The risk of obesity by assessing infant growth against the UK-WHO charts compared to the UK90 reference: findings from the Born in Bradford birth cohort study.
The new growth charts in the UK, the UK-WHO charts, comprise prescriptive data from the WHO standard between two weeks and four years of age. Little is known about the development of obesity risk in normal UK infants, who are necessarily not fed according to the WHO recommendations and do not live in constraint-free environments (the selection criteria of the WHO standard source sample), using the new charts. Here, we investigated infant growth trajectories and traits indicative of childhood obesity using the UK-WHO charts, with the aim to clearly document the implications of adopting the new charts on UK growth monitoring practice. Mixed effects models were applied to serial weight and length data from 2181 infants (1187 White; 994 Pakistani) in the Born in Bradford birth cohort study to produce curves from 10 days to 15 months of age. Individual monthly estimates were converted to Z-scores and were plotted by sex and ethnic group. The relative risks (RR) of traits indicative of childhood obesity, including high BMI and rapid weight gain, using the UK-WHO charts compared to the previously used UK90 reference were calculated for all infants together and for White and Pakistani infants separately. Both ethnic groups demonstrated patterns of growth similar to the UK-WHO charts in length but not in weight. The resulting pattern for BMI was remarkable, with an average gain of 1.0 Z-score between two and 12 months of age. The UK-WHO charts were significantly (p < 0.05) more likely than the UK90 reference to classify BMI above the 91st centile after age six months (RR 1.427-2.151) and weight and BMI gain between birth (one month for BMI) and 12 months of age greater than two centile bands (RR 1.214 and 1.470, respectively). The change to the UK-WHO charts means that normal UK infants risk being diagnosed as being on a trajectory toward childhood obesity. National estimates of obesity will have to be recalculated for previous years to allow longitudinal comparison. The new charts do not allow a focused prevention effort for targeting programmes at infants most at risk of becoming obese, because the use of the 91st or 98th centile on the UK-WHO charts will identify many more infants as being at risk than the same centiles on the UK90 reference. Now more than ever, research is needed to develop a large scale childhood obesity prevention programme which could ideally be integrated with routine infant growth monitoring practice.


Risk factors for catheter-related bloodstream infections in adult hospitalized patients - multicenter cohort study.
Risk factors for catheter-related bloodstream infections (CRBSIs) may change over time with progress in infection control. This study was undertaken to explore the current risk factors for CRBSIs in hospitalized patients. Adult patients with non-tunneled central venous catheters (CVCs) in 12 Japanese referral hospitals were prospectively enrolled between December 2009 and January 2012. Patients were monitored for CRBSIs for up to 8 weeks from CVC insertion; data were collected regarding patient characteristics, the purpose of CVC insertion, insertion methods, mechanical complications during insertion, and post-insertion catheter care. A total of 892 patients were enrolled in this study. The overall incidence of CRBSIs was 0.40 infections per 1000 catheter-days. Univariate analysis using the Fisher's exact test identified one of the participating hospitals (hospital A; p < 0.001), internal jugular vein catheterization (IJVC) (p = 0.0013), not using maximal sterile barrier precautions (p = 0.030), and the Seldinger technique for catheter insertion (p = 0.025) as significant risk factors for CRBSI. After excluding data from hospital A, only IJVC remained a significant risk factor for CRBSI (p = 0.025). The cumulative probability of remaining without CRBSI was significantly lower in patients with IJVCs than in patients with other catheter routes (p < 0.001; log-rank test). Similarly, the cumulative probability of remaining without catheter removal due to a suspected infection was significantly lower in patients with IJVCs (p = 0.034; log-rank test). The current study suggests that IJVC might be a risk factor for CRBSI under current infection control conditions.


Tonic firing rate controls dendritic Ca2+ signaling and synaptic gain in substantia nigra dopamine neurons.
Substantia nigra dopamine neurons fire tonically resulting in action potential backpropagation and dendritic Ca(2+) influx. Using Ca(2+) imaging in acute mouse brain slices, we find a surprisingly steep relationship between tonic firing rate and dendritic Ca(2+). Increasing the tonic rate from 1 to 6 Hz generated Ca(2+) signals up to fivefold greater than predicted by linear summation of single spike-evoked Ca(2+)-transients. This "Ca(2+) supralinearity" was produced largely by depolarization of the interspike voltage leading to activation of subthreshold Ca(2+) channels and was present throughout the proximal and distal dendrites. Two-photon glutamate uncaging experiments show somatic depolarization enhances NMDA receptor-mediated Ca(2+) signals >400 μm distal to the soma, due to unusually tight electrotonic coupling of the soma to distal dendrites. Consequently, we find that fast tonic firing intensifies synaptically driven burst firing output in dopamine neurons. These results show that modulation of background firing rate precisely tunes dendritic Ca(2+) signaling and provides a simple yet powerful mechanism to dynamically regulate the gain of synaptic input.


Estimating the proportion of healthcare-associated infections that are reasonably preventable and the related mortality and costs.
To estimate the proportion of healthcare-associated infections (HAIs) in US hospitals that are "reasonably preventable," along with their related mortality and costs. To estimate preventability of catheter-associated bloodstream infections (CABSIs), catheter-associated urinary tract infections (CAUTIs), surgical site infections (SSIs), and ventilator-associated pneumonia (VAP), we used a federally sponsored systematic review of interventions to reduce HAIs. Ranges of preventability included the lowest and highest risk reductions reported by US studies of "moderate" to "good" quality published in the last 10 years. We used the most recently published national data to determine the annual incidence of HAIs and associated mortality. To estimate incremental cost of HAIs, we performed a systematic review, which included costs from studies in general US patient populations. To calculate ranges for the annual number of preventable infections and deaths and annual costs, we multiplied our infection, mortality, and cost figures with our ranges of preventability for each HAI. As many as 65%-70% of cases of CABSI and CAUTI and 55% of cases of VAP and SSI may be preventable with current evidence-based strategies. CAUTI may be the most preventable HAI. CABSI has the highest number of preventable deaths, followed by VAP. CABSI also has the highest cost impact; costs due to preventable cases of VAP, CAUTI, and SSI are likely less. Our findings suggest that 100% prevention of HAIs may not be attainable with current evidence-based prevention strategies; however, comprehensive implementation of such strategies could prevent hundreds of thousands of HAIs and save tens of thousands of lives and billions of dollars.


ANG-2 for quantitative Na(+) determination in living cells by time-resolved fluorescence microscopy.
Sodium ions (Na(+)) play an important role in a plethora of cellular processes, which are complex and partly still unexplored. For the investigation of these processes and quantification of intracellular Na(+) concentrations ([Na(+)]i), two-photon coupled fluorescence lifetime imaging microscopy (2P-FLIM) was performed in the salivary glands of the cockroach Periplaneta americana. For this, the novel Na(+)-sensitive fluorescent dye Asante NaTRIUM Green-2 (ANG-2) was evaluated, both in vitro and in situ. In this context, absorption coefficients, fluorescence quantum yields and 2P action cross-sections were determined for the first time. ANG-2 was 2P-excitable over a broad spectral range and displayed fluorescence in the visible spectral range. Although the fluorescence decay behaviour of ANG-2 was triexponential in vitro, its analysis indicates a Na(+)-sensitivity appropriate for recordings in living cells. The Na(+)-sensitivity was reduced in situ, but the biexponential fluorescence decay behaviour could be successfully analysed in terms of quantitative [Na(+)]i recordings. Thus, physiological 2P-FLIM measurements revealed a dopamine-induced [Na(+)]i rise in cockroach salivary gland cells, which was dependent on a Na(+)-K(+)-2Cl(-) cotransporter (NKCC) activity. It was concluded that ANG-2 is a promising new sodium indicator applicable for diverse biological systems.


Late-onset septicemia in a Norwegian national cohort of extremely premature infants receiving very early full human milk feeding.
To investigate the occurrence of and risk factors for late-onset septicemia (LOS) in a national cohort of extremely premature infants who received very early full human milk feeding. A prospective study of all infants born in Norway in 1999 and 2000 with gestational age of <28 weeks or birth weight of <1000 g was performed. Extensive clinical information, including data on feeding practices and episodes of septicemia, was collected on predefined forms. LOS was defined as growth of bacteria or fungi in blood cultures in conjunction with clinical symptoms consistent with systemic infection occurring after day 6 of life. Cox regression models, including models allowing for time-dependent covariates, were applied in the analysis of LOS. Of 464 eligible infants, 462 (99.6%) were enrolled and 405 (87.7%) survived until day 7. LOS was diagnosed for 80 (19.7%). The predominant pathogens were coagulase-negative staphylococci, followed by Candida spp. Case fatality rates associated with septicemia were 10% in general and 43% for Candida spp septicemia. Necrotizing enterocolitis or bowel perforation was diagnosed for 19 infants (4%). Enteral feeding with human milk was initiated within the third day for 98% of patients, and 92% were receiving full enteral feeding (FEF) with human milk within the third week. Both high Clinical Risk Index for Babies scores and an umbilical venous catheter in situ at 7 days of age significantly predicted LOS. However, the overall most influential risk factor for LOS was the number of days without establishment of FEF with human milk, with an adjusted relative risk of 3.7 (2.0-6.9) for LOS if FEF was not established within the second week of life. The incidence and case fatality rate of septicemia for this cohort of extremely preterm infants were lower than values in comparable studies. The main difference, compared with other studies, was the feeding practice, and the data suggest that very early FEF with human milk significantly reduces the risk of LOS among extremely premature infants.


