Effect of deployment on the occurrence of child maltreatment in military and nonmilitary families.
War has a profound emotional impact on military personnel and their families, but little is known about how deployment-related stress impacts the occurrence of child maltreatment in military families. This time-series analysis of Texas child maltreatment data from 2000 to 2003 examined changes in the occurrence of child maltreatment in military and nonmilitary families over time and the impact of recent deployment increases. The rate of occurrence of substantiated maltreatment in military families was twice as high in the period after October 2002 (the 1-year anniversary of the September 11th attacks) compared with the period prior to that date (rate ratio = 2.15, 95% confidence interval: 1.85, 2.50). Among military personnel with at least one dependent, the rate of child maltreatment in military families increased by approximately 30% for each 1% increase in the percentage of active duty personnel departing to (rate ratio = 1.28, 95% confidence interval: 1.20, 1.37) or returning from (rate ratio = 1.31, 95% confidence interval: 1.16, 1.48) operation-related deployment. These findings indicate that both departures to and returns from operational deployment impose stresses on military families and likely increase the rate of child maltreatment. Intervention programs should be implemented to mitigate family dysfunction in times of potential stress.


Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions: A Novel Model for Preclinical Studies.
Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp PCSK9 (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene. Ossabaw and Landrace PCSK9 gain-of-function founders were generated by Sleeping Beauty transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw PCSK9 gain-of-function animals receiving standard or atherogenic diets in a 6-month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10% of coronary plaques. The Ossabaw PCSK9 gain-of-function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large-animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease.


Criterion validation of nutrient profiling systems: a systematic review and meta-analysis.
Nutrient profiling systems (NPSs) use algorithms to evaluate the nutritional quality of foods and beverages. Criterion validation, which assesses the relationship between consuming foods rated as healthier by the NPS and objective measures of health, is essential to ensure the accuracy of NPSs. We examined and compared NPSs that have undergone criterion validity testing in relation to diet-related disease risk and risk markers. Academic databases were searched for prospective cohort and cross-sectional studies published before November, 2022. NPSs were eligible if they incorporated multiple nutrients or food components using an algorithm to determine an overall summary indicator (e.g., a score or rank) for individual foods. Studies were included if they assessed the criterion validity of an eligible NPS. Validation evidence was first summarized in narrative form by NPS, with random effects meta-analysis where ≥2 prospective cohort studies assessed the same NPS and outcomes. Of 4519 publications identified, 29 describing 9 NPSs were included in the review. The Nutri-Score NPS was assessed as having substantial criterion validation evidence. Highest compared with lowest diet quality as defined by the Nutri-Score was associated with significantly lower risk of cardiovascular disease (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.59, 0.93; n = 6), cancer (HR: 0.75; 95% CI: 0.59, 0.94; n = 5), all-cause mortality (HR: 0.74; 95% CI; 0.59, 0.91; n = 4) and change in body mass index (HR: 0.68; 95% CI: 0.50, 0.92; n = 3). The Food Standards Agency NPS, Health Star Rating, Nutrient Profiling Scoring Criterion, Food Compass, Overall Nutrition Quality Index, and the Nutrient-Rich Food Index were determined as having intermediate criterion validation evidence. Two other NPSs were determined as having limited criterion validation evidence. We found limited criterion validation studies compared with the number of NPSs estimated to exist. Greater emphasis on conducting and reporting on criterion validation studies across varied contexts may improve the confidence in existing NPSs.


Crystal structure prediction is changing from basic science to applied technology.
Over the past three decades, the development of methods for Crystal Structure Prediction (CSP) has primarily been curiosity-driven. Because of the obvious potential for economic gain from CSP, commercial interests can be assumed to eventually take over as the main driving force of development. We argue that this transition is happening right now, not only for commercial CSP providers, but also for consumers within industry. In the context of industry-wide efforts, we describe the exploration in CSP research and algorithm development by one large pharmaceutical company, Eli Lilly and Company, and the impact that this has had on experimental solid form screening and selection. We expect that, once CSP is sufficiently reliable and automated, it will become a standard tool for analytical chemistry, on par with X-ray diffraction, calorimetry and spectroscopy.


Wetting and prewetting of water on top of a single sheet of hexagonal boron nitride.
Wetting of a single hexagonal boron nitride sheet by liquid water has been investigated by molecular dynamics simulations within a temperature range between 278 and 373 K. The wetting temperature was found to be ~310 K, while the onset of prewetting happens around the much higher temperature of 354 K. The static (hydrogen-bond populations, density profiles, energy per molecule) and dynamic (diffusion coefficients) properties of water in the stable phases in this temperature range were also studied and compared to those of water on graphene. The results indicate that hydrophobicity of boron nitride is milder than that of graphene.


A changing landscape of physician quality reporting: analysis of patients' online ratings of their physicians over a 5-year period.
Americans increasingly post and consult online physician rankings, yet we know little about this new phenomenon of public physician quality reporting. Physicians worry these rankings will become an outlet for disgruntled patients. To describe trends in patients' online ratings over time, across specialties, to identify what physician characteristics influence online ratings, and to examine how the value of ratings reflects physician quality. We used data from RateMDs.com, which included over 386,000 national ratings from 2005 to 2010 and provided insight into the evolution of patients' online ratings. We obtained physician demographic data from the US Department of Health and Human Services' Area Resource File. Finally, we matched patients' ratings with physician-level data from the Virginia Medical Board and examined the probability of being rated and resultant rating levels. We estimate that 1 in 6 practicing US physicians received an online review by January 2010. Obstetrician/gynecologists were twice as likely to be rated (P < .001) as other physicians. Online reviews were generally quite positive (mean 3.93 on a scale of 1 to 5). Based on the Virginia physician population, long-time graduates were more likely to be rated, while physicians who graduated in recent years received higher average ratings (P < .001). Patients gave slightly higher ratings to board-certified physicians (P = .04), those who graduated from highly rated medical schools (P = .002), and those without malpractice claims (P = .1). Online physician rating is rapidly growing in popularity and becoming commonplace with no evidence that they are dominated by disgruntled patients. There exist statistically significant correlations between the value of ratings and physician experience, board certification, education, and malpractice claims, suggesting a positive correlation between online ratings and physician quality. However, the magnitude is small. The average number of ratings per physician is still low, and most rating variation reflects evaluations of punctuality and staff. Understanding whether they truly reflect better care and how they are used will be critically important.


Can reduced folic acid and vitamin B12 levels cause deficient DNA methylation producing mutations which initiate atherosclerosis?
Atherosclerosis of the vascular system has classically been attributed to elevated serum cholesterol concentrations. Recently, it has been found that reduced serum levels of folic acid, vitamin B12, and vitamin B6 are related to the etiology of atherosclerosis and coronary heart disease. These deficiencies lead to inadequate production of S-adenosyl-methionine, creating a condition of hypomethylation. It is hypothesized that this causes hypomethylation of the DNA in cells in the arterial intima resulting in mutation and proliferation of smooth-muscle cells which lead to the formation of atheroma. It is further hypothesized that such action can be reversed by supraphysiological doses of these three vitamins to reduce or remove existing atheroma. It is recommended that all patients suffering from atherosclerosis and having deficiencies of any of these three vitamins and/or an elevation of serum homocysteine receive supplementation to prevent worsening of their condition.


Assessment of transfemoral amputees using C-Leg and Power Knee for ascending and descending inclines and steps.
Adding active power to a prosthetic knee unit may improve function and reduce the potential for overuse injuries in persons with transfemoral amputation (TFA). Servicemembers who have sustained a TFA are often young and motivated to perform at high functional levels. The goal of this article is to compare the biomechanics of ramp and stair descent and ascent for participants using the C-Leg and the Power Knee (PK). Subjects were asked to ascend and descend an instrumented staircase and 12 degree ramp at their comfortable pace while equipped with retroreflective markers. Temporal-spatial and kinetic data were collected. Knee power generated by the nondisabled limb during stair ascent for subjects wearing the C-Leg was significantly greater than for those wearing the PK. Knee power generated by prosthetic knee units was significantly greater for subjects while wearing the PK. Although the PK reduced the power required from the nondisabled knee during stair climbing, it does not appear to be superior to the C-Leg for other tasks. Adding power to a prosthetic knee may reduce wear on the nondisabled limb; however, there are still limitations that require improvement.


[Ozone Therapy in Knee Osteoarthritis: A Systematic Review].
The aim of this study was to conduct a systematic review in order to examine the effectiveness of ozone therapy on knee osteoarthritis. The objectives were to evaluate the effect over time of ozone therapy in terms of knee pain, functional improvement and radiographic progression. A search was carried out on PubMed, Embase, Cochrane Library, Scopus and Web of Science databases to identify randomized and controlled studies focusing on this association. The following descriptors were used in English: ozone therapy, knee osteoarthritis. A descriptive summary and quality assessment was made of all studies included for analysis. Six randomized and controlled studies were identified. The risk of bias assessment demonstrated that one study was considered as having a moderate risk of bias and the remainder a high risk of bias. No quantitative analysis of the data was performed, as the studies included were not sufficiently homogeneous. The participants in the studies were generally elderly patients with mild to moderate knee osteoarthritis. The variability of ozone therapy and the comparators demonstrates that there is no standardized therapy. Few studies reported adverse effects, and where they occurred, they were mild and associated with the procedure. Ozone therapy proved effective in the short-term in relation to placebo and when combined with hyaluronic acid, but it was not superior to other current treatments. More randomised and controlled studies are needed to evaluate the risks/benefits of ozone therapy, both in the short term and the medium/long term.


Extraformational sediment recycling on Mars.
Extraformational sediment recycling (old sedimentary rock to new sedimentary rock) is a fundamental aspect of Earth's geological record; tectonism exposes sedimentary rock, whereupon it is weathered and eroded to form new sediment that later becomes lithified. On Mars, tectonism has been minor, but two decades of orbiter instrument-based studies show that some sedimentary rocks previously buried to depths of kilometers have been exposed, by erosion, at the surface. Four locations in Gale crater, explored using the National Aeronautics and Space Administration's Curiosity rover, exhibit sedimentary lithoclasts in sedimentary rock: At Marias Pass, they are mudstone fragments in sandstone derived from strata below an erosional unconformity; at Bimbe, they are pebble-sized sandstone and, possibly, laminated, intraclast-bearing, chemical (calcium sulfate) sediment fragments in conglomerates; at Cooperstown, they are pebble-sized fragments of sandstone within coarse sandstone; at Dingo Gap, they are cobble-sized, stratified sandstone fragments in conglomerate derived from an immediately underlying sandstone. Mars orbiter images show lithified sediment fans at the termini of canyons that incise sedimentary rock in Gale crater; these, too, consist of recycled, extraformational sediment. The recycled sediments in Gale crater are compositionally immature, indicating the dominance of physical weathering processes during the second known cycle. The observations at Marias Pass indicate that sediment eroded and removed from craters such as Gale crater during the Martian Hesperian Period could have been recycled to form new rock elsewhere. Our results permit prediction that lithified deltaic sediments at the Perseverance (landing in 2021) and Rosalind Franklin (landing in 2023) rover field sites could contain extraformational recycled sediment.


Sustained mechanical release of dexamethasone sodium phosphate from a foldable capsular vitreous body.
Since 300-nm-mili apertures were present in the capsule of the foldable capsular vitreous body (FCVB), the authors tested whether the FCVB could mechanically release dexamethasone sodium phosphate (DexP) from its capsule. In the in vitro study, DexP at concentrations of 0.25, 0.5, 1, 2, and 4 mg/mL in a balanced salt solution were injected into the capsules, which were immersed in cups of modified Franz diffusion cells. Two hundred microliters of liquid was aspirated at time intervals of 10, 20, 40, 60, 120, 180, 240, 300, and 360 minutes. In the in vivo study, the capsule was folded and implanted into the vitreous cavities of five rabbits. Approximately 0.6 mL DexP (2 mg/mL) was then injected into the capsule. An intravitreal injection with DexP was performed on another five rabbits as the control group. Aqueous humor was aspirated on days 1, 3, 7, 14, 28, and 42 after implantation. The DexP contents in the cups and aqueous humor were detected by HPLC-MS/MS. FCVB released DexP in a time-dependent and dose-dependent manner in vitro with five dosages from 10 to 360 minutes. Especially in the 0.25 mg/mL DexP group, the content (y) had good linear relationships with time (x), as shown by y = 0.7635x + 10.205. The DexP contents in the aqueous humor were detected until day 28 and were undetectable on day 42. However, the DexP contents were detected only before day 3 in the controls. FCVB can sustainably and mechanically release DexP by capsule apertures in a time-dependent and dose-dependent manner in addition to serving as a vitreous substitute.


Abnormal germling development by brown rust and powdery mildew on cer barley mutants.
The barley leaf rust fungus forms appressoria over host leaf stomata and penetrates via the stomatal pore. High levels of avoidance to leaf rust fungi have been described in some wild accessions of Hordeum species where a prominent wax layer on the stomata inhibits triggering of fungal appressorium differentiation. Leaf rust avoidance has not yet been found in H. vulgare. Since cuticular leaf waxes are implicated in the avoidance trait, we screened 27 eceriferum (cer) mutant lines of H. vulgare for avoidance to barley leaf rust. These mutations affect leaf waxes. Reduction in numbers of germ tubes forming appressoria over stomata was found in some lines, but the greatest reduction (ca 30%) was less than previously found in wild barley spp. or in an accession of H. chilense used here as a check. In one line (cer-zh654), avoidance was due to a combination of factors. Firstly, fewer germ tubes oriented towards stomata and so failed to contact them. Secondly, some germ tubes that encountered stomata did not form appressoria but over-grew them. In this line, therefore, the fungus tended to fail both to locate and to respond to stomata. The appressoria of barley powdery mildew form on leaf epidermal cells that they penetrate directly. On certain cer lines, a proportion of germlings of the barley powdery mildew fungus developed abnormally, suggesting that germlings failed to recognise and/or respond to the leaf surface waxes on these mutants.


Electrically enhanced hot hole driven oxidation catalysis at the interface of a plasmon-exciton hybrid.
In this work, an electro-optical device based on a graphene-Ag nanoparticle hybrid is fabricated as the substrate of graphene mediated surface enhanced Raman scattering (G-SERS) manipulated by the gate and bias voltages. Plasmon-exciton coupling promotes co-driven surface catalytic reactions, where the density of states (DOS) of holes and electrons on graphene is well controlled by the gate voltage, and the kinetic energy of holes and electrons is driven by the bias voltage (or current). Our experimental results reveal that the hot holes on graphene mainly contribute to plasmon-exciton co-driven oxidation reactions. The contribution of hot electrons to oxidation reactions is less important. Our novel electro-optical device can be potentially applied in controlling plasmon-exciton co-driven oxidation or reduction reactions by tuning the gate and bias voltages.


Depressive symptoms in Parkinson's disease are related to reduced [123I]FP-CIT binding in the caudate nucleus.
Depression is a common neuropsychiatric symptom in Parkinson's disease (PD). In previous research, PD-related depression was associated with striatal dopaminergic deficits, presumably due to degeneration of brainstem dopaminergic projections. Segregated areas of the striatum are crucially involved in various parallelly arranged cortical-striatal-thalamocortical circuits and serve functions in, among others, motor control or emotion. This suggests regional specificity of dopaminergic deficits in the striatum in motor and depressive symptoms in PD. In this cross-sectional retrospective study, we correlated severity scores of depressive and motor symptoms in 100 non-demented PD patients (median Hoehn & Yahr stage: 2) with dopamine loss in specific regions of the striatum as measured by [(123)I]FP-CIT SPECT tracer binding to the dopamine transporter (DaT). Depressive symptoms were related to lower DaT binding in the right caudate nucleus, while motor symptoms were associated with decreased DaT binding in the right putamen. This double dissociation was most pronounced in early-stage PD patients. These results suggest that depressive symptoms in PD are associated with dopamine loss in the caudate nucleus, possibly related to degeneration of dopaminergic projections from the ventral tegmental area, while motor symptoms are associated with low dopamine signalling to the putamen and loss of nigrostriatal projections. This is consistent with the neuroanatomy of partially segregated cortical-striatal-thalamocortical circuits and supports the role of dysfunctional associative and motivational circuits in PD-related depression.


Allele frequency distributions in pooled DNA samples: applications to mapping complex disease genes.
Genetic studies of complex hereditary disorders require for their mapping the determination of genotypes at several hundred polymorphic loci in several hundred families. Because only a minority of markers are expected to show linkage and association in family data, a simple screen of genetic markers to identify those showing linkage in pooled DNA samples can greatly facilitate gene identification. All studies involving pooled DNA samples require the comparison of allele frequencies in appropriate family samples and subsamples. We have tested the accuracy of allele frequency estimates, in various DNA samples, by pooling DNA from multiple individuals prior to PCR amplification. We have used the ABI 377 automated DNA sequencer and GENESCAN software for quantifying total amplification using a 5' fluorescently labeled forward PCR primer and relative peak heights to estimate allele frequencies in pooled DNA samples. In these studies, we have genotyped 11 microsatellite markers in two separate DNA pools, and an additional four markers in a third DNA pool, and compared the estimated allele frequencies with those determined by direct genotyping. In addition, we have evaluated whether pooled DNA samples can be used to accurately assess allele frequencies on transmitted and untransmitted chromosomes, in a collection of families for fine-structure gene mapping using allelic association. Our studies show that accurate, quantitative data on allele frequencies, suitable for identifying markers for complex disorders, can be identified from pooled DNA samples. This approach, being independent of the number of samples comprising a pool, promises to drastically reduce the labor and cost of genotyping in the initial identification of disease loci. Additional applications of DNA pooling are discussed. These developments suggest that new statistical methods for analyzing pooled DNA data are required.


Quality of HIV laboratory testing in Tanzania: a situation analysis.
Tanzania is scaling up prevention, treatment, care and support of individuals affected with HIV. There is therefore a need for high quality and reliable HIV infection testing and AIDS staging. The objective of this study was to assess laboratories capacities of services in terms of HIV testing and quality control. A baseline survey was conducted from December 2004 to February 2005 in 12 laboratories which were conveniently selected to represent all the zones of Tanzania. The questionnaires comprised of questions on laboratory particulars, internal and external quality control for HIV testing and quality control of reagents. Source and level of customer satisfaction of HIV test kits supply was established. Of 12 laboratories, nine used rapid tests for screening and two used rapid tests for diagnosis. In the 12 laboratories, four used double ELISA and five used single ELISA and three did not use ELISA. Confirmatory tests observed were Western Blot in three laboratories, DNA PCR in two laboratories, CD4 counting in seven laboratories, and viral load in two laboratories. Although all laboratories conducted quality control (QC) of the HIV kits, only two laboratories had Standard Operating Procedures (SOPs). Internal and external quality control (EQC) was done at varied proportions with the highest frequency of 55.6% (5/9) for internal quality control (IQC) for rapid tests and EQC for ELISA, and the lowest frequency of 14.3% (1/ 7) for IQC for CD4 counting. None of the nine laboratories which conducted QC for reagents used for rapid tests and none of the five which performed IQC and EQC had SOPs. HIV kits were mainly procured by the Medical Store Department and most of laboratories were not satisfied with the delay in procurement procedures. Most of the laboratories used rapid tests only, while some used both rapid tests and ELISA method for HIV testing. In conclusion, the survey revealed inadequacy in Good Laboratory Practice and poor laboratory quality control process for HIV testing reagents, internal and external quality control.


Does Cry1Ab protein affect learning performances of the honey bee Apis mellifera L. (Hymenoptera, Apidae)?
Genetically modified Bt crops are increasingly used worldwide but side effects and especially sublethal effects on beneficial insects remain poorly studied. Honey bees are beneficial insects for natural and cultivated ecosystems through pollination. The goal of the present study was to assess potential effects of two concentrations of Cry1Ab protein (3 and 5000 ppb) on young adult honey bees. Following a complementary bioassay, our experiments evaluated effects of the Cry1Ab on three major life traits of young adult honey bees: (a) survival of honey bees during sub-chronic exposure to Cry1Ab, (b) feeding behaviour, and (c) learning performance at the time that honey bees become foragers. The latter effect was tested using the proboscis extension reflex (PER) procedure. The same effects were also tested using a chemical pesticide, imidacloprid, as positive reference. The tested concentrations of Cry1Ab protein did not cause lethal effects on honey bees. However, honey bee feeding behaviour was affected when exposed to the highest concentration of Cry1Ab protein, with honey bees taking longer to imbibe the contaminated syrup. Moreover, honey bees exposed to 5000 ppb of Cry1Ab had disturbed learning performances. Honey bees continued to respond to a conditioned odour even in the absence of a food reward. Our results show that transgenic crops expressing Cry1Ab protein at 5000 ppb may affect food consumption or learning processes and thereby may impact honey bee foraging efficiency. The implications of these results are discussed in terms of risks of transgenic Bt crops for honey bees.


Vasoactive intestinal polypeptide and peptide histidine methionine. Presence in human follicular fluid and effects on DNA synthesis and steroid secretion in cultured human granulosa/lutein cells.
Vasoactive intestinal polypeptide (VIP) and peptide histidine methionine (PHM) originate from the same precursor molecule, prepro VIP. In the present study we examined the concentrations of VIP and PHM in human follicular fluid and their effects on cultured human granulosa/lutein cells. Follicular fluid and cells were obtained from patients undergoing in-vitro fertilization for tubal infertility. The concentrations of VIP and PHM in pre-ovulatory human follicular fluid were measured radioimmunochemically. Granulosa/lutein cells isolated from follicular fluid were cultured under serum-free conditions with VIP and PHM in varying concentrations (0.1, 10, 1000 nmol/l). [3H]Thymidine incorporation in the cells and oestradiol as well as progesterone concentrations in the culture medium were measured. The mean (+/- SEM) concentrations of VIP and PHM were 6.8 +/- 0.1 and 7.7 +/- 0.8 pmol/l, respectively. VIP at a concentration of 10 nmol/l caused a significant increase in [3H]thymidine incorporation, and at 1000 nmol/l a significant increase in oestradiol secretion was observed. VIP had no effect on progesterone secretion. PHM at the concentrations tested did not influence any of the activities. We conclude that VIP and PHM are present in human preovulatory follicular fluid and that VIP stimulates DNA synthesis and oestradiol secretion in cultured human granulosa/lutein cells. This indicates that VIP and perhaps PHM participate in the local nervous regulation of human ovarian function.


Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein.
We have recently identified the Raf kinase inhibitor protein (RKIP) as a physiological endogenous inhibitor of the Raf-1/MEK/extracellular signal-regulated kinase (ERK) pathway. RKIP interfered with MEK phosphorylation and activation by Raf-1, resulting in the suppression of both Raf-1-induced transformation and AP-1-dependent transcription. Here we report the molecular mechanism of RKIP's inhibitory function. RKIP can form ternary complexes with Raf-1, MEK, and ERK. However, whereas MEK and ERK can simultaneously associate with RKIP, Raf-1 binding to RKIP and that of MEK are mutually exclusive. RKIP is able to dissociate a Raf-1-MEK complex and behaves as a competitive inhibitor of MEK phosphorylation. Mapping of the binding domains showed that MEK and Raf-1 bind to overlapping sites in RKIP, whereas MEK and RKIP associate with different domains in Raf-1, and Raf-1 and RKIP bind to different sites in MEK. Both the Raf-1 and the MEK binding sites in RKIP need to be destroyed in order to relieve RKIP-mediated suppression of the Raf-1/MEK/ERK pathway, indicating that binding of either Raf-1 or MEK is sufficient for inhibition. The properties of RKIP reveal the specific sequestration of interacting components as a novel motif in the cell's repertoire for the regulation of signaling pathways.


Current and future perspectives on drug-eluting bioresorbable coronary scaffolds.
Despite improvements in stent platform, polymer and drug elution, the permanent metallic stents have significant limitations as they distort vessel physiology, predispose to late thrombosis and may preclude surgical revascularization. Bioresorbable scaffold (BRS) technology has evolved over the last few years to overcome these drawbacks. Actually, different BRS are either available or under clinical and preclinical investigation. However, the use of BRS has largely been restricted to patients recruited into clinical trials with a relatively small number of 'real world' patients treated with these devices. Here, we highlight the potentialities of these devices, describe the evidence from the recent clinical trials and discuss the potential advantages, as well as challenges, that this novel technology may face in routine clinical practice.


Success in the prevention of infant walker-related injuries: an analysis of national data, 1990-2001.
Here we describe the epidemiologic characteristics and secular trends of infant walker-related injuries among children who are younger than 15 months in the United States. A retrospective analysis was conducted of data from the National Electronic Injury Surveillance System of the US Consumer Product Safety Commission, 1990-2001. Sample weights that were provided by the National Electronic Injury Surveillance System were used in all analyses to adjust for the inverse probability of case selection and make national projections regarding infant walker-related injuries. An estimated 197200 infant walker-related injuries occurred among children who were younger than 15 months and treated in US emergency departments from 1990 through 2001. Five percent of these children required admission to the hospital. The number of infant walker-related injuries remained relatively constant from 1990 through 1994, averaging 23,000 cases per year. After the introduction in 1994 of stationary activity centers as an alternative to mobile infant walkers and the implementation of the revised American Society for Testing and Materials F977 voluntary infant walker standard in 1997, there was a marked decrease in the number of infant walker-related injuries. Overall, there was a 76% decrease in the number of injuries from 1990 to 2001 from 20,900 injuries in 1990 to 5100 in 2001. Soft tissue injuries and lacerations represented 63% of the injuries. Trauma to the head region occurred in 91% of cases. Skull fractures were the most common (62%) type of fracture. Falls down stairs was the mechanism of injury in 74% of cases. The adoption of passive injury-prevention strategies, such as use of stationary activity centers as alternatives to mobile infant walkers and redesign of infant walkers to prevent falls down stairs, were associated with a marked decrease in the number of infant walker-related injuries.


Moderate alcohol consumption is associated with decreased platelet activity in patients presenting with acute myocardial infarction.
Moderate alcohol consumption (MAC) and platelet inhibition have been independently associated with a reduced risk for the development of acute myocardial infarction (AMI). The effects of MAC on the initial platelet status in patients presenting with AMI are not elucidated. Here we sought to define the effects of MAC on platelet characteristics in AMI patients before applying any reperfusion strategies. The study was designed as an analysis within the cohort study in 23 patients with AMI enrolled in the GUSTO-III. Platelets were investigated by different techniques, including aggregometry, flow cytometry, and ELISA. MAC patients exhibited mild, but consistent, inhibition of platelet aggregability, surface receptor expression, and released substances as compared to non-alcohol consuming patients. These differences were significant for 5 microM ADP (p = 0.04), 10 microM ADP-induced aggregation (p = 0.02); P-selectin (p = 0.01), and PECAM-1 (p = 0.02) platelet-bound expression. Our study confirms that moderate alcohol consumption is associated with diminished platelet activation in patients presenting with AMI. The ability of MAC to favorably modulate the pre-reperfusion platelet status in such patients is of clinical importance, and further investigation in large-scale clinical trials seem warranted.


Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain.
The cell fate determinant Numb influences developmental decisions by antagonizing the Notch signaling pathway. However, the underlying molecular mechanism of this inhibition is poorly understood. Here we report that the mammalian Numb protein promotes the ubiquitination of membrane-bound Notch1 receptor. Furthermore, Numb expression resulted in the degradation of the Notch intracellular domain following activation, which correlated with a loss of Notch-dependent transcriptional activation of the Hes1 promoter as measured by a Hes1 luciferase reporter assay. The phosphotyrosine-binding (PTB) domain of Numb was required for both Notch1 ubiquitination and down-regulation of Notch1 nuclear activity. Numb-mediated ubiquitination of Notch1 was not dependent on the PEST region, which was previously shown to mediate Sel10-dependent ubiquitination of Notch in the nucleus, suggesting a distinct E3 ubiquitin ligase is involved. In agreement we demonstrate that Numb interacts with the cytosolic HECT domain-containing E3 ligase Itch and that Numb and Itch act cooperatively to promote ubiquitination of membrane-tethered Notch1. These results suggest that Numb recruits components of the ubiquitination machinery to the Notch receptor thereby facilitating Notch1 ubiquitination at the membrane, which in turn promotes degradation of the intracellular domain circumventing its nuclear translocation and downstream activation of Notch1 target genes.


Comprehensive scenario management of sustainable spatial planning and urban water services.
Adaptations of existing central water supply and wastewater disposal systems to demographic, climatic and socioeconomic changes require a profound knowledge about changing influencing factors. The paper presents a scenario management approach for the identification of future developments of drivers influencing water infrastructures. This method is designed within a research project with the objective of developing an innovative software-based optimisation and decision support system for long-term transformations of existing infrastructures of water supply, wastewater and energy in rural areas. Drivers of water infrastructures comprise engineering and spatial factors and these are predicted by different methods and techniques. The calculated developments of the drivers are illustrated for a model municipality. The developed scenario-manager enables the generation of comprehensive scenarios by combining different drivers. The scenarios are integrated into the optimisation model as input parameters. Furthermore, the result of the optimisation process - an optimal transformation strategy for water infrastructures - can have impacts on the existing fee system. General adaptation possibilities of the present fee system are presented.


Point-of-care blood ketone testing: screening for diabetic ketoacidosis at the emergency department.
We piloted the use of a blood beta-hydroxybutyrate meter as a point-of-care testing in an emergency department (ED) to establish its role in distinguishing ketosis/ketoacidosis from simple hyperglycaemia, and develop guidelines for its use in the ED. 111 consecutive patients presenting with capillary glucose levels exceeding 14 mmol/L had a simultaneous blood ketone measurement at triage. This was correlated with clinical diagnosis, venous bicarbonate levels and urine ketone testing. The median beta-hydroxybutyrate levels was 5.7 (range 4.3-6.0) mmol/L for patients with diabetic ketoacidosis (DKA) and 0.1 (0.0-3.2) mmol/L for the remaining patients. Only 47.7 percent could provide urine samples in the ED. A blood ketone result of 3.5 mmol/L yielded 100 percent specificity and sensitivity for the diagnosis of DKA. This is a useful tool that allows clinicians to immediately distinguish between simple hyperglycaemia and potentially life-threatening ketotic states. We formulated simple guidelines for its utilisation in an ED setting.


Disorder-Induced Quantum Spin Liquid in Spin Ice Pyrochlores.
We propose that in a certain class of magnetic materials, known as non-Kramers "spin ice," disorder induces quantum entanglement. Instead of driving glassy behavior, disorder provokes quantum superpositions of spins throughout the system and engenders an associated emergent gauge structure and set of fractional excitations. More precisely, disorder transforms a classical phase governed by a large entropy, classical spin ice, into a quantum spin liquid governed by entanglement. As the degree of disorder is increased, the system transitions between (i) a "regular" Coulombic spin liquid, (ii) a phase known as "Mott glass," which contains rare gapless regions in real space, but whose behavior on long length scales is only modified quantitatively, and (iii) a true glassy phase for random distributions with large width or large mean amplitude.


Inorganic Molecular Electride Mg4 O3 : Structure, Bonding, and Nonlinear Optical Properties.
Growing demands of material science and, in particular, in the field of nonlinear optics (NLO) encourage us to look for stable highly polarizable molecules with excess diffuse electrons. An unusual class of compounds called electrides comply with these requirements. Many attempts have been made, yet only few electrides have been synthesized as solids and none of them as molecular species. In this paper, a new theoretically designed molecular species with electride characteristics is reported. The idea of this molecular electride comes from the formation of electride-like features in the MgO crystal with defect F-centers. The geometry of the investigated molecule can be described as a Mg4 O4 cube with one oxygen atom removed. In Mg4 O3 , two 3s electrons are pushed out from the inner area of the molecule forming a diffuse electride multicentered bond. Our calculations show that this electride-like cluster possesses a noticeably large first hyperpolarizability β=5733 au. At the same time, a complete cube Mg4 O4 and Mg4 O3 2+ without electride electron pair have much smaller β: 0 au and 741 au, respectively. This fact indicates the decisive role of the electride electron pair in NLO properties. Additionally, vertical detachment energies of isomers (VDE), excitation energies ΔE, polarizabilities α, and IR spectra were calculated. These properties, including β, are supposed to be observable experimentally and can serve as indirect evidence of the stable molecular electride formation.


Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is an etiologically heterogeneous cardiac disease characterized by left ventricular dilation and systolic dysfunction. Approximately 25-30% of DCM patients show a family history of mainly autosomal dominant inheritance. We and others have previously demonstrated that mutations in the giant muscle filament titin (TTN) can cause DCM. However, the prevalence of titin mutations in familial DCM is unknown. In this paper, we report a novel heterozygous 1-bp deletion mutation (c.62890delG) in TTN that cosegregates with DCM in a large Australian pedigree (A3). The TTN deletion mutation c.62890delG causes a frameshift, thereby generating a truncated A-band titin due to a premature stop codon (p.E20963KfsX10) and the addition of ten novel amino acid residues. The clinical phenotype of DCM in kindred A3 demonstrates incomplete penetrance and variable expressivity. Finally, protein analysis of a skeletal muscle biopsy sample from an affected member did not reveal the predicted truncated titin isoform although the aberrant mRNA was present, suggesting posttranslational modification and degradation of the truncated protein. The identification of a novel disease-causing mutation in the giant titin gene in a third large family with DCM indicates that mutations in titin may account for a significant portion of the genetic etiology in familial DCM.


[Molecular biology and pharmacology of natriuretic peptide system].
The natriuretic peptide system comprises at least three endogenous ligands, namely, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and three receptors for natriuretic peptides (NPR), that is, NPR-A, NPR-B and clearance receptor (NPR-C). Three natriuretic peptides derived from the distinct genes share a common ring structure with 17 amino acids formed by a disulfide linkage which confers the unique biological property on these peptides. ANP and BNP are elucidated to be the cardiac hormone mainly secreted from the atrium, and from the ventricle, respectively. CNP, first recognized as the neuropeptide, is now identified within the vascular wall, especially in endothelial cells and considered to be the peptidic endothelium-derived relaxing factor (EDRF). While NPR-A shows the high affinity to ANP and BNP, NPR-B is the selective receptor for CNP. These two types of "biologically active" NPR are the membrane-bound guanylate cyclase itself, and mediate the wide range of biological actions of natriuretic peptides through cyclic GMP-dependent cascade. The clearance receptor shows the ligand-binding affinity with the rank order of ANP > CNP > BNP and is considered to be involved in the clearance of the peptides. The natriuretic peptide system as an endocrine and paracrine/autocrine system serves as one of the key modulatory systems for blood pressure, body fluid homeostasis and vascular remodeling.


Histone gene expression and chromatin structure in mammalian cell hybrids.
DNA isolated from mammalian cell nuclear reveals discrete size patterns when partially digested with micrococcal nuclease. The DNA repeat lengths from different tissues within a species or from different species may vary. These differences have been attributed to the presence of different species of histone H1. To examine the nature of regulation of DNA repeat lengths and their possible relationship to histone H1, we have selected several mouse and human cell lines that differ in their DNA repeat lengths and examined them and their cell hybrids. 24 mouse X human and five mouse X mouse hybrid cell lines were analyzed. All the interspecific hybrids exhibited the repeat pattern characteristic of the murine parent. The mouse intraspecific hybrids had a repeat pattern of only one of the parents. We conclude that the partial human chromosome complements retained in the hybrids assume the repeat lengths exhibited by the mouse cells. Because H1 histones have been implicated in the determination of DNA repeat lengths, we also investigated the regulation of H1 histone expression in these cell hybrids. Purified H1 histones were radioactively labeled in vitro, and individual subfractions were subjected to proteolysis followed by gel electrophoresis. The resulting partial peptide maps off H1 histone subfractions A and B were distinguishable from one another and from different cell lines. In the mouse X human hybrids analyzed, only the mouse H1 histones were detected. These observations were extended to H2b by analysis of the hybrid cell histone by Triton-acid-urea gels. Neither the DNA repeat length nor histone expression is affected by the presence of any specific human chromosome. The fact that human genes are expressed in these hybrids suggests that the H1 histones of one species is able to interact with the chromatin of another species in a biologically funtional conformation. Analysis of the intraspecific PG19 X B82 (mouse X mouse) hybrids reveals the presence of H1 histone subfractions of the B82 mouse cells. Because these hybrids exhibit the nucleosome repeat length only of the PG19 cells, it appears that if histone H1 plays a role in determining the repeat length it does so in consort with other nonhistone chromosomal proteins.


Symptomatic adrenal insufficiency during inhaled corticosteroid treatment.
Symptomatic adrenal insufficiency, presenting as hypoglycaemia or poor weight gain, may occur on withdrawal of corticosteroid treatment but has not previously been reported during inhaled corticosteroid treatment. This case series illustrates the occurrence of clinically significant adrenal insufficiency in asthmatic children while patients were on inhaled corticosteroid treatment and the unexpected modes of presentation. General practitioners and paediatricians need to be aware that this unusual but acute serious complication may occur in patients treated with inhaled corticosteroids.


Biological Tissues as Active Nematic Liquid Crystals.
Live tissues can self-organize and be described as active materials composed of cells that generate active stresses through continuous injection of energy. In vitro reconstituted molecular networks, as well as single-cell cytoskeletons show that their filamentous structures can portray nematic liquid crystalline properties and can promote nonequilibrium processes induced by active processes at the microscale. The appearance of collective patterns, the formation of topological singularities, and spontaneous phase transition within the cell cytoskeleton are emergent properties that drive cellular functions. More integrated systems such as tissues have cells that can be seen as coarse-grained active nematic particles and their interaction can dictate many important tissue processes such as epithelial cell extrusion and migration as observed in vitro and in vivo. Here, a brief introduction to the concept of active nematics is provided, and the main focus is on the use of this framework in the systematic study of predominantly 2D tissue architectures and dynamics in vitro. In addition how the nematic state is important in tissue behavior, such as epithelial expansion, tissue homeostasis, and the atherosclerosis disease state, is discussed. Finally, how the nematic organization of cells can be controlled in vitro for tissue engineering purposes is briefly discussed.


Low-frequency oscillations in default mode subnetworks are associated with episodic memory impairments in Alzheimer's disease.
Disruptions to functional connectivity in subsystems of the default mode network are evident in Alzheimer's disease (AD). Functional connectivity estimates correlations in the time course of low-frequency activity. Much less is known about other potential perturbations to this activity, such as changes in the amplitude of oscillations and how this relates to cognition. We examined the amplitude of low-frequency fluctuations in 44 AD patients and 128 cognitively normal participants and related this to episodic memory, the core deficit in AD. We show higher amplitudes of low-frequency oscillations in AD patients. Rather than being compensatory, this appears to be maladaptive, with greater amplitude in the ventral default mode subnetwork associated with poorer episodic memory. Perturbations to default mode subnetworks in AD are evident in the amplitude of low-frequency oscillations in the resting brain. These disruptions are associated with episodic memory demonstrating their behavioral and clinical relevance in AD.


Mapping tree species vulnerability to multiple threats as a guide to restoration and conservation of tropical dry forests.
Understanding the vulnerability of tree species to anthropogenic threats is important for the efficient planning of restoration and conservation efforts. We quantified and compared the effects of future climate change and four current threats (fire, habitat conversion, overgrazing and overexploitation) on the 50 most common tree species of the tropical dry forests of northwestern Peru and southern Ecuador. We used an ensemble modelling approach to predict species distribution ranges, employed freely accessible spatial datasets to map threat exposures, and developed a trait-based scoring approach to estimate species-specific sensitivities, using differentiated trait weights in accordance with their expected importance in determining species sensitivities to specific threats. Species-specific vulnerability maps were constructed from the product of the exposure maps and the sensitivity estimates. We found that all 50 species face considerable threats, with an average of 46% of species' distribution ranges displaying high or very high vulnerability to at least one of the five threats. Our results suggest that current levels of habitat conversion, overexploitation and overgrazing pose larger threats to most of the studied species than climate change. We present a spatially explicit planning strategy for species-specific restoration and conservation actions, proposing management interventions to focus on (a) in situ conservation of tree populations and seed collection for tree planting activities in areas with low vulnerability to climate change and current threats; (b) ex situ conservation or translocation of populations in areas with high climate change vulnerability; and (c) active planting or assisted regeneration in areas under high current threat vulnerability but low climate change vulnerability, provided that interventions are in place to lower threat pressure. We provide an online, user-friendly tool to visualize both the vulnerability maps and the maps indicating priority restoration and conservation actions.


Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof-of-concept study.
The interleukin (IL)-12 signaling cascade has been associated with primary biliary cholangitis (PBC). This multicenter, open-label, proof-of-concept study evaluated the anti-IL12/23 monoclonal antibody, ustekinumab (90 mg subcutaneous at weeks 0 and 4, then every 8 weeks through week 20), in adults with PBC and an inadequate response to ursodeoxycholic acid therapy (i.e., alkaline phosphatase [ALP] >1.67× upper limit of normal [ULN] after ≥6 months). ALP response was defined as a >40% decrease from baseline and ALP remission as ALP normalization (if baseline ALP 1.67×-2.8× ULN) or <1.67× ULN (if baseline ALP >2.8× ULN). Changes in Enhanced Liver Fibrosis (ELF) scores and serum bile acids were also assessed. At baseline, patients had median disease duration of 3.2 years, median ELF score of 9.8, and highly elevated total bile acid concentration (median, 43.3 μmol/L); 13 of 20 (65%) patients had baseline ALP >3× ULN. Although steady-state serum ustekinumab concentrations were reached by week 12, no patient achieved ALP response or remission. Median percent ALP reduction from baseline to week 28 was 12.1%. ELF score decreased slightly from baseline to week 28 (median reduction: 0.173), and total serum bile acid concentrations decreased from baseline to week 28 (median reduction: 8.8 μmol/L). No serious infections or discontinuations resulting from adverse events were reported through week 28. One patient had a serious upper gastrointestinal hemorrhage considered unrelated to test agent by the investigator. Open-label ustekinumab therapy, though associated with a modest decrease in ALP after 28 weeks of therapy, did not otherwise appreciably change ALP and overt proof-of-concept was not established as per prespecified primary endpoint of proposed efficacy. No new ustekinumab safety signals were observed. (Hepatology 2016;64:189-199).


Product plots.
We propose a new framework for visualising tables of counts, proportions and probabilities. We call our framework product plots, alluding to the computation of area as a product of height and width, and the statistical concept of generating a joint distribution from the product of conditional and marginal distributions. The framework, with extensions, is sufficient to encompass over 20 visualisations previously described in fields of statistical graphics and infovis, including bar charts, mosaic plots, treemaps, equal area plots and fluctuation diagrams.


Positive Implicit Associations for Physical Activity Predict Physical Activity and Affective Responses During Exercise.
The purpose of this study was to investigate the relationships of implicit associations and explicit evaluations with affective responses during an aerobic exercise session, physical activity, and sedentary behavior in adults. Fifty adults (70% women; median age = 31 years; 25th, 75th percentiles: 24.50, 40.50 years old; body mass index = 25.29 ± 4.97 kg/m2) not engaged in regular physical activity completed an implicit association test and a questionnaire of explicit evaluations and wore an accelerometer for 7 days. After the 7-day period, the participants performed 30 min of moderate-intensity aerobic exercise. Every 5 min, the affective response and the perception of effort were recorded. Participants who had more positive implicit associations toward physical activity (vs. sedentary behavior) reported higher affective responses during exercise and engaged in more moderate to vigorous physical activity. Encouraging pleasant physical activity may act to partially improve future physical activity through automatic motivational processes.


Examining psychological inflexibility as a transdiagnostic process across psychological disorders.
The current cross-sectional study examined psychological inflexibility, a process in which behavior is rigidly guided by psychological reactions rather than direct contingencies or personal values, as a transdiagnostic process relevant to a range of depressive, anxiety, substance use and eating disorders. A sample of 972 first-year college students between 17 and 20 years of age completed self-report measures of psychological inflexibility and psychological distress as well as a structured diagnostic interview. Psychological inflexibility was significantly higher across a range of current and lifetime depressive and anxiety disorders as well as lifetime history of eating disorders, relative to students with no disorder, even after controlling for general psychological distress. Findings were mixed for substance use disorders, with a more consistent pattern for lifetime history than for current disorders. Psychological inflexibility was also related to having comorbid depressive, anxiety, and substance use disorders relative to only having one of these diagnoses. Results are discussed in relation to research on psychological inflexibility as a transdiagnostic pathological process and target for interventions.


Annurca Apple Nutraceutical Formulation Enhances Keratin Expression in a Human Model of Skin and Promotes Hair Growth and Tropism in a Randomized Clinical Trial.
Several pharmaceutical products have been formulated over the past decades for the treatment of male and female alopecia, and pattern baldness, but relatively few metadata on their efficacy have been published. For these reasons, the pharmaceutical and medical attention has recently focused on the discovery of new and safer remedies. Particularly, great interest has been attracted by oligomeric procyanidin bioactivity, able to promote hair epithelial cell growth as well as to induce the anagen phase. Specifically, the procyanidin B2, a dimeric derivative extracted from apples, has demonstrated to be one of the most effective and safest natural compounds in promoting hair growth, both in vitro and in humans by topical applications. By evaluating the polyphenolic content of different apple varieties, we have recently found in the apple fruits of cv Annurca (AFA), native to Southern Italy, one of the highest contents of oligomeric procyanidins, and, specifically, of procyanidin B2. Thus, in the present work we explored the in vitro bioactivity of AFA polyphenolic extract as a nutraceutical formulation, named AppleMets (AMS), highlighting its effects on the cellular keratin expression in a human experimental model of adult skin. Successively, testing the effects of AMS on hair growth and tropism in healthy subjects, we observed significant results in terms of increased hair growth, density, and keratin content, already after 2 months. This study proves for the first time the impact of apple procyanidin B2 on keratin biosynthesis in vitro, and highlights its effect as a nutraceutical on human hair growth and tropism.


Layer-Wise Relevance Propagation for Explaining Deep Neural Network Decisions in MRI-Based Alzheimer's Disease Classification.
Deep neural networks have led to state-of-the-art results in many medical imaging tasks including Alzheimer's disease (AD) detection based on structural magnetic resonance imaging (MRI) data. However, the network decisions are often perceived as being highly non-transparent, making it difficult to apply these algorithms in clinical routine. In this study, we propose using layer-wise relevance propagation (LRP) to visualize convolutional neural network decisions for AD based on MRI data. Similarly to other visualization methods, LRP produces a heatmap in the input space indicating the importance/relevance of each voxel contributing to the final classification outcome. In contrast to susceptibility maps produced by guided backpropagation ("Which change in voxels would change the outcome most?"), the LRP method is able to directly highlight positive contributions to the network classification in the input space. In particular, we show that (1) the LRP method is very specific for individuals ("Why does this person have AD?") with high inter-patient variability, (2) there is very little relevance for AD in healthy controls and (3) areas that exhibit a lot of relevance correlate well with what is known from literature. To quantify the latter, we compute size-corrected metrics of the summed relevance per brain area, e.g., relevance density or relevance gain. Although these metrics produce very individual "fingerprints" of relevance patterns for AD patients, a lot of importance is put on areas in the temporal lobe including the hippocampus. After discussing several limitations such as sensitivity toward the underlying model and computation parameters, we conclude that LRP might have a high potential to assist clinicians in explaining neural network decisions for diagnosing AD (and potentially other diseases) based on structural MRI data.


Outbreak of pertussis in a fully immunized adolescent and adult population.
To evaluate the spread of pertussis in a fully immunized eighth-grade class and the household contacts of two coindex cases of pertussis. Survey of infected subjects and their contacts was performed using culture, direct fluorescent antibody assay, and serological assays to establish the diagnosis of Bordetella pertussis. Middle-class parochial school. A volunteer sample of 15 eighth-grade students and 13 household contacts of two identified cases of B pertussis infection. All participants had medical histories (including immunization status) and laboratory evaluation for B pertussis infection (including nasopharyngeal specimens and serum samples) obtained initially and 30 days later. After initial evaluation, all subjects received erythromycin ethyl succinate therapy. Assessment of B pertussis infection as defined by positive nasopharyngeal culture, direct fluorescent antibody, or serological tests. Laboratory evidence of B pertussis infection was found in eight (47%) of 17 immunized eighth-grade classmates and in three (23%) of 13 household contacts, all of whom were 12 years of age or older. Vaccine-induced immunity wanes by early adolescence. These older age groups may be infected with B pertussis and may serve as reservoirs of infection for other susceptible individuals.


Malaria in Pregnancy Interacts with and Alters the Angiogenic Profiles of the Placenta.
Malaria in pregnancy remains a substantial public health problem in malaria-endemic areas with detrimental outcomes for both the mother and the foetus. The placental changes that lead to some of these detrimental outcomes have been studied, but the mechanisms that lead to these changes are still not fully elucidated. There is some indication that imbalances in cytokine cascades, complement activation and angiogenic dysregulation might be involved in the placental changes observed. Nevertheless, the majority of studies on malaria in pregnancy (MiP) have come from areas where malaria transmission is high and usually restricted to Plasmodium falciparum, the most pathogenic of the malaria parasite species. We conducted a cross-sectional study in Cruzeiro do Sul, Acre state, Brazil, an area of low transmission and where both P. vivax and P. falciparum circulate. We collected peripheral and placental blood and placental biopsies, at delivery from 137 primigravid women and measured levels of the angiogenic factors angiopoietin (Ang)-1, Ang-2, their receptor Tie-2, and several cytokines and chemokines. We measured 4 placental parameters (placental weight, syncytial knots, placental barrier thickness and mononuclear cells) and associated these with the levels of angiogenic factors and cytokines. In this study, MiP was not associated with severe outcomes. An increased ratio of peripheral Tie-2:Ang-1 was associated with the occurrence of MiP. Both Ang-1 and Ang-2 had similar magnitudes but inverse associations with placental barrier thickness. Malaria in pregnancy is an effect modifier of the association between Ang-1 and placental barrier thickness.


Constrained intracellular survival of Mycobacterium tuberculosis in human dendritic cells.
Dendritic cells (DCs) are likely to play a key role in immunity against Mycobacterium tuberculosis, but the fate of the bacterium in these cells is still unknown. Here we report that, unlike macrophages (Mphis), human monocyte-derived DCs are not permissive for the growth of virulent M. tuberculosis H37Rv. Mycobacterial vacuoles are neither acidic nor fused with host cell lysosomes in DCs, in a mode similar to that seen in mycobacterial infection of Mphis. However, uptake of the fluid phase marker dextran, and of transferrin, as well as accumulation of the recycling endosome-specific small GTPase Rab11 onto the mycobacterial phagosome, are almost abolished in infected DCs, but not in Mphis. Moreover, communication between mycobacterial phagosomes and the host-cell biosynthetic pathway is impaired, given that <10% of M. tuberculosis vacuoles in DCs stained for the endoplasmic reticulum-specific proteins Grp78/BiP and calnexin. This correlates with the absence of the fusion factor N-ethylmaleimide-sensitive factor onto the vacuolar membrane in this cell type. Trafficking between the vacuoles and the host cell recycling and biosynthetic pathways is strikingly reduced in DCs, which is likely to impair access of intracellular mycobacteria to essential nutrients and may thus explain the absence of mycobacterial growth in this cell type. This unique location of M. tuberculosis in DCs is compatible with their T lymphocyte-stimulating functions, because M. tuberculosis-infected DCs have the ability to specifically induce cytokine production by autologous T lymphocytes from presensitized individuals. DCs have evolved unique subcellular trafficking mechanisms to achieve their Ag-presenting functions when infected by intracellular mycobacteria.


Scope of policy issues in eHealth: results from a structured literature review.
eHealth is widely used as a tool for improving health care delivery and information. However, distinct policies and strategies are required for its proper implementation and integration at national and international levels. To determine the scope of policy issues faced by individuals, institutions, or governments in implementing eHealth programs. We conducted a structured review of both peer-reviewed and gray literature from 1998-2008. A Medline search for peer-reviewed articles found 40 papers focusing on different aspects of eHealth policy. In addition, a Google search found 20 national- and international-level policy papers and documents. We reviewed these articles to extract policy issues and solutions described at different levels of care. The literature search found 99 policy issues related to eHealth. We grouped these issues under the following themes: (1) networked care, (2) interjurisdictional practice, (3) diffusion of eHealth/digital divide, (4) eHealth integration with existing systems, (5) response to new initiatives, (6) goal-setting for eHealth policy, (7) evaluation and research, (8) investment, and (9) ethics in eHealth. We provide a list of policy issues that should be understood and addressed by policy makers at global, jurisdictional, and institutional levels, to facilitate smooth and reliable planning of eHealth programs.


Survival in patients with incident dementia compared with a control group: a five-year follow-up.
Dementia is an important disease in older age. Existing studies on dementia mortality face limitations. For instance, they are based on prevalent, small, or geographically limited samples or do not include controls. We aimed to study survival after the first diagnosis of dementia compared with a control group. We analyzed claims data of a German health insurance company, including 1,818 incident dementia cases and 7,235 age- and sex-matched non-dementia controls (53% male; mean age 78.8 years). The follow-up was five years. We assessed survival with the Kaplan-Meier curves and performed Cox proportional hazard regression, also including nursing care dependency and comorbidities. The cumulative five-year mortality was 53.5% in the dementia cases and 31.1% in the control group (hazard ratio: 2.1). Even after adjusting for comorbidities and nursing care, the mortality risk was 1.5 times higher for patients with incident dementia than for controls. Nursing care dependency showed high influence on mortality, likewise in dementia patients and controls. Although some factors, such as education or the type and severity of dementia, could not be included in the analyses, our study shows a clear influence of dementia on mortality irrespective of age, sex, care dependency, and comorbidities. The strongest influence on mortality was found for dementia patients with nursing care dependency. Taking into account their mortality of around 70% in care level 1 and up to 80% in care levels 2 and 3, healthcare delivery to these patient groups should strongly consider elements of palliative care focusing on the quality of life.


Endometriosis-Associated Ovarian Cancer: Population Characteristics and Prognosis.
The aim of this study was to analyze and compare the clinicopathologic features and prognosis of clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (EOC) associated or not with endometriosis. This was a reconstituted cohort study from a single-institution Brazilian cancer center approved under review board no. 68150617.7.0000.5404 with 50 patients with CCOC and EOC diagnosed between 1995 and 2016, followed up until 2017. Clinicopathologic characteristics and survival outcomes were analyzed. There were 23 women (46%) with CCOC and 27 with EOC (54%); 80% of those women had histologic confirmation of endometriosis; 42% were nulliparous, and 42% were premenopausal; and cancer antigen 125 was elevated in both International Federation of Gynecology and Obstetrics stages I-II disease (mean, 614.7 Ui/mL; range, 3-6030 Ui/mL) or International Federation of Gynecology and Obstetrics stages III-IV disease (mean, 2361.2 Ui/mL; range, 8-12771 Ui/mL). Women with EOC were 7 years younger than those with CCOC. When associated with endometriosis, CCOCs were more likely diagnosed at earlier stages. Endometrioid ovarian carcinoma and CCOC at initial stage and EOC at advanced stage share similar good prognosis. Univariate analysis showed that CCOC not associated with endometriosis has worse overall survival (OS). However, multivariate analysis showed that only abnormally elevated levels of cancer antigen 125 and advanced stage at diagnosis were significantly associated with reduced progression-free survival. Tumor stage remains the only prognostic factor for OS. The presence of coexisting endometriosis did not change the prognosis of EOC but was associated with better OS in patients with CCOC. Patients with CCOC and EOC at initial stages and EOC at advanced stages have a good prognosis; however, CCOC at advanced stages had a sooner recurrence and shorter OS.


[Studies in oocyte maturation and embryonic development].
A clearer understanding of biochemical properties of oocytes and embryos and their changes in oocyte maturation and embryonic development may have significant clinical implications, especially for in vitro fertilization techniques. Microtechniques and highly sensitive methods such as enzymatic cycling, micro-Western analysis, reverse transcription polymerase chain reaction and so on were employed to study these processes. Low hexokinase activity and high activities of enzymes in the phosphate pathway were characteristic of immature oocytes. During maturation, the activities of hexokinase and phosphofructokinase increased significantly. These changes were used to analyze involvement of epidermal growth factor (EGF) and prostaglandins (PG) in oocyte maturation. EGF is shown to stimulate maturation by increasing PG production in granulosa cells. Electrophysiologically, the sensitivity of oocyte to inositol triphosphate increased and Ca2+ release system developed during maturation. Progesterone production of oocyte and embryos are shown by enzymatic cycling and other methods using radiometry. This hormone produced by embryos themselves may play a role in embryonic development in intracrine fasion. There is 100-fold increase in glucose uptake from oocyte to blastocyst in mice. A switch in substrate preference of the embryo from pyruvate to glucose during preimplantation development may be explained by increases in the activity of hexokinase and expression of glucose transporter, GLUT1. Hexokinase activities determined by NADP cycling increased 20-fold while expression of GLUT1 assessed by micro-Western method 10-fold. GLUT1 expression was also analyzed by RT-PCR, which indicated that the expression is regulated at transcription level. There is a delay in the developmental changes in glucose uptake, hexokinase activity and GLUT1 expression when the embryos are developed in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)


NIR-driven water splitting by layered bismuth oxyhalide sheets for effective photodynamic therapy.
Two major issues of finding the appropriate photosensitizer and raising the penetration depth of irradiation light exist in further developing of photodynamic therapy (PDT). The excited ultraviolet/visible (UV/vis) irradiation light has a relatively shallow depth of penetration and UV light itself may have sufficient energy to damage normal tissues; these are substantial limitations to successful cancer therapy. Herein, we for the first time report a novel multifunctional nanoplatform for a single 980 nm near-infrared (NIR) light-triggered PDT based on NaGdF4:Yb,Tm@NaGdF4 upconversion nanoparticles (UCNPs) integrated with bismuth oxyhalide (BiOCl) sheets, designated as UCNPs@BiOCl. And UCNPs@BiOCl was fabricated by a convenient, efficient, green, and inexpensive method. Excitingly, layered bismuth oxyhalide materials possess a high photocatalytic performance, unique layered structures and wide light response to a broad wavelength range of ultraviolet to visible light. And the loaded UCNPs can convert NIR light into UV/vis region emissions, which drives the pure water splitting of BiOCl sheets to produce plenty of reactive oxygen species (ROS) to damage tumor cells. The excellent antitumor efficiency of the complex has been evidently attested by comparing experimental results. Our work may make a contribution to the wide application of BiOCl-based materials in biomedicine.


Molecular fragmentation as a way to reveal early electron dynamics induced by attosecond pulses.
We present a theoretical study of the electron and nuclear dynamics that would arise in an attosecond two-color XUV-pump/XUV-probe experiment in glycine. In this scheme, the broadband pump pulse suddenly ionizes the molecule and creates an electronic wave packet that subsequently evolves under the influence of the nuclear motion until it is finally probed by the second XUV pulse. To describe the different steps of such an experiment, we have combined a multi-reference static-exchange scattering method with a trajectory surface hopping approach. We show that by changing the central frequency of the pump pulse, i.e., by engineering the initial electronic wave packet with the pump pulse, one can drive the cation dynamics into a specific fragmentation pathway. Reminiscence of this early electron dynamics can be observed in specific fragmentation channels (not all of them) as a function of the pump-probe delay and in time-resolved photoelectron spectra at specific photoelectron energies. The optimum conditions to visualize the initial electronic coherence in photoelectron and photo-ion spectra depend very much on the characteristics of the pump pulse as well as on the electronic structure of the molecule under study.


Fifty consecutive hemispherectomies: outcomes, evolution of technique, complications, and lessons learned.
Techniques for achieving hemispheric disconnection in patients with epilepsy continue to evolve. To review the outcomes of the first 50 hemispherectomy surgeries performed by a single surgeon with an emphasis on outcomes, complications, and how these results led to changes in practice. The first 50 hemispherectomy cases performed by the lead author were identified from a prospectively maintained database. Patient demographics, surgical details, clinical outcomes, and complications were critically reviewed. From 2004 to 2012, 50 patients underwent hemispherectomy surgery (mean follow-up time, 3.5 years). Modified lateral hemispherotomy became the preferred technique and was performed on 44 patients. Forty patients (80%) achieved complete seizure freedom (Engel I). Presurgical and postsurgical neuropsychological evaluations demonstrated cognitive stability. Two cases were performed for palliation only. Previous hemispherectomy surgery was associated with worsened seizure outcome (2 of 6 seizure free; P .005). The use of Avitene was associated with a higher incidence of postoperative hydrocephalus (56% vs 18%; P = .03). In modified lateral hemispherotomy patients without the use of Avitene, the incidence of hydrocephalus was 13%. Complications included infection (n = 3), incomplete disconnection requiring reoperation (n = 1), reversible ischemic neurological deficit (n = 1), and craniosynostosis (n = 1). There were no (unanticipated) permanent neurological deficits or deaths. Minor technique modifications were made in response to specific complications. The modified lateral hemispherotomy is effective and safe for both initial and revision hemispherectomy surgery. Avitene use appears to result in a greater incidence of postoperative hydrocephalus.


Revisiting Clickers: In-Class Questions Followed by At-Home Reflections Are Associated with Higher Student Performance on Related Exam Questions.
Clicker questions are a commonly used active learning technique that stimulates student interactions to help advance understanding of key concepts. Clicker questions are often administered with an initial vote, peer discussion, and a second vote, followed by broader classroom explanation. While clickers can promote learning, some studies have questioned whether students maintain this performance on later exams, highlighting the need to further understand how student answer patterns relate to their understanding of the material and to identify ways for clickers to benefit a broader range of students. Systematic requizzing of concepts during at-home assignments represents a promising mechanism to improve student learning. Thus, we paired clicker questions with at-home follow-up reflections to help students articulate and synthesize their understandings. This pairing of clickers with homework allowed us to decipher how student answer patterns related to their underlying conceptions and to determine if revisiting concepts provided additional benefits. We found that students answering both clicker votes correctly performed better on isomorphic exam questions and that students who corrected their answers after the first vote did not show better homework or exam performance than students who maintained an incorrect answer across both votes. Furthermore, completing the follow-up homework assignment modestly boosted exam question performance. Our data suggest that longer-term benefits of clickers and associated homework may stem from students having repeated opportunities to retrieve, refine, and reinforce emerging conceptions.


Attitudes and behaviour of general practitioners and their prescribing costs: a national cross sectional survey.
General practitioner (GP) prescribing accounts for about 10% of NHS expenditure. GPs at the top of the range have annual prescribing costs that are almost twice as much as those at the bottom of the range. This variation cannot be accounted for purely in terms of differences in underlying need for health care. To describe the relationship between GPs' prescribing costs and their attitudes towards prescribing decisions and prescribing information sources, and to identify potentially modifiable attitudinal and behavioural factors associated with high cost prescribing. A postal questionnaire was designed on the basis of hypotheses developed from a literature search and an earlier qualitative survey. This questionnaire was sent to a national sample of GPs with equal numbers of practices in the upper, middle, and lowest quintile of prescribing costs. GP practices in England. 1714 GPs in NHS practice. GPs' self-reported practices, attitudes and personal characteristics. There was a 64% response rate. Responders were more likely to be from larger practices, in less deprived areas, and with lower prescribing costs than were non-responders. Multivariable analysis showed that GPs with high prescribing costs were significantly more likely to work in dispensing practices, in practices with low income populations, in single handed practices, and in practices without a GP trainer. They were also significantly more likely to see drug company representatives more frequently, to prescribe newly available drugs more freely, to prescribe more readily to patients who expect a prescription, to report high levels of frustration from lack of time in the consultation, to find unsatisfactory those consultations which ended in advice only, and to express dissatisfaction with their review methods for repeat prescribing. They were significantly less likely to find useful criticism of prescribing habits by colleagues, and to check the BNF rather than other sources when uncertain about an aspect of drug treatment. While they cannot be held to have a causal relationship, the pattern of attitudes towards prescribing of GPs in the highest quintile of prescribing costs provide the basis for developing an educational intervention which may be an acceptable method of modifying the attitudes of GPs and consequently reducing their prescribing costs.


Native-valve endocarditis caused by Staphylococcus lugdunensis.
Coagulase-negative staphylococci cause about 5% of native-valve endocarditis. Staphylococcus lugdunensis, a recently-described species of coagulase-negative staphylococci, has been reported to cause destructive native-valve endocarditis with a high mortality. We report four consecutive cases of definite Staphylococcus lugdunensis native-valve endocarditis by the Duke criteria over a 4-year period. All patients required urgent aortic valve replacement 1-5 days after admission, and recovered. An intriguing, aspect in the presentation of these patients was a history of vasectomy and inguinal skin breaks in the immediate period preceding the occurrence of endocarditis.


Cyclodextrin-siRNA conjugates as versatile gene silencing agents.
Functional siRNAs (luciferase and PLK1) have been conjugated to β-cyclodextrin and the ability of the conjugates to retain gene knockdown activity has been assessed by delivery to cancer cell lines using various formulations. Initially two formulations used complexation with polycations, namely Lipofectamine 2000 and an amphiphilic polycationic cyclodextrin. Gene knockdown results for human glioblastoma cells (U87) and prostate cancer cells (PC3, DU145) showed that conjugation to the cyclodextrin did not reduce gene silencing by the RNA. A third mode of delivery involved formation of targeted nanoparticles in which the conjugate was first complexed with adamantyl-PEG-ligands (targeting ligand RVG peptide or dianisamide) by adamantyl inclusion in the cyclodextrin cavities of the conjugates, followed by charge neutralisation with the cationic polymer chitosan. Enhanced knockdown was achieved by these ligand-targeted formulations. In summary, while this study illustrated the gene silencing efficacy of a simple cyclodextrin-siRNA conjugate it is envisaged that future studies will explore the use of conjugates with a modified cyclodextrin which would be self-delivering. Detailed data such as stability, lysosomal escape etc. will then be reported for each conjugate, since this will be appropriate for conjugates which are intended to exploit, rather than merely demonstrate, the concept. The present paper was intended to demonstrate the viability and generality of this novel concept.


Health sector reform in the Occupied Palestinian Territories (OPT): targeting the forest or the trees?
Since the signing of the Oslo Peace Accords and the establishment of the Palestinian Authority in 1994, reform activities have targeted various spheres, including the health sector. Several international aid and UN organizations have been involved, as well as local and international non-governmental organizations, with considerable financial and technical investments. Although important achievements have been made, it is not evident that the quality of care has improved or that the most pressing health needs have been addressed, even before the second Palestinian Uprising that began in September 2000. The crisis of the Israeli re-invasion of Palestinian-controlled towns and villages since April 2002 and the attendant collapse of state structures and services have raised the problems to critical levels. This paper attempts to analyze some of the obstacles that have faced reform efforts. In our assessment, those include: ongoing conflict, frail Palestinian quasi-state structures and institutions, multiple and at times inappropriate donor policies and practices in the health sector, and a policy vacuum characterized by the absence of internal Palestinian debate on the type and direction of reform the country needs to take. In the face of all these considerations, it is important that reform efforts be flexible and consider realistically the political and economic contexts of the health system, rather than focus on mere narrow technical, managerial and financial solutions imported from the outside.


Effects of lumbar arthrodesis on adjacent segments: differences between surgical techniques.
A finite element analysis. To evaluate the differences between surgical techniques in terms of the effects of arthrodesis on adjacent segments. Augmentation with posterior rigid fixation combined with transpedicular screw insertion, which is one of the most popular techniques for lumbar arthrodesis, shows benefits in immediate stabilization and a higher fusion rate but is reportedly correlated with greater stress on adjacent segments. However, the increased stress on adjacent segments needs further evaluation because the differences of the effects on adjacent segments between surgical techniques, including anterior lumbar interbody fusion, posterior lumbar interbody fusion, and semirigid fixation, have not yet been determined. A finite element model of the human lumbar spine was developed. Three spinal segments (L2-L5) were used to investigate. The intact spinal model was validated by comparing it with previously reported models. Then, 4 arthrodesis models were analyzed and compared: (1) anterior lumbar interbody fusion model; (2) posterior lumbar interbody fusion model; (3) semirigid fixation model combined with posterior lumbar interbody fusion; and (4) rigid fixation model combined with posterior lumbar interbody fusion. Among these 4 models, the rigid fixation model showed the greatest amount of stress, with increased intervertebral disc pressure and contact force of the facet joints of both upper and lower adjacent segments. The second highest stress levels were seen in the semirigid fixation model and the lowest stress levels were seen in the anterior lumbar interbody fusion model. Although bony fusion had been completed, the effects of lumbar arthrodesis on adjacent segments could vary according to the surgical technique used for arthrodesis. Semirigid fixation combined with arthrodesis deserves careful consideration and further detailed study because it may cause less stress on adjacent segments than rigid fixation while maintaining the benefits of the latter procedure.


Smoking cessation for improving mental health.
There is a common perception that smoking generally helps people to manage stress, and may be a form of 'self-medication' in people with mental health conditions. However, there are biologically plausible reasons why smoking may worsen mental health through neuroadaptations arising from chronic smoking, leading to frequent nicotine withdrawal symptoms (e.g. anxiety, depression, irritability), in which case smoking cessation may help to improve rather than worsen mental health. To examine the association between tobacco smoking cessation and change in mental health. We searched the Cochrane Tobacco Addiction Group's Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, and the trial registries clinicaltrials.gov and the International Clinical Trials Registry Platform, from 14 April 2012 to 07 January 2020. These were updated searches of a previously-conducted non-Cochrane review where searches were conducted from database inception to 13 April 2012. SELECTION CRITERIA: We included controlled before-after studies, including randomised controlled trials (RCTs) analysed by smoking status at follow-up, and longitudinal cohort studies. In order to be eligible for inclusion studies had to recruit adults who smoked tobacco, and assess whether they quit or continued smoking during the study. They also had to measure a mental health outcome at baseline and at least six weeks later. We followed standard Cochrane methods for screening and data extraction. Our primary outcomes were change in depression symptoms, anxiety symptoms or mixed anxiety and depression symptoms between baseline and follow-up. Secondary outcomes included change in symptoms of stress, psychological quality of life, positive affect, and social impact or social quality of life, as well as new incidence of depression, anxiety, or mixed anxiety and depression disorders. We assessed the risk of bias for the primary outcomes using a modified ROBINS-I tool. For change in mental health outcomes, we calculated the pooled standardised mean difference (SMD) and 95% confidence interval (95% CI) for the difference in change in mental health from baseline to follow-up between those who had quit smoking and those who had continued to smoke. For the incidence of psychological disorders, we calculated odds ratios (ORs) and 95% CIs. For all meta-analyses we used a generic inverse variance random-effects model and quantified statistical heterogeneity using I2. We conducted subgroup analyses to investigate any differences in associations between sub-populations, i.e. unselected people with mental illness, people with physical chronic diseases. We assessed the certainty of evidence for our primary outcomes (depression, anxiety, and mixed depression and anxiety) and our secondary social impact outcome using the eight GRADE considerations relevant to non-randomised studies (risk of bias, inconsistency, imprecision, indirectness, publication bias, magnitude of the effect, the influence of all plausible residual confounding, the presence of a dose-response gradient). We included 102 studies representing over 169,500 participants. Sixty-two of these were identified in the updated search for this review and 40 were included in the original version of the review. Sixty-three studies provided data on change in mental health, 10 were included in meta-analyses of incidence of mental health disorders, and 31 were synthesised narratively. For all primary outcomes, smoking cessation was associated with an improvement in mental health symptoms compared with continuing to smoke: anxiety symptoms (SMD -0.28, 95% CI -0.43 to -0.13; 15 studies, 3141 participants; I2 = 69%; low-certainty evidence); depression symptoms: (SMD -0.30, 95% CI -0.39 to -0.21; 34 studies, 7156 participants; I2 = 69%' very low-certainty evidence); mixed anxiety and depression symptoms (SMD -0.31, 95% CI -0.40 to -0.22; 8 studies, 2829 participants; I2 = 0%; moderate certainty evidence). These findings were robust to preplanned sensitivity analyses, and subgroup analysis generally did not produce evidence of differences in the effect size among subpopulations or based on methodological characteristics. All studies were deemed to be at serious risk of bias due to possible time-varying confounding, and three studies measuring depression symptoms were judged to be at critical risk of bias overall. There was also some evidence of funnel plot asymmetry. For these reasons, we rated our certainty in the estimates for anxiety as low, for depression as very low, and for mixed anxiety and depression as moderate. For the secondary outcomes, smoking cessation was associated with an improvement in symptoms of stress (SMD -0.19, 95% CI -0.34 to -0.04; 4 studies, 1792 participants; I2 = 50%), positive affect (SMD 0.22, 95% CI 0.11 to 0.33; 13 studies, 4880 participants; I2 = 75%), and psychological quality of life (SMD 0.11, 95% CI 0.06 to 0.16; 19 studies, 18,034 participants; I2 = 42%). There was also evidence that smoking cessation was not associated with a reduction in social quality of life, with the confidence interval incorporating the possibility of a small improvement (SMD 0.03, 95% CI 0.00 to 0.06; 9 studies, 14,673 participants; I2 = 0%). The incidence of new mixed anxiety and depression was lower in people who stopped smoking compared with those who continued (OR 0.76, 95% CI 0.66 to 0.86; 3 studies, 8685 participants; I2 = 57%), as was the incidence of anxiety disorder (OR 0.61, 95% CI 0.34 to 1.12; 2 studies, 2293 participants; I2 = 46%). We deemed it inappropriate to present a pooled estimate for the incidence of new cases of clinical depression, as there was high statistical heterogeneity (I2 = 87%). Taken together, these data provide evidence that mental health does not worsen as a result of quitting smoking, and very low- to moderate-certainty evidence that smoking cessation is associated with small to moderate improvements in mental health. These improvements are seen in both unselected samples and in subpopulations, including people diagnosed with mental health conditions. Additional studies that use more advanced methods to overcome time-varying confounding would strengthen the evidence in this area.


How hallucinations may arise from brain mechanisms of learning, attention, and volition.
This article suggests how brain mechanisms of learning, attention, and volition may give rise to hallucinations during schizophrenia and other mental disorders. The article suggests that normal learning and memory are stabilized through the use of learned top-down expectations. These expectations learn prototypes that are capable of focusing attention upon the combinations of features that comprise conscious perceptual experiences. When top-down expectations are active in a priming situation, they can modulate or sensitize their target cells to respond more effectively to matched bottom-up information. They cannot, however, fully activate these target cells. These matching properties are shown to be essential towards stabilizing the memory of learned representations. The modulatory property of top-down expectations is achieved through a balance between top-down excitation and inhibition. The learned prototype is the excitatory on-center in this top-down network. Phasic volitional signals can shift the balance between excitation and inhibition to favor net excitatory activation. Such a volitionally mediated shift enables top-down expectations, in the absence of supportive bottom-up inputs, to cause conscious experiences of imagery and inner speech and thereby to enable fantasy and planning activities to occur. If these volitional signals become tonically hyperactive during a mental disorder, the top-down expectations can give rise to conscious experiences in the absence of bottom-up inputs and volition. These events are compared with data about hallucinations. The article predicts where these top-down expectations and volitional signals may act in the laminar circuits of visual cortex and, by extension, in other sensory and cognitive neocortical areas, and how the level of abstractness of learned prototypes may covary with the abstractness of hallucinatory content. A similar breakdown of volition may lead to delusions of control in the motor system.


Are fit indices used to test psychopathology structure biased? A simulation study.
Structural models of psychopathology provide dimensional alternatives to traditional categorical classification systems. Competing models, such as the bifactor and correlated factors models, are typically compared via statistical indices to assess how well each model fits the same data. However, simulation studies have found evidence for probifactor fit index bias in several psychological research domains. The present study sought to extend this research to models of psychopathology, wherein the bifactor model has received much attention, but its susceptibility to bias is not well characterized. We used Monte Carlo simulations to examine how various model misspecifications produced fit index bias for 2 commonly used estimators, WLSMV and MLR. We simulated binary indicators to represent psychiatric diagnoses and positively skewed continuous indicators to represent symptom counts. Across combinations of estimators, indicator distributions, and misspecifications, complex patterns of bias emerged, with fit indices more often than not failing to correctly identify the correlated factors model as the data-generating model. No fit index emerged as reliably unbiased across all misspecification scenarios. Although, tests of model equivalence indicated that in one instance fit indices were not biased-they favored the bifactor model, albeit not unfairly. Overall, results suggest that comparisons of bifactor models to alternatives using fit indices may be misleading and call into question the evidentiary meaning of previous studies that identified the bifactor model as superior based on fit. We highlight the importance of comparing models based on substantive interpretability and their utility for addressing study aims, the methodological significance of model equivalence, as well as the need for implementation of statistical metrics that evaluate model quality. (PsycINFO Database Record (c) 2019 APA, all rights reserved).