods in Mexico City: Comparisons across Socioeconomic Areas and Store Types.
The contributions of processed foods to the overweight and obesity problem in Latin America are well known. Engagement with the private and public sectors on possible solutions requires deeper insights into where and how these products are sold and the related implications for diet quality. This article characterizes the diversity of wheat and maize processed foods (WMPFs) available to consumers in Mexico City. Data were gathered across nine product categories at different points of sale (supermarkets, small grocery stores, convenience stores) in high and low socioeconomic (SE) areas. We assessed WMPFs based on Nutri-Score profile, price, and health and nutrition claims. Roughly 17.4% of the WMPFs were considered healthy, of which 62.2% were pastas and breads. Availability of healthy WMPFs was scarce in most stores, particularly in convenience stores Compared to supermarkets in the low SE area, those in the high SE area exhibited greater variety in access to healthy WMPFs across all product categories. In the low SE area, healthy WMPFs were priced 16-69% lower than unhealthy WMPFs across product categories. The extensive variety of unhealthy WMPFs, the limited stock of healthy WMPFs in most retail outlets, and the confusing health and nutrition claims on packaging make it difficult for urban consumers to find and choose healthy WMPFs.


Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors: Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial.
We recently conducted a randomized double-blind study in which we demonstrated that moderate/severe chronic graft-versus-host disease (cGVHD) but not cGVHD-free survival was reduced in patients receiving anti-T lymphocyte globulin (ATLG) versus placebo. In a companion study we performed immunophenotypic analysis to determine the impact of ATLG on immune reconstitution (IR) and to correlate IR with clinical outcomes. The randomized study (n = 254) included patients (aged 18 to 65 years) who underwent myeloablative transplants for acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia from HLA-matched unrelated donors. Ninety-one patients consented for the companion IR study (ATLG = 44, placebo = 47). Blood samples were collected on days 30, 100, 180, and 360 after hematopoietic cell transplantation (HCT), and multiparameter flow cytometry was performed in a blinded fashion. Reconstitution of CD3+ and CD4+ T cells was delayed up to 6 months post-HCT in the ATLG arm, whereas absolute regulatory T cell (Treg) (CD4+25+127-) numbers were lower only in the first 100 days. Analysis of the CD4+ Treg and conventional T cells (Tconv) (CD4+25-127+) compartments showed a profound absence of naive Tregs and Tconv in the first 100 days post-HCT, with very slow recovery for 1 year. B cell and natural killer cell recovery were similar in each arm. Higher absolute counts of CD3+, CD4+, CD8+ T, Tregs, and Tconv were associated with improved overall survival, progression-free survival, and nonrelapse mortality but not moderate/severe cGVHD. Although ATLG delays CD3+ and CD4+ T cell recovery post-transplant, it has a relative Treg sparing effect after the early post-HCT period, with possible implications for protection from cGVHD. ATLG severely compromises the generation of naive CD4+ cells (Treg and Tconv), potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection.


Cognitive effects of non-surgical brain stimulation for major depressive disorder: protocol for a systematic review and meta-analysis.
Non-surgical brain stimulation techniques may be considered as alternative or add-on treatments for patients with major depressive disorder who failed to respond to pharmacological interventions. Electroconvulsive therapy has been shown to be highly effective in reducing depressive symptoms but stakeholders remain concerned about adverse cognitive effects. Repetitive transcranial magnetic stimulation and transcranial direct current stimulation may be associated with more benign adverse effect profiles and may indeed improve certain cognitive functions such as memory and attention. To guide clinical decision-making, we will carry out a systematic review and meta-analysis of the cognitive effects of eight non-surgical brain stimulation techniques. A systematic literature search of the Embase, PubMed/MEDLINE and PsycINFO databases, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and OpenGrey will be performed. We will include both randomised clinical trials which report on at least one cognitive measure post treatment as well as non-randomised trials and pre-post intervention studies. There are no restrictions to the type of cognitive outcome measures, except that the tests are standardised and psychometrically validated. The Revised Cochrane tool for assessing risk of bias in randomised trials (RoB 2.0) will be used to evaluate included trials. Pre-post studies will be evaluated using the quality assessment tool developed by the US National Heart, Lung and Blood Institute. Meta-analysis, meta-regression, subgroup and sensitivity analyses will be conducted where sufficient data are available. No ethical approval is needed to conduct this work. The findings will be submitted for publication in peer-reviewed journals and presented at scientific meetings. CRD42018118850.


Injectable collagen in laryngeal rehabilitation.
Glottic insufficiency has been successfully managed by Teflon augmentation of paretic vocal cords over the past two decades. Collagen fulfills the criteria for a suitable bioimplant and is an attractive alternative as it is a normal constituent of the extracellular protein matrix. This study explores the use of modified bovine collagen injected into the canine larynx. Clinical situations are simulated by creating lesions and injecting collagen at different sites. The technique permits precise placement and quantification. Histologic study of the collagen implant fails to show evidence of significant foreign body reaction. The injected collagen appears similar to viable connective tissue and is colonized by host fibroblasts and nourishing capillaries.


Adsorption/desorption of human serum albumin on hydroxyapatite: a critical analysis of the Langmuir model.
We studied the adsorption of human albumin onto synthetic hydroxyapatite, using a radiotracer technique and a special flow cell. Adsorption was studied under various conditions corresponding to different thermodynamic paths. It appears that (i) as is the usual case, the isotherms obtained within a short time range (a few hours) do not correspond to a true equilibrium situation; (ii) when the adsorption process is followed for longer times, which is necessary at low bulk concentrations, one always reaches the plateau surface adsorption; (iii) this plateau value is independent of the "history" of the adsorption process and corresponds well to the jamming limit predicted by the random sequential adsorption model; and (iv) surface denaturation, leading to enhanced surface binding and thus decreasing desorption constants, is the important phenomenon that can partly and qualitatively explain our observations. Its time dependence, however, remains to be clarified.


Assessment and Diagnosis of Musculoskeletal Shoulder Disorders over the Internet.
Shoulder disorders are common, debilitating, and represent a considerable burden on society. As primary contact practitioners, physiotherapists play a large role in the management and rehabilitation of people with these conditions. For those living outside of urban areas, however, access to physiotherapy can be limited. The aim of this study was to evaluate the validity and reliability of using a telerehabilitation system to collect physical examination findings and correctly identify disorders of the shoulder. Twenty-two participants with 28 shoulder disorders were recruited and underwent a face-to-face physical examination and a remote telerehabilitation examination. Examination findings and diagnoses from the two modes of assessment were used to determine validity and reliability of the new method. Diagnostic agreement and agreement on individual findings between the two methods were found to be consistent with the reliability of conventional assessment methods. This study provides important preliminary findings on the validity and reliability of musculoskeletal examinations conducted via telerehabilitation.


Lymphatic vessels in the uterine endometrium of virgin rats.
Uteri from four diestrous rats fixed by perfusion were examined histologically for the presence of lymphatic vessels in the endometrium, using 1 micron epoxy sections stained with toluidine blue. For each animal, multiple random sections were prepared from 3 tissue samples. In all sections, lymphatics were readily apparent in the myometrium, being identified by their irregular shape and contents of stained lymph proteins, which contrasted with the clear, empty blood vessels. While similar lymphatics were not seen in the endometrium of most tissue samples, one sample from each of three females revealed a small lymphatic vessel near the bases of the uterine glands, clearly in the endometrium. One of these was followed in serial alternating light and electron microscopic sections. The vessel maintained its relative position to the endometrial glands for a considerable distance, and also joined with two separate branches that appeared along its course. Ultrastructural observations, including a thin endothelium without a continuous basal lamina, the presence of anchoring filaments, and only mononuclear cells and cellular debris in the lumen, confirmed the vessel's identification as a lymphatic. The vessel's size was normally large enough to be followed by light microscopy; however, at some places along its course, the lumen narrowed to such a degree that it was only identifiable ultramicroscopically . These observations refute claims that there are no lymphatic vessels in rodent uterine endometrium, but indicate that they are small and sparsely distributed.