Predictive accuracy of triage nurses evaluation in risk stratification of syncope in the emergency department.
Syncope is a common clinical problem that accounts for 1-3% of all emergency department (ED) visits. Its prognosis is extremely variable with a 1-year mortality that may reach 30%. There are no available data about the accuracy of nursing triage in identifying high-risk syncope. The aim of our study was to evaluate the predictive accuracy of nursing triage in identifying high-risk syncope. We conducted a retrospective study on 678 consecutive patients who presented with syncope at four EDs. For each patient, nursing triage, comorbidities, clinical features and adverse events that occurred both in the ED and at 10-day follow-up were assessed. Adverse events included death, readmission to ED, need for major therapeutic procedures, cardiopulmonary resuscitation, intensive care unit admittance, acute antiarrhythmic therapy and major causes of syncope identified during the ED evaluation. Predictive accuracy of nursing triage was evaluated. We observed a total of 55 (8.1%) adverse events. Eight of them (9.4%) occurred among the 85 patients who were identified as high priority by nursing triage. Sensitivity (Sn) and specificity (Sp) of urgent nursing triage in identifying adverse outcomes in the ED (19 patients) were 21% (95% CI 3% to 39%) and 88% (95% CI 85% to 90%), while the positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were 1.7 and 0.9, respectively. Sn and Sp for 10-day adverse events were 15% (95% CI 5% to 24%) and 88% (95% CI 85% to 90%), respectively, with a LR+ of 1.18 and a LR- of 0.98. Nursing triage was characterised by a low predictive accuracy in identifying high-risk individuals.


Methodological Aspects of Cognitive Rehabilitation with Eye Movement Desensitization and Reprocessing (EMDR).
A variety of nervous system components such as medulla, pons, midbrain, cerebellum, basal ganglia, parietal, frontal and occipital lobes have role in Eye Movement Desensitization and Reprocessing (EMDR) processes. The eye movement is done simultaneously for attracting client's attention to an external stimulus while concentrating on a certain internal subject. Eye movement guided by therapist is the most common attention stimulus. The role of eye movement has been documented previously in relation with cognitive processing mechanisms. A series of systemic experiments have shown that the eyes' spontaneous movement is associated with emotional and cognitive changes and results in decreased excitement, flexibility in attention, memory processing, and enhanced semantic recalling. Eye movement also decreases the memory's image clarity and the accompanying excitement. By using EMDR, we can reach some parts of memory which were inaccessible before and also emotionally intolerable. Various researches emphasize on the effectiveness of EMDR in treating and curing phobias, pains, and dependent personality disorders. Consequently, due to the involvement of multiple neural system components, this palliative method of treatment can also help to rehabilitate the neuro-cognitive system.


HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir.
The persistence of latently infected, resting CD4+ T cells is considered to be a major obstacle in preventing the eradication of HIV-1 even in patients who have received effective antiviral therapy for an average duration of 5 years. Although previous studies have suggested that the latent HIV reservoir in the resting CD4+ T cell compartment is virologically quiescent in the absence of activating stimuli, evidence has been mounting to suggest that low levels of ongoing viral replication persist and in turn, prolong the overall half-life of HIV in patients receiving antiviral therapy. Here, we demonstrate the persistence of replication-competent virus in CD4+ T cells in a cohort of patients who had received uninterrupted antiviral therapy for up to 9.1 years that rendered them consistently aviremic throughout that time. Surprisingly, substantially higher levels of HIV proviral DNA were found in activated CD4+ T cells when compared with resting CD4+ T cells in the majority of patients we studied. Phylogenetic analyses revealed evidence for cross infection between the resting and activated CD4+ T cell compartments, suggesting that ongoing reactivation of latently infected, resting CD4+ T cells and spread of virus by activated CD4+ T cells may occur in these patients. Such events may allow continual replenishment of the CD4+ T cell reservoir and resetting of the half-life of the latently infected, resting CD4+ T cells despite prolonged periods of aviremia.


Function of a Foxp3 cis-element in protecting regulatory T cell identity.
The homeostasis of multicellular organisms requires terminally differentiated cells to preserve their lineage specificity. However, it is unclear whether mechanisms exist to actively protect cell identity in response to environmental cues that confer functional plasticity. Regulatory T (Treg) cells, specified by the transcription factor Foxp3, are indispensable for immune system homeostasis. Here, we report that conserved noncoding sequence 2 (CNS2), a CpG-rich Foxp3 intronic cis-element specifically demethylated in mature Tregs, helps maintain immune homeostasis and limit autoimmune disease development by protecting Treg identity in response to signals that shape mature Treg functions and drive their initial differentiation. In activated Tregs, CNS2 helps protect Foxp3 expression from destabilizing cytokine conditions by sensing TCR/NFAT activation, which facilitates the interaction between CNS2 and Foxp3 promoter. Thus, epigenetically marked cis-elements can protect cell identity by sensing key environmental cues central to both cell identity formation and functional plasticity without interfering with initial cell differentiation.


Structure of the catalytic domain of human polo-like kinase 1.
Polo-like kinase 1 (Plk1) is an attractive target for the development of anticancer agents due to its importance in regulating cell-cycle progression. Overexpression of Plk1 has been detected in a variety of cancers, and expression levels often correlate with poor prognosis. Despite high interest in Plk1-targeted therapeutics, there is currently no structure publicly available to guide structure-based drug design of specific inhibitors. We determined the crystal structures of the T210V mutant of the kinase domain of human Plk1 complexed with the nonhydrolyzable ATP analogue adenylylimidodiphosphate (AMPPNP) or the pyrrolo-pyrazole inhibitor PHA-680626 at 2.4 and 2.1 A resolution, respectively. Plk1 adopts the typical kinase domain fold and crystallized in a conformation resembling the active state of other kinases. Comparison of the kinetic parameters determined for the (unphosphorylated) wild-type enzyme, as well as the T210V and T210D mutants, shows that the mutations primarily affect the kcat of the reaction, with little change in the apparent Km for the protein or nucleotide substrates (kcat = 0.0094, 0.0376, and 0.0049 s-1 and Km(ATP) = 3.2, 4.0, and 3.0 microM for WT, T210D, and T210V, respectively). The structure highlights features of the active site that can be exploited to obtain Plk1-specific inhibitors with selectivity over other kinases and Plk isoforms. These include the presence of a phenylalanine at the bottom of the ATP pocket, combined with a cysteine (as opposed to the more commonly found leucine) in the roof of the binding site, a pocket created by Leu132 in the hinge region, and a cluster of positively charged residues in the solvent-exposed area outside of the adenine pocket adjacent to the hinge region.


Rapid reviews versus full systematic reviews: an inventory of current methods and practice in health technology assessment.
This review assessed current practice in the preparation of rapid reviews by health technology assessment (HTA) organizations, both internationally and in the Australian context, and evaluated the available peer-reviewed literature pertaining to the methodology used in the preparation of these reviews. A survey tool was developed and distributed to a total of fifty International Network of Agencies for Health Technology Assessment (INAHTA) members and other selected HTA organizations. Data on a broad range of themes related to the conduct of rapid reviews were collated, discussed narratively, and subjected to simple statistical analysis where appropriate. Systematic searches of the Cochrane Library, EMBASE, MEDLINE, and the Australian Medical Index were undertaken in March 2007 to identify literature pertaining to rapid review methodology. Comparative studies, guidelines, program evaluations, methods studies, commentaries, and surveys were considered for inclusion. Twenty-three surveys were returned (46 percent), with eighteen agencies reporting on thirty-six rapid review products. Axiomatic trends were identified, but there was little cohesion between organizations regarding the contents, methods, and definition of a rapid review. The twelve studies identified by the systematic literature search did not specifically address the methodology underpinning rapid review; rather, many highlighted the complexity of the area. Authors suggested restricted research questions and truncated search strategies as methods to limit the time taken to complete a review. Rather than developing a formalized methodology by which to conduct rapid reviews, agencies should work toward increasing the transparency of the methods used for each review. It is perhaps the appropriate use, not the appropriate methodology, of a rapid review that requires future consideration.


The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis.
We have developed a cell-based model of hemostasis. This model suggests that the defect in hemophilia is specifically a failure of platelet-surface factor Xa (FXa) generation, leading to a failure of platelet surface thrombin generation. Activation of FX by FVIIa/tissue factor (TF) does not compensate for a lack of FXa activation on the platelet surface by the FVIIIa/FIXa complex. This is because plasma protease inhibitors prevent FXa from moving through the fluid phase from the TF-bearing cell to the platelet surface. We have previously proposed a platelet-dependent mechanism of action for high-dose factor VIIa (FVIIa; Novoseven, Novo Nordisk, Copenhagen, Denmark). Our data suggest that, when present at high levels, FVIIa binds to activated platelets and activates small amounts of FX independent of TF. This platelet-surface FXa can partially restore platelet-surface thrombin generation in hemophilia. Recently, van't Veer and colleagues reported results from an in vitro model in which coagulation reactions were initiated by relipidated TF. The authors concluded that high-dose FVIIa may exert a hemostatic effect in hemophilia by overcoming inhibition of FVIIa/TF activity by zymogen FVII. By contrast, we found that plasma levels of FVII did not slow thrombin generation in a model system initiated with cell-associated TF. This discrepancy highlights the potential differences between the studies of the coagulation reactions assembled on living cells compared to phospholipid vesicles. Our data suggest that in a cellular system high-dose FVIIa acts primarily by enhancing the rate of thrombin generation on platelet surfaces and not by overcoming inhibition by zymogen FVII of TF-dependent activation of FX.


Role of the renin-angiotensin system in the control of vasopressin and ACTH secretion during the development of renal hypertension in dogs.
Experiments were performed to determine if the activation of the renin-angiotensin system that occurs during the development of two-kidney, one clip Goldblatt hypertension in dogs is accompanied by increases in vasopressin and adrenocorticotrophic hormone (ACTH) secretion. Following renal artery constriction, there were marked increases in arterial blood pressure, plasma renin activity (PRA), and plasma angiotensin II (AII) concentration. These changes were accompanied by an increase in plasma vasopressin concentration during the second week following constriction, and there were significant correlations between plasma vasopressin concentration and PRA (r = 0.57, p less than 0.001), and between plasma vasopressin concentration and plasma AII concentration (r = 0.59, p less than 0.001). In contrast, plasma corticosteroid concentration, used as an index of changes in ACTH secretion, did not change significantly. Acute blockade of the renin-angiotensin system with captopril or saralasin produced the expected changes in blood pressure, PRA, and plasma AII concentration but did not decrease plasma vasopressin or corticosteroid concentrations. These results indicate that during the development of renal hypertension in dogs, there may be an interaction between the renin-angiotensin system and vasopressin, but not between the renin-angiotensin system and the pituitary-adrenal axis. They also show that the antihypertensive action of captopril in this experimental model is not mediated via suppression of vasopressin, ACTH, or corticosteroid secretion.


