Prevalence of PTSD in Survivors of Stroke and Transient Ischemic Attack: A Meta-Analytic Review.
Posttraumatic stress disorder (PTSD) is common in survivors of acute life-threatening illness, but little is known about the burden of PTSD in survivors of stroke and transient ischemic attack (TIA). This study estimated the prevalence of stroke or TIA-induced posttraumatic stress disorder (PTSD) using systematic review and meta-analysis. Potentially relevant peer-reviewed journal articles were identified by searching the Ovid MEDLINE, PsycINFO, PILOTS Database, The Cochrane Library and Scopus from inception to January 2013; all searches were conducted on January 31, 2013. Observational cohort studies that assessed PTSD with specific reference to a stroke or TIA that occurred at least 1 month prior to the PTSD assessment were included. PTSD rates and characteristics of the study and sample were abstracted from all included studies. The coding of all articles included demographics, sample size, study country, and method and timing of PTSD assessment. Nine studies (N = 1,138) met our inclusion criteria. PTSD rates varied significantly across studies by timing of PTSD assessment (i.e., within 1 year of stroke/TIA versus greater than 1 year post-stroke/TIA; 55% of heterogeneity explained; Q 1 = 10.30; P = .001). Using a random effects model, the estimated rate of PTSD following stroke or TIA was 23% (95% CI, 16%-33%) within 1 year of the stroke or TIA and 11% (95% CI, 8%-14%) after 1 year. Although PTSD is commonly thought to be triggered by external events such as combat or sexual assault, these results suggest that 1 in 4 stroke or TIA survivors develop significant PTSD symptoms due to the stroke or TIA. Screening for PTSD in a large population-based prospective cohort study with cardiovascular outcome assessments is needed to yield definitive prevalence, and determine whether stroke or TIA-induced PTSD is a risk factor for subsequent cardiovascular events or mortality.


Flight kinematics of the barn swallow (Hirundo rustica) over a wide range of speeds in a wind tunnel.
Two barn swallows (Hirundo rustica) flying in the Lund wind tunnel were filmed using synchronised high-speed cameras to obtain posterior, ventral and lateral views of the birds in horizontal flapping flight. We investigated wingbeat kinematics, body tilt angle, tail spread and angle of attack at speeds of 4-14 ms(-1). Wingbeat frequency showed a clear U-shaped relationship with air speed with minima at 8.9 ms(-1)(bird 1) and 8.7 ms(-1) (bird 2). A method previously used by other authors of estimating the body drag coefficient (C(D,par)) by obtaining agreement between the calculated minimum power (V(min)) and the observed minimum wingbeat frequency does not appear to be valid in this species, possibly due to upstroke pauses that occur at intermediate and high speeds, causing the apparent wingbeat frequency to be lower. These upstroke pauses represent flap-gliding, which is possibly a way of adjusting the force generated to the requirements at medium and high speeds, similar to the flap-bound mode of flight in other species. Body tilt angle, tail spread and angle of attack all increase with decreasing speed, thereby providing an additional lift surface and suggesting an important aerodynamic function for the tail at low speeds in forward flight. Results from this study indicate the high plasticity in the wingbeat kinematics and use of the tail that birds have available to them in order to adjust the lift and power output required for flight.


Ultrasonographic findings in horses with right dorsal colitis: five cases (2000-2001).
To determine whether ultrasonography would be useful in the diagnosis of right dorsal colitis in horses. Retrospective study. 5 horses with right dorsal colitis and 15 healthy adult horses. Mural thickness and appearance of the right dorsal colon were determined from ultrasonographic images obtained at right intercostal spaces 10, 11, 12, 13, and 14. The right dorsal colon could be imaged most consistently at the right 11th, 12th, and 13th intercostal spaces, below the margin of the lung and axial to the liver. Mural thickness measured from ultrasonographic images was significantly greater in horses with right dorsal colitis than in healthy horses. The right dorsal colon in affected horses had a prominent hypoechoic layer associated with submucosal edema and inflammatory infiltrates. Successful treatment of 1 horse with right dorsal colitis was associated with a decrease in mural thickness coincident with an increase in serum albumin and total protein concentrations and weight gain. A decrease in mural thickness was also observed in a second horse treated for right dorsal colitis that was not associated with healing of the right dorsal colon or an increase in serum albumin concentration but rather thinning of a segment of the right dorsal colon that eventually ruptured. Results suggest that ultrasonographic measurement of mural thickness and evaluation of the appearance of the right dorsal colon may be useful in the diagnosis of right dorsal colitis in horses.