Intraoperative Seizures in Awake Craniotomy for Perirolandic Glioma Resections That Undergo Cortical Mapping.
Perirolandic motor area gliomas present invasive eloquent region tumors within the precentral gyrus that are difficult to resect without causing neurologic deficits. This study evaluates the role of awake craniotomy and motor mapping on neurologic outcome and extent of resection (EOR) of tumor in the perirolandic motor region. It also analyzes preoperative risk factors for intraoperative seizures. We evaluated 57 patients who underwent an awake craniotomy for a perirolandic motor area eloquent region glioma. Patients who had positive mapping (PM) or intraoperative identification of motor regions in the cortex using direct cortical stimulation were compared with patients with no positive motor mapping following direct cortical stimulation and negative mapping (NM). Preoperative risks, intraoperative seizures, perioperative outcomes, tumor characteristics, and EOR were also compared. A logistic regression model was used to evaluate the predictors for intraoperative seizures in this patient cohort. Overall, 33 patients were in the PM cohort; 24 were in the NM cohort. Our study showed an 8.8% incidence of intraoperative seizures during cortical and subcortical mapping for awake craniotomies in the perirolandic motor area, none of which aborted the case. PM patients had significantly more intraoperative and postoperative seizures (15.5% and 30.3%, respectively) compared with the NM patients (0% and 8.3%, respectively; p = 0.046 and 0.044). New transient postoperative motor deficits were found more often in the PM group (51.5%) versus the NM group (12.5%; p = 0.002). A univariate logistic regression showed that PM (odds ratio [OR]: 1.16; 95% confidence interval [CI], 1.01-1.34; p = 0.035) and preoperative tumor volume (OR: 0.998; 95% CI, 0.996-0.999; p = 0.049) were significant predictors for intraoperative seizures in patients with perirolandic gliomas. Awake craniotomies in the perirolandic motor region can be safely performed with a similar incidence of intraoperative seizures as reported for the language cortex. PM in this region may increase the likelihood of perioperative seizures or motor deficits compared with NM. Craniotomies that minimize cortical exposure for perirolandic gliomas that may not localize motor regions can still allow for extensive tumor resection with a good postoperative outcome.


A structure-based model fails to probe the mechanical unfolding pathways of the titin I27 domain.
We discuss the use of a structure based Cα-Go model and Langevin dynamics to study in detail the mechanical properties and unfolding pathway of the titin I27 domain. We show that a simple Go-model does detect correctly the origin of the mechanical stability of this domain. The unfolding free energy landscape parameters x(u) and ΔG(‡), extracted from dependencies of unfolding forces on pulling speeds, are found to agree reasonably well with experiments. We predict that above v = 10(4) nm/s the additional force-induced intermediate state is populated at an end-to-end extension of about 75 Å. The force-induced switch in the unfolding pathway occurs at the critical pulling speed v(crit) ≈ 10(6)-10(7) nm/s. We argue that this critical pulling speed is an upper limit of the interval where Bell's theory works. However, our results suggest that the Go-model fails to reproduce the experimentally observed mechanical unfolding pathway properly, yielding an incomplete picture of the free energy landscape. Surprisingly, the experimentally observed intermediate state with the A strand detached is not populated in Go-model simulations over a wide range of pulling speeds. The discrepancy between simulation and experiment is clearly seen from the early stage of the unfolding process which shows the limitation of the Go model in reproducing unfolding pathways and deciphering the complete picture of the free energy landscape.


Increasing screening mammography in asymptomatic women: evaluation of a second-generation, theory-based program.
Two theory-based programs to increase mammography screening rates among asymptomatic women were implemented and evaluated in the community. One program (E) was based on the Health Belief Model (HBM); the second program (EP) added exercises adapted from the social psychology of compliance. Program impact on screening among 295 primarily Caucasian, middle-class women was evaluated against untreated controls (C) over a 6-month period. Both programs led to increases in HBM components (Perceived Susceptibility, and Perceived Benefits) and Intentions to obtain a mammogram. Screening rates 2 to 3 times higher were observed in the EP and E over C conditions; EP and E did not differ. A mediational model of compliance illustrated the interplay of HBM components in the compliance process.


Symptom response to mobilization and outcomes in patients with subacromial pain syndrome: A cohort study.
The objectives of this study were the following: (1) to determine if there was a difference in outcomes between immediate responders to glenohumeral mobilizations at the initial evaluation, 2-week, 4-week, and 6-month follow-up as compared to those that do not respond in participants with subacromial pain syndrome; (2) to see if there were statistically significant differences in outcomes within these groups between these time frames of interest, and (3) to see if symptom response at the initial evaluation was predictive of a favorable recovery. This was a prospective, single-group observational design. Clinicians pragmatically identified positive responders as improving at least two points on the Numeric Pain Rating Scale and/or a 20° improvement in shoulder active range of motion (AROM) following shoulder mobilization at the initial evaluation. Data were collected for the subjective and objective variables of interest at the initial evaluation, 2-week, 4-week, and 6-month follow-up. The prevalence of responders at the initial evaluation was 99 (81.8%). There were no statistically significant between-group differences for the variables of interest except for the Global Rating of Change (GRoC; f = 2.79, p = 0.006). The shoulder abduction AROM between-group difference exceeded the minimal detectable change at 4 weeks. The pair-wise comparison showed statistically significant differences for the outcomes of interest at each time point except for the GRoC between 4 weeks and 6 months. There was a statistically significant correlation between responders at the initial evaluation and shoulder abduction AROM at the 4-week follow-up (rpb (112) = 0.27, p = 0.004). Individuals with SAPS may benefit from shoulder mobilization independent of their within-session response to shoulder mobilization at the initial evaluation. Future research should seek to differentiate if these improvements are related to the within-session positive treatment response at the initial evaluation in individuals who are randomized to receive shoulder mobilization or not.


Program characteristics and the length of time clients are in substance abuse treatment.
Is there a relationship between the characteristics of drug addiction treatment programs and an important correlate of better outcomes, the length of time clients are in treatment? Previous research has consistently shown longer periods in treatment and a range of services each have a salutary effect on client outcomes after treatment. Much of this research has examined the characteristics of clients. Program attributes are another important consideration. Multivariate analysis of data collected from a national survey of outpatient drug addiction treatment programs shows offering a range of services along with several other program characteristics are relevant to the duration of treatment. When a range of services are available, this has a positive association with both the number of months programs report clients are in treatment and with the number of counseling sessions programs report clients receive over the course of treatment. Ultimately, this should lead to better outcomes for clients.


The Role of Cognitive Control in Tinnitus and Its Relation to Speech-in-Noise Performance.
Self-reported difficulties in speech-in-noise (SiN) recognition are common among tinnitus patients. Whereas hearing impairment that usually co-occurs with tinnitus can explain such difficulties, recent studies suggest that tinnitus patients with normal hearing sensitivity still show decreased SiN understanding, indicating that SiN difficulties cannot be solely attributed to changes in hearing sensitivity. In fact, cognitive control, which refers to a variety of top-down processes that human beings use to complete their daily tasks, has been shown to be critical for SiN recognition, as well as the key to understand cognitive inefficiencies caused by tinnitus. In this article, we review studies investigating the association between tinnitus and cognitive control using behavioral and brain imaging assessments, as well as those examining the effect of tinnitus on SiN recognition. In addition, three factors that can affect cognitive control in tinnitus patients, including hearing sensitivity, age, and severity of tinnitus, are discussed to elucidate the association among tinnitus, cognitive control, and SiN recognition. Although a possible central or cognitive involvement has always been postulated in the observed SiN impairments in tinnitus patients, there is as yet no direct evidence to underpin this assumption, as few studies have addressed both SiN performance and cognitive control in one tinnitus cohort. Future studies should aim at incorporating SiN tests with various subjective and objective methods that evaluate cognitive performance to better understand the relationship between SiN difficulties and cognitive control in tinnitus patients.


Chronic bronchitis and acute infections as new risk factors for ischemic stroke and the lack of protection offered by the influenza vaccination.
Acute and chronic infections may play a role in promoting complications of atherosclerotic disease. We evaluated the importance of acute infections and chronic bronchitis (CB; as a chronic inflammatory state) in several subtypes of ischemic stroke, and we investigated whether the influenza vaccination was independently associated with a reduced likelihood of stroke. A case-control study was performed on 393 consecutive ischemic stroke patients and 393 control subjects matched for age, sex and time of year. Data were collected by a structured interview that assessed risk factors, acute infections within the preceding 2 months, CB and whether they had received the influenza vaccination. Infections within the 2 months before stroke onset and CB were more common among patients than control subjects [23.3 vs. 16.3% (p = 0.014) and 17.2 vs. 8.5% (p = 0.001), respectively]. After adjustment for traditional risk factors, the risk of stroke was increased in the subjects with CB (OR = 1.83, 95% CI = 1.35-2.48, p = 0.016), but not with acute infection (OR = 1.32, 95% CI = 0.98-1.78, p = 0.16). Acute infections and CB increased the risk of ischemic events in all age groups; this reached significance for patients older than 60 years. The profile of vascular risk factors was similar in patients with and without previous infections. The influenza vaccination did not prevent ischemic stroke, and it did not reduce the rate of acute previous infections in stroke patients. CB and infections over the previous 2 months predicted the risk of ischemic stroke. The influenza vaccination was not associated with a reduction in the incidence of stroke in our group of patients.