The two complete plastomes from Scrophularia (Scrophulariaceae): Scrophularia buergeriana and S. takesimensis.
The plastome sequences of Scrophularia buergeriana and S. takesimensis are completed in family Scrophulariaceae. The structure of two Scrophularia plastomes shows similar characteristic with the typical plastome of angiosperm. The lengths of two plastomes are 153,631bp and 152,436bp, respectively. They are divided into LSC region (84,454bp and 83,542bp) and SSC region (17,929bp and 17,938bp) by two IR regions (25,624bp and 25,478bp). Both plastomes contain 113 genes including 79 protein coding genes, 30 tRNA genes and 4 rRNA genes. Eight protein-coding, seven tRNA and four rRNA genes are duplicated in the IR regions. Eighteen genes have one or two intron(s). The overall A-T contents of two genomes are 62.0% and 61.9%, respectively. The A-T content in the non-coding (both 64.5%) is higher than in the coding (60.2% and 60.1%) region. Forty-four and forty-one simple sequence repeat (SSR) loci are identified in the S. buergeriana and S. takesimensis plastomes, respectively. In phylogenetic analysis, the genus Scrophularia shows closed relationship with Plantaginaceae.


Identification of compounds with anti-West Nile Virus activity.
The lack of antiviral compounds targeting flaviviruses represents a significant problem in the development of strategies for treating West Nile Virus (WNV), Dengue, and Yellow Fever infections. Using WNV high-throughput screening techniques developed in our laboratories, we report the identification of several small molecule anti-WNV compounds belonging to four different structural classes including pyrazolines, xanthanes, acridines, and quinolines. The initial set of "hits" was further refined using cell viability-cytotoxicity assays to two 1,3,5-triaryl pyrazoline compounds: 1-(4-chlorophenylacetyl)-5-(4-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole and 1-benzoyl-5-(4-chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole. On the basis of their activity and favorable therapeutic indexes, these compounds were identified as viable leads and subjected to additional evaluation using an authentic viral titer reduction assay employing an epidemic strain of WNV. The compounds were further evaluated in a transient replicon reporting system to gain insight into the mechanism of action by identifying the step at which inhibition takes place during viral replication. The results indicate the pyrazolines inhibit RNA synthesis, pointing to viral RNA polymerase, RNA helicase, or other viral replication enzymes as potential targets. Progress was also made in understanding the structural requirements for activity by synthesizing a focused chemical library of substituted pyrazolines. Preliminary SAR data are presented that show the aryl-rings are required for activity against WNV. More importantly, the results indicate WNV activity is tolerant to aryl-substitutions paving the way for the design and development of much larger combinatorial libraries with varied physicochemical properties.


Marginal characteristics of different filling materials and filling methods with standardized cavity preparation.
The aim of the present study was to investigate the influence of different filling materials and methods on marginal integrity in Black Class I fillings. Standardized occlusal cavities were prepared in 80 extracted human molars. The preparations were filled with composite resin (1), with composite resin using the incremental technique (2), an experimental glass-fiber-reinforced (3) and polyester-reinforced (4) composite resin, a direct composite inlay (5), a ceramic insert (6), a Cerafil inlay (7), and with an experimental direct filling using Dyract AP compomer (8). Allocation of the teeth to the test groups was randomized; further processing was done on a blind basis. After the preparation of replicas, the teeth were subjected to a thermomechanical cycling process of 2,000 temperature cycles (5 degrees C/55 degrees C) and 50,000 stress cycles (50 N). This was followed by production of a second set of replicas and quantitative margin analysis by SEM (200X). A dye penetration test was then performed on the mesiodistal section. Groups 1, 2, 5, 6 and 7 displayed a good primary marginal quality, with the proportion of continuous margins reaching more than 85%. Significantly poorer results were recorded for the experimental glass-fiber-reinforced composite resins and Dyract compomer, where the proportion of perfect margins was only between 36% and 73%. In groups 1, 2, 5, 6 and 7, marginal integrity remained stable after the thermomechanical stress cycles, with the Cerafil inlays recording the best values: 89% perfect margins and 3% marginal gaps. In contrast, the experimental composite resins and the compomer underwent a significant (p < 0.05) increase in the proportion of marginal gaps and a significant (p < 0.05) reduction in the proportion of continuous margin. The results of this study show that neither Dyract compomer nor the glass-fiber-reinforced composite resins tested can be recommended for use in the occlusally stressed posterior region, whereas the other filling materials and methods were sufficiently stress resistant.


[Functions of metallothioneins and a system of antioxidant defense under the effect of Co- and Zn-containing nanocomposites on crucian carp (Carassius auratus gibelio)].
The effect of metal-nanocomposites (Me-NC) of cobalt and zinc (Co- and Zn-NC, correspondingly) synthecized on the basis of vinylpyrrolidone (PS) on the metal-accumulative proteins with antioxidant potential metallothioneins (MT) in crucian carp (Carassius auratus gibelio) was studied. Fish was subjected to the effect of Co-NC, Zn-NC, Co2+, Zn2+ or polymer carrier (PC) in the concentrations correspondent to 50 microg x Co/l or 100 microg x Zn/l during 14 days. It was shown that the MTs response is highly specific for the nature of metal, both in ion and Me-NC form: the effect of Co and Co-NC provoked the elevation of total MT concentration (MT-SH) and activation of antioxidant defence, whereas Zn and Zn-NC induced the decrease of the concentration of MT-SH and the inhibition of antioxidant defense. All the exposures provoked the decrease of the concentration of immunoreactive chelating MT form (MTi) and reduced glutathione, activation of anaerobiosys and Mn-superoxide dismutase, and also decrease of the concentration of proteins and lipids oxidative injury products. It was accompanied by the increase of the content of erythrocytes with nuclear abnormalities but did not cause the decrease of choline esterase activity. According to the rate of MT-SH and MTi concentrations, antioxidant potential of MTs is determined by its apoform. Our data indicate that partial biodegradation of Me-NC occurs in the organism of crucian carp.


Hemodynamic and ventilatory effects of volume or pressure controlled ventilation in dogs submitted to pneumoperitoneum. Comparative study.
Pressure controlled ventilation (PCV) is available in anesthesia machines, but there are no studies on its use during CO2 pneumoperitoneum (CPP). This study aimed at evaluating pressure-controlled ventilation and hemodynamic and ventilatory changes during CPP, as compared to conventional volume controlled ventilation (VCV). This study involved 16 dogs anesthetized with thiopental, fentanyl and pancuronium, which were randomly assigned to two groups: VC - volume controlled ventilation (n=8) and PC - pressure controlled ventilation (n=8). Hemodynamic and ventilatory parameters were monitored and recorded in 4 moments: M1 (before CPP), M2 (30 minutes after CPP = 10 mmHg), M3 (30 minutes after CPP=15 mmHg) and M4 (30 minutes after deflation). With CPP, there has been significant increase in tidal volume in PC group; there has been increase in airway pressures (peak and plateau), decrease in compliance with increase in CPP pressure, increase in heart rate, maintenance of mean blood pressure with higher values in the VC group in all stages; there was also increase in right atrium pressure with significant decrease after deflation, decrease in arterial pH with minor variations in PC group, greater arterial pCO2 stability in PC group, and no significant changes in arterial pO2. There were some differences in hemodynamic and ventilatory data between both ventilation control modes (VC and PC). It is possible to use pressure controlled ventilation during CPP, but the anesthesiologist must monitor and take a close look at alveolar ventilation, adjusting inspiratory pressure to ensure proper CO2 elimination and oxygenation.


Medical cannabis in the UK: From principle to practice.
In the UK, medical cannabis was approved in November 2018, leading many patients to believe that the medicine would now be available on the NHS. Yet, to date, there have been only 12 NHS prescriptions and less than 60 prescriptions in total. In marked contrast, a recent patient survey by the Centre for Medical Cannabis (Couch, 2020) found 1.4 m people are using illicit cannabis for medical problems. Such a mismatch between demand and supply is rare in medicine. This article outlines some of the current controversies about medical cannabis that underpin this disparity, beginning by contrasting current medical evidence from research studies with patient-reported outcomes. Although definite scientific evidence is scarce for most conditions, there is significant patient demand for access to medical cannabis. This disparity poses a challenge for prescribers, and there are many concerns of physicians when deciding if, and how, to prescribe medical cannabis which still need to be addressed. Potential solutions are outlined as to how the medical profession and regulators could respond to the strong demand from patients and families for access to medical cannabis to treat chronic illnesses when there is often a limited scientific evidence base on whether and how to use it in many of these conditions. There is a need to maximise both clinical research and patient benefit, in a safe, cautious and ethical manner, so that those patients for whom cannabis is shown to be effective can access it. We hope our discussion and outlines for future progress offer a contribution to this process.


Accidental injuries and cutaneous contaminations during general surgical operations in a Nigerian teaching hospital.
To determine the prevalence of accidental injuries and body contaminations among the operating personnel during general surgical operation, those involved, the circumstances surrounding the injuries or body contaminations and the factors affecting the prevalence in a unit of a teaching hospital in Nigeria. Patients operated for general surgical conditions in a unit of a Teaching Hospital Complex during a period of two years (1997-1998) were studied. A proforma was designed to enter personal biodata, preoperative and intra-postoperative clinical information of all the patients. Wesley Guild Hospital a unit of teaching hospital complex serving the large agrarian rural and semi-urban Nigerians. Five hundred and eighty nine consecutive general surgical patients. All types of general surgical operations were included, emergency or elective, major or minor, carried out during the day or at night. All the patients were operated and operating personnel observed for sharp injuries and body contamination. Incidence of sharp injuries and cutaneous contamination and personnel at risk determined. Operating personnel sustained 62 sharp injuries (10.5%), these were caused by suture needle in 57 cases (92.0%), towel clips in three (4.8%), knife cut in two (3.2%). Operating physicians sustained 56 cases of sharp injuries (90.3%) and Scrub Nurses in six (9.7 %). Self-inflicted sharp injuries in 49 (79 %) and in 12 cases (21%) injuries were inflicted by the surgeons or their assistants. Left hand was injured in 39 cases (63%) and right in 23 (37%). Cutaneous or mucosa membrane contamination with blood or body fluid occurred in 232 cases (39.4 %). These were made up of wet gown contamination in 124(53.5 %), glove failure in 72(31%) and splashing of blood or fluids into the face or eyes in 36 cases (15.5 %). Contamination occurred in more than one operating personnel in more than half of the cases. Operating surgeons were affected in 211 cases (91%). The risks of accidental injuries and blood and body fluid contamination were significant, if the duration of the operation was more than one hour, among the operating surgeons and if the operation was major (p<0.05). This study has demonstrated that cutaneous, percutaneous, and mucous membrane exposure to patients blood and body fluids are common events during general surgical operations. Most accidental injuries were due to solid suture needle-sticks, mostly injured personnel were the primary operating surgeons, injuries occurred predominantly on the left hand. This may poses a significant risk of infection with blood borne pathogens when operating on infected patients.


Dek overexpression in murine epithelia increases overt esophageal squamous cell carcinoma incidence.
Esophageal cancer occurs as either squamous cell carcinoma (ESCC) or adenocarcinoma. ESCCs comprise almost 90% of cases worldwide, and recur with a less than 15% five-year survival rate despite available treatments. The identification of new ESCC drivers and therapeutic targets is critical for improving outcomes. Here we report that expression of the human DEK oncogene is strongly upregulated in esophageal SCC based on data in the cancer genome atlas (TCGA). DEK is a chromatin-associated protein with important roles in several nuclear processes including gene transcription, epigenetics, and DNA repair. Our previous data have utilized a murine knockout model to demonstrate that Dek expression is required for oral and esophageal SCC growth. Also, DEK overexpression in human keratinocytes, the cell of origin for SCC, was sufficient to cause hyperplasia in 3D organotypic raft cultures that mimic human skin, thus linking high DEK expression in keratinocytes to oncogenic phenotypes. However, the role of DEK over-expression in ESCC development remains unknown in human cells or genetic mouse models. To define the consequences of Dek overexpression in vivo, we generated and validated a tetracycline responsive Dek transgenic mouse model referred to as Bi-L-Dek. Dek overexpression was induced in the basal keratinocytes of stratified squamous epithelium by crossing Bi-L-Dek mice to keratin 5 tetracycline transactivator (K5-tTA) mice. Conditional transgene expression was validated in the resulting Bi-L-Dek_K5-tTA mice and was suppressed with doxycycline treatment in the tetracycline-off system. The mice were subjected to an established HNSCC and esophageal carcinogenesis protocol using the chemical carcinogen 4-nitroquinoline 1-oxide (4NQO). Dek overexpression stimulated gross esophageal tumor development, when compared to doxycycline treated control mice. Furthermore, high Dek expression caused a trend toward esophageal hyperplasia in 4NQO treated mice. Taken together, these data demonstrate that Dek overexpression in the cell of origin for SCC is sufficient to promote esophageal SCC development in vivo.


Nonequilibrium Hole Dynamics in Antiferromagnets: Damped Strings and Polarons.
We develop a nonperturbative theory for hole dynamics in antiferromagnetic spin lattices, as described by the t-J model. This is achieved by generalizing the self-consistent Born approximation to nonequilibrium systems, making it possible to calculate the full time-dependent many-body wave function. Our approach reveals three distinct dynamical regimes, ultimately leading to the formation of magnetic polarons. Following the initial ballistic stage of the hole dynamics, coherent formation of string excitations gives rise to characteristic oscillations in the hole density. Their damping eventually leaves behind magnetic polarons that undergo ballistic motion with a greatly reduced velocity. The developed theory provides a rigorous framework for understanding nonequilibrium physics of defects in quantum magnets and quantitatively explains recent observations from cold-atom quantum simulations in the strong coupling regime.


An evaluation study of the implementation of stroke best practice guidelines using a Knowledge Transfer Team approach.
Strokes will become an increasing burden on the Canadian health care and social systems in coming years. Caring for people who have experienced a stroke is a challenging issue. The Registered Nurses Association of Ontario (RNAO) developed Stroke Assessment Across the Continuum Best Practice Guidelines (BPGs) to support the best possible care for this population. This article reports the findings of an evaluation of the implementation of recommendations from the stroke BPGs using a Knowledge Transfer Team (KTT) at Mackenzie Health's Integrated Stroke Unit in Richmond Hill, Ontario. Over a 12-month period, an evaluation of the implementation activities using structure, process, and outcome indicators, as well as identifying effective strategies for system-wide dissemination of BPG implementation and outcomes was completed. Data were collected from the staff, KTT members, and patients and their providers. The results clearly illustrate that all of the health care professionals involved in the study felt the KT approach was an effective method of implementing and disseminating the stroke BPGs. The main limitations perceived by staff and KTT members were time constraints, difficulty recruiting a larger sample size, competing priorities, lack of compliance, changes to charting, staff attrition, and a lack of financial support. The KTT approach resulted in improved patient care and outcomes, as illustrated by the high patient satisfaction levels.


Prophylactic total gastrectomy in hereditary diffuse gastric cancer: identification of two novel CDH1 gene mutations-a clinical observational study.
Inactivating mutations in the CDH1 (E-cadherin) gene are the predisposing cause of gastric cancer in most families with hereditary diffuse gastric cancer (HDGC). The lifetime risk of cancer in mutation positive members is more than 80 % and prophylactic total gastrectomy is recommended. Not all mutations in the CDH1 gene are however pathogenic and it is important to classify mutations before this major operation is performed. Probands from two Danish families with gastric cancer and a history suggesting HDGC were screened for CDH1 gene mutations. Two novel CDH1 gene mutations were identified and found pathogenic. In silico and mini-gene assay were used to predict the functional consequence in one of them. Mutation carriers were offered endoscopy and total gastrectomy. The gastric specimens were completely sectioned and examined histologically. Seven asymptomatic mutation carriers were operated. Hospital stay was 6-8 days and there were no complications. Small foci of diffuse gastric cancer were found in all patients-intramucosal in six and advanced in one. Preoperative endoscopic biopsies had revealed a microscopic cancer focus in two of the patients. Our data confirmed the pathogenic nature of both mutations and strongly support the recommendation of total gastrectomy in asymptomatic CDH1 gene mutation carriers. The functional consequences of novel CDH1 gene mutations with uncertain effects should be tested before correct advice and treatment can be given.


Month of birth and risk of multiple sclerosis: confounding and adjustments.
A month of birth effect on multiple sclerosis (MS) risk has been reported from different countries. Recent critics have suggested that this finding is caused by confounding and that adequately adjusting for year and place of birth would markedly reduce this effect. All inhabitants in Norway are registered in the Norwegian Population Registry (Statistics Norway), making this an ideal area for performing adjusted analyses. Using the entire Norwegian population born between 1930 and 1979 (n = 2,899,260), we calculated the excess between observed and expected number of births for each month for 6649 Norwegian MS patients, 5711 mothers, 5247 fathers, and 8956 unaffected siblings. The analyses were adjusted for year of birth and place of birth according to the 19 counties in Norway. An unadjusted analysis revealed 13% fewer MS births than expected in February (P = 0.0015; Bonferroni corrected P = 0.018), 10% more in April (P = 0.0083; Bonferroni corrected P = 0.0996) and 15% more in December (P = 0.00058; Bonferroni corrected P = 0.007). Adjustments for both year and place of birth significantly altered our results for February and December, but even after these adjustments there were still 10% more MS births than expected in April (P = 0.00796; Bonferroni corrected P = 0.096). MS patients had a higher incidence of April births than their siblings (Fisher-exact test; P = 0.011), mothers (Fisher-exact test; P = 0.004), and fathers (Fisher-exact test; P = 0.011) without MS. Adjustments for confounding significantly affected our results. However, even after adjustments, there appears to be a persistent higher than expected frequency of April births in the MS population.


Ionic charge, radius, and potential control root/soil concentration ratios of fifty cationic elements in the organic horizon of a beech (Fagus sylvatica) forest podzol.
The root/organic soil concentration ratio; R/S) of 50 cationic mineral elements was related to their ionic properties, including ionic radius (r), ionic charge (z), and ionic potential (z/r or z2/r). The materials studied were ectomycorrhizal beech (Fagus sylvatica L.) roots and their almost purely organic soil substrate, the O-horizon (mor; raw humus) of a Podzol in South Sweden, developed in a site which has been untouched by forestry or other mechanical disturbance since at least 50 years and located in an area with no local sources of pollution. Elements determined by ICP-AES were aluminium, barium, calcium, iron, potassium, magnesium, manganese, sodium and strontium. Determined by ICP-MS were silver, beryllium, bismuth, cadmium, cerium, cobalt, chromium, caesium, copper, dysprosium, erbium, europium, gallium, gadolinium, hafnium, mercury, holmium, indium, lanthanum, lithium, lutetium, niobium, neodymium, nickel, lead, praseodymium, rubidium, scandium, samarium, tin, terbium, thorium, titanium, thallium, thulium, uranium, vanadium, yttrium, ytterbium, zinc and zirconium. The R/S ratios were most clearly related to the ionic potential of the cationic elements studied, which accounted for approximately 60% of the variability in R/S among elements. The ionic charge of an element was more important than the ionic radius. Elements with high ionic charge had low R/S ratios and vice versa. No clear differences in R/S between essential and non-essential plant nutrients were observed, especially when ions of similar charge were compared.


Hinged circular fixator construct for correction of congenital metatarsal deformity in a foal.
A five-week-old American Quarter Horse colt was presented for evaluation of a left hindlimb deformity and lameness. Radiographs of the left hindlimb revealed a varus deformity with recurvatum originating in the mid-diaphysis of the third metatarsal bone. Surgical correction was undertaken by performing an osteotomy through the centre of rotation of angulation located within the mid-diaphysis of the third metatarsal bone, and a four-ring hinged circular external fixator construct was applied. Distraction of the osteotomy site was performed over an 11 day period. Notable complications included failure of a fixation pin, infection of the surgical site, and temporary laxity of the supporting tendons and ligaments of the contralateral metatarsophalangeal joint. The fixator was maintained until there was sufficient bone formation to allow frame removal, 152 days after the initial surgery. Use of a hinged circular construct allowed for partial correction of the deformity with resultant lengthening and resolution of the lameness in this colt.


Automated segmentation by pixel classification of retinal layers in ophthalmic OCT images.
Current OCT devices provide three-dimensional (3D) in-vivo images of the human retina. The resulting very large data sets are difficult to manually assess. Automated segmentation is required to automatically process the data and produce images that are clinically useful and easy to interpret. In this paper, we present a method to segment the retinal layers in these images. Instead of using complex heuristics to define each layer, simple features are defined and machine learning classifiers are trained based on manually labeled examples. When applied to new data, these classifiers produce labels for every pixel. After regularization of the 3D labeled volume to produce a surface, this results in consistent, three-dimensionally segmented layers that match known retinal morphology. Six labels were defined, corresponding to the following layers: Vitreous, retinal nerve fiber layer (RNFL), ganglion cell layer & inner plexiform layer, inner nuclear layer & outer plexiform layer, photoreceptors & retinal pigment epithelium and choroid. For both normal and glaucomatous eyes that were imaged with a Spectralis (Heidelberg Engineering) OCT system, the five resulting interfaces were compared between automatic and manual segmentation. RMS errors for the top and bottom of the retina were between 4 and 6 μm, while the errors for intra-retinal interfaces were between 6 and 15 μm. The resulting total retinal thickness maps corresponded with known retinal morphology. RNFL thickness maps were compared to GDx (Carl Zeiss Meditec) thickness maps. Both maps were mostly consistent but local defects were better visualized in OCT-derived thickness maps.


The Effects of Turner Syndrome, 45,X on Obstetric and Neonatal Outcomes: A Retrospective Cohort Evaluation.
Objective This study aims to evaluate the perinatal and neonatal outcomes associated with prenatal diagnosis of 45,X, both with and without fetal cardiac anomalies. Study Design A retrospective cohort of singleton pregnancies in California, 2005 to 2008, using vital statistics and International Classification of Diseases, Ninth Revision data, identifying prenatally diagnosed 45,X. Outcomes included preterm delivery, preeclampsia, intrauterine fetal demise (IUFD), cesarean section, small for gestational age (SGA), neonatal death, and infant death. Bivariate and multivariate analyses were used to compare pregnancies and neonates with and without 45,X. Prenatally diagnosed cardiac anomalies were also considered. Results Of the 2,029,000 deliveries, 138 had prenatally diagnosed 45,X. Out of these 138 deliveries, 22 had a prenatally diagnosed cardiac anomaly. Compared with unaffected pregnancies, those with fetal 45,X had higher rates of preterm delivery (19.5 vs. 9.9%, p = 0.001), cesarean section (44.2 vs. 30.2%, p < 0.0001), and SGA (21.5 vs. 6.3%, p < 0.0001). The affected cohort had no IUFDs. Neonatal death was 14.5 times higher in the 45,X cohort (p < 0.0001). Of only infants with cardiac anomalies, neonatal death was significantly more likely in those with 45,X (p = 0.005). In adjusted analysis, risk of SGA (< 3rd percentile), neonatal death, and infant death remained increased for infants with 45,X while controlling for fetal cardiac anomalies. Conclusion Prenatally diagnosed 45,X was associated with increased risk of cesarean section, and adverse neonatal outcomes, including mortality.


Regions within a single epidermal cell of Drosophila can be planar polarised independently.
Planar cell polarity (PCP), the coordinated and consistent orientation of cells in the plane of epithelial sheets, is a fundamental and conserved property of animals and plants. Up to now, the smallest unit expressing PCP has been considered to be an entire single cell. We report that, in the larval epidermis of Drosophila, different subdomains of one cell can have opposite polarities. In larvae, PCP is driven by the Dachsous/Fat system; we show that the polarity of a subdomain within one cell is its response to levels of Dachsous/Fat in the membranes of contacting cells. During larval development, cells rearrange (Saavedra et al., 2014) and when two subdomains of a single cell have different types of neighbouring cells, then these subdomains can become polarised in opposite directions. We conclude that polarisation depends on a local comparison of the amounts of Dachsous and Fat within opposing regions of a cell's membrane.


The use of hepatitis B core antibody-positive donor livers does not appear to have a deleterious effect on graft survival in liver transplantation for hepatitis C.
The use of hepatitis B core antibody-positive donor livers (HBcAb(+)) has steadily increased. According to a recent multivariate analysis of United Network for Organ Sharing (UNOS) data, there was no significant increase in the risk of using these donors. The increased risk among the hepatitis C virus (HCV)-positive subgroup noted in a univariate model disappeared upon multivariate analysis. However, deeper scrutiny may show that HCV-positive recipients may be at increased risk with HBcAb(+) donor livers, as they require simultaneous treatment with two antiviral regimens there may be deleterious interactions between the two viruses. Thus, the issue of HBcAb(+) donors for HCV-positive recipients merits more detailed analysis. Using UNOS registry data of all liver transplantations performed during the Model for End-Stage Liver Disease era from February 2002 through November 2007, we analyzed graft survival using Kaplan-Meier and Cox regression analyses. Of the 12,543 HCV-positive recipients, 2,543 received HBcAb(-) livers and 853 received HBcAb(+) livers. While Kaplan-Meier analysis showed significantly lower graft survival among HCV-negative recipients of HBcAb(+) livers (P = .0001), there was no significant effect on graft survival among the HCV-positive population (P = .2). To detect an early effect in HCV-positive recipients, we examined 1-year graft survival, observing no significant difference (P = .3). To exclude a possible late effect, we examined graft survival in the HCV-positive population conditional upon surviving at least 1 year after transplantation; no significant difference was observed (P = .6). The elimination of potentially confounding codiagnoses, such as hepatitis B virus, alcoholism, acute graft failure, and hepatocellular cancer did not alter the findings. On univariate analysis, the lack of a significant effect persisted among the HCV population. However, the significant effect observed in the univariate model for the HCV-negative population became insignificant when combined with other risk factors in the multivariate model. The use of HBcAb(+) livers in recipients with HCV did not appear to have a significant impact on graft survival.


Out of the reach of children? Young people's health-seeking practices and agency in Africa's newly-emerging therapeutic landscapes.
Despite a dominant view within Western biomedicine that children and medicines should be kept apart, a growing literature suggests that children and adolescents often take active roles in health-seeking. Here, we consider young people's health-seeking practices in Ghana: a country with a rapidly-changing therapeutic landscape, characterised by the recent introduction of a National Health Insurance Scheme, mass advertising of medicines, and increased use of mobile phones. Qualitative and quantitative data are presented from eight field-sites in urban and rural Ghana, including 131 individual interviews, focus groups, plus a questionnaire survey of 1005 8-to-18-year-olds. The data show that many young people in Ghana play a major role in seeking healthcare for themselves and others. Young people's ability to secure effective healthcare is often constrained by their limited access to social, economic and cultural resources and information; however, many interviewees actively generated, developed and consolidated such resources in their quest for healthcare. Health insurance and the growth of telecommunications and advertising present new opportunities and challenges for young people's health-seeking practices. We argue that policy should take young people's medical realities as a starting point for interventions to facilitate safe and effective health-seeking.


'They do not care how much you know until they know how much you care': a qualitative meta-synthesis of patient experience in the emergency department.
Patient experience is positively associated with both clinical effectiveness and patient safety and should be a priority for emergency care providers. While both quantitative and qualitative approaches can be used to evaluate patient experience in the emergency department (ED), the latter is well aligned to develop a detailed understanding of features influencing the lived experience of ED patients. This study aimed to systematically review the literature of qualitative studies to identify determinants of adult patient experience in the ED. A Preferred Reporting Items for Systematic review and Meta-Analysis compliant systematic review was conducted using PubMed, CINAHL, EMBASE, BNI and bibliography searches to identify qualitative studies exploring patient experiences in ED published in English between 1997 and 2018. Quality assessment was conducted using the Critical Appraisal Skills Programme checklist. Descriptive text and quotations relating to patient experience were extracted from included studies and a meta-synthesis conducted using thematic analysis. A total of 625 records were screened from which 40 studies underwent full review and 22 were included. Results were coded by two researchers (BG and JML). Meta-synthesis identified 198 discrete units of analysis which were clustered around five analytical themes. These were based on the perceived 'needs' of patients visiting the ED and were defined as communication, emotional, competent care, physical/environmental and waiting needs. Findings were translated into a conceptual model for optimising patient experience in the ED. This meta-synthesis provides a framework for understanding the determinants of patient experience in the ED. The resulting conceptual model and recommendations may have the potential to directly inform practice and improve the patient experience.


Swedish Registered Nurses' incentives to use nursing diagnoses in clinical practice.
The purpose of this study was to describe Registered Nurses' incentives to use nursing diagnoses in clinical practice. The use of nursing diagnoses is scarce in Swedish patient records. However, there are hospital wards were all nurses formulate and use nursing diagnoses in their daily work. This leads to the question of what motivates these nurses who do use nursing diagnoses in clinical practice. A qualitative descriptive design. A purposeful sampling of 12 Registered Nurses was used. Qualitative interviews to collect data and a content analysis were performed. Five categories were identified: identification of the patient as an individual and as a whole, a working tool for facilitating nursing care, increasing awareness within nursing, support from the management and influence on the professional role. The principle findings of this study were: (i) that the Registered Nurses perceived that nursing diagnoses clarified the patient's individual needs and thereby enabled them to decide on more specific nursing interventions, (ii) that nursing diagnoses were found to facilitate communication between colleagues concerning patient care and thus promoted continuity of care and saved time and (iii) that nursing diagnoses were perceived to increase the Registered Nurses' reflective thinking leading to a continuous development of professional knowledge. The present findings suggest that the incentives to use nursing diagnoses originate from effects generated from performing a deeper analysis of the patient's nursing needs. Further research is needed to test and validate the usability and consequences of using nursing diagnoses in clinical practice. Motivating factors found in this study may be valuable to Registered Nurses for the use and development of nursing diagnoses in clinical care. Moreover, these factors may be of relevance in other countries that are in a similar situation as Sweden concerning application of nursing diagnoses.


Drug discovery in a multidimensional world: systems, patterns, and networks.
Despite great strides in revealing and understanding the physiological and molecular bases of cardiovascular disease, efforts to translate this understanding into needed therapeutic interventions continue to lag far behind the initial discoveries. Although pharmaceutical companies continue to increase investments into research and development, the number of drugs gaining federal approval is in decline. Many factors underlie these trends, and a vast number of technological and scientific innovations are being sought through efforts to reinvigorate drug discovery pipelines. Recent advances in molecular profiling technologies and development of sophisticated computational approaches for analyzing these data are providing new, systems-oriented approaches towards drug discovery. Unlike the traditional approach to drug discovery which is typified by a one-drug-one-target mindset, systems-oriented approaches to drug discovery leverage the parallelism and high-dimensionality of the molecular data to construct more comprehensive molecular models that aim to model broader bimolecular systems. These models offer a means to explore complex molecular states (e.g., disease) where thousands to millions of molecular entities comprising multiple molecular data types (e.g., proteomics and gene expression) can be evaluated simultaneously as components of a cohesive biomolecular system. In this paper, we discuss emerging approaches towards systems-oriented drug discovery and contrast these efforts with the traditional, unidimensional approach to drug discovery. We also highlight several applications of these system-oriented approaches across various aspects of drug discovery, including target discovery, drug repositioning and drug toxicity. When available, specific applications to cardiovascular drug discovery are highlighted and discussed.


Evaluation of concurrent analysis of cerebrospinal fluid samples collected from the cerebellomedullary cistern and lumbar subarachnoid space for the diagnosis of steroid-responsive meningitis arteritis in dogs.
To evaluate whether concurrent analysis of CSF samples from 2 collection sites (cerebellomedullary cistern [CMC] and lumbar subarachnoid space [LSS]) versus only 1 site could improve the diagnostic sensitivity of CSF analysis for dogs with suspected steroid-responsive meningitis arteritis (SRMA). 111 client-owned dogs with SRMA diagnosed at 3 veterinary referral hospitals between 2011 and 2017. Only dogs with CSF collected from both sites (CMC and LSS) and with no previous history of corticosteroid administration were included. Medical record data and logistic regression were used to identify factors associated with having a total nucleated cell concentration (TNCC) within the reference interval in a CSF sample from 1 collection site. The TNCC was within the reference interval (TNCC < 5 cells/μL) in the CSF sample from 1 collection site for 8 of 111 (7%) dogs and was only slightly high (TNCC, 5 to 9 cells/μL) in the sample from 1 or both sites for 10 (11%) other dogs. For each of these 18 dogs, results for samples from 1 site were consistent with SRMA. The proportion of CSF samples that had a TNCC within the reference interval was comparable between sites. As age increased, so did the risk of having an unremarkable TNCC in the CSF sample from 1 site, albeit only slightly (OR, 1.08; 95% confidence interval, 1.01 to 1.16). CSF samples from both the CMC and LSS should be analyzed when evaluating dogs with suspected SRMA to improve the chance of detecting a high TNCC.


Prevalence and correlates of bulimia nervosa and bulimic behaviors in a racially diverse sample of undergraduate students in two universities in southeast Texas.
This cross-sectional survey used a self-report questionnaire to measure the prevalence and correlates of bulimia nervosa and bulimic behaviors in a sample of undergraduate students enrolled in two state-supported universities in Texas in 1990. In one university, the student population was predominantly white; in the other, it was predominantly nonwhite. Bulimia status was assessed using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R), of the American Psychiatric Association and was operationalized using the Revised Bulimia Test. Overall, 0.9% of the sample, 1.3% of the females, and 0.2% of the males were classified as having bulimia nervosa. The prevalence of bulimic behaviors was 5.4% overall, 6.6% for females, and 3.6% for males. There was no racial/ethnic difference in the prevalence of bulimia nervosa or bulimic behaviors; 1.5% of the whites (n = 459) and 0.4% of the nonwhites (n = 693) were classified as having bulimia nervosa, while 5.5% of the whites and 5.3% of the nonwhites reported bulimic behaviors. In univariate analysis, female sex, obesity, dieting behavior, and a family history of alcoholism, drug abuse, and depression were statistically associated with bulimic behaviors. After adjustment for covariates, only obesity and dieting behavior were statistically significant. We concluded that the sex difference in bulimic behaviors reported in other studies may be due to the failure to control for confounding factors.


Airborne Doppler lidar techniques for observing severe thunderstorms.
On 30 June 1981 the wind fields around an Oklahoma severe thunderstorm were observed in detail using an airborne Doppler lidar operated by NASA. Despite uncertainties caused by inertial navigation errors and problems in sampling some of the aircraft attitude and motion parameters, reasonably clear pictures of the distributions of relative reflectivity, horizontal wind velocity, and velocity spectral width near the cloud base have been obtained. Aspects of the design and functioning of the NASA lidar relevant to the collection and analysis of the data are described.


Sexual economics: sex as female resource for social exchange in heterosexual interactions.
A heterosexual community can be analyzed as a marketplace in which men seek to acquire sex from women by offering other resources in exchange. Societies will therefore define gender roles as if women are sellers and men buyers of sex. Societies will endow female sexuality, but not male sexuality, with value (as in virginity, fidelity, chastity). The sexual activities of different couples are loosely interrelated by a marketplace, instead of being fully separate or private, and each couple's decisions may be influenced by market conditions. Economic principles suggest that the price of sex will depend on supply and demand, competition among sellers, variations in product, collusion among sellers, and other factors. Research findings show gender asymmetries (reflecting the complementary economic roles) in prostitution, courtship, infidelity and divorce, female competition, the sexual revolution and changing norms, unequal status between partners, cultural suppression of female sexuality, abusive relationships, rape, and sexual attitudes.


MO-E-211-01: ABR 2014: Trained for Competence.
Medical physicists are the only non-physician professionals recognized by the American Board of Medical Specialties through certification by the American Board of Radiology (ABR). The ABR has always set high standards of clinical competency and now with the endorsement of the AAPM, is able to raise these standards by mandating that in 2014, to sit as a candidate for board certification, enrollment in an accredited physics residency program is required. This is an enormous step to elevate our profession, as now we have the means to specify only one method for achieving board certification that is through an accredited residency program, which leads to an increase of clinical competency. This will have a positive impact on our profession's recognition. Most challenges have been met, namely the number of residency positions has increased exponentially to meet the manpower needs. In addition, funding mechanisms are being sought for government support of such training programs. However, we have to ensure that pathways for a residency and certification do not eliminate strong scientists; if for example, they do not have the prior educational pre-requisite. Our profession has always, and must continue to breed strong scientists who have clinical expertise though may not be seeking a clinical career. This requires developing skill sets that prepare scientists to be researchers or residents who can perform research. We will discuss the benefits of the 2014 mandate along with the challenges that still exist. 1. The ABR requirements c2014: Why they're needed and how they were established 2. Physics Residency Programs: Importance for our profession and methods to fund 3. Essential elements for competency: didactic, scientific and clinical.


Pooling analysis of genetic data: the association of leptin receptor (LEPR) polymorphisms with variables related to human adiposity.
Analysis of raw pooled data from distinct studies of a single question generates a single statistical conclusion with greater power and precision than conventional metaanalysis based on within-study estimates. However, conducting analyses with pooled genetic data, in particular, is a daunting task that raises important statistical issues. In the process of analyzing data pooled from nine studies on the human leptin receptor (LEPR) gene for the association of three alleles (K109R, Q223R, and K656N) of LEPR with body mass index (BMI; kilograms divided by the square of the height in meters) and waist circumference (WC), we encountered the following methodological challenges: data on relatives, missing data, multivariate analysis, multiallele analysis at multiple loci, heterogeneity, and epistasis. We propose herein statistical methods and procedures to deal with such issues. With a total of 3263 related and unrelated subjects from diverse ethnic backgrounds such as African-American, Caucasian, Danish, Finnish, French-Canadian, and Nigerian, we tested effects of individual alleles; joint effects of alleles at multiple loci; epistatic effects among alleles at different loci; effect modification by age, sex, diabetes, and ethnicity; and pleiotropic genotype effects on BMI and WC. The statistical methodologies were applied, before and after multiple imputation of missing observations, to pooled data as well as to individual data sets for estimates from each study, the latter leading to a metaanalysis. The results from the metaanalysis and the pooling analysis showed that none of the effects were significant at the 0.05 level of significance. Heterogeneity tests showed that the variations of the nonsignificant effects are within the range of sampling variation. Although certain genotypic effects could be population specific, there was no statistically compelling evidence that any of the three LEPR alleles is associated with BMI or waist circumference in the general population.