Phosphoinositides and membrane traffic at the trans-Golgi network.
Cargo proteins moving along the secretory pathway are sorted at the TGN (trans-Golgi network) into distinct carriers for delivery to the plasma membrane or endosomes. Recent studies in yeast and mammals have shown that formation of these carriers is regulated by PtdIns(4)P. This phosphoinositide is abundant at the TGN and acts to recruit components required for carrier formation to the membrane. Other phosphoinositides are also present on the TGN, but the extent to which they regulate trafficking is less clear. Further characterization of phosphoinositide kinases and phosphatases together with identification of new TGN-associated phosphoinositide-binding proteins will reveal the extent to which different phosphoinositides regulate TGN trafficking, and help define the molecular mechanisms involved.


Outpatient versus inpatient uterine polyp treatment for abnormal uterine bleeding: randomised controlled non-inferiority study.
To compare the effectiveness and acceptability of outpatient polypectomy with inpatient polypectomy. Pragmatic multicentre randomised controlled non-inferiority study. Outpatient hysteroscopy clinics in 31 UK National Health Service hospitals. 507 women who attended as outpatients for diagnostic hysteroscopy because of abnormal uterine bleeding and were found to have uterine polyps. Participants were randomly assigned to either outpatient uterine polypectomy under local anaesthetic or inpatient uterine polypectomy under general anaesthesia. Data were collected on women's self reported bleeding symptoms at baseline and at 6, 12, and 24 months. Data were also collected on pain and acceptability of the procedure at the time of polypectomy. The primary outcome was successful treatment, determined by the women's assessment of bleeding at six months, with a prespecified non-inferiority margin of 25%. Secondary outcomes included generic (EQ-5D) and disease specific (menorrhagia multi-attribute scale) quality of life, and feasibility and acceptability of the procedure. 73% (166/228) of women in the outpatient group and 80% (168/211) in the inpatient group reported successful treatment at six months (intention to treat relative risk 0.91, 95% confidence interval 0.82 to 1.02; per protocol relative risk 0.92, 0.82 to 1.02). Failure to remove polyps was higher (19% v 7%; relative risk 2.5, 1.5 to 4.1) and acceptability of the procedure was lower (83% v 92%; 0.90, 0.84 to 0.97) in the outpatient group Quality of life did not differ significantly between the groups. Four uterine perforations, one of which necessitated bowel resection, all occurred in the inpatient group. Outpatient polypectomy was non-inferior to inpatient polypectomy. Failure to remove a uterine polyp was, however, more likely with outpatient polypectomy and acceptability of the procedure was slightly lower. International Clinical Trials Registry 65868569.


Characterization and localization of [125I]RTI-55-labeled cocaine binding sites in fetal and adult rat brain.
The present studies examined the characteristics of fetal (gestational day 20) and adult rat brain cocaine recognition sites labeled with the potent cocaine congener [125I]RTI-55 [3 beta-(4-iodophenyl)-tropane-2 beta-carboxylic acid methyl ester]. Saturation analyses of [125I]RTI-55 binding to membrane fractions from both fetal and adult whole-brain yielded curvilinear Scatchard plots that were resolved by nonlinear curve-fitting into high- and low-affinity components. Mean Kd values were 0.13 nM and 12 nM for fetal brain high- and low-affinity sites, respectively, compared to 0.26 and 18 nM for adult brain. The Kd for high-affinity binding was significantly different between the groups, suggesting a possible developmental change in the properties of [125I]RTI-55 binding sites. Drug displacement studies with various monoamine uptake inhibitors indicated that at a 10 pM concentration of [125I]RTI-55, almost all binding to fetal brain membranes could be accounted for by interaction with the serotonin (5-HT) and (to a lesser extent) dopamine (DA) transporters. This conclusion was supported by autoradiographic studies of both adult and fetal brain, demonstrating a predominance of [125I]RTI-55 binding in areas with high densities of 5-HT and/or DA uptake sites. The present results are in accordance with our previous demonstration of [3H]cocaine binding sites in fetal brain (Meyer et al., 1993) and further suggest that [125I]RTI-55 should be a useful ligand for assessing the effects of prenatal cocaine exposure on the subsequent development of cocaine recognition sites on the DA and 5-HT transporters.


Recurrent strokes under anticoagulation therapy: Sticky platelet syndrome combined with a patent foramen ovale.
The sticky platelet syndrome (SPS) is a congenital disorder characterized by platelet hyperaggregability to epinephrine and/or adenosine diphosphate; this predisposes affected individuals to acute myocardial infarction, ischemic optic neuropathy, recurrent venous thromboembolism, and transient ischemic cerebral attacks and strokes. Here, we describe an unusual case with recurrent cerebrovascular accidents due to SPS, in the presence of a patent foramen ovale (PFO). We report an unusual case of a 56-year-old female patient with a PFO, who suffered from recurrent strokes despite long-term medication with clopidogrel for SPS. The patient underwent successful transcatheter closure of the PFO, and, in addition, she has been placed on low-dose acetylsalicylic acid. After 18-month follow-up, she demonstrated an intact atrial septum without any vegetations on the percutaneous device until today. She has had no further thromboembolic events.