Diagnostic performance of non-invasive imaging for stable coronary artery disease: A meta-analysis.
To determine diagnostic performance of non-invasive tests using invasive fractional flow reserve (FFR) as reference standard for coronary artery disease (CAD). Medline, Embase, and citations of articles, guidelines, and reviews for studies were used to compare non-invasive tests with invasive FFR for suspected CAD published through March 2017. Seventy-seven studies met inclusion criteria. The diagnostic test with the highest sensitivity to detect a functionally significant coronary lesion was coronary computed tomography (CT) angiography [88%(85%-90%)], followed by FFR derived from coronary CT angiography (FFRCT) [85%(81%-88%)], positron emission tomography (PET) [85%(82%-88%)], stress cardiac magnetic resonance (stress CMR) [81%(79%-84%)], stress myocardial CT perfusion combined with coronary CT angiography [79%(74%-83%)], stress myocardial CT perfusion [77%(73%-80%)], stress echocardiography (Echo) [72%(64%-78%)] and stress single-photon emission computed tomography (SPECT) [64%(60%-68%)]. Specificity to rule out CAD was highest for stress myocardial CT perfusion added to coronary CT angiography [91%(88%-93%)], stress CMR [91%(90%-93%)], and PET [87%(86%-89%)]. A negative coronary CT angiography has a higher test performance than other index tests to exclude clinically-important CAD. A positive stress myocardial CT perfusion added to coronary CT angiography, stress cardiac MR, and PET have a higher test performance to identify patients requiring invasive coronary artery evaluation.


Nontargeted metabolite profiling discriminates diet-specific biomarkers for consumption of whole grains, fatty fish, and bilberries in a randomized controlled trial.
Nontargeted metabolite profiling allows for concomitant examination of a wide range of metabolite species, elucidating the metabolic alterations caused by dietary interventions. The aim of the current study was to investigate the effects of dietary modifications on the basis of increasing consumption of whole grains, fatty fish, and bilberries on plasma metabolite profiles to identify applicable biomarkers for dietary intake and endogenous metabolism. Metabolite profiling analysis was performed on fasting plasma samples collected in a 12-wk parallel-group intervention with 106 participants with features of metabolic syndrome who were randomly assigned to 3 dietary interventions: 1) whole-grain products, fatty fish, and bilberries [healthy diet (HD)]; 2) a whole-grain-enriched diet with the same grain products as in the HD intervention but with no change in fish or berry consumption; and 3) refined-wheat breads and restrictions on fish and berries (control diet). In addition, correlation analyses were conducted with the food intake data to define the food items correlating with the biomarker candidates. Nontargeted metabolite profiling showed marked differences in fasting plasma after the intervention diets compared with the control diet. In both intervention groups, a significant increase was observed in 2 signals identified as glucuronidated alk(en)-ylresorcinols [corrected P value (Pcorr) < 0.05], which correlated strongly with the intake of whole-grain products (r = 0.63, P < 0.001). In addition, the HD intervention increased the signals for furan fatty acids [3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF)], hippuric acid, and various lipid species incorporating polyunsaturated fatty acids (Pcorr < 0.05). In particular, plasma CMPF correlated strongly with the intake of fish (r = 0.47, P < 0.001) but not with intakes of any other foods. Novel biomarkers of the intake of health-beneficial food items included in the Nordic diet were identified by the metabolite profiling of fasting plasma and confirmed by the correlation analyses with dietary records. The one with the most potential was CMPF, which was shown to be a highly specific biomarker for fatty fish intake. This trial was registered at clinicaltrials.gov as NCT00573781.


Analysis of five-year trends in self-reported language preference and issues of item non-response among Hispanic persons in a large cross-sectional health survey: implications for the measurement of an ethnic minority population.
Significant differences in health outcomes have been documented among Hispanic persons, the fastest-growing demographic segment of the United States. The objective of this study was to examine trends in population growth and the collection of health data among Hispanic persons, including issues of language preference and survey completion using a national health survey to highlight issues of measurement of an increasingly important demographic segment of the United States. Data from the 2003-2007 United States Census and the Behavioral Risk Factor Surveillance System were used to compare trends in population growth and survey sample size as well as differences in survey response based on language preference among a Hispanic population. Percentages of item non-response on selected survey questions were compared for Hispanic respondents choosing to complete the survey in Spanish and those choosing to complete the survey in English. The mean number of attempts to complete the survey was also compared based on language preference among Hispanic respondents. The sample size of Hispanic persons in the Behavioral Risk Factor Surveillance System saw little growth compared to the actual growth of the Hispanic population in the United States. Significant differences in survey item non-response for nine of 15 survey questions were seen based on language preference. Hispanic respondents choosing to complete the survey in Spanish had a significantly fewer number of call attempts for survey completion compared to their Hispanic counterparts choosing to communicate in English. Including additional measures of acculturation and increasing the sample size of Hispanic persons in a national health survey such as the Behavioral Risk Factor Surveillance System may result in more precise findings that could be used to better target prevention and health care needs for an ethnic minority population.


Myosin VI is required for the proper maturation and function of inner hair cell ribbon synapses.
The ribbon synapses of auditory inner hair cells (IHCs) undergo morphological and electrophysiological transitions during cochlear development. Here we report that myosin VI (Myo6), an actin-based motor protein involved in genetic forms of deafness, is necessary for some of these changes to occur. By using post-embedding immunogold electron microscopy, we showed that Myo6 is present at the IHC synaptic active zone. In Snell's waltzer mutant mice, which lack Myo6, IHC ionic currents and ribbon synapse maturation proceeded normally until at least post-natal day 6. In adult mutant mice, however, the IHCs displayed immature potassium currents and still fired action potentials, as normally only observed in immature IHCs. In addition, the number of ribbons per IHC was reduced by 30%, and 30% of the remaining ribbons were morphologically immature. Ca2+-dependent exocytosis probed by capacitance measurement was markedly reduced despite normal Ca2+ currents and the large proportion of morphologically mature synapses, which suggests additional defects, such as loose Ca2+-exocytosis coupling or inefficient vesicular supply. Finally, we provide evidence that Myo6 and otoferlin, a putative Ca2+ sensor of synaptic exocytosis also involved in a genetic form of deafness, interact at the IHC ribbon synapse, and we suggest that this interaction is involved in the recycling of synaptic vesicles. Our findings thus uncover essential roles for Myo6 at the IHC ribbon synapse, in addition to that proposed in membrane turnover and anchoring at the apical surface of the hair cells.


Postperovskite phase transition of ZnGeO3: comparative crystal chemistry of postperovskite phase transition from germanate perovskites.
The postperovskite phase of ZnGeO3 was confirmed by laser heating experiments of the perovskite phase under 110-130 GPa at high temperature. Ab initio calculations indicated that the phase transition occurs at 133 GPa at 0 K. This postperovskite transition pressure is significantly higher than those reported for other germanates, such as MnGeO3 and MgGeO3. The comparative crystal chemistry of the perovskite-to-postperovskite transition suggests that a relatively elongated b-axis in the low-pressure range resulted in the delay in the transition to the postperovskite phase. Similar to most GdFeO3-type perovskites that transform to the CaIrO3-type postperovskite phase, ZnGeO3 perovskite eventually transformed to the CaIrO3-type postperovskite phase at a critical rotational angle of the GeO6 octahedron. The formation of the postperovskite structure at a very low critical rotational angle for MnGeO3 suggests that relatively large divalent cations likely break down the corner-sharing GeO6 frameworks without a large rotation of GeO6 to form the postperovskite phase.


2019 WACEM - Academic College of Emergency Experts Consensus Recommendations on Admission Criteria to Pediatric Intensive Care Unit from the Emergency Departments in India.
There is a global variation in policies that define clear indications for pediatric intensive care unit (PICU) admissions. In resource-limited countries where PICU service availability is limited, the admission criteria to PICU are urgently needed to optimize the utilization of available intensive care services and to maximize patient benefit. The objective of these consensus recommendations on PICU admission criteria is to provide a framework and reference for future policy development by professional societies and governments. The consensus recommendations were developed by a multidisciplinary consensus task force comprised of international experts in pediatric critical care, emergency medicine, trauma, critical care, and health policy stakeholders during the 2016 annual INDUSEM WORLD CONGRESS in Bengaluru, India. A task force steering committee completed a global literature search about PICU admission criteria development, reviewed PICU admission guidelines published by a variety of professional organizations worldwide, and performed a literature review of relevant publications. The objectives of this task force is to provide a framework for validated approach to determine appropriateness of intensive care unit (ICU) admission in India (resource-limited setting) based on (a) prioritization modeling; (b) general clinical criteria; (c) clinical and objective parameters; and (d) other criteria. The expert consensus panel then discussed and ranked proposed criteria according to scientific evidence, the current standard of care, and expert opinion in the context of the Indian health system. The general subject was addressed in sections: admission criteria and benefits of different levels of care. Following the appraisal of the literature, discussion, and consensus, recommendations were written. Although these are consensus recommendations, the subjects addressed encompass complex ethical and medicolegal aspects of patient care that affect daily clinical practice. The scarcity of high-quality evidence made it difficult to answer all the questions asked related to ICU admission. Despite these limitations, the members of the task force believe that these recommendations provide a comprehensive framework to guide practitioners in making informed decisions during the admission process. This publication is designed to assist in future development of health policies to ensure effective resource allocation, maximize healthcare benefits, and improve access to quality care for children.


Effect of HIV infection on menstrual cycle length.
HIV serostatus and menstrual function were examined using prospectively collected menstrual data from 802 HIV-seropositive and 273 HIV-seronegative women, ages 20 to 44, enrolled in two cohort studies of HIV infection in North American women. The associations between HIV serostatus and the probabilities of having a cycle lasting >40 days (n = 541 cycles), >90 days (n = 67 cycles), <18 days (n = 316 cycles) and mean length and variability of 18 to 40 day cycles (n = 3,634) were assessed. After adjustment for demographic characteristics, body mass index, and substance use, seropositivity increased the odds of having a very short cycle (< 18 days, odds ratio [OR], 1.45; 95% confidence interval [CI], 1.00-2.11) and a very long cycle (>90 days, OR, 1.32; 95% CI, 0.68-2.58) slightly, although the latter CIs include one. Seropositivity did not increase the odds of having a moderately long cycle (>40 days, OR, 1.14) or affect mean cycle length or variability (beta, 0.30 +/- 0.20; between-woman standard deviation [SD], 2.2 days [HIV-seronegative] and 1.9 days [HIV-seropositive]; within-woman SD, 3.5 days for both). Although seropositivity may slightly increase the probability of very short cycles, HIV serostatus has little overall effect on amenorrhea, menstrual cycle length, or variability. Among HIV-seropositive women, higher viral loads and lower CD4+ counts were associated with increased cycle variability and polymenorrhea.


Parent health beliefs, social determinants of health, and child health services utilization among U.S. school-age children with autism.
Substantial variation exists in autism spectrum disorder (ASD) care by race, ethnicity, and socioeconomic status; however, the role of parent health beliefs in this variation is poorly understood. Study goals were to (1) examine variation in parent beliefs about ASD prognosis and treatment according to social determinants of health (SDH) and (2) assess whether this variation was associated with variable health services utilization, among 1420 children with special health care needs (CSHCN) having ASD. We used linked data from the 2011 Survey of Pathways to Diagnosis and Treatment and the 2009-2010 National Survey of Children with Special Health Care Needs. Bivariate and multivariate analyses assessed variation in parent beliefs according to race/ethnicity, household income, and parent educational attainment. Further analyses assessed whether variation in beliefs was associated with the use of psychotropic medication, traditional therapy, or complementary/alternative therapy for ASD. Parents of lower educational attainment or who had lower income were more likely to think that their child's condition was a mystery. Near-poor families were less likely to believe that they had the power to change the child's condition. Parents of minority children were more likely than white children to view their child's condition as temporary. However, these differences in beliefs only had modest associations with variation in use of the health services analyzed. Some SDH-related variation exists in health beliefs among parents of children with ASD, but these differences may not be the main factors accounting for ASD health care disparities.


Provision of care for chronic kidney disease by non-nephrologists in a developing nation: a national survey.
The prevalence of chronic kidney disease (CKD) in developing countries has increased dramatically. This study aimed to explore the practice patterns of non-dialysis-dependent CKD care in an affluent developing country. Primary and specialised healthcare facilities of public and private sectors in the United Arab Emirates. 159 non-nephrologist physicians practising in the United Arab Emirates. A 28-item online self-administered questionnaire based on CKD clinical practice guidelines. The physicians' approach to identifying and managing patients with CKD. The survey was completed by 159 non-nephrologists, of whom 135 reported having treated patients with CKD. Almost all the respondents screen patients with hypertension and diabetes for CKD, but one-third of them do not screen patients with cardiovascular disease and elderly patients for CKD. The use of accurate CKD screening tests (estimated glomerular filtration rate and albumin/creatinine ratio) was suboptimal (77% and 59% of physicians used the procedures, respectively). One-third of the physicians do not offer treatment with inhibitors of the renin-angiotensin system to patients with CKD, and only 66% offer antilipid treatment. In general, the primary healthcare physicians are more familiar than secondary healthcare physicians with the diagnosis and management of patients with CKD. We identified substantial physician-declared deficiencies in the practice of identifying and managing early CKD. Integration of quality CKD care within the healthcare system is required to face the increasing burden of CKD in the United Arab Emirates and possibly in other developing nations.


Geographic variation in resource use for coronary artery bypass surgery. IHD Port Investigators.
The purpose of this study was to examine the national variability in patient-level cost and length of stay for coronary artery bypass grafting (CABG) in Medicare patients. Retrospective multivariate regression analysis was done using Medicare administrative files and American Hospital Association files. Patients in the study had an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure code for CABG, with accompanying 1990 procedure data, in the Medicare Provider Analysis and Review File (n = 92,449). Outcome measures used were inpatient cost (exclusive of professional fees) and inpatient length of stay associated with bypass admission. The national average cost of bypass surgery was $22,847 (median $18,783), with an accompanying average length of stay of 16 days (median 13 days). Multivariate regression analysis revealed that patient-level cost and length of stay were related to clinical, demographic, hospital, and regional characteristics (R2 = 25% and 16%, respectively). After accounting for these characteristics at the patient level, considerable variation among states persisted in both cost and length of stay. In addition, states with similar adjusted lengths of stay varied widely with respect to adjusted cost. No relation was found at the state level between level of resource use and either procedural mortality or 60-day mortality/readmission rates. Considerable variability exists among states in patient-level cost and length of stay for CABG surgery, after adjusting to the extent possible for clinical, demographic, hospital, and regional characteristics. The lack of association at the state level between resource use and rates of mortality and hospital readmission suggests that costs could be reduced in many areas of the United States without compromising quality of care.


Self-perception of aging and acute medical events in chronically institutionalized middle-aged and older persons with schizophrenia.
To examine the relationship between self-perceptions of aging and acute medical events in chronically institutionalized middle-aged and older persons with schizophrenia. Participants were 83 persons with schizophrenia (30% women; mean age = 58.48, SD = 8.14) residing in a long-stay care home, who were without organic mental disorders, mental retardation, serious audiovisual impairment, and serious cognitive and physical impairment. They received assessments in body mass index, functional health, and global mental status, and responded to measures of self-perception of aging at baseline. Acute events that required medical attention were recorded for the next 3 months. 8% of the participants had acute medical events. Bivariate analysis suggested that number of comorbid medical conditions, mobility, Mini-Mental State Examination, and negative self-perception of aging were predictive of acute medical events. However, multivariate analysis (logistic regression) showed that only mobility (OR = 0.78, p = 0.04) and negative self-perception of aging (OR = 3.38, p = 0.02) had independent effects on acute medical events, with the latter being the stronger predictor. Positive aging self-perception, body mass index, and smoking were unrelated to medical events. Physical vulnerabilities may not be sufficient to explain the development of acute medical events in late-life schizophrenia. How individuals perceive their aging process, which is expected to regulate health behavior and help-seeking, may be an even more important factor. Further research should investigate whether such self-perceptions, which are probably rooted in stereotypes about aging socialized early in life, are modifiable in this population.


VIP17/MAL expression modulates epithelial cyst formation and ciliogenesis.
The polarized organization of epithelial cells is required for vectorial solute transport and may be altered in renal cystic diseases. Vesicle integral protein of 17 kDa (VIP17/MAL) is involved in apical vesicle transport. VIP17/MAL overexpression in vivo results in renal cystogenesis of unknown etiology. Renal cystogenesis can occur as a consequence of defects of the primary cilium. To explore the role of VIP17/MAL in renal cystogenesis and ciliogenesis, we examined the polarization and ciliary morphology of wild-type and VIP17/MAL overexpressing Madin-Darby canine kidney renal epithelial cells grown in two-dimensional (2D) and three-dimensional (3D) cyst culture. VIP17/MAL is apically localized when expressed in cells maintained in 2D and 3D culture. VIP17/MAL overexpressing cells produce more multilumen cysts compared with controls. While the distributions of basolateral markers are not affected, VIP17/MAL expression results in aberrant sorting of the apical marker gp135 to the primary cilium. VIP17/MAL overexpression is also associated with shortened or absent cilia. Immunofluorescence analysis performed on kidney sections from VIP17/MAL transgenic mice also demonstrates fewer and shortened cilia within dilated lumens (P < 0.01). These studies demonstrate that VIP17/MAL overexpression results in abnormal cilium and cyst development, in vitro and in vivo, suggesting that VIP17/MAL overexpressing mice may develop cysts secondary to a ciliary defect.


Pneumonia among adults hospitalized with laboratory-confirmed seasonal influenza virus infection-United States, 2005-2008.
Influenza and pneumonia combined are the leading causes of death due to infectious diseases in the United States. We describe factors associated with pneumonia among adults hospitalized with influenza. Through the Emerging Infections Program, we identified adults ≥ 18 years, who were hospitalized with laboratory-confirmed influenza during October 2005 through April 2008, and had a chest radiograph (CXR) performed. Pneumonia was defined as the presence of a CXR infiltrate and either an ICD-9-CM code or discharge summary diagnosis of pneumonia. Among 4,765 adults hospitalized with influenza, 1392 (29 %) had pneumonia. In multivariable analysis, factors associated with pneumonia included: age ≥ 75 years, adjusted odds ratio (AOR) 1.27 (95 % confidence interval 1.10-1.46), white race AOR 1.24 (1.03-1.49), nursing home residence AOR 1.37 (1.14-1.66), chronic lung disease AOR 1.37 (1.18-1.59), immunosuppression AOR 1.45 (1.19-1.78), and asthma AOR 0.76 (0.62-0.92). Patients with pneumonia were significantly more likely to require intensive care unit (ICU) admission (27 % vs. 10 %), mechanical ventilation (18 % vs. 5 %), and to die (9 % vs. 2 %). Pneumonia was present in nearly one-third of adults hospitalized with influenza and was associated with ICU admission and death. Among patients hospitalized with influenza, older patients and those with certain underlying conditions are more likely to have pneumonia. Pneumonia is common among adults hospitalized with influenza and should be evaluated and treated promptly.


Wigner distribution and fractional Fourier transform for two-dimensional symmetric optical beams.
A useful relationship between the fractional Fourier transform power spectra of a two-dimensional symmetric optical beam, on the one hand, and its Wigner distribution, on the other, is established. This relationship allows a significant simplification of the standard procedure for the reconstruction of the Wigner distribution from the field intensity distributions in the fractional Fourier domains. The Wigner distribution of a symmetric optical beam is analyzed, both in the coherent and in the partially coherent case.


Influence of scale on electrostatic forces and torques in AC particulate electrokinetics.
Dielectrophoretic forces and torques move and manipulate biological cells, typically of the order of 10 mum ( approximately 10(-5) m) in diameter and ordinarily suspended in aqueous liquids, using electrodes with dimensions around 100 mum ( approximately 10(-4) m). The ability to exploit these same electromechanical effects for particles below 1 mum, that is, <10(-6) m, creates opportunities for remote manipulation and handling of subcellular components, biological macromolecules, and DNA. In this paper, Trimmer's bracket notation is adapted for systematic examination of the scaling laws governing electrokinetic behaviour. The purpose is to shed light on how critical performance measures relevant to the laboratory on a chip are affected by reducing particle sizes and electrode dimensions into the nanometre range. The scaling methodology facilitates consideration of the effect of electrode structure and particle size reduction on voltage, electric field, heating, and response time. Particles with induced moments, dipolar and quadrupolar, as well as permanent dipoles are examined. Separate consideration is given to electrical torque and its application in electrorotation and particle alignment. An eventual goal of these scaling studies is to identify the lower limit on the size of particles that can be manipulated effectively using electrokinetic phenomena.


Changes in massive transfusion over time: an early shift in the right direction?
Increasing evidence suggests that high fresh frozen plasma:packed red blood cell (FFP:PRBC) and platelet:PRBC (PLT:PRBC) transfusion ratios may prevent or reduce the morbidity associated with early coagulopathy which complicates massive transfusion (MT). We sought to characterize changes in resuscitation which have occurred over time in a cohort severely injured patients requiring MT. Data were obtained from a multicenter prospective cohort study evaluating outcomes in blunt injured adults with hemorrhagic shock. MT was defined as requiring ≥10 units PRBCs within 24 hours postinjury. Mean PRBC, FFP, and PLT requirements (per unit; 6 hours, 12 hours, and 24 hours) were determined over time (2004-2009). Sub-MT, those patients just below the threshold for MT, were defined as requiring ≥7 and <10 units PRBCs in the initial 24 hours. The percent of resuscitation given at 6 hours relative to 24 hours total (6 of 24%) was determined and compared across "early" (admission until December 2007) and "recent" (after December 2007) periods for each component. Over the study time period (2004-2009) for the MT group (n = 526), initial base deficit and presenting international normalized ratio were unchanged, while Injury Severity Score was significantly higher. The percent of patients who required MT overall significantly decreased over time. No significant differences were found over time for six-hour, 12-hour, or 24-hour FFP:PRBC and PLT:PRBC transfusion ratios in MT patients. Sub-MT patients (n = 344) had significantly higher six-hour FFP:PRBC ratios and significantly higher six-hour,12-hour, and 24-hour PLT:PRBC ratios in the recent time period. The six h/24 h% total for FFP and PLT transfusion was significantly greater in the recent time period. (FFP: 54% vs.70%; p = 0.004 and PLT 46% vs. 61%; p = 0.048). In a severely injured cohort requiring MT, FFP:PRBC and PLT:PRBC ratios have not changed over time, whereas the rate of MT overall has significantly decreased. During the recent time period (after December 2007), significantly higher transfusion ratios and a greater percent of 6-hour/24-hour FFP and PLT were found in the sub-MT group, those patients just below the PRBC transfusion threshold definition of MT. These data suggest early, more aggressive attainment of high transfusions ratios may reduce the requirement for MT and may shift overall blood requirements below those which currently define MT. Further prospective evidence is required to verify these findings.


The Arabidopsis pattern recognition receptor EFR enhances fire blight resistance in apple.
Fire blight disease, caused by the bacterium Erwinia amylovora (E. amylovora), is responsible for substantial losses in cultivated apples worldwide. An important mechanism of plant immunity is based on the recognition of conserved microbial molecules, named pathogen-associated or microbe-associated molecular patterns (PAMPs or MAMPs), through pattern recognition receptors (PRRs), leading to pattern-triggered immunity (PTI). The interspecies transfer of PRRs represents a promising strategy to engineer broad-spectrum and durable disease resistance in crops. EFR, the Arabidopsis thaliana PRR for the PAMP elf18 derived from the elongation factor thermal unstable (EF-Tu) proved to be effective in improving bacterial resistance when expressed into Solanaceae and other plant species. In this study, we tested whether EFR can affect the interaction of apple with E. amylovora by its ectopic expression in the susceptible apple rootstock M.26. Stable EFR expression led to the activation of PAMP-triggered immune response in apple leaves upon treatment with supernatant of E. amylovora, as measured by the production of reactive oxygen species and the induction of known defense genes. The amount of tissue necrosis associated with E. amylovora infection was significantly reduced in the EFR transgenic rootstock compared to the wild-type. Our results show that the expression of EFR in apple rootstock may be a valuable biotechnology strategy to improve the resistance of apple to fire blight.


The effect of continuous positive airway pressure treatment on physical activity in patients with obstructive sleep apnoea: A randomised controlled trial.
Continuous positive airway pressure (CPAP) improves daytime sleepiness in patients with obstructive sleep apnoea (OSA). The effect of CPAP on physical activity is unclear. We hypothesized that activity would increase after CPAP treatment. A double blind, parallel, randomised, controlled trial using therapeutic and placebo CPAP was performed in men with newly diagnosed OSA (more than 10>4% SaO(2) dips/hour and Epworth Sleepiness Score [ESS] 9). Activity was measured by wrist actigraphy before and after three months of CPAP therapy. Thirty-six men completed 1 week of continuous actigraphy before and after therapeutic CPAP (n=16) or placebo CPAP (n=20). The two groups were well-matched at baseline, with no significant differences in mean age, body mass index, ESS and SaO(2) dips/hour. Mean (SD) ESS and modified maintenance of wakefulness test (OSLER) improved significantly after CPAP. ESS change in the therapeutic group was -6.1 (4.4), compared to placebo, -2.8 (5.0); difference between groups p=0.04; OSLER (minutes), therapeutic +10.4 (14.4), placebo -5.0 (12.0), p=0.003. There was no significant difference between groups in mean hourly activity levels for the seven days at baseline; activity levels did not significantly change in either group after CPAP [daytime activity (arbitrary units): therapeutic -13.9 (93.1) vs. placebo +8.3 (62.9), p=0.4]. There was no correlation between change in activity and CPAP use. Activity does not increase after CPAP in men with OSA, despite improvements in daytime sleepiness. The reasons for this are not clear, but may be due to longstanding, habitual patterns of activity.


Doing Good with Good OR: Supporting Cost-effective Hepatitis B Interventions.
In an era of limited healthcare budgets, mathematical models can be useful tools to identify cost-effective programs and to support policymakers in informed decision making. This paper reports results of our work carried out over several years with the Asian Liver Center at Stanford University, a nonprofit outreach and advocacy organization that is an international leader in the fight against hepatitis B and liver cancer. Hepatitis B is a vaccine-preventable viral disease that, if untreated, can lead to death from cirrhosis and liver cancer. Infection with hepatitis B is a major public health problem, particularly in Asian populations. We used new combinations of decision analysis and Markov models to analyze the cost-effectiveness of several interventions to combat hepatitis B in the United States and China. The results of our OR-based analyses have helped change United States public health policy on hepatitis B screening for millions of people and have helped encourage policymakers in China to enact legislation to provide free catch-up vaccination for hundreds of millions of children. These policies are an important step in eliminating health disparities, reducing discrimination, and ensuring that millions of people who need it can now receive hepatitis B vaccination or lifesaving treatment.


Psychiatric outcomes at age seven for very preterm children: rates and predictors.
Uncertainty remains about the rate of specific psychiatric disorders and associated predictive factors for very preterm (VPT) children. The aims of this study were to document rates of psychiatric disorders in VPT children aged 7 years compared with term born children, and to examine potential predictive factors for psychiatric diagnoses in VPT children. Participants were 177 VPT and 65 term born children. Perinatal medical data were collected, which included brain abnormalities detected using magnetic resonance imaging. The Infant-Toddler Social-Emotional Assessment (ITSEA) and Strengths and Difficulties Questionnaire (SDQ) were administered at 2 and 5 years respectively. At 7 years of age, the Developmental and Well-being Assessment (DAWBA) was used to indicate psychiatric diagnoses. Compared with term born children, VPT children had three times the odds of meeting criteria for any psychiatric diagnosis at age 7 years (odds ratio 3.03; 95% confidence interval 1.23, 7.47, p = .02). The most common diagnoses were anxiety disorders (11% VPT, 8% term), attention-deficit/hyperactivity disorder (10% VPT, 3% term) and autism spectrum disorder (4.5% VPT, 0% term). For VPT children, those with severe global brain abnormalities (p = .02), those who displayed social-emotional problems at age 5 (p = .000) and those with higher social risk at age 7 (p = .001) were more likely to meet criteria for a psychiatric illness at age 7. Compared with term born children, VPT children have higher rates of psychiatric diagnoses at early school age, predicted by neonatal brain abnormalities, prior social-emotional problems and social factors.


Dermatologic and dental aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements.
The 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference was convened to update the last consensus statement in 1998. Skin and dental lesions are common in tuberous sclerosis complex (TSC) and are a frequent concern for patients. Recognition of these lesions is imperative for early diagnosis, given the treatment advances that may improve patient outcomes. To detail recommendations for the diagnosis, surveillance, and management of skin and dental lesions in TSC. The TSC Dermatology and Dentistry Subcommittee, 1 of 12 subcommittees, reviewed the relevant literature from 1997 to 2012. A consensus on skin and dental issues was achieved within the Dermatology and Dentistry Subcommittee before recommendations were presented, discussed, and agreed on in a group meeting of all subcommittees from June 14 to 15, 2012. Skin and dental findings comprise 4 of 11 major features and 3 of 6 minor features in the diagnostic criteria. A definite diagnosis of TSC is defined as the presence of at least 2 major features or 1 major and 2 or more minor features; in addition, a pathological mutation in TSC1 or TSC2 is diagnostic. Skin and oral examinations should be performed annually and every 3 to 6 months, respectively. Intervention may be indicated for TSC skin or oral lesions that are bleeding, symptomatic, disfiguring, or negatively affecting function. Options presented include surgical excision, laser(s), or use of a mammalian target of rapamycin inhibitor.


Is it acceptable to contact an anonymous egg donor to facilitate diagnostic genetic testing for the donor-conceived child?
We discuss a case where medically optimal investigations of health problems in a donor-conceived child would require their egg donor to participate in genetic testing. We argue that it would be justified to contact the egg donor to ask whether she would consider this, despite her indicating on a historical consent form that she did not wish to take part in future research and that she did not wish to be informed if she was found to be a carrier of a 'harmful inherited condition'. We suggest that we cannot conjecture what her current answer might be if, by participating in clinical genetic testing, she might help reach a diagnosis for the donor-conceived child. At the point that she made choices regarding future contact, it was not yet evident that the interests of the donor-conceived child might be compromised by her answers, as it was not foreseen that the egg donor's genome might one day have the potential to enable diagnosis for this child. Fertility consent forms tend to be conceptualised as representing incontrovertible historical boundaries, but we argue that rapid evolution in genomic practice means that consent in such cases is better seen as an ongoing and dynamic process. It cannot be possible to compel the donor to aid in the diagnosis of the donor-conceived child, but she should be given the opportunity to do so.


Predictors of early death and survival among children, adolescents and young adults with acute myeloid leukaemia in California, 1988-2011: a population-based study.
A better understanding of factors associated with early death and survival among children, adolescents and young adults with acute myeloid leukaemia (AML) may guide health policy aimed at improving outcomes in these patients. We examined trends in early death and survival among 3935 patients aged 0-39 years with de novo AML in California during 1988-2011 and investigated the associations between sociodemographic and selected clinical factors and outcomes. Early death declined from 9·7% in 1988-1995 to 7·1% in 2004-2011 (P = 0·062), and survival improved substantially over time. However, 5-year survival was still only 50% (95% confidence interval 47-53%) even in the most recent treatment period (2004-2011). Overall, the main factors associated with poor outcomes were older age at diagnosis, treatment at hospitals not affiliated with National Cancer Institute-designated cancer centres, and black race/ethnicity. For patients diagnosed during 1996-2011, survival was lower among those who lacked health insurance compared to those with public or private insurance. We conclude that mortality after AML remained strikingly high in California and increased with age. Possible strategies to improve outcomes include wider insurance coverage and treatment at specialized cancer centres.


Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta-analysis.
Lipoarabinomannan (LAM) is a potential marker of active tuberculosis (TB). We performed a systematic review and meta-analysis regarding use of urinary LAM assays for diagnosing active TB. We systematically searched for published and unpublished studies that evaluated urinary LAM for active TB diagnosis. Extracted data were pooled using bivariate random effects models and hierarchical summary receiver operating characteristic curves. Heterogeneity was explored through subgroup analysis and meta-regression. Quality was assessed according to standardised QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. In seven studies that assessed test accuracy in microbiologically confirmed cases only, estimates of sensitivity ranged from 13% to 93%, while specificity ranged from 87% to 99%. In five studies that assessed accuracy in clinical and confirmed TB cases, sensitivity ranged from 8% to 80%, while specificity ranged from 88% to 99%. In five studies with results stratified by HIV status, sensitivity was 3-53% higher in HIV-positive than HIV-negative subgroups; sensitivity was highest with advanced immunosuppression. The LAM urinary assay has several characteristics that make it attractive for diagnosing active TB, but has suboptimal sensitivity for routine clinical use. Further studies are needed to evaluate the potential value of the LAM assay in individuals with advanced HIV or for diagnosis of paediatric TB.


Association of multiple preventive therapies postdischarge and long-term health outcomes after acute myocardial infarction.
Statins, beta-blockers, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers have been advocated by guidelines as secondary prevention medications to improve the long-term outcomes of post-acute myocardial infarction (AMI) patients. However, adequate drug adherence has always been challenging, and different treatment regimens may lead to divergent outcomes that remain unclear under current myocardial infarction (MI) care standards. This study investigated the association between use of different preventive regimens post-AMI and patients' long-term outcomes. This cohort study used data files from the Taiwan National Health Insurance Research Database. A total of 77 520 people who were hospitalized with AMI between 2002 and 2015 were assessed. On the basis of medication possession ratio (MPR) to individual medications, eight treatment groups were examined in this study. Receiving therapy was defined as MPR ≥40%. We investigated the association between different treatment groups and all-cause mortality in 24 months. Overall, 51 322 patients with ST-elevation MI and 26 198 with non-ST-elevation MI were included in the study. Patients received all three preventive medications show the lowest mortality in 24 months follow-up periods among all treatment groups. Patients who did not usage of any of these three preventive medications had the highest mortality in 24 months (adjusted hazard ratio, 1.78; 95% CI, 1.64-1.93). This mortality rate had the same pattern across the three cohort generations (2002-2005, 2006-2010, and 2011-2015). In this large population-based real-world study, usage of three preventive therapies post-MI was associated with the lowest rate of all-cause mortality.


Lymphoid development in mice congenitally lacking T cell receptor alpha beta-expressing cells.
Vertebrate T cells express either an alpha beta or gamma delta T cell receptor (TCR). The developmental relatedness of the two cell types is unresolved. alpha beta + T cells respond to specific pathogens by collaborating with immunoglobulin-producing B cells in distinct lymphoid organs such as the spleen and Peyer's patches. The precise influence of alpha beta + T cells on B cell development is poorly understood. To investigate the developmental effects of alpha beta + T cells on B cells and gamma delta + T cells, mice homozygous for a disrupted TCR alpha gene were generated. The homozygotes showed elimination of alpha beta + T cells and the loss of thymic medullae. Despite this, gamma delta + T cells developed in normal numbers, and there was an increase in splenic B cells.


A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma.
Preclinical studies suggest that interleukin-9 may be a central mediator in the development and maintenance of airway inflammation in asthma. The aim of this study was therefore to evaluate the effects of MEDI-528, an anti-interleukin-9 monoclonal antibody, in adults with confirmed uncontrolled moderate-to-severe asthma. In this prospective double-blind, multicenter, parallel-group study, 329 subjects were randomized (1:1:1:1) to subcutaneous placebo or MEDI-528 (30, 100, 300 mg) every 2 weeks for 24 weeks, in addition to their usual asthma medications. The primary endpoint was change in mean Asthma Control Questionnaire-6 (ACQ-6) score at week 13. Secondary endpoints included weighted asthma exacerbation rates and pre-bronchodilator forced expiratory volume in 1 second (FEV1) at weeks 13 and 25, as well as Asthma Quality of Life Questionnaire scores at weeks 12 and 25 and the safety of MEDI-528 throughout the study period. The primary endpoint was analyzed using analysis of covariance. The study population (n = 327) was predominantly female (69%) with a mean age of 43 years (range 18-65). The mean (SD) baseline ACQ-6 score for placebo (n = 82) and combined MEDI-528 (n = 245) was 2.8 (0.7) and 2.8 (0.8); FEV1 % predicted was 70.7% (15.9) and 71.5% (16.7). Mean (SD) change from baseline to week 13 in ACQ-6 scores for placebo vs combined MEDI-528 groups was -1.2 (1.0) vs -1.2 (1.1) (p = 0.86). Asthma exacerbation rates (95% CI) at week 25 for placebo vs MEDI-528 were 0.58 (0.36-0.88) vs 0.49 (0.37-0.64) exacerbations/subject/year (p = 0.52). No significant improvements in FEV1 % predicted were observed between the placebo and MEDI-528 groups. Adverse events were comparable for placebo (82.9%) and MEDI-528 groups (30 mg, 76.5%; 100 mg, 81.9%; 300 mg, 85.2%). The most frequent were asthma (placebo vs MEDI-528, 30.5% vs 33.5%), upper respiratory tract infection (14.6% vs 17.1%), and headache (9.8% vs 9.8%). The addition of MEDI-528 to existing asthma controller medications was not associated with any improvement in ACQ-6 scores, asthma exacerbation rates, or FEV1 values, nor was it associated with any major safety concerns. ClinicalTrials.gov: NCT00968669.


Prospective associations of cardiovascular disease with physical performance and disability : A longitudinal cohort study in the Osteoarthritis Initiative.
Literature regarding cardiovascular disease (CVD) and incident physical performance limitations and disability in older people is equivocal. This study aimed to investigate whether CVD is longitudinally associated with incident physical performance limitations and disability in a large population-based sample. This was an 8‑year prospective study using data collected as part of the Osteoarthritis Initiative. Participants were community-dwelling adults with knee osteoarthritis or at high risk for this condition. Diagnosed CVD was self-reported. Physical performance was assessed with measures of chair stand time and gait speed, whereas disability was assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Longitudinal associations between CVD and changes in physical performance tests (chair stand time and gait speed) and disability score were analyzed using generalized linear models with repeated measurements. The analyzed sample comprised 4796 adults (mean age 61.2 years, 58.5% female), of whom 313 people (6.5%) reported CVD at baseline. During 8 years of follow-up, after adjustment for 11 potential confounders measured at baseline, those with CVD experienced a worse profile in chair stand time over the 8‑year follow-up period than those without CVD (p = 0.006). In a cohort of middle-aged and older adults with knee osteoarthritis or at high risk for this condition those with CVD experienced a worse profile in chair stand time over the 8‑year follow-up period than those without CVD; however, CVD was not significantly associated with an increased incidence of poor gait speed and disability over 8 years of follow-up. Importantly, no associations were observed when utilizing propensity score matching.


Mutations in the Bordetella pertussis bvgS gene that confer altered expression of the fhaB gene in Escherichia coli.
The bvg locus of Bordetella pertussis, required for coordinate regulation of virulence genes in response to environmental signals, encodes two proteins, BvgS and BvgA, that belong to the bacterial two-component signal transduction systems. We have isolated spontaneous mutations of the bvg locus in Escherichia coli and analyzed their effects on the expression of fhaB::lacZY transcriptional fusions. The mutations, localized in the linker and transmitter domain of BvgS, result in increased activation of fhaB and/or in insensitivity to a modulating agent, nicotinic acid.


The effectiveness of quality improvement collaboratives in improving stroke care and the facilitators and barriers to their implementation: a systematic review.
To successfully reduce the negative impacts of stroke, high-quality health and care practices are needed across the entire stroke care pathway. These practices are not always shared across organisations. Quality improvement collaboratives (QICs) offer a unique opportunity for key stakeholders from different organisations to share, learn and 'take home' best practice examples, to support local improvement efforts. This systematic review assessed the effectiveness of QICs in improving stroke care and explored the facilitators and barriers to implementing this approach. Five electronic databases (MEDLINE, CINAHL, EMBASE, PsycINFO, and Cochrane Library) were searched up to June 2020, and reference lists of included studies and relevant reviews were screened. Studies conducted in an adult stroke care setting, which involved multi-professional stroke teams participating in a QIC, were included. Data was extracted by one reviewer and checked by a second. For overall effectiveness, a vote-counting method was used. Data regarding facilitators and barriers was extracted and mapped to the Consolidated Framework for Implementation Research (CFIR). Twenty papers describing twelve QICs used in stroke care were included. QICs varied in their setting, part of the stroke care pathway, and their improvement focus. QIC participation was associated with improvements in clinical processes, but improvements in patient and other outcomes were limited. Key facilitators were inter- and intra-organisational networking, feedback mechanisms, leadership engagement, and access to best practice examples. Key barriers were structural changes during the QIC's active period, lack of organisational support or prioritisation of QIC activities, and insufficient time and resources to participate in QIC activities. Patient and carer involvement, and health inequalities, were rarely considered. QICs are associated with improving clinical processes in stroke care; however, their short-term nature means uncertainty remains as to whether they benefit patient outcomes. Evidence around using a QIC to achieve system-level change in stroke is equivocal. QIC implementation can be influenced by individual and organisational level factors, and future efforts to improve stroke care using a QIC should be informed by the facilitators and barriers identified. Future research is needed to explore the sustainability of improvements when QIC support is withdrawn. Protocol registered on PROSPERO ( CRD42020193966 ).


Functional Insights From the Evolutionary Diversification of Big Defensins.
Big defensins are antimicrobial polypeptides believed to be the ancestors of β-defensins, the most evolutionary conserved family of host defense peptides (HDPs) in vertebrates. Nevertheless, big defensins underwent several independent gene loss events during animal evolution, being only retained in a limited number of phylogenetically distant invertebrates. Here, we explore the evolutionary history of this fascinating HDP family and investigate its patchy distribution in extant metazoans. We highlight the presence of big defensins in various classes of lophotrochozoans, as well as in a few arthropods and basal chordates (amphioxus), mostly adapted to life in marine environments. Bivalve mollusks often display an expanded repertoire of big defensin sequences, which appear to be the product of independent lineage-specific gene tandem duplications, followed by a rapid molecular diversification of newly acquired gene copies. This ongoing evolutionary process could underpin the simultaneous presence of canonical big defensins and non-canonical (β-defensin-like) sequences in some species. The big defensin genes of mussels and oysters, two species target of in-depth studies, are subjected to gene presence/absence variation (PAV), i.e., they can be present or absent in the genomes of different individuals. Moreover, big defensins follow different patterns of gene expression within a given species and respond differently to microbial challenges, suggesting functional divergence. Consistently, current structural data show that big defensin sequence diversity affects the 3D structure and biophysical properties of these polypeptides. We discuss here the role of the N-terminal hydrophobic domain, lost during evolution toward β-defensins, in the big defensin stability to high salt concentrations and its mechanism of action. Finally, we discuss the potential of big defensins as markers for animal health and for the nature-based design of novel therapeutics active at high salt concentrations.


Developmental responses of amphibians to solar and artificial UVB sources: a comparative study.
Many amphibian species, in widely scattered locations, currently show population declines and/or reductions in range, but other amphibian species show no such declines. There is no known single cause for these declines. Differential sensitivity to UVB radiation among species might be one contributing factor. We have focused on amphibian eggs, potentially the most UVB-sensitive stage, and compared their resistance to UVB components of sunlight with their levels of photolyase, typically the most important enzyme for repair of the major UV photoproducts in DNA, cyclobutane pyrimidine dimers. Photolyase varied 100-fold among eggs/oocytes of 10 species. Among three species-Hyla regilla, Rana cascadae, and Bufo boreas-for which resistance of eggs to solar UVB irradiance in their natural locations was measured, hatching success correlated strongly with photolyase. Two additional species, Rana aurora and Ambystoma gracile, now show similar correlations. Among the low-egg-photolyase species, R. cascadae and B. boreas are showing declines, and the status of A. gracile is not known. Of the two high-photolyase species, populations of H. regilla remain robust, but populations of R. aurora are showing declines. To determine whether levels of photolyase or other repair activities are affected by solar exposures during amphibian development, we have initiated an extended study of H. regilla and R. cascadae, and of Xenopus laevis, laboratory-reared specimens of which previously showed very low photolyase levels. Hyla regilla and R. cascadae tadpoles are being reared to maturity in laboratories supplemented with modest levels of UV light or light filtered to remove UVB wavelengths. Young X. laevis females are being reared indoors and outdoors. Initial observations reveal severe effects of both UVA and UVB light on H. regilla and R. cascadae tadpoles and metamorphs, including developmental abnormalities and high mortalities. Assays of photolyase levels in the skins of young animals roughly parallel previous egg/oocyte photolyase measurements for all three species.


Survey of the nob5 mutation in C3H substrains.
A no b-wave (nob) electroretinography (ERG) phenotype arose spontaneously in a colony of C3H mice and was named nob5. A mutation was identified in the Gpr179 gene in homozygous nob5 mice. There is a concern that this mutation is also present in additional C3H sublines and may compromise retinal research performed using these lines. In this report, therefore, we provide a phenotype and genotype survey of nob5 in six C3H substrains present at the Jackson Laboratory. Fundus changes were evaluated in the six C3H substrains with image-guided optical coherence tomography (OCT), and retinal function was assessed with ERG. The substrains were genotyped with PCR using appropriate primers for the nob5 mutation. Additionally, the genomic sequences of C3H/HeJ, available from the Jackson Laboratory, and C3H/HeH, available from the Wellcome Trust Sanger Institute, were examined for the Gpr179(nob5) mutation. Two C3H congenic strains, C3Sn.BLiA-Pde6b(+) /DnJ and C3A.BLiA-Pde6b(+) /J, wild-type for Pde6b, used as the sighted control strains and had normal fundi, OCT, and ERG responses. Four C3H strains C3H/HeJ, C3HeB/FeJ, C3H/HeOuJ, and C3H/HeSnJ bearing the Pde6b(rd1) allele exhibited a grainy fundus appearance, retinal degeneration on OCT, and no rod and cone ERG responses. The nob5 mutation was not observed in the six C3H strains assessed with PCR genotyping. Further, the genomic sequences of C3H/HeJ and C3H/HeH did not contain the nob5 mutation. The Gpr179(nob5) allele is not present in C3H substrains at the Jackson Laboratory. Therefore, the usefulness of these C3H strains as commonly used models to study the effects of photoreceptor degeneration is not compromised.


Risks and responses to universal drinking water security.
Risks to universal drinking water security are accelerating due to rapid demographic, climate and economic change. Policy responses are slow, uneven and largely inadequate to address the nature and scale of the global challenges. The challenges relate both to maintaining water security in increasingly fragile supply systems and to accelerating reliable access to the hundreds of millions who remain water-insecure. A conceptual framework illustrates the relationship between institutional, operational and financial risks and drinking water security outcomes. We apply the framework to nine case studies from rural and urban contexts in South Asia and sub-Saharan Africa. Case studies are purposively selected based on established and emerging examples of political, technological or institutional reforms that address water security risks. We find broad evidence that improved information flows reduce institutional costs and promote stronger and more transparent operational performance to increase financial sustainability. However, political barriers need to be overcome in all cases through internal or external interventions that require often decadal time frames and catalytic investments. No single model exists, though there is sufficient evidence to demonstrate that risks to drinking water security can be reduced even in the most difficult and challenging contexts.


Monitoring dynamic alterations in calcium homeostasis by T (1)-weighted and T (1)-mapping cardiac manganese-enhanced MRI in a murine myocardial infarction model.
Manganese has been used as a T(1)-weighted MRI contrast agent in a variety of applications. Because manganese ions (Mn(2+)) enter viable myocardial cells via voltage-gated Ca(2+) channels, manganese-enhanced MRI is sensitive to the viability and inotropic state of the heart. In spite of the established importance of Ca(2+) regulation in the heart both before and after myocardial injury, monitoring strategies to assess Ca(2+) homeostasis in affected cardiac tissues are limited. This study implements a T(1)-mapping method to obtain quantitative information both dynamically and over a range of MnCl(2) infusion doses. To optimize the current Mn(2+) infusion protocols, we performed both dose-dependent and temporal washout studies. A non-linear relationship between infused MnCl(2) solution dose and increase in left ventricular wall relaxation rate (DeltaR(1)) was observed. Control mice also exhibited significant Mn(2+) clearance over time, with a decrease in DeltaR(1) of approximately 50% occurring in just 2.5 h. The complicated efflux time dependence possibly suggests multiple efflux mechanisms. With the use of the measured relationship between infused Mn(2+) dose, DeltaR(1), and inductively coupled plasma mass spectrometry data analysis provided a means of estimating the absolute heart Mn concentration in vivo. We show that this technique has the sensitivity to observe or monitor potential alterations in Ca(2+) handling in vivo because of the physiological remodeling after myocardial infarction. Left ventricular free wall DeltaR(1) values were significantly lower (P = 0.005) in the adjacent zone, surrounding the injured myocardial tissue, than in healthy tissue. This inferred reduction in Mn concentration can be used to estimate potentially salvageable myocardium in vivo for future treatment or evaluation of disease progression.