Influence of the nitrogen source on Saccharomyces cerevisiae anaerobic growth and product formation.
To prevent the loss of raw material in ethanol production by anaerobic yeast cultures, glycerol formation has to be reduced. In theory, this may be done by providing the yeast with amino acids, since the de novo cell synthesis of amino acids from glucose and ammonia gives rise to a surplus of NADH, which has to be reoxidized by the formation of glycerol. An industrial strain of Saccharomyces cerevisiae was cultivated in batch cultures with different nitrogen sources, i.e., ammonium salt, glutamic acid, and a mixture of amino acids, with 20 g of glucose per liter as the carbon and energy source. The effects of the nitrogen source on metabolite formation, growth, and cell composition were measured. The glycerol yields obtained with glutamic acid (0.17 mol/mol of glucose) or with the mixture of amino acids (0.10 mol/mol) as a nitrogen source were clearly lower than those for ammonium-grown cultures (0.21 mol/mol). In addition, the ethanol yield increased for growth on both glutamic acid (by 9%) and the mixture of amino acids (by 14%). Glutamic acid has a large influence on the formation of products; the production of, for example, alpha-ketoglutaric acid, succinic acid, and acetic acid, increased compared with their production with the other nitrogen sources. Cultures grown on amino acids have a higher specific growth rate (0.52 h-1) than cultures of both ammonium-grown (0.45 h-1) and glutamic acid-grown (0.33 h-1) cells. Although the product yields differed, similar compositions of the cells were attained. The NADH produced in the amino acid, RNA, and extracellular metabolite syntheses was calculated together with the corresponding glycerol formation. The lower-range values of the theoretically calculated yields of glycerol were in good agreement with the experimental yields, which may indicate that the regulation of metabolism succeeds in the most efficient balancing of the redox potential.


Multilocus species identification and fungal DNA barcoding: insights from blue stain fungal symbionts of the mountain pine beetle.
There is strong community-wide interest in applying molecular techniques to fungal species delimitation and identification, but selection of a standardized region or regions of the genome has not been finalized. A single marker, the ribosomal DNA internal transcribed spacer region, has frequently been suggested as the standard for fungi. We used a group of closely related blue stain fungi associated with the mountain pine beetle (Dendroctonus ponderosae Hopkins) to examine the success of such single-locus species identification, comparing the internal transcribed spacer with four other nuclear markers. We demonstrate that single loci varied in their utility for identifying the six fungal species examined, while use of multiple loci was consistently successful. In a literature survey of 21 similar studies, individual loci were also highly variable in their ability to provide consistent species identifications and were less successful than multilocus diagnostics. Accurate species identification is the essence of any molecular diagnostic system, and this consideration should be central to locus selection. Moreover, our study and the literature survey demonstrate the value of using closely related species as the proving ground for developing a molecular identification system. We advocate use of a multilocus barcode approach that is similar to the practice employed by the plant barcode community, rather than reliance on a single locus.


Cochlear Implant Electrode Migration due to Cholesterol Granuloma: Cues from a Case.
This paper aims to describe a rare case of cochlear implant (CI) failure due to electrode array migration and review the literature on the topic. A 72-year-old woman complained of retroauricolar pain two years after receiving a left CI, with deterioration of the auditory skills and an increased impedance of electrodes. Temporal bone computed tomographic scans revealed a soft density tissue involving the left mastoid and the middle ear. It also revealed a lateral displacement of the array into the middle ear. Surgery with CI re-implantation was performed. The specimen examination disclosed the presence of a cholesterol granuloma. According to the literature, array migration after CI due to cholesterol granuloma is very rare. When patient's auditory performances decline and electrodes impedance increases, computed tomography (CT) scans should be performed to detect possible electrode issues, as in this case. Middle ear and mastoid cholesterol granuloma represent a possible, rare, cause of electrode array migration, even in absence of cochlear erosions.


Fundamental Limits to Radiative Heat Transfer: The Limited Role of Nanostructuring in the Near-Field.
In a previous Letter, we derived fundamental limits to radiative heat transfer applicable in near- through far-field regimes, based on the choice of material susceptibilities and bounding surfaces enclosing arbitrarily shaped objects; the limits exploit algebraic properties of Maxwell's equations and fundamental principles such as electromagnetic reciprocity and passivity. In this Letter, we apply these bounds to two different geometric configurations of interest, namely dipolar particles or extended structures of infinite area in the near field of one another. We find that while near-field radiative heat transfer between dipolar particles can saturate purely geometric "Landauer" limits, bounds on extended structures cannot, instead growing very slowly with respect to a material response figure of merit (an "inverse resistivity" for metals) due to the deleterious effects of multiple scattering between bodies. While nanostructuring can produce infrared resonances, it is generally unable to further enhance the resonant energy transfer spectrum beyond what is practically achieved by planar media at the surface polariton condition.


Lunar impact basins and crustal heterogeneity: new Western limb and far side data from galileo.
Multispectral images of the lunar western limb and far side obtained from Galileo reveal the compositional nature of several prominent lunar features and provide new information on lunar evolution. The data reveal that the ejecta from the Orientale impact basin (900 kilometers in diameter) lying outside the Cordillera Mountains was excavated from the crust, not the mantle, and covers pre-Orientale terrain that consisted of both highland materials and relatively large expanses of ancient mare basalts. The inside of the far side South Pole-Aitken basin (>2000 kilometers in diameter) has low albedo, red color, and a relatively high abundance of iron- and magnesium-rich materials. These features suggest that the impact may have penetrated into the deep crust or lunar mantle or that the basin contains ancient mare basalts that were later covered by highlands ejecta.


Radiation-induced autophagy in normal and cancer cells: towards novel cytoprotection and radio-sensitization policies?
Autophagy or Type II programmed cell death (PCD) is a major intracellular pathway for the degradation and recycling of proteins, ribosomes and entire organelles. The role of this pathway in the antitumor effect of radiotherapy and in radiation toxicity is obscure. A complicated machinery of genes and proteins is involved in the regulation of autophagy as a response to a variety of stress factors including hypoxia, nutrient deprivation, cytotoxic agents and radiotherapy. Continuously accumulating data suggest that autophagic response of cancer cells to radiotherapy is a major pathway which, in contrast to apoptosis that leads to death, may lead to either death or cellular survival. A variety of agents have been recognized that induce or block autophagy, directly interfering with the cytotoxic effect of radiotherapy. Simultaneous targeting of autophagy and apoptosis during radiotherapy seems to further augment the antitumor effect. Radiobiology research should focus on the differential effect of fractionation on the induction of autophagy in different tumors and on the manipulation of this with autophagy triggering agents. Whether manipulation of this pathway in normal tissues may be used to confer cytoprotection also deserves thorough investigation. Moreover, the role of pretreatment autophagic indices in tumor cells in predicting radiotherapy and chemotherapy outcome should be examined in translational studies.


The role of imaging in diagnosing neuromyelitis optica spectrum disorder.
Early identification of neuromyelitis optica allows aggressive acute and prophylactic relapse management aimed at preventing disability. Since the discovery of pathogenic aquaporin-4 antibodies the neuromyelitis optica spectrum has widened significantly: brain lesions no longer preclude the diagnosis and there are reports of symptoms of cerebral origin presenting as the first manifestation of the condition, prior to optic nerve or spinal cord disease. Defining antibody negative neuromyelitis optica, and distinguishing it from other inflammatory disorders such as multiple sclerosis can therefore be a challenge. In this review we discuss the role of conventional imaging in the diagnosis of neuromyelitis optica, and the scope of quantitative MRI modalities to identify more specific pathophysiological features to aid in the differentiation from other conditions and assess treatment response.


Age-related changes in cell surface antigens of preleukemic AKR thymocytes.
Thymocytes from preleukemic AKR mice aged 5-6 mo have an altered pattern of cell surface antigens. The expression of four MuLV-related antigens on the cell surface (GIX, GCSA, gp70, p30) is markedly increased in comparison to 2-mo-old AKR mice and approximates the heightened levels of these antigens found on thymic leukemia cells. H-2 and Thy-1 alloantigens also show characteristic modifications in relation to age and leukemia development. In contrast to the high Thy-1/low H-2 levels on 2-mo-old AKR thymocytes, thymocytes from 6-mo-old mice and thymic leukemia cells frequently show a low Thy-1/high H-2 surface phenotype. As thymocytes from mouse strains with a low incidence of leukemia do not show these changes, they appear to represent a stage in the conversion of normal cells to leukemia cells.


Efficient and specific removal of albumin from human serum samples.
Patient serum or plasma is frequently monitored for biochemical markers of disease or physiological status. Many of the rapidly evolving technologies of proteome analysis are being used to find additional clinically informative protein markers. The unusually high abundance of albumin in serum can interfere with the resolution and sensitivity of many proteome profiling techniques. We have used monoclonal antibodies against human serum albumin (HSA) to develop an immunoaffinity resin that is effective in the removal of both full-length HSA and many of the HSA fragments present in serum. This resin shows markedly better performance than dye-based resins in terms of both the efficiency and specificity of albumin removal. Immunoglobulins are another class of highly abundant serum protein. When protein G resin is used together with our immunoaffinity resin, Ig proteins and HSA can be removed in a single step. This strategy could be extended to the removal of any protein for which specific antibodies or affinity reagents are available.


Annexin-1 downregulation in thyroid cancer correlates to the degree of tumor differentiation.
We investigated the expression of annexin-1 (ANXA1) in thyroid carcinoma cell lines and in thyroid cancers with a different degree of differentiation. The highest level of ANXA1 expression examined by Western blotting was detected in the papillary carcinoma cells (NPA) and in the follicular cells (WRO). On the other hand, the most undifferentiated thyroid carcinoma cells (ARO and FRO) presented the lowest level of ANXA1 expression. In surgical tissue specimens from 32 patients with thyroid cancers, we found high immunoreactivity for ANXA1 in papillary (PTC) and follicular (FTC) thyroid cancers while in undifferentiated thyroid cancers (UTC) the expression of the protein was barely detectable. Control thyroid tissue resulted positive for ANXA1. In summary, 70% of UTC examined weakly expressed ANXA1, whereas 65% of PTC or FTC specimens tested showed high expression of the protein. Thus ANXA1 expression may correlate with the tumorigenesis suggesting that the protein may represent an effective differentiation marker in thyroid cancer.


Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases.
Epidemiology is the study of the distribution and determinants of disease in human populations. Over the past decade there has been considerable progress in our understanding of the fundamental descriptive epidemiology (levels of disease frequency: incidence and prevalence, comorbidity, mortality, trends over time, geographic distributions, and clinical characteristics) of the rheumatic diseases. This progress is reviewed for the following major rheumatic diseases: rheumatoid arthritis (RA), juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, giant cell arteritis, polymyalgia rheumatica, gout, Sjögren's syndrome, and ankylosing spondylitis. These findings demonstrate the dynamic nature of the incidence and prevalence of these conditions--a reflection of the impact of genetic and environmental factors. The past decade has also brought new insights regarding the comorbidity associated with rheumatic diseases. Strong evidence now shows that persons with RA are at a high risk for developing several comorbid disorders, that these conditions may have atypical features and thus may be difficult to diagnose, and that persons with RA experience poorer outcomes after comorbidity compared with the general population. Taken together, these findings underscore the complexity of the rheumatic diseases and highlight the key role of epidemiological research in understanding these intriguing conditions.


MyGrief.ca.
Bereavement represents a significant public health concern as grievers often suffer from co-morbid health problems, increased use of health care resources, periodic hospitalizations, and even mortality in the first 2 years after the death. Furthermore, grievers frequently encounter major obstacles when seeking formal support, including lack of access to specialized grief support due to temporal, financial or geographic constraints. To address these gaps in service, the Canadian Virtual Hospice, in collaboration with pan-Canadian partners developed MyGrief.ca, the world's first evidence-based, online psycho-educational tool to support those who do not or cannot access existing in-person loss and grief supports and as a supplementary resource for those who do. The tool also serves as a rich educative tool for health providers. The content was developed with families and international leaders in the field of bereavement, with attentiveness to issues of cultural diversity. Funding was providing by the Canadian Partnership against Cancer. MyGrief.ca includes nine self-directed modules that cover a diversity of topics across the bereavement trajectory. Embedded within each module is a great variety of video testimonials detailing grief narratives that represent diverse age, cultural, gender, and sexual orientation groups. Attendees will be given an in-depth tour of MyGrief.ca, followed by an interactive conversation on the tool with a bereft family member, health provider and educator on their unique perspectives and the overall impact of using MyGrief.ca. Bereavement represents a significant public health issue with grievers often presenting with concurrent health difficulties in the first 2 years after the death. This workshop will present a novel tool developed by the Canadian Virtual Hospice, specifically an online self-directed bereavement resource to support patients, families and health providers.


COVID-19 and Public Transportation: Current Assessment, Prospects, and Research Needs.
The COVID-19 pandemic poses a great challenge for contemporary public transportation worldwide, resulting from an unprecedented decline in demand and revenue. In this paper, we synthesize the state-of-the-art, up to early June 2020, on key developments regarding public transportation and the COVID-19 pandemic, including the different responses adopted by governments and public transportation agencies around the world, and the research needs pertaining to critical issues that minimize contagion risk in public transportation in the so-called post-lockdown phase. While attempts at adherence to physical distancing (which challenges the very concept of mass public transportation) are looming in several countries, the latest research shows that for closed environments such as public transportation vehicles, the proper use of face masks has significantly reduced the probability of contagion. The economic and social effects of the COVID-19 outbreak in public transportation extend beyond service performance and health risks to financial viability, social equity, and sustainable mobility. There is a risk that if the public transportation sector is perceived as poorly transitioning to post-pandemic conditions, that viewing public transportation as unhealthy will gain ground and might be sustained. To this end, this paper identifies the research needs and outlines a research agenda for the public health implications of alternative strategies and scenarios, specifically measures to reduce crowding in public transportation. The paper provides an overview and an outlook for transit policy makers, planners, and researchers to map the state-of-affairs and research needs related to the impacts of the pandemic crisis on public transportation. Some research needs require urgent attention given what is ultimately at stake in several countries: restoring the ability of public transportation systems to fulfill their societal role.


Medical students' patterns of using ChatGPT as a feedback tool and perceptions of ChatGPT in a Leadership and Communication course in Korea: a cross-sectional study.
This study aimed to analyze patterns of using ChatGPT before and after group activities and to explore medical students' perceptions of ChatGPT as a feedback tool in the classroom. The study included 99 2nd-year pre-medical students who participated in a "Leadership and Communication" course from March to June 2023. Students engaged in both individual and group activities related to negotiation strategies. ChatGPT was used to provide feedback on their solutions. A survey was administered to assess students' perceptions of ChatGPT's feedback, its use in the classroom, and the strengths and challenges of ChatGPT from May 17 to 19, 2023. The students responded by indicating that ChatGPT's feedback was helpful, and revised and resubmitted their group answers in various ways after receiving feedback. The majority of respondents expressed agreement with the use of ChatGPT during class. The most common response concerning the appropriate context of using ChatGPT's feedback was "after the first round of discussion, for revisions." There was a significant difference in satisfaction with ChatGPT's feedback, including correctness, usefulness, and ethics, depending on whether or not ChatGPT was used during class, but there was no significant difference according to gender or whether students had previous experience with ChatGPT. The strongest advantages were "providing answers to questions" and "summarizing information," and the worst disadvantage was "producing information without supporting evidence." The students were aware of the advantages and disadvantages of ChatGPT, and they had a positive attitude toward using ChatGPT in the classroom.


Medically supervised water-only fasting in the treatment of hypertension.
Hypertension-related diseases are the leading cause of morbidity and mortality in industrially developed societies. Although antihypertensive drugs are extensively used, dietary and lifestyle modifications also are effective in the treatment of patients with hypertension. One such lifestyle intervention is the use of medically supervised, water-only fasting as a safe and effective means of normalizing blood pressure and initiating health-promoting behavioral changes. One hundred seventy-four consecutive hypertensive patients with blood pressure in excess of 140 mm Hg systolic, 90 mm Hg diastolic (140/90 mm Hg), or both were treated in an inpatient setting under medical supervision. The treatment program consisted of a short prefasting period (approximately 2 to 3 days on average) during which food consumption was limited to fruits and vegetables, followed by medically supervised water-only fasting (approximately 10 to 11 days on average) and a refeeding period (approximately 6 to 7 days on average) introducing a low-fat, low-sodium, vegan diet. Almost 90% of the subjects achieved blood pressure less than 140/90 mm Hg by the end of the treatment program. The average reduction in blood pressure was 37/13 mm Hg, with the greatest decrease being observed for subjects with the most severe hypertension. Patients with stage 3 hypertension (those with systolic blood pressure greater than 180 mg Hg, diastolic blood pressure greater than 110 mg Hg, or both) had an average reduction of 60/17 mm Hg at the conclusion of treatment. All of the subjects who were taking antihypertensive medication at entry (6.3% of the total sample) successfully discontinued the use of medication. Medically supervised water-only fasting appears to be a safe and effective means of normalizing blood pressure and may assist in motivating health-promoting diet and lifestyle changes.


A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors.
Purpose Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate used in the treatment of several types of lymphomas. Expression of the target antigen has also been reported on a variety of malignant tumors of nonlymphoid origin. This phase 2, open-label study evaluated the safety and antitumor activity of BV in patients with CD30-expressing nonlymphomatous malignancies. Methods Patients were dosed with 1.8 or 2.4 mg/kg BV once every three weeks. Antitumor activity was assessed at Cycles 2, 4, and every 4 cycles thereafter. Patients with stable disease or better were eligible to continue treatment until disease progression, unacceptable toxicity, or study closure. Results Of the 2693 patients screened, 3.8% had solid tumors with CD30 expression and 63 eligible patients with solid tumors enrolled in this study. The most common CD30 positive solid tumors were testicular cancer and mesothelioma. Both subtypes had more than one patient with an objective response. The median duration of BV exposure was 6.1 weeks. The disease control rate, defined as achieving stable disease or better at any point during the study, was 55%. The objective response rate was 11%, with a median duration of response of 2.92 months. The most common adverse events reported were fatigue (57%), nausea (33%), and decreased appetite (32%). Conclusion The safety profile of BV in patients with solid tumors was similar to the known safety profile of BV. In solid tumors, BV had modest activity as a single agent, which was similar to other second-line treatments already available to patients.


The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity.
The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization. Co-immunoprecipitation studies establish that γ-secretase associates with CRFR1; this is mediated by β-arrestin binding motifs. Additionally, CRFR1 and γ-secretase co-localize in lipid raft fractions, with increased γ-secretase accumulation upon CRF treatment. CRF treatment also increases γ-secretase activity in vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ-secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ-secretase.


The influence of cemented femoral stem choice on the incidence of revision for periprosthetic fracture after primary total hip arthroplasty: an analysis of national joint registry data.
Periprosthetic fracture (PF) after primary total hip arthroplasty (THA) is an uncommon but potentially devastating complication. This study aims to investigate the influence of cemented stem designs on the risk of needing a revision for a PF. We analysed data on 257 202 primary THAs with cemented stems and 390 linked first revisions for PF recorded in the National Joint Registry (NJR) of England, Wales and Northern Ireland to determine if a cemented femoral stem brand was associated with the risk of having revision for a PF after primary THA. All cemented femoral stem brands with more than 10 000 primary operations recorded in the NJR were identified. The four most commonly used cemented femoral stems were the Exeter V40 (n = 146 409), CPT (n = 24 300), C-Stem (n = 15 113) and Charnley (n = 20 182). We compared the revision risk ratios due to PF amongst the stems using a Poisson regression model adjusting for patient factors. Compared with the Exeter V40, the age, gender and ASA grade adjusted revision rate ratio was 3.89 for the cemented CPT stem (95% confidence interval (CI) 3.07 to 4.93), 0.89 for the C-Stem (95% CI 0.57 to 1.41) and 0.41 for the Charnley stem (95% CI 0.24 to 0.70). The limitations of the study include incomplete data capture, analysis of only PF requiring revision and that observation does not imply causality. Nevertheless, this study demonstrates that the choice of a cemented stem may influence the risk of revision for PF. Cite this article: Bone Joint J 2016;98-B:1347-54.