Heat stress and hydrocortisone are independent stimulators of triiodothyronine-induced growth hormone production in cultured rat somatotrophic tumour cells.
We have reported that, in cultured GC cells, the stress of incubation at 41 degrees C enhances thyroid hormone stimulation of growth hormone (GH) in a manner similar to the effects observed in a model of nonthyroidal disease in rats. Since glucocorticoids are potentially involved in stress responses both in vivo and in cell culture, we studied the role of glucocorticoid in the enhancement of (which are rat somatotrophic tumor cells) triiodothyronine (T3)-induced GH synthesis due to heat stress. Hydrocortisone addition increased T3-induced GH synthesis and GH mRNA content in cultured GC cells at both 37 degrees C and 41 degrees C. Depletion of glucocorticoid endogenous to serum supplement of the tissue culture medium did not prevent the enhancement of T3-induced GH synthesis that occurred during incubation at 41 degrees C. The levels and affinity of glucocorticoid cytosolic receptors were not enhanced during incubation at 41 degrees C. Lastly, no change in the sedimentation coefficient of the cytosolic glucocorticoid receptor or in its translocation into the nucleus occurred during incubation at 41 degrees C. Thus, the enhancement of T3-induced GH production in GC cells by heat stress appeared independent of the effect of glucocorticoids and not mediated through glucocorticoid receptors.


Development and preliminary validation of the Constructive and Unconstructive Worry Questionnaire: A measure of individual differences in constructive versus unconstructive worry.
This article presents a measure of individual differences in the tendencies to worry constructively and unconstructively, called the Constructive and Unconstructive Worry Questionnaire (CUWQ). The measure is based on a control theory perspective of worry and separates the tendency to worry in a way that facilitates goal-pursuit and threat reduction (constructive worry) from the tendency to worry in a way that hinders goal-pursuit while sustaining threat awareness (unconstructive worry). CUWQ scores were validated in 2 independent nonclinical samples, including North American (Sample 1, N = 295) and Australian (Sample 2, N = 998) residents. Final factor items were selected based on Sample 1, and the measure showed good model fit through a confirmatory factor analysis in Sample 2. In addition, scores on the 2 worry factors showed criterion-related validity by statistically predicting a variety of outcomes in both samples: Constructive worry was positively associated with punctuality and wildfire preparedness and negatively associated with trait-anxiety and amount of worry. Unconstructive worry, on the other hand, was positively associated with trait-anxiety and amount of worry, and negatively associated with punctuality and wildfire preparedness. The 2 factor scores were uncorrelated in Sample 1 and positively correlated in Sample 2, thereby showing that having a tendency to worry in an unconstructive manner does not prohibit 1 from worrying in a constructive manner as well. Understanding how the 2 tendencies to worry differ from each other and separating their measurement enables a better understanding of the role of worry in both normal behavior and psychopathology. (PsycINFO Database Record


Cooperative solution of constraint satisfaction problems.
It is widely believed that a group of cooperating agents engaged in problem solving can solve a task faster than either a single agent or the same group of agents working in isolation from each other. Nevertheless, little is known about the quantitative improvements that result from cooperation. A number of experimental results are presented on constraint satisfaction that both test the predictions of a theory of cooperative problem solving and assess the value of cooperation for this class of problems. These experiments suggest an alternative methodology to existing techniques for solving constraint satisfaction problems in computer science and distributed artificial intelligence.


The long-term psychological impact of Bloody Sunday on families of the victims as measured by The Revised Impact of Event Scale.
In 1972, 13 civil rights marchers were killed in Londonderry, Northern Ireland, on what is known as Bloody Sunday. This study aimed to assess the psychological impact of this event on the families of victims as measured by the Revised Impact of Event Scale. Cross-sectional self-report based study. The Impact of Event Scale-Revised was administered to 72 members of the families (immediate family, children of immediate family, cousins, and second cousins) of those killed on Bloody Sunday. High levels of intrusion, avoidance, and hyperarousal were found. In addition, significant group differences were found. Those family members closest to the victims reported the highest levels of psychological distress. The findings were discussed within the transgenerational trauma context.


