Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality.
The efficacy of mammographic screening in the reduction of breast carcinoma mortality has been demonstrated in randomized controlled trials. However, the evaluation of organized screening outside of research settings (so-called "service screening") faces unique methodologic and conceptual challenges. The current study describes the evaluation of organized mammography screening in a clinical setting and demonstrates the benefit obtained from service screening in two Swedish counties. In the group of subjects ages 20--69 years, there were 6807 women diagnosed with breast carcinoma over a 29-year period in 2 counties in Sweden and 1863 breast carcinoma deaths. All patients were classified from patient charts based on their screening status (i.e., whether they had been invited to undergo screening and whether they actually had undergone screening). The number of women who lived in the 2 counties during the 29-year study period was provided by the Central Bureau of Statistics. Breast carcinoma-specific mortality was compared across three time periods: 1) 1968--1977, when no screening was taking place because mammography had not been introduced; 2) 1978--1987, the approximate period of the Two-County randomized controlled trial of screening in women ages 40--74 years; and 3) 1988--1996, when all women in the 2 counties ages 40--69 years were invited to undergo screening (service screening). When comparing breast carcinoma mortality in screened women with that in women diagnosed before screening was introduced, a correction for self-selection bias was incorporated to prevent overestimation of the benefit of screening. The mortality from incident breast carcinoma diagnosed in women ages 40-69 years who actually were screened during the service screening period (1988--1996) declined significantly by 63% (relative risk [RR] = 0.37; 95% CI, 0.30--0.46) compared with breast carcinoma mortality during the time period when no screening was available (1968--1977). The mortality decline was 50% (RR = 0.50; 95% CI, 0.41--0.60) when breast carcinoma mortality among all women who were invited to undergo screening (nonattendees included) was compared with breast cancer mortality during the time period when no screening was available (1968--1977). The reduction in mortality observed during the service screening period, adjusted for selection bias, was 48% (RR = 0.52; 95% CI, 0.43--0.63). No significant change in breast carcinoma mortality was observed over the three time periods in women who did not undergo screening. This group included women ages 20--39 years because these individuals were never invited to undergo screening, and women ages 40--69 years who did not undergo screening (not invited during the randomized trial or invited during the second and third time periods but declined). Regular mammographic screening resulted in a 63% reduction in breast carcinoma death among women who actually underwent screening. The policy of invitation to organized screening with mammography appears to have reduced breast carcinoma mortality by 50% in these 2 counties.


Initial experiences with the enhanced recovery after surgery (ERAS) protocol in open radical cystectomy.
This article describes the authors' experiences with the implementation of the Enhanced Recovery After Surgery (ERAS) protocol for open radical cystectomy (ORC). Adherence to the ERAS cystectomy protocol was assessed; secondary outcome measures were impact on perioperative complication rate (Clavien-Dindo classification), time to first defecation, postoperative length of stay and hospital readmission rate. This retrospective feasibility study compared outcomes with patients in a historical control group. The study group (ERAS) consisted of 31 consecutive patients undergoing ORC and urinary diversion during 1 year from 1 January to 31 December 2011. The control group (pre-ERAS) comprised 39 consecutive patients operated on during 2010. Follow-up was 30 days. There were no significant demographic differences between the two groups, and no differences in complications graded Clavien III or above, or in total length of stay. The ERAS group had statistically significantly shorter mean time to first passage of stool and statistically significantly lower readmission frequency than the pre-ERAS group. The number of patients was small and the study was not randomized; moreover, the use of historical controls inevitably introduced different types of bias. Introduction of the ERAS protocol is clearly feasible in cystectomy, and may improve clinical outcomes in terms of faster return of bowel function and reduction of readmission within 30 days. However, more and larger studies are needed to prove the efficacy of ERAS for patients undergoing ORC.


SPARC regulates microgliosis and functional recovery following cortical ischemia.
Secreted protein acidic rich in cysteine (SPARC) is a matricellular protein that modulates the activity of growth factors, cytokines, and extracellular matrix to play multiple roles in tissue development and repair, such as cellular adhesion, migration, and proliferation. Throughout the CNS, SPARC is highly localized in mature ramified microglia, but its role in microglia--in development or during response to disease or injury--is not understood. In the postnatal brain, immature amoeboid myeloid precursors only induce SPARC expression after they cease proliferation and migration, and transform into mature, ramified resting microglia. SPARC null/CX3CR1-GFP reporter mice reveal that SPARC regulates the distribution and branching of mature microglia, with significant differences between cortical gray and white matter in both controls and SPARC nulls. Following ischemic and excitotoxic lesion, reactive, hypertrophic microglia rapidly downregulate and release SPARC at the lesion, concomitant with reactive, hypertrophic perilesion astrocytes upregulating SPARC. After photothrombotic stroke in the forelimb sensorimotor cortex, SPARC nulls demonstrate enhanced microgliosis in and around the lesion site, which accompanies significantly enhanced functional recovery by 32 d after lesion. Microglia from SPARC nulls also intrinsically proliferate at a greater rate in vitro--an enhanced effect that can be rescued by the addition of exogenous SPARC. SPARC is thus a novel regulator of microglial proliferation and structure, and, in addition to regulating glioma progression, may play an important role in differently regulating the gray and white matter microglial responses to CNS lesion--and modulating behavioral recovery--after injury.


New and Emerging Treatment Options for Gastroenteropancreatic Neuroendocrine Tumors.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare, generally indolent neoplasms that can arise throughout the gastrointestinal system. Some GEP-NETs, known as functional, secrete hormones that can lead to a complex of symptoms. Classical carcinoid syndrome is associated with flushing, diarrhea, bronchospasm, and symptoms of valvular heart disease. GEP-NETs are classified according to the primary tumor site, functionality of the disease, and histology. Treatment is guided by the resectability of the tumor, the location and extent of metastases, and the presence of clinical symptoms. Typically, first-line treatment of patients with unresectable disease includes the use of somatostatin analogs, such as octreotide LAR depot or lanreotide depot/autogel, which was recently approved by the US Food and Drug Administration for treatment of GEP-NETs. Somatostatin analogs can improve the severe diarrhea/flushing episodes that may be associated with metastatic carcinoid tumors. For patients with pancreatic NETs, additional approved treatment options include the targeted agents everolimus and sunitinib, which have demonstrated antitumor activity. Chemotherapy may also have a selective role, particularly in pancreatic NETs. Localized approaches, including cytoreductive surgery, hepatic arterial embolization, and ablative therapies, may be used for palliative treatment in patients with liver metastases.


Personal Protective Equipment for Infectious Disease Preparedness: A Human Factors Evaluation.
OBJECTIVE To identify issues during donning and doffing of personal protective equipment (PPE) for infectious diseases and to inform PPE procurement criteria and design. DESIGN A mixed methods approach was used. Usability testing assessed the appropriateness, potential for errors, and ease of use of various combinations of PPE. A qualitative constructivist approach was used to analyze participant feedback. SETTING Four academic health sciences centers: 2 adult hospitals, 1 trauma center, and 1 pediatric hospital, in Toronto, Canada. PARTICIPANTS Participants (n=82) were representative of the potential users of PPE within Western healthcare institutions. RESULTS None of the tested combinations provided a complete solution for PPE. Environmental factors, such as anteroom layout, and the design of protocols and instructional material were also found to impact safety. The study identified the need to design PPE as a complete system, rather than mixing and matching components. CONCLUSIONS Healthcare institutions are encouraged to use human factors methods to identify risk and failure points with the usage of their selected PPE, and to modify on the basis of iterative evaluations with representative end users. Manufacturers of PPE should consider usability when designing the next generation of PPE. Infect Control Hosp Epidemiol 2016;37:1022-1028.


Hartmann test of aspherical mirrors.
Astronomical aspherical mirrors may be tested in the optical shop with a Hartmann null test. A null test is obtained by placing small wedges over each hole of the Hartmann screen. The wedges have an angle between the two faces such that the spherical aberration with the object and the image at the center of curvature is just compensated.


Immunohistological studies of lymphoproliferative lesions in a fatal case of Epstein-Barr virus infection.
A fatal case of infectious mononucleosis occurred in a young adult. Abnormal serological features were noted in his mother, although there was no other family history suggesting an inherited defect of immune response to Epstein-Barr virus (EBV). The cellular infiltrate observed in tissues obtained at necropsy was analysed with a range of specific monoclonal and polyclonal antibodies. Polyclonal plasmacytoid B cell proliferation had occurred in many tissues. These cells were positive for EBV nuclear antigen, but viral particles were not seen on ultrastructural examination, and the virus was not isolated, suggesting a non-permissive infection.


Evaluation of a short Food Frequency Questionnaire to assess cardiovascular disease-related diet and lifestyle factors.
The Vascular lifestyle-Intervention and Screening in phArmacies (VISA) study investigates diet and lifestyle factors associated with risk of cardiovascular disease (CVD). As part of the study methodology, a short Food Frequency Questionnaire (FFQ), the VISA-FFQ, was adapted from the Norwegian NORDIET-FFQ. The aim of this study was to evaluate the VISA-FFQ and its ability to estimate intakes of foods and lifestyle factors in screening for elevated risk of CVD. The evaluation included assessment of relative validity of intake of milk fat and assessment of reproducibility of several foods and lifestyle factors. Relative validity of milk fat estimated from the VISA-FFQ was assessed in 307 participants by comparing estimated dietary intake of the fatty acids pentadecanoic acid (15:0) and heptadecanoic acid (17:0), from milk fat with whole blood biomarkers 15:0 and 17:0. Reproducibility was evaluated in 122 participants by comparing consistency in intakes of different foods and lifestyle factors reported by the VISA-FFQ and administered twice with a 4-week interval. Dietary 15:0 milk fat estimated from the VISA-FFQ correlated positively with whole blood 15:0 (r = 0.32, P < 0.05). Men presented higher correlations than women did. Acceptable and consistent reproducibility (r = 0.44-0.94 and no large difference between test and retest) was observed for most beverages, milk products, spreads on bread and meat (all of which included food items categorised into at least two fat categories) and also for eggs, fruits and vegetables, nuts, pasta and rice, dessert/sweets, smoking and physical activity. Reproducibility did not consistently meet a satisfactory standard (r ≤ 0.41 or large difference between test and retest) for unsweetened cereals, fatty fish, cakes, oils, white-, bread, crispbread and rice. The validity of the VISA-FFQ was acceptable for intake of milk fat, and there was an overall satisfactory, though variable, reproducibility for intake of several foods and lifestyle factors in the VISA-FFQ.


NCCN Guidelines Insights: Antiemesis, Version 2.2017.
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis address all aspects of management for chemotherapy-induced nausea and vomiting. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Antiemesis, specifically those regarding carboplatin, granisetron, and olanzapine.


Meta-analysis of clinical outcomes of patients who underwent percutaneous coronary interventions for chronic total occlusions.
Successful percutaneous coronary intervention (PCI) for chronic total occlusions (CTOs) has been associated with clinical benefit. There are no randomized controlled trials on long-term clinical outcomes after CTO PCI, limiting the available evidence to observational cohort studies. We sought to perform a weighted meta-analysis of the long-term outcomes of successful versus failed CTO PCI. A total of 25 studies, published from 1990 to 2014, with 28,486 patients (29,315 CTO PCI procedures) were included. We analyzed data on mortality, subsequent coronary artery bypass grafting (CABG), myocardial infarction, major adverse cardiac events, angina pectoris, stroke, and target vessel revascularization using random-effects models. Procedural success was 71% (range 51% to 87%). During a weighted mean follow-up of 3.11 years, compared with unsuccessful, successful CTO PCI was associated with lower mortality (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.43 to 0.63), less residual angina (OR 0.38, 95% CI 0.24 to 0.60), lower risk for stroke (OR 0.72, 95% CI 0.60 to 0.88), less need for subsequent coronary artery bypass grafting (OR 0.18, 95% CI 0.14 to 0.22), and lower risk for major adverse cardiac events (0.59, 95% CI 0.44 to 0.79). There was no difference in the incidence of target vessel revascularization (OR 0.66, 95% CI 0.36 to 1.23) or myocardial infarction (OR 0.73, 95% CI 0.52 to 1.03). Outcomes were similar in patients who underwent balloon angioplasty only or stenting with bare metal or drug-eluting stents. Compared with failed procedures, successful CTO PCIs are associated with a lower risk of death, stroke, and coronary artery bypass grafting and less recurrent angina pectoris.


Benchmarking health technology assessment agencies-methodological challenges and recommendations.
The objectives of the study were to establish a benchmarking tool to collect metrics to enable increased clarity regarding the differences and similarities across health technology assessment (HTA) agencies, to assess performance within and across HTA agencies, identify areas in the HTA processes in which time is spent and to enable ongoing performance improvement. Common steps and milestones in the HTA process were identified for meaningful benchmarking among agencies. A benchmarking tool consisting of eighty-six questions providing information on HTA agency organizational aspects and information on individual new medicine review timelines and outcomes was developed with the input of HTA agencies and validated in a pilot study. Data on 109 HTA reviews from five HTA agencies were analyzed to demonstrate the utility of this tool. This study developed an HTA benchmarking methodology, comparative metrics showed considerable differences among the median timelines from assessment and appraisal to final HTA recommendation for the five agencies included in this analysis; these results were interpreted in conjunction with agency characteristics. It is feasible to find consensus among HTA agencies regarding the common milestones of the review process to map jurisdiction-specific processes against agreed metrics. Data on characteristics of agencies such as their scope and remit enabled results to be interpreted in the appropriate local context. This benchmarking tool has promising potential utility to improve the transparency of the review process and to facilitate both quality assurance and performance improvement in HTA agencies.


Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD.
Gain-of-function mutations in the gene encoding the V2 vasopressin receptor (V2R) cause nephrogenic syndrome of inappropriate antidiuresis. To date, reported mutations lead to the substitution of arginine 137 by either a cysteine or leucine (R137C/L). Here, we describe a 3-month-old hyponatremic infant found to have a phenylalanine 229 to valine (F229V) substitution in V2R. Characterization of this substitution in vitro revealed that it leads to high constitutive activity of the receptor, compatible with spontaneous antidiuresis. In contrast to R137C/L mutant receptors, F229V receptors do not undergo spontaneous desensitization, which results in sustained, high basal activity. Notably, the V2R-selective inverse agonists tolvaptan and satavaptan completely silenced the constitutive signaling activity of the F229V mutant receptor, indicating that this substitution does not lock the receptor in an irreversible active state. Thus, inverse agonists might prove to be effective therapies for treating patients with this or other spontaneously activating mutations that do not lock the V2R in its active state. These results emphasize the importance of genetic testing and the functional characterization of mutant receptors for patients with nephrogenic syndrome of inappropriate antidiuresis because the results might inform treatment decisions.


Significance of the amide functionality on DOPA-based monolayers on gold.
The adhesive proteins secreted by marine mussels contain an unusual amino acid, 3,4-dihydroxyphenylalanine (DOPA), that is responsible for the cohesive and adhesive strength of this natural glue and gives mussels the ability to attach themselves to rocks, metals, and plastics. Here we report a detailed structural and spectroscopic investigation of the interface between N-stearoyldopamine and a single-crystalline Au(111) model surface and an amide-absent molecule, 4-stearylcatechol, also on Au(111), with the aim of understanding the role of the amide functionality in the packing, orientation, and fundamental interaction between the substrate and the monolayer formed from an aqueous environment by the Langmuir-Blodgett technique. The organization of monolayers on gold was observed directly and studied in detail by X-ray photoelectron spectroscopy (XPS), contact angle measurements (CA), surface-enhanced Raman spectroscopy (SERS), infrared reflection-absorption spectroscopy (IRRAS), and atomic force microscopy (AFM). Our study shows that within the monolayer the catecholic oxygen atoms are coordinated to the gold surface, having a more perpendicular orientation with respect to the aromatic ring and the apparently tilted alkyl chains, whereas the amide functionality stabilizes the monolayer that is formed.


Neurobiological Mechanisms for Semantic Feature Extraction and Conceptual Flexibility.
Signs and symbols relate to concepts and can be used to speak about objects, actions, and their features. Theories of semantic grounding address the question how the latter two, concepts and real-world entities, come into play and interlink in symbol learning. Here, a neurobiological model is used to spell out concrete mechanisms of symbol grounding, which implicate the "association" of information about sign and referents and, at the same time, the extraction of semantic features and the formation of abstract representations best described as conjoined and disjoined feature sets that may or may not have a real-life equivalent. The mechanistic semantic circuits carrying these feature sets are not static conceptual entries, but exhibit rich activation dynamics related to memory, prediction, and contextual modulation. Four key issues in specifying these activation dynamics will be highlighted: (a) the inner structure of semantic circuits, (b) mechanisms of semantic priming, (c) task specificity in semantic activation, and (d) context-dependent semantic circuit activation in the processing of referential, existential, and universal statements. These linguistic-semantic examples show that specific mechanisms are required to account for context-dependent semantic function or conceptual "flexibility." Static context-independent concepts as such are insufficient to account for these different semantic functions. Whereas abstract amodal models of concepts did so far not spell out concrete mechanisms for context-dependent semantic function, neuronal assembly mechanisms offer a workable perspective.


NECAPs are negative regulators of the AP2 clathrin adaptor complex.
Eukaryotic cells internalize transmembrane receptors via clathrin-mediated endocytosis, but it remains unclear how the machinery underpinning this process is regulated. We recently discovered that membrane-associated muniscin proteins such as FCHo and SGIP initiate endocytosis by converting the AP2 clathrin adaptor complex to an open, active conformation that is then phosphorylated (Hollopeter et al., 2014). Here we report that loss of ncap-1, the sole C. elegans gene encoding an adaptiN Ear-binding Coat-Associated Protein (NECAP), bypasses the requirement for FCHO-1. Biochemical analyses reveal AP2 accumulates in an open, phosphorylated state in ncap-1 mutant worms, suggesting NECAPs promote the closed, inactive conformation of AP2. Consistent with this model, NECAPs preferentially bind open and phosphorylated forms of AP2 in vitro and localize with constitutively open AP2 mutants in vivo. NECAPs do not associate with phosphorylation-defective AP2 mutants, implying that phosphorylation precedes NECAP recruitment. We propose NECAPs function late in endocytosis to inactivate AP2.


Kinetic disposition and hemodynamic effects of tetrandrine in anesthetized dogs.
The kinetic disposition and hemodynamic effects ot tetrandrine, l3 mg/kg i.v., over 30 s were studied in five anesthetized dogs during continuous monitoring of the ECG and systemic arterial pressure. Repeated determinations of cardiac output (CO) and pulmonary capillary wedge pressure (PCWP) were made via a flow-directed thermodilution catheter in the pulmonary artery. Blood samples were drawn at intervals for determination of plasma tetrandrine or erythrocyte binding of the drug. Maximal reductions in mean and diastolic arterial pressures of 23 +/- 4% were observed within 5 min of the drug infusion without a change in systolic pressure. CO was increased maximally 52% and systemic resistance reduced 5l% at l0 min, gradually returning to baseline values in l-2 h. PCWP was increased transiently at 5-l0 min. The PR interval was prolonged slightly without alteration in the R-R interval, QRS, or QTc. Changes in MAP and PR interval were correlated significantly with plasma tetrandrine concentrations over time, which followed a two-compartment kinetic model with a distribution t1/2 of 7 min and an elimination tl/2 of 88 min. The apparent volume of distribution at steady state was 57 L/kg. Plasma tetrandrine was greater than 90% bound to plasma proteins, and approximately 44% of whole blood tetrandrine was associated with erythrocytes. Tetrandrine is a potent arteriolar vasodilator drug with slight effects on AV conduction, but without significant negative inotropic effects in anesthetized dogs.


Evaluation of arylmethylaminopropanediols by a novel in vitro pharmacodynamic assay: correlation with antitumor activity in vivo.
The pharmacodynamics of a new series of antitumor DNA intercalators, known as arylmethylaminopropanediols (AMAPs), has been evaluated in vitro against adherent (MCF-7 human breast cancer) and nonadherent (P388 murine leukemia) cell lines. Previous work had shown that the in vitro antitumor activity of the model AMAP crisnatol was a function of exposure (Cn x T), rather than concentration alone. A unique exposure parameter, the minimum C x T, was proposed as an end point for antitumor activity in cell culture. Comparison of crisnatol to several established agents by the minimum C x T versus the standard concentration producing 10% survival indicated that these end points were not equivalent. The current work examined the validity of the pharmacodynamic approach using AMAP isomers from three different ring systems that were known to exhibit a spectrum of activity against the P388 tumor in vivo. The results indicated that antiproliferative, but not cytotoxic, activity of AMAPs in the pharmacodynamic assay correlated with their differential activity in vivo, expressed as percentage of increase in life span. In contrast, the concentration producing 10% survival either at 1 h or after continuous exposure did not show a similar correlation. The pharmacodynamic assay also revealed that certain AMAPs, while equipotent by concentration alone, required significantly less time and therefore less overall exposure for efficacy. Finally, the activity of AMAP isomers in P388 cells differed from that in MCF-7 cells, which may indicate AMAP selectivity for certain tumor types. Since AMAP action was a function of exposure, drug effects on cellular targets could likewise depend on exposure rather than concentration. These findings emphasize the importance of relating drug mechanisms to the pharmacodynamics of anticancer agents.


Molecular characterization of bovine CD26 upregulated by a staphylococcal superantigen.
In this report, we describe the cloning, sequencing, and expression of the bovine orthologue of CD26 (BoCD26). Several monoclonal antibodies specific for a molecule, activation molecule 3 (ACT3), aberrantly expressed on superantigen-stimulated bovine CD8(+) lymphocytes, reacted with recombinant BoCD26 expressed in COS-7 and CHO cells. We also showed that human CD8(+) T cells stimulated by a superantigen expressed CD26 at high levels. These results demonstrate that ACT3 is identical to BoCD26 and suggest that CD26 upregulation on CD8(+) T cells is a general phenomenon of superantigens and not limited to their effects on bovine cells.


Allograft-prosthetic composite reconstruction for massive bone loss including catastrophic failure in total elbow arthroplasty.
Revision total elbow arthroplasty with an allograft-prosthetic composite is a difficult salvage procedure due to massive bone loss and a compromised soft-tissue envelope. High failure rates in prior studies of patients treated with allograft-prosthetic composites and an increased burden of revision total elbow arthroplasties necessitate optimized reconstructive techniques to improve incorporation of allograft-prosthetic composites. The goal of this report is to describe novel techniques for, and outcomes of, reconstructions done with an allograft-prosthetic composite. From 2003 through 2008, twenty-five patients underwent revision total elbow arthroplasty with an allograft-prosthetic composite in the humerus (six), ulna (eighteen), or both (one). Indications included aseptic implant loosening with a fracture or cortical breach (eleven), aseptic implant loosening without fracture (three), infection (seven), failed implants (one), bone loss after hemiarthroplasty (one), nonunion (one), and resection arthroplasty (one). Three reconstructive strategies were used: intussusception of the allograft-prosthesis-composite (Type I), strut-like coaptation (Type II), and side-to-side contact between the cortices of the allograft-prosthetic composite and the host bone (Type III). The outcomes that were examined included the Mayo Elbow Performance Score (MEPS), radiographic union, and overall revision and complication rates. The mean MEPS improved from 30 points preoperatively to 84 points at the time of follow-up. Ninety-two percent of the allograft-prosthetic composites incorporated. There were eight major and four minor complications in nine patients, leading to nine reoperations in six patients. Complications included infection (three), fracture (three), nonunion (one), malunion (one), skin necrosis (one), triceps insufficiency/weakness (two), and ulnar nerve paresthesia (one). Four of the twenty-five patients had definitive resection arthroplasty, one had osteosynthesis, and one had a successful revision, so twenty-one (84%) of the twenty-five had a functional elbow. Five of seven infected joints were salvaged with staged allograft-prosthesis-composite procedures. Larger graft-host contact areas in the three types of allograft-prosthetic composites provided good functional outcomes and a high rate of union compared with prior experience and resection arthroplasty. Allograft-prosthetic composites can be a safe, reliable option with an acceptable complication rate for revision total elbow arthroplasty.


A mathematical model of action potentials of mouse sinoatrial node cells with molecular bases.
Genetically modified mice are popular experimental models for studying the molecular bases and mechanisms of cardiac arrhythmia. A postgenome challenge is to classify the functional roles of genes in cardiac function. To unveil the functional role of various genetic isoforms of ion channels in generating cardiac pacemaking action potentials (APs), a mathematical model for spontaneous APs of mouse sinoatrial node (SAN) cells was developed. The model takes into account the biophysical properties of membrane ionic currents and intracellular mechanisms contributing to spontaneous mouse SAN APs. The model was validated by its ability to reproduce the physiological exceptionally short APs and high pacing rates of mouse SAN cells. The functional roles of individual membrane currents were evaluated by blocking their coding channels. The roles of intracellular Ca(2+)-handling mechanisms on cardiac pacemaking were also investigated in the model. The robustness of model pacemaking behavior was evaluated by means of one- and two-parameter analyses in wide parameter value ranges. This model provides a predictive tool for cellular level outcomes of electrophysiological experiments. It forms the basis for future model development and further studies into complex pacemaking mechanisms as more quantitative experimental data become available.


Jet and underlying event properties as a function of charged-particle multiplicity in proton-proton collisions at [Formula: see text].
Characteristics of multi-particle production in proton-proton collisions at [Formula: see text] are studied as a function of the charged-particle multiplicity, Nch. The produced particles are separated into two classes: those belonging to jets and those belonging to the underlying event. Charged particles are measured with pseudorapidity |η|<2.4 and transverse momentum pT>0.25 GeV/c. Jets are reconstructed from charged-particles only and required to have pT>5 GeV/c. The distributions of jet pT, average pT of charged particles belonging to the underlying event or to jets, jet rates, and jet shapes are presented as functions of Nch and compared to the predictions of the pythia and herwig event generators. Predictions without multi-parton interactions fail completely to describe the Nch-dependence observed in the data. For increasing Nch, pythia systematically predicts higher jet rates and harder pT spectra than seen in the data, whereas herwig shows the opposite trends. At the highest multiplicity, the data-model agreement is worse for most observables, indicating the need for further tuning and/or new model ingredients.


Urban air pollution and chronic obstructive pulmonary disease-related emergency department visits.
Patients with chronic obstructive pulmonary disease (COPD) can have recurrent disease exacerbations triggered by several factors, including air pollution. Visits to the emergency respiratory department can be a direct result of short-term exposure to air pollution. The aim of this study was to investigate the relationship between the daily number of COPD emergency department visits and the daily environmental air concentrations of PM(10), SO(2), NO(2), CO and O(3) in the City of São Paulo, Brazil. The sample data were collected between 2001 and 2003 and are categorised by gender and age. Generalised linear Poisson regression models were adopted to control for both short- and long-term seasonal changes as well as for temperature and relative humidity. The non-linear dependencies were controlled using a natural cubic spline function. Third-degree polynomial distributed lag models were adopted to estimate both lag structures and the cumulative effects of air pollutants. PM(10) and SO(2) readings showed both acute and lagged effects on COPD emergency department visits. Interquartile range increases in their concentration (28.3 microg/m(3) and 7.8 microg/m(3), respectively) were associated with a cumulative 6-day increase of 19% and 16% in COPD admissions, respectively. An effect on women was observed at lag 0, and among the elderly the lag period was noted to be longer. Increases in CO concentration showed impacts in the female and elderly groups. NO(2) and O(3) presented mild effects on the elderly and in women, respectively. These results indicate that air pollution affects health in a gender- and age-specific manner and should be considered a relevant risk factor that exacerbates COPD in urban environments.


First Report of "Candidatus Liberibacter solanacearum" Associated with Psyllid-Infested Tobacco in Nicaragua.
In April of 2012, tobacco (Nicotiana tabacum) plants with symptoms resembling those caused by viral infection were observed in commercial fields in several departments in Nicaragua, including Esteli and Nueva Segovia. Heavy infestations of the psyllid Bactericera cockerelli, a major insect pest of potato and other solanaceous crops and vector of the bacterium "Candidatus Liberibacter solanacearum" (Lso) (2,3), were observed in the affected fields. All cultivars grown were affected and 5 to 100% of plants in each field were symptomatic. Symptoms on affected plants included apical leaf curling and stunting, overall chlorosis and plant stunting, young plant deformation with cabbage-like leaves, wilting, internal vascular necrosis of stems and leaf petioles, and overall poor leaf quality. Plant samples were collected from a total of three psyllid-infested fields in the municipalities of Esteli, Condega, and Jalapa (one field/municipality). The plant samples were first tested for viruses, including Potato virus Y, Tobacco mosaic virus, Cucumber mosaic virus, and Impatiens necrotic spot virus, using Immunostrips (Agdia, Elkhart, IN) and no virus was detected. Total DNA was extracted from leaf tissues of a total of 22 plants, including 17 symptomatic plants and five asymptomatic plants from two cultivars (Corojo and Habano) with the cetyltrimethylammonium bromide (CTAB) buffer extraction method (2,4). The DNA samples were tested by PCR using specific primer pairs OA2/OI2c and OMB 1482f/2086r, to amplify a portion of 16S rDNA and the outer membrane protein (OMB) genes, respectively, of Lso (2). 16 rDNA and OMB gene-derived fragments of 1,168 and 605 bp, respectively, were amplified from the DNA of 13 of 17 (76.5%) symptomatic plants, indicating the presence of Lso. No Lso was detected in the five asymptomatic plants. DNA amplicons of three plant samples (one plant/field) with each primer pair were cloned and two to four clones of each of the six amplicons were sequenced. BLASTn analysis of the 16S rDNA consensus sequences was the same for all three locations (GenBank Accession Nos. KC768323, KC768324, and KC768325) and showed 100% identity to numerous 16 rDNA sequences of Lso in GenBank, including accessions HM245242, JF811596, and JX559779. Similarly, identical OMB consensus sequences were observed in all three locations (KC768331 and KC768332 for Jalapa and Condega, respectively) that are 97 to 100% identical to a number of Lso sequences in GenBank (e.g., CP002371, FJ914617, JN848754, and JN848752). A second OMB sequence was isolated from the Esteli sample (KC768333) that was 98% identical with the consensus sequences from this and other sites and 100% identical to an OMB sequence from Lso in GenBank (JN848754). To our knowledge, this is the first report of Lso associated with tobacco. Tobacco is an important crop in many parts of the world, including Central and South America. This bacterium has also caused millions of dollars in losses to potato and several other solanaceous crops in the Americas and New Zealand (3). In addition, this plant pathogen has been reported as serious pest of carrot in Europe, where it is associated with the psyllids Trioza apicalis and B. trigonica (1,4). References: (1) A. Alfaro-Fernandez et al. Plant Dis. 96:581, 2012. (2) J. M. Crosslin. Southwest. Entomol. 36:125, 2011. (3) J. E. Munyaneza. Am. J. Pot. Res. 89:329, 2012. (4) J. E. Munyaneza et al. J. Econ. Entomol. 103:1060, 2010.


The burden of HIV-associated neurocognitive disorder (HAND) in post-HAART era: a multidisciplinary review of the literature.
The purpose of the present multidisciplinary review is to give an updated insight into the most recent findings regarding the pathophysiology, diagnosis and therapeutics of HIV-associated neurocognitive disorder (HAND). We performed a comprehensive search, through electronic databases (Pubmed - MEDLINE) and search engines (Google Scholar), of peer-reviewed publications (articles and reviews) and conferences proceedings on HAND pathophysiology, diagnosis, and therapy, from 1999 to 2016. It seems to be increasingly clear that neurodegeneration in HIV-1 affected patients is a multi-faceted disease involving numerous factors, from chronic inflammation to central nervous system (CNS) compartmentalization of HIV. Diagnosis of HAND may benefit from both laboratory analysis and advanced specific neuroimaging techniques. As regards HAND therapy, modified HAART combinations and simplification strategies have been tested, while novel exciting frontiers seem to involve the use of nanoparticles with the ability to cross the Blood-Brain Barrier (BBB). Albeit highly active antiretroviral therapy (HAART) allowed a major decrease in morbidity and mortality for AIDS patients, CNS involvement still represents a challenge in HIV patients even today, affecting up to 50% of patients with access to combination antiretroviral therapy (cART). Future studies will have to focus on CNS compartmentalization, drugs' ability to penetrate and suppress viral replication in this compartment, and on new approaches to reduce HIV-associated neuroinflammation.


NK Cells in Ascites From Liver Disease Patients Display a Particular Phenotype and Take Part in Antibacterial Immune Response.
Background and Aims: Ascites and spontaneous bacterial peritonitis (SBP) are frequent complications of liver cirrhosis. In spite of the clinical impact, knowledge about ascites as an immune cell compartment in liver disease is limited. Therefore, we analyzed NK cells in blood, ascites, and liver. Methods: Mononuclear cells from blood, ascites, and liver explants of patients with advanced liver disease were extracted by density gradient centrifugation. Phenotyping and analysis of functional responses were carried out using flow cytometry. Migratory potential was investigated with transwell chamber assays. NK cell metabolism was assessed by Seahorse technology. Results: NK cell frequency was increased in uninfected ascites compared to blood, but not to liver. Ascites NK cells were predominantly CD16positive. CD56bright ascites NK cells did not share the typical phenotype of their liver counterparts. In contrast to the inhibitory receptor NKG2A, expression of the activating receptor NKG2D was decreased on ascites and liver CD16positive NK cells. Ascites NK cells expressed higher levels of CXCR3 than blood or liver NK cells, corresponding to increased ascites levels of CXCL10. Blood NK cells migrated toward ascites. Stimulation of mononuclear cells with Escherichia coli led to downregulation of NKG2D expression and IL-12 and IL-18 mediated secretion of interferon-γ by ascites and liver, but not blood NK cells. In-vivo, ascites NK cells expressed higher levels of the activation marker CD69 and lower levels of NKG2D during SBP compared to uninfected ascites. Conclusion: Ascites NK cells display a particular phenotype and are implicated in local immune defense against translocating bacteria.


Preserved executive function in high-performing elderly is driven by large-scale recruitment of prefrontal cortical mechanisms.
High-density electrical mapping of event-related potentials was used to investigate the neural processes that permit some elderly subjects to preserve high levels of executive functioning. Two possibilities pertain: (1) high-performance in elderly subjects is underpinned by similar processing mechanisms to those seen in young adults; that is, these individuals display minimal functional decay across the lifespan, or (2) preserved function relies on successfully recruiting and amplifying control processes to compensate for normal sensory-perceptual decline with age. Fifteen young and nineteen elderly participants, the latter split into groups of high and low performers, regularly alternated between a letter and a number categorization task, switching between tasks every third trial (AAA-BBB-AAA...). This allowed for interrogation of performance during switch, repeat, and preparatory pre-switch trials. Robust effects of age were observed in both frontal and parietal components of the task-switching network. Greatest differences originated over prefrontal regions, with elderly subjects generating amplified, earlier, and more differentiated patterns of activity. This prefrontal amplification was evident only in high-performing (HP) elderly, and was strongest on pre-switch trials when participants prepared for an upcoming task-switch. Analysis of the early transient and late sustained activity using topographic analyses and source localization collectively supported a unique and elaborated pattern of activity across frontal and parietal scalp in HP-elderly, wholly different to that seen in both young and low-performing elderly. On this basis, we propose that preserved executive function in HP-elderly is driven by large-scale recruitment and enhancement of prefrontal cortical mechanisms.


Percutaneous Cryoablation for Renal Cell Carcinoma.
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. Nephron sparing resection (partial nephrectomy) has been the "gold standard" for the treatment of resectable disease. With the widespread use of cross sectional imaging techniques, more cases of renal cell cancers are detected at an early stage, i.e. stage 1A or 1B. This has provided an impetus for expanding the nephron sparing options and especially, percutaneous ablative techniques. Percutaneous ablation for RCC is now performed as a standard therapeutic nephron-sparing option in patients who are poor candidates for resection or when there is a need to preserve renal function due to comorbid conditions, multiple renal cell carcinomas, and/or heritable renal cancer syndromes. During the last few years, percutaneous cryoablation has been gaining acceptance as a curative treatment option for small renal cancers. Clinical studies to date indicate that cryoablation is a safe and effective therapeutic method with acceptable short and long term outcomes and with a low risk, in the appropriate setting. In addition it seems to offer some advantages over radio frequency ablation (RFA) and other thermal ablation techniques for renal masses.


Fiber-optic interferometer for surface profile measurement with vibration suppression.
We describe an improved design of fiber-optic interferometer intended to measure surface profiles with enhanced capability of vibration suppression. The reference wavefront is generated directly from the measurement wave using a multi-mode fiber that eliminates only the spatial wavefront distortion by means of bend loss. The temporal fluctuation caused by vibration is consequently cancelled out in the process of interference since it becomes to exist in both the measurement and reference waves. Further, an injection locking technique is incorporated to stabilize the reference wave intensity and hence make stable the interferometric fringe intensity. Experimental result proves that the proposed fiber-optic interferometer is capable of producing sub-wavelength measurement precision even in the presence of severe vibration with 100-μm amplitude.


Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway.
Accumulation of mitochondrial reactive oxygen species (mROS) has been implicated in the pathogenesis of fluorosis. As the main mitochondrial deacetylase, SIRT3 is closely associated with oxidative stress. To investigate the role of SIRT3 in response to sodium fluoride (NaF)-induced nephrotoxicity. Our results showed that NaF treatment impaired mitochondrial ultrastructure, decreased cell viability and increased apoptosis in TCMK-1 cells. Oxidative stress, detected by mROS and 8-Hydroxy-2'-deoxyguanosine (8-OHdG) were higher in NaF-treated cells, accompanied by decreased level of reduced glutathione (GSH). NaF reduces manganese superoxide dismutase (SOD2) expression through SIRT3-mediated DNA-binding activity of FoxO3a and decrease SOD2 activity by inhibiting SIRT3-mediated deacetylation. These effects were ameliorated by overexpression of SIRT3. Peroxisome proliferator-activated receptor-coactivator 1a (PGC-1α) interacted with nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) that bound to SIRT3 promoter to regulate SIRT3 expression. The study provides new insights into a critical NRF2/PGC-1α-SIRT3 pathway in response to NaF-induced nephritic oxidative injury. In vivo treatment of SIRT3-expressing adenovirus protects against NaF-induced nephritic injury in mice. Moreover, mechanistic study revealed that ERK1/2 activation was associated with increased apoptosis induced by NaF. In conclusion, these data shedding light on new approaches for treatment of NaF-induced nephrotoxicity.


Novel Paradigm to Record Bilateral Click-Evoked Auditory Brainstem Responses Simultaneously (BiSi-ABR).
The current study proposes a new and fast technique to record the auditory brainstem responses (ABRs) simultaneously (BiSi-ABR) from two ears. The BiSi-ABR technique can be used to record the ABRs two times faster than with a conventional ABR recording method. The objective of the study was to show the proof of concept and to compare the BiSi-ABR technique with that of a conventional ABRs recording method to test its clinical feasibility. A repeated-measures design was used, wherein ABRs recorded in the BiSi-ABR were compared with that of conventional ABRs recordings. Twenty-five normal-hearing adults participated in the study. ABRs were recorded using the BiSi-ABR technique, as well as the conventional method. The peak latencies (in ms) of waves III and V between the new technique and conventional method were compared. The minimum intensity at which the wave V was present was tracked using both the methods. The wave latencies and thresholds of ABR using the BiSi-ABR technique were remarkably similar to those recorded in the conventional ABR technique. The ABR wave latencies and thresholds did not differ significantly between the new technique and the conventional method. ABRs recorded with the BiSi-ABR technique can be used to estimate ear-specific hearing thresholds with the same reliability as that of conventional ABRs, in half the recording time. The results of the study have strong implications for screening, diagnostic, and research purposes as they aid in cutting down the ABR testing time.


Metabolic channeling: predictions, deductions, and evidence.
With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks operate with maximal catalytic efficiency and minimal interference? A logical answer was the postulate of metabolic channeling, which in its simplest embodiment assumes that the product generated by one enzyme passes directly to a second without diffusion into the surrounding medium. This tight coupling of activities might increase a pathway's metabolic flux and/or serve to sequester unstable/toxic/reactive intermediates as well as prevent their access to other networks. Here, we present evidence for this concept, commencing with enzymes that feature a physical molecular tunnel, to multi-enzyme complexes that retain pathway substrates through electrostatics or enclosures, and finally to metabolons that feature collections of enzymes assembled into clusters with variable stoichiometric composition. Lastly, we discuss the advantages of reversibly assembled metabolons in the context of the purinosome, the purine biosynthesis metabolon.


Effect of plant root symbionts on performance of native woody species in competition with an invasive grass in multispecies microcosms.
The majority of terrestrial plants form mutualistic associations with arbuscular mycorrhizal fungi (AMF) and rhizobia (i.e., nitrogen-fixing bacteria). Understanding these associations has important implications for ecological theory and for restoration practice. Here, we tested whether the presence of AMF and rhizobia influences the performance of native woody plants invaded by a non-native grass in experimental microcosms. We planted eight plant species (i.e., Acacia acuminata, A. microbotrya, Eucalyptus loxophleba subsp. loxophleba, E. astringens, Calothamnus quadrifidus, Callistemon phoeniceus, Hakea lissocarpha and H. prostrata) in microcosms of field-conditioned soil with and without addition of AMF and rhizobia in a fully factorial experimental design. After seedling establishment, we seeded half the microcosms with an invasive grass Bromus diandrus. We measured shoot and root biomass of native plants and Bromus, and on roots, the percentage colonization by AMF, number of rhizobia-forming nodules and number of proteaceous root clusters. We found no effect of plant root symbionts or Bromus addition on performance of myrtaceous, and as predicted, proteaceous species as they rely little or not at all on AMF and rhizobia. Soil treatments with AMF and rhizobia had a strong positive effect (i.e., larger biomass) on native legumes (A. microbotrya and A. acuminata). However, the beneficial effect of root symbionts on legumes became negative (i.e., lower biomass and less nodules) if Bromus was present, especially for one legume, i.e., A. acuminata, suggesting a disruptive effect of the invader on the mutualism. We also found a stimulating effect of Bromus on root nodule production in A. microbotrya and AMF colonization in A. acuminata which could be indicative of legumes' increased resource acquisition requirement, i.e., for nitrogen and phosphorus, respectively, in response to the Bromus addition. We have demonstrated the importance of measuring belowground effects because the aboveground effects gave limited indication of the effects occurring belowground.


Systematic Analysis of Protein Targets Associated with Adverse Events of Drugs from Clinical Trials and Postmarketing Reports.
Adverse drug reactions (ADRs) are undesired effects of medicines that can harm patients and are a significant source of attrition in drug development. ADRs are anticipated by routinely screening drugs against secondary pharmacology protein panels. However, there is still a lack of quantitative information on the links between these off-target proteins and the reporting of ADRs in humans. Here, we present a systematic analysis of associations between measured and predicted in vitro bioactivities of drugs and adverse events (AEs) in humans from two sources of data: the Side Effect Resource, derived from clinical trials, and the Food and Drug Administration Adverse Event Reporting System, derived from postmarketing surveillance. The ratio of a drug's therapeutic unbound plasma concentration over the drug's in vitro potency against a given protein was used to select proteins most likely to be relevant to in vivo effects. In examining individual target bioactivities as predictors of AEs, we found a trade-off between the positive predictive value and the fraction of drugs with AEs that can be detected. However, considering sets of multiple targets for the same AE can help identify a greater fraction of AE-associated drugs. Of the 45 targets with statistically significant associations to AEs, 30 are included on existing safety target panels. The remaining 15 targets include 9 carbonic anhydrases, of which CA5B is significantly associated with cholestatic jaundice. We include the full quantitative data on associations between measured and predicted in vitro bioactivities and AEs in humans in this work, which can be used to make a more informed selection of safety profiling targets.


Building the cellular puzzle: control in multi-level reaction networks.
Quantitative conceptual tools dealing with control and regulation of cellular processes have been mostly developed for and applied to the pathways of intermediary metabolism. Yet, cellular processes are organized in different levels, metabolism forming the lowest level in a cascade of processes. Well-known examples are the DNA-mRNA-enzyme-metabolism cascade and the signal transduction cascades consisting of covalent modification cycles. The reaction network that constitutes each level can be viewed as a "module" in which reactions are linked by mass transfer. Although in principle all of these cellular modules are ultimately linked by mass transfer, in practice they can often be regarded as "isolated" from each other in terms of mass transfer. Here modules can interact with each other only by means of regulatory or catalytic effects-a chemical species in one module may affect the rate of a reaction in another module by binding to an enzyme or transport system or by acting as a catalyst. This paper seeks to answer two questions about the control and regulation of such multi-level reaction networks: (i) How can the control properties of the system as a whole be expressed in terms of the control properties of individual modules and the effects between modules? (ii) How do the control properties of a module in its isolated state change when it is embedded in the whole system through its connections with the other modules? In order to answer these questions a quantitative theoretical framework is developed and applied to systems containing two, three or four fully interacting modules; it is shown how it can be extended in principle to n modules. This newly developed theory therefore makes it possible to quantitatively dissect intermodular, internal and external regulation in multi-level systems.


Association between depressive symptoms and poor sleep quality among Han and Manchu ethnicities in a large, rural, Chinese population.
To estimate the relationship between sleep quality and depression, among Han and Manchu ethnicities, in a rural Chinese population. A sample of 8,888 adults was selected using a multistage cluster and random sampling method. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Depressive symptoms were assessed via the Center for Epidemiological Survey, Depression Scale (CES-D). Logistic regression was conducted to assess associations between sleep quality and depression. The prevalence of poor sleep quality and depression in the Manchus (20.74% and 22.65%) was significantly lower than that in the Hans (29.57% and 26.25%), respectively. Depressive participants had higher odds ratios of global and all sub PSQI elements than non-depressive participants, both among the Hans and the Manchus. Additive interactions were identified between depressive symptoms and ethnicity with global and four sub-PSQI elements, including subjective sleep quality, sleep disturbance, use of sleep medication and daytime dysfunction. The findings revealed that the prevalence of poor sleep quality and depression among the Hans was greater than among the Manchus. Depression was associated with higher odds of poor sleep quality.


Hormonal Control of Sex Attractant Production in the Cuban Cockroach.
Virgin females of Byrsotria fumigata (Guérin) and several other species of Blattidae produce volatile substances which attract males and release in them characteristic precopulatory behavior. The removal of the corpora allata from females shortly after the imaginal molt results in a failure of production of sex attractant, as assayed by male behavior. Implantation of corpora allata can effect recovery.


Effect of improved navigation performance on the accuracy of implant placement in total hip arthroplasty with a CT-based navigation system.
A computed tomography (CT)-based navigation system is one of the support tools to place implant with appropriate alignment and position in total hip arthroplasty (THA). To determine whether the higher performance of the navigation would further improve the accuracy of implant placement in the clinical setting, we retrospectively compared the navigation accuracy of two different versions of a navigation system. The newer version of the navigation system had an upgraded optical sensor with superior positional accuracy. Navigation accuracy, defined as differences between postoperative measurements on CT images and intraoperative records on the navigation system, of 49 THAs performed with the newer version of the navigation system was compared with that of 49 THAs performed with the older version. With the newer version, the mean absolute accuracy (95% limits of agreement) of implant alignment was 1.2° (± 3.3°) for cup inclination, 1.0° (± 2.4°) for cup anteversion, 2.0° (± 4.9°) for stem anteversion, and 1.1° (± 2.4°) for stem valgus angle. The accuracy of the implant position was 1.5 mm (± 3.1 mm), 1.3 mm (± 3.0 mm), and 1.5 mm (± 3.1 mm) for cup x-, y-, and z-axes, respectively, 1.6 mm (± 3.2 mm), 1.4 mm (± 2.9 mm), and 1.5 mm (± 2.7 mm) for stem x-, y-, and z-axes, respectively, and 2.4 mm (± 4.5 mm) for leg length discrepancy. The values for the newer version were significantly more accurate with less variation compared to those of the older version. With upgraded navigation performance, more accurate implant placement was demonstrated in the clinical setting.


Regulation of interferon pathway in 2-methoxyestradiol-treated osteosarcoma cells.
Osteosarcoma is a bone tumor that often affects children and young adults. Although a combination of surgery and chemotherapy has improved the survival rate in the past decades, local recurrence and metastases still develop in 40% of patients. A definite therapy is yet to be determined for osteosarcoma. Anti- tumor compound and a metabolite of estrogen, 2-methoxyestradiol (2-ME) induces cell death in osteosarcoma cells. In this report, we have investigated whether interferon (IFN) pathway is involved in 2-ME-induced anti-tumor effects in osteosarcoma cells. 2-ME effects on IFN mRNA levels were determined by Real time PCR analysis. Transient transfections followed by reporter assays were used for investigating 2-ME effects on IFN-pathway. Western blot analyses were used to measure protein and phosphorylation levels of IFN-regulated eukaryotic initiation factor-2 alpha (eIF-2α). 2-ME regulates IFN and IFN-mediated effects in osteosarcoma cells. 2 -ME induces IFN gene activity and expression in osteosarcoma cells. 2-ME treatment induced IFN-stimulated response element (ISRE) sequence-dependent transcription and gamma-activated sequence (GAS)-dependent transcription in several osteosarcoma cells. Whereas, 2-ME did not affect IFN gene and IFN pathways in normal primary human osteoblasts (HOB). 2-ME treatment increased the phosphorylation of eIF-2α in osteosarcoma cells. Furthermore, analysis of osteosarcoma tissues shows that the levels of phosphorylated form of eIF-2α are decreased in tumor compared to normal controls. 2-ME treatment triggers the induction and activity of IFN and IFN pathway genes in 2-ME-sensitive osteosarcoma tumor cells but not in 2-ME-resistant normal osteoblasts. In addition, IFN-signaling is inhibited in osteosarcoma patients. Thus, IFN pathways play a role in osteosarcoma and in 2-ME-mediated anti-proliferative effects, and therefore targeted induction of IFN signaling could lead to effective treatment strategies in the control of osteosarcoma.


Early maladaptive schemas and child and adult attachment: a 15-year longitudinal study.
To examine the relation between early maladaptive schemas (EMS), as defined in schema therapy, and both child and adult attachment. A 15-year longitudinal design in which child attachment groups (secure, avoidant, ambivalent, and disorganized) were compared in early adulthood on their profile of scores across EMS domains. A similar strategy was used to examine EMS profiles as a function of adult attachment groups (secure, preoccupied, and fearful). Sixty participants, recruited from Montreal day-care centres, were assessed at 6 (Time 1) and 21 years of age (Time 2). Time 1 attachment was assessed using a separation-reunion procedure and Time 2 attachment, using the Experiences in Close Relationships questionnaire. EMS were evaluated with the Young Schema Questionnaire (Time 2). There were more signs of EMS among young adults with either an insecure ambivalent child attachment, or an insecure preoccupied adult attachment style, compared to their secure peers. These differences were not specific to one domain of EMS; they were reported for various EMS. The results suggest that specific elements of representational models are more likely to be related to the development of EMS: high anxiety over abandonment, negative self-view, and explicit manifestations of personal distress. Unmet childhood needs for secure attachment may lead to a large variety of EMS as defined in schema therapy.


Consent by Proxy for Nonurgent Pediatric Care.
Minor-aged patients are often brought to the pediatrician for nonurgent acute medical care, physical examinations, or health supervision visits by someone other than their legally authorized representative, which, in most situations, is a parent. These surrogates or proxies can be members of the child's extended family, such as a grandparent, adult sibling, or aunt/uncle; a noncustodial parent or stepparent in cases of divorce and remarriage; an adult who lives in the home but is not biologically or legally related to the child; or even a child care provider (eg, au pair, nanny, private-duty nurse/nurse's aide, group home supervisor). This report identifies common situations in which pediatricians may encounter "consent by proxy" for nonurgent medical care for minors, including physical examinations, and explains the potential for liability exposure associated with these circumstances. The report suggests practical steps that balance the need to minimize the physician's liability exposure with the patient's access to health care. Key issues to be considered when creating or updating office policies for obtaining and documenting consent by proxy are offered.


Multi-criteria optimization of regulation in metabolic networks.
Determining the regulation of metabolic networks at genome scale is a hard task. It has been hypothesized that biochemical pathways and metabolic networks might have undergone an evolutionary process of optimization with respect to several criteria over time. In this contribution, a multi-criteria approach has been used to optimize parameters for the allosteric regulation of enzymes in a model of a metabolic substrate-cycle. This has been carried out by calculating the Pareto set of optimal solutions according to two objectives: the proper direction of flux in a metabolic cycle and the energetic cost of applying the set of parameters. Different Pareto fronts have been calculated for eight different "environments" (specific time courses of end product concentrations). For each resulting front the so-called knee point is identified, which can be considered a preferred trade-off solution. Interestingly, the optimal control parameters corresponding to each of these points also lead to optimal behaviour in all the other environments. By calculating the average of the different parameter sets for the knee solutions more frequently found, a final and optimal consensus set of parameters can be obtained, which is an indication on the existence of a universal regulation mechanism for this system.The implications from such a universal regulatory switch are discussed in the framework of large metabolic networks.


The ethics of compulsory notification of tuberculosis.
The Government of India has passed a notification making the non-reporting of tuberculosis (TB) by a clinical establishment a punishable offence. This article examines this move from an ethical standpoint. One of the main ethical concerns relates to the violation of patient confidentiality that may result from this. Also as regards improvement in patient care, there appears to be a poor cost-benefit ratio in terms of the actionable data obtained by this There may be possible adverse consequences by a limiting of access to care due to penalising of non-reporting. In terms of the bigger picture, the notification may lead to an increased tension between the private sector and Government. Moreover, it is the position of the authors that such a step distracts attention from the more important issues that plague TB care in India today.


Hexabundles: imaging fiber arrays for low-light astronomical applications.
We demonstrate a novel imaging fiber bundle ("hexabundle") that is suitable for low-light applications in astronomy. The most successful survey instruments at optical-infrared wavelengths use hundreds to thousands of multimode fibers fed to one or more spectrographs. Since most celestial sources are spatially extended on the celestial sphere, a hexabundle provides spectroscopic information at many distinct locations across the source. We discuss two varieties of hexabundles: (i) lightly fused, closely packed, circular cores; (ii) heavily fused non-circular cores with higher fill fractions. In both cases, we find the important result that the cladding can be reduced to ~2 μm over the short fuse length, well below the conventional ~10λ thickness employed more generally, with a consequent gain in fill factor. Over the coming decade, it is to be expected that fiber-based instruments will be upgraded with hexabundles in order to increase the spatial multiplex capability by two or more orders of magnitude.


Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study.
Men with high serum prostate specific antigen usually undergo transrectal ultrasound-guided prostate biopsy (TRUS-biopsy). TRUS-biopsy can cause side-effects including bleeding, pain, and infection. Multi-parametric magnetic resonance imaging (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. We did this multicentre, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy [TPM-biopsy]). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. This study is registered on ClinicalTrials.gov, NCT01292291. Between May 17, 2012, and November 9, 2015, we enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88-96%) than TRUS-biopsy (48%, 42-55%; p<0·0001) and less specific (41%, 36-46% for MP-MRI vs 96%, 94-98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis. Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer. PROMIS is funded by the UK Government Department of Health, National Institute of Health Research-Health Technology Assessment Programme, (Project number 09/22/67). This project is also supported and partly funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL).


Stakeholders' perspective on ecological modeling in environmental risk assessment of pesticides: challenges and opportunities.
The article closely examines the role of mechanistic effect models (e.g., population models) in the European environmental risk assessment (ERA) of pesticides. We studied perspectives of three stakeholder groups on population modeling in ERA of pesticides. Forty-three in-depth, semi-structured interviews were conducted with stakeholders from regulatory authorities, industry, and academia all over Europe. The key informant approach was employed in recruiting our participants. They were first identified as key stakeholders in the field and then sampled by means of a purposive sampling, where each stakeholder identified as important by others was interviewed and asked to suggest another potential participant for our study. Our results show that participants, although having different institutional backgrounds often presented similar perspectives and concerns about modeling. Analysis of repeating ideas and keywords revealed that all stakeholders had very high and often contradicting expectations from models. Still, all three groups expected effect models to become integrated in future ERA of pesticides. Main hopes associated with effect models were to reduce the amount of expensive and complex testing and field monitoring, both at the product development stage, and as an aid to develop mitigation measures. Our analysis suggests that, although the needs of stakeholders often overlapped, subtle differences and lack of trust hinder the process of introducing mechanistic effect models into ERA.


The use of mechanical restraint in Pacific Rim countries: an international epidemiological study.
The use of mechanical restraint is a challenging area for psychiatry. Although mechanical restraint remains accepted as standard practice in some regions, there are ethical, legal and medical reasons to minimise or abolish its use. These concerns have intensified following the Convention on the Rights of Persons with Disabilities. Despite national policies to reduce use, the reporting of mechanical restraint has been poor, hampering a reasonable understanding of the epidemiology of restraint. This paper aims to develop a consistent measure of mechanical restraint and compare the measure within and across countries in the Pacific Rim. We used the publicly available data from four Pacific Rim countries (Australia, New Zealand, Japan and the United States) to compare and contrast the reported rates of mechanical restraint. Summary measures were computed so as to enable international comparisons. Variation within each jurisdiction was also analysed. International rates of mechanical restraint in 2017 varied from 0.03 (New Zealand) to 98.9 (Japan) restraint events per million population per day, a variation greater than 3000-fold. Restraint in Australia (0.17 events per million) and the United States (0.37 events per million) fell between these two extremes. Variation as measured by restraint events per 1000 bed-days was less extreme but still substantial. Within all four countries there was also significant variation in restraint across districts. Variation across time did not show a steady reduction in restraint in any country during the period for which data were available (starting from 2003 at the earliest). Policies to reduce or abolish mechanical restraint do not appear to be effecting change. It is improbable that the variation in restraint within the four examined Pacific Rim countries is accountable for by psychopathology. Greater efforts at reporting, monitoring and carrying out interventions to achieve the stated aim of reducing restraint are urgently needed.


Care coordination program for Washington State Medicaid enrollees reduced inpatient hospital costs.
Managing clinically complex populations poses a major challenge for state agencies trying to control health care costs and improve quality of care for Medicaid beneficiaries. In Washington State a care coordination intervention, the Chronic Care Management program, was implemented for clinically complex Medicaid beneficiaries who met risk criteria defined by a predictive modeling algorithm. We used propensity score matching to evaluate the program's impact on health care spending and utilization and mortality. We found large and significant reductions in inpatient hospital costs ($318 per member per month) among patients who used the program. The estimated reduction in overall medical costs of $248 per member per month exceeded the cost of the intervention but did not reach statistical significance. These results suggest that well-designed targeted care coordination services could reduce health care spending for Medicaid beneficiaries with complex health care needs.


Nucleotide sequence and host La protein interactions of rabies virus leader RNA.
Rabies virus leader RNA was detected in infected BHK-21 cell extracts by hybridization to end-labeled genomic RNA. Similar to the leader RNA of vesicular stomatitis virus, the leader RNA of rabies virus was also found to be associated with the La protein by specific immunoprecipitation with antisera from lupus patients. The 3' end of the genomic RNA of rabies virus was sequenced, and the size and termination site of leader RNA were determined. In addition, extension of the sequence into the nucleocapsid gene of rabies virus showed an open reading frame for at least 37 amino acid residues. Sequence relationships between rabies virus and vesicular stomatitis virus leader genes and the possible involvement of the La protein in rhabdovirus biology are discussed.


Design and Analytical Performances of a Diclofenac Biosensor for Water Resources Monitoring.
Because the broadly consumed pain killer diclofenac (DCF) is a recognized pollutant, monitoring of its concentration is routinely performed in surface waters. As a valuable alternative to chromatographic and immunochemical assays, we developed a piezoelectric immunosensor to quantify DCF, first in buffer (PBS) and then in river water samples. A sensing layer comprising DCF was built up on the surface of silica-coated quartz sensors using a robust coupling chemistry. Binding of a highly affine monoclonal anti-DCF antibody was monitored in real time by quartz crystal microbalance with dissipation (QCM-D) measurements from which were determined a dissociation constant KD of 0.24 nM and an acoustic antibody surface coverage of 1120 ng/cm2 at saturation. On the other hand, an optical antibody surface coverage of 260 ng/cm2 was determined by combined nanoplasmonic sensing measurement, giving a hydration percentage of 75% for the antibody monolayer. DCF assay was further set up following a competitive format for which binding of antibody to the sensing layer is inhibited by DCF in solution. The piezoelectric sensor response expressed as frequency shift ΔF was inversely related to the concentration of DCF with a dynamic range of 15-46 nM and a limit of detection (LoD) of 9.5 nM (2.8 μg/L) in PBS. This piezoelectric immunosensor was eventually applied to the assay of DCF in surface water samples taken at three different locations in the Seine and Marne rivers. The calculated concentration of DCF in these samples was in good agreement with official data published by the French center of water analysis eaufrance.


Holographic optical generation of prism anamorphs.
Analyses of prism anamorphic optical systems with single and multiple prisms in plane and spherical wave illumination geometries are presented. A theoretical evaluation and experimental demonstration of a new technique for recording holographic anamorphic elements by using prism anamorphic optical systems is discussed. It is seen that this technique offers the advantage of generating elements with low f/number. Another advantage of this recording is the easy generation of elements with different anamorphic factors by using a single configuration.


High-efficiency, ultra low-noise all-fiber photon-pair source.
We demonstrate an all-fiber photon-pair source with the highest coincidence-to-accidental ratio (CAR) reported to date in the fiber-optic telecom C-band. We achieve this through careful optimization of pairproduction efficiency as well as careful characterization and minimization of all sources of background photons, including Raman generation in the nonlinear fiber, Raman generation in the single-mode fiber, and leakage of pump photons. We cool the nonlinear fiber to 4 K to eliminate most of the Raman scattering, and we reduce other noise photon counts through careful system design. This yields a CAR of 1300 at a pair generation rate of 2 kHz. This CAR is a factor of 12 higher than previously reported results in the C-band. Measured data agree well with theoretical predictions.


Tracheostomy in the COVID-19 era: global and multidisciplinary guidance.
Global health care is experiencing an unprecedented surge in the number of critically ill patients who require mechanical ventilation due to the COVID-19 pandemic. The requirement for relatively long periods of ventilation in those who survive means that many are considered for tracheostomy to free patients from ventilatory support and maximise scarce resources. COVID-19 provides unique challenges for tracheostomy care: health-care workers need to safely undertake tracheostomy procedures and manage patients afterwards, minimising risks of nosocomial transmission and compromises in the quality of care. Conflicting recommendations exist about case selection, the timing and performance of tracheostomy, and the subsequent management of patients. In response, we convened an international working group of individuals with relevant expertise in tracheostomy. We did a literature and internet search for reports of research pertaining to tracheostomy during the COVID-19 pandemic, supplemented by sources comprising statements and guidance on tracheostomy care. By synthesising early experiences from countries that have managed a surge in patient numbers, emerging virological data, and international, multidisciplinary expert opinion, we aim to provide consensus guidelines and recommendations on the conduct and management of tracheostomy during the COVID-19 pandemic.


A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation.
A synthetic peptidemimetic substrate of the human immunodeficiency virus 1 (HIV-1) protease with a nonhydrolyzable pseudodipeptidyl insert at the protease cleavage site was prepared. The peptide U-81749 inhibited recombinant HIV-1 protease in vitro (inhibition constant Ki of 70 nanomolar) and HIV-1 replication in human peripheral blood lymphocytes (inhibitory concentration IC50 of 0.1 to 1 micromolar). Moreover, 10 micromolar concentrations of U-81749 significantly inhibited proteolysis of the HIV-1 gag polyprotein (p55) to the mature viral structural proteins p24 and p17 in cells infected with a recombinant vaccinia virus expressing the HIV-1 gag-pol genes. The HIV-1 like particles released from inhibitor-treated cells contained almost exclusively p55 and other gag precursors, but not p24. Incubation of HIV-like particles recovered from drug-treated cultures in drug-free medium indicated that inhibition of p55 proteolysis was at least partially reversible, suggesting that U-81749 was present within the particles.


Preferences for a self-management e-health tool for patients with chronic kidney disease: results of a patient-oriented consensus workshop.
Electronic health (e-health) tools may support patients' self-management of chronic kidney disease. We aimed to identify preferences of patients with chronic kidney disease, caregivers and health care providers regarding content and features for an e-health tool to support chronic kidney disease self-management. A patient-oriented research approach was taken, with 6 patient partners (5 patients and 1 caregiver) involved in study design, data collection and review of results. Patients, caregivers and clinicians from across Canada participated in a 1-day consensus workshop in June 2018. Using personas (fictional characters) and a cumulative voting technique, they identified preferences for content for 8 predetermined topics (understanding chronic kidney disease, diet, finances, medication, symptoms, travel, mental and physical health, work/school) and features for an e-health tool. There were 24 participants, including 11 patients and 6 caregivers, from across Canada. The following content suggestions were ranked the highest: basic information about kidneys, chronic kidney disease and disease progression; reliable information on diet requirements for chronic kidney disease and comorbidities, renal-friendly foods; affordability of medication, equipment, food, financial resources and planning; common medications, adverse effects, indications, cost and coverage; symptom types and management; travel limitations, insurance, access to health care, travel checklists; screening and supports to address mental health, cultural sensitivity, adjusting to new normal; and support to help integrate at work/school, restrictions. Preferred features included visuals, the ability to enter and track health information and interact with health care providers, "on-the-go" access, links to resources and access to personal health information. A consensus workshop developed around personas was successful for identifying detailed subject matter for 8 predetermined topic areas, as well as preferred features to consider in the codevelopment of a chronic kidney disease self-management e-health tool. The use of personas could be applied to other applications in patient-oriented research exploring patient preferences and needs in order to improve care and relevant outcomes.


The overdiagnosis of Lyme disease.
To analyze the diagnoses, serological test results, and treatment results of the patients evaluated in a Lyme disease clinic, both prior to referral and from current evaluation. Retrospective case survey of prescreened patients. Research and diagnostic Lyme disease clinic in a university hospital. All 788 patients referred to the clinic during a 4.5-year period who were thought by the referring physician or the patient to have a diagnosis of Lyme disease. Symptoms and signs of disease, immunodiagnostic tests of Lyme disease, and tests of neurological function. Of the 788 patients, 180 (23%) had active Lyme disease, usually arthritis, encephalopathy, or polyneuropathy. One hundred fifty-six patients (20%) had previous Lyme disease and another current illness, most commonly chronic fatigue syndrome or fibromyalgia; and in 49 patients, these symptoms began soon after objective manifestations of Lyme disease. The remaining 452 patients (57%) did not have Lyme disease. The majority of these patients also had the chronic fatigue syndrome or fibromyalgia; the others usually had rheumatic or neurological diseases. Of the patients who did not have Lyme disease, 45% had had positive serological test results for Lyme disease in other laboratories, but all were seronegative in our laboratory. Prior to referral, 409 of the 788 patients had been treated with antibiotic therapy. In 322 (79%) of these patients, the reason for lack of response was incorrect diagnosis. Only a minority of the patients referred to the clinic met diagnostic criteria for Lyme disease. The most common reason for lack of response to antibiotic therapy was misdiagnosis.


Cystic fibrosis transmembrane conductance regulator: using differential reactivity toward channel-permeant and channel-impermeant thiol-reactive probes to test a molecular model for the pore.
The sixth transmembrane segment (TM6) of the CFTR chloride channel has been intensively investigated. The effects of amino acid substitutions and chemical modification of engineered cysteines (cysteine scanning) on channel properties strongly suggest that TM6 is a key component of the anion-conducting pore, but previous cysteine-scanning studies of TM6 have produced conflicting results. Our aim was to resolve these conflicts by combining a screening strategy based on multiple, thiol-directed probes with molecular modeling of the pore. CFTR constructs were screened for reactivity toward both channel-permeant and channel-impermeant thiol-directed reagents, and patterns of reactivity in TM6 were mapped onto two new, molecular models of the CFTR pore: one based on homology modeling using Sav1866 as the template and a second derived from the first by molecular dynamics simulation. Comparison of the pattern of cysteine reactivity with model predictions suggests that nonreactive sites are those where the TM6 side chains are occluded by other TMs. Reactive sites, in contrast, are generally situated such that the respective amino acid side chains either project into the predicted pore or lie within a predicted extracellular loop. Sites where engineered cysteines react with both channel-permeant and channel-impermeant probes occupy the outermost extent of TM6 or the predicted TM5-6 loop. Sites where cysteine reactivity is limited to channel-permeant probes occupy more cytoplasmic locations. The results provide an initial validation of two, new molecular models for CFTR and suggest that molecular dynamics simulation will be a useful tool for unraveling the structural basis of anion conduction by CFTR.


Asymptomatic Clostridium difficile colonization: epidemiology and clinical implications.
The epidemiology of Clostridium difficile infection (CDI) has changed over the past decades with the emergence of highly virulent strains. The role of asymptomatic C. difficile colonization as part of the clinical spectrum of CDI is complex because many risk factors are common to both disease and asymptomatic states. In this article, we review the role of asymptomatic C. difficile colonization in the progression to symptomatic CDI, describe the epidemiology of asymptomatic C. difficile colonization, assess the effectiveness of screening and intensive infection control practices for patients at risk of asymptomatic C. difficile colonization, and discuss the implications for clinical practice. A narrative review was performed in PubMed for articles published from January 1980 to February 2015 using search terms 'Clostridium difficile' and 'colonization' or 'colonisation' or 'carriage'. There is no clear definition for asymptomatic CDI and the terms carriage and colonization are often used interchangeably. The prevalence of asymptomatic C. difficile colonization varies depending on a number of host, pathogen, and environmental factors; current estimates of asymptomatic colonization may be underestimated as stool culture is not practical in a clinical setting. Asymptomatic C. difficile colonization presents challenging concepts in the overall picture of this disease and its management. Individuals who are colonized by the organism may acquire protection from progression to disease, however they also have the potential to contribute to transmission in healthcare settings.


Self-reported Instances of Major Discrimination, Race/Ethnicity, and Inflammation Among Older Adults: Evidence From the Health and Retirement Study.
This study examines the relationship between self-reported instances of major discrimination and inflammation among older adults, and explores whether this relationship varies in accordance with race/ethnicity. We hypothesized that self-reported instances of major discrimination would be associated with higher levels of high-risk inflammation and that this relationship would be stronger for racial/ethnic minorities than whites. Data from the 2006/2008 Health and Retirement Study, an ongoing biennial nationally representative sample of older adults in the United States, were used to collect measures of self-reported instances of major discrimination and high-risk C-reactive protein (CRP), which was assayed from blood samples. Modified Poisson regression with robust standard errors was applied to estimate the prevalence ratios of self-reported instances of major discrimination, as it relates to high-risk CRP (CRP ≥ 22 kg/m2), and test whether this relationship varies by race/ethnicity. Respondents who experienced any instances of major discrimination had a higher likelihood of high-risk CRP (prevalence ratio [PR]: 1.14, 95% confidence interval [CI] = 1.07-1.22) than those who did not report experiencing any instances of major discrimination. This association was independent of differences in newly diagnosed health conditions and socioeconomic status. The relationship between any self-reported instance of major discrimination and high-risk CRP was weaker for blacks than whites (PR: 0.81, 95% CI = 0.69-0.95). Our study confirms that self-reported instances of major lifetime discrimination is a psychosocial factor that is adversely associated with high-risk CRP among older adults; this association is especially pronounced among older whites. Future studies among this population are required to examine whether the relationship between self-reported instances of major discrimination and high-risk CRP changes over time.


Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome.
Sex hormone-binding globulin (SHBG) is the main transport binding protein for sex steroid hormones in plasma and regulates their accessibility to target cells. Plasma SHBG is secreted by the liver under the control of hormones and nutritional factors. In the human hepatoma cell line (HepG2), thyroid and estrogenic hormones, and a variety of drugs including the antioestrogen tamoxifen, the phytoestrogen, genistein and mitotane (Op'DDD) increase SHBG production and SHBG gene promoter activity. In contrast, monosaccharides (glucose or fructose) effectively decrease SHBG expression by inducing lipogenesis, which reduces hepatic HNF-4alpha levels, a transcription factor that play a critical role in controlling the SHBG promoter. Interestingly, diminishing hepatic lipogenesis and free fatty acid liver biosynthesis also appear to be associated with the positive effects of thyroid hormones and PPARgamma antagonists on SHBG expression. This mechanism provides a biological explanation for why SHBG is a sensitive biomarker of insulin resistance and the metabolic syndrome, and why low plasma SHBG levels are a risk factor for developing hyperglycemia and type 2 diabetes, especially in women. These important advances in our knowledge of the regulation of SHBG expression in the liver open new approaches for identifying and preventing metabolic disorder-associated diseases early in life.


Maternal experiences of caring for an infant with neurological impairment after neonatal encephalopathy in Uganda: a qualitative study.
The study investigated maternal experiences of caring for a child affected by neurological impairment after neonatal encephalopathy (NE) ("birth asphyxia") in Uganda. Between September 2011 and October 2012 small group and one-on-one in-depths interviews were conducted with mothers recruited to the ABAaNA study examining outcomes from NE in Mulago hospital, Kampala. Data were analysed thematically with the aid of Nvivo 8 software. Mothers reported caring for an infant with impairment was often complicated by substantial social, emotional and financial difficulties and stigma. High levels of emotional distress, feelings of social isolation and fearfulness about the future were described. Maternal health-seeking ability was exacerbated by high transport costs, lack of paternal support and poor availability of rehabilitation and counselling services. Meeting and sharing experiences with similarly affected mothers was associated with more positive maternal caring experiences. Mothering a child with neurological impairment after NE is emotionally, physically and financially challenging but this may be partly mitigated by good social support and opportunities to share caring experiences with similarly affected mothers. A facilitated, participatory, community-based approach to rehabilitation training may have important impacts on maximising participation and improving the quality of life of affected mothers and infants. Implications for Rehabilitation Caring for an infant with neurological impairment after NE in Uganda has substantial emotional, social and financial impacts on families and is associated with high levels of emotional stress, feelings of isolation and stigma amongst mothers. Improved social support and the opportunity to share experiences with other similarly affected mothers are associated with a more positive maternal caring experience. High transport costs, lack of paternal support and poor availability of counselling and support services were barriers to maternal healthcare seeking. Studies examining the feasibility, acceptability and impact of early intervention programmes are warranted to maximise participation and improve the quality of life for affected mothers and their infants.


Epidemiology and outcomes of injuries in Kenya: A multisite surveillance study.
Injury is a leading cause of disability and death worldwide, accounting for over 5 million deaths each year. The injury burden is higher in low- and middle-income countries where more than 90% of injury-related deaths occur. Despite this burden, the use of prospective trauma registries to describe injury epidemiology and outcomes is limited in low- and middle-income countries. Kenya lacks robust data to describe injury epidemiology and care. The objective of this study was to investigate the epidemiology and outcomes of injuries at 4 referral hospitals in Kenya using hospital-based trauma registries. From January 2014 to May 2015, all injured patients presenting to the casualty departments of Kenyatta National, Thika Level 5, Machakos Level 5, and Meru Level 5 Hospitals were enrolled prospectively. Data collected included demographic characteristics, type of prehospital care received, prehospital time, injury pattern, and outcomes. A total of 14,237 patients were enrolled in our study. Patients were predominantly male (76.1%) and young (mean age 28 years). The most common mechanisms of injury were road traffic injuries (36.8%), falls (26.4%), and being struck/hit by a person or object (20.1%). Burn was the most common mechanism of injury in the age category under 5 years. Body regions commonly injured were lower extremity (35.1%), upper extremity (33.4%), and head (26.0%). The overall mortality rate was 2.4%. Significant predictors of mortality from multivariate analysis were Glasgow Coma Scale ≤12, estimated injury severity score ≥9, burns, and gunshot injuries. Hospital-based trauma registries can be important sources of data to study the epidemiology of injuries in low- and middle-income countries. Data from such trauma registries can highlight key needs and be used to design public health interventions and quality-of-care improvement programs.


Effect of position on sleep, heart rate variability, and QT interval in preterm infants at 1 and 3 months' corrected age.
Prone sleeping position has a strong link to sudden infant death syndrome (SIDS), and the "Back to Sleep" campaign has played an important role in reducing SIDS. We tested the hypothesis that the mechanism of the sleep position effect is based on changes in sleep, arousal, heart rate variability (HRV), and the QT interval of the electrocardiogram. We studied 16 premature infants longitudinally, at 1 and 3 months' corrected age. Videosomnography recordings were made during the infants' normal daytime naps. Each infant was recorded in both supine and prone positions. The recordings were analyzed in 30-second epochs, which were classified as awake, active sleep (AS), quiet sleep (QS), or indeterminate sleep. Electrocardiogram data were sampled with an accuracy of 1 millisecond. Time domain analysis of HRV was measured by standard deviation of all R-R intervals and by the square root of the mean of the sum of the squares of the differences between adjacent R-R intervals. Frequency domain analysis was done for low frequency (0.04-0.14 Hz) and high frequency (0.15-0.5 Hz) HRV. We measured QT, JT, and R-R intervals during AS and QS for each position. We found no significant differences between supine and prone position, either in total sleep time or in percentage of QS. Percentage of AS was significantly lower in the supine position, but only at 1 month corrected age. The incidence of short, spontaneous, sleep transitions was significantly higher in supine, also only at 1 month corrected age. Time domain analysis of HRV showed a significantly lower variability in prone, but only during QS. Frequency domain analysis of HRV showed no differences between the 2 sleeping positions. Both QT and JT intervals were significantly longer in prone during QS, but only at 1 month corrected age. Despite the commonly held belief, prone position did not substantially increase total sleep at these ages. On the other hand, prone sleeping decreased the number of sleep transitions at 1 month corrected age, increased QT and JT intervals, and reduced HRV, thereby potentially increasing the vulnerability for SIDS. This study supports "Back to Sleep" as the position of choice not only for term but also for preterm infants after discharge home.