A Systematic Review on the Effects of Acute Aerobic Exercise on Neurophysiological, Molecular, and Behavioral Measures in Chronic Stroke.
A single bout of aerobic exercise (AE) can produce changes in neurophysiological and behavioral measures in healthy individuals and those with stroke. However, the effects of AE-priming effects on neuroplasticity markers and behavioral measures are unclear. This systematic review aimed to examine the effects of AE on neuroplasticity measures, such as corticomotor excitability (CME), molecular markers, cortical activation, motor learning, and performance in stroke. A literature search was performed in MEDLINE, CINAHL, Scopus, and PsycINFO databases. Randomized and non-randomized studies incorporating acute AE in stroke were selected. Two reviewers independently assessed the risk of bias and methodological rigor of the studies and extracted data on participant characteristics, exercise interventions, and neuroplasticity related outcomes. The quality of transcranial magnetic stimulation reported methods was assessed using a standardized checklist. A total of 16 studies were found suitable for inclusion. Our findings suggest mixed evidence for the effects of AE on CME, limited to no effects on intracortical inhibition and facilitation and some evidence for modulating brain derived neurotrophic factor levels, motor learning, and cortical activation. Exercise intensities in the moderate to vigorous range showed a trend towards better effects on neuroplasticity measures. It appears that choosing a moderate to vigorous exercise paradigm for at least 20 to 30 minutes may induce changes in some neuroplasticity parameters in stroke. However, these findings necessitate prudent consideration as the studies were diverse and had moderate methodological quality. There is a need for a consensus on an exercise priming paradigm and for good-quality, larger controlled studies.


DL4-mediated Notch signaling is required for the development of fetal αβ and γδ T cells.
T-cell development depends upon interactions between thymocytes and thymic epithelial cells (TECs). The engagement of delta-like 4 (DL4) on TECs by Notch1 expressed by blood-borne BM-derived precursors is essential for T-cell commitment in the adult thymus. In contrast to the adult, the earliest T-cell progenitors in the embryo originate in the fetal liver and migrate to the nonvascularized fetal thymus via chemokine signals. Within the fetal thymus, some T-cell precursors undergo programmed TCRγ and TCRδ rearrangement and selection, giving rise to unique γδ T cells. Despite these fundamental differences between fetal and adult T-cell lymphopoiesis, we show here that DL4-mediated Notch signaling is essential for the development of both αβ and γδ T-cell lineages in the embryo. Deletion of the DL4 gene in fetal TECs results in an early block in αβ T-cell development and a dramatic reduction of all γδ T-cell subsets in the fetal thymus. In contrast to the adult, no dramatic deviation of T-cell precursors to alternative fates was observed in the fetal thymus in the absence of Notch signaling. Taken together, our data reveal a common requirement for DL4-mediated Notch signaling in fetal and adult thymopoiesis.


Use of combination antihypertensive therapy initiation in older Americans without prevalent cardiovascular disease.
To describe new users of antihypertensive medications and identify predictors of combination therapy initiation in older Americans. Retrospective observational cohort study. Population-based study using U.S. Medicare fee-for-service healthcare claims (2007-2010). Medicare beneficiaries aged 65 and older with no recent diagnoses, procedures, or medications for cardiovascular disease who newly initiated an antihypertensive therapy (n = 275,493; 210,605 initiated monotherapy, 64,888 initiated combination therapy). Multivariable Poisson regression was used to assess factors associated with initiation of combination therapy versus monotherapy, including participant characteristics, prescriber characteristics, and participant encounters with the healthcare system. Initiation of combination therapy increased from 21.9% in 2007 to 24.7% in 2010. The most frequently initiated combinations were angiotensin-converting enzyme inhibitors with thiazide (29.7%) and angiotensin II receptor antagonists with thiazide (18.7%). Blacks (prevalence ratio (PR) = 1.48, 95% confidence interval (CI) = 1.45-1.51 vs. whites), individuals seeing a generalist (PR = 1.10, 95% CI = 1.07-1.14), individuals seeing more than one doctor (PR = 3.38, 95% CI = 3.33-3.44), and participants with no pharmacy claims in the previous 6 months (PR = 1.34, 95% CI = 1.30-1.37 vs. ≥3 unique drug classes) were more likely to initiate combination therapy, whereas those who had more outpatient visits in the previous 12 months were less likely to initiate combination therapy (per five visits, PR = 0.82, 95% CI = 0.80-0.83). Nearly one in four new users of antihypertensive medications aged 65 and older started treatment with combination therapy. Blacks, individuals living in the south, and those with fewer outpatient physician office visits were more likely to initiate combination therapy. Further research is needed to determine whether this approach to managing hypertension is being well targeted to individuals who will require combination treatment.


Superspreading and the effect of individual variation on disease emergence.
Population-level analyses often use average quantities to describe heterogeneous systems, particularly when variation does not arise from identifiable groups. A prominent example, central to our current understanding of epidemic spread, is the basic reproductive number, R(0), which is defined as the mean number of infections caused by an infected individual in a susceptible population. Population estimates of R(0) can obscure considerable individual variation in infectiousness, as highlighted during the global emergence of severe acute respiratory syndrome (SARS) by numerous 'superspreading events' in which certain individuals infected unusually large numbers of secondary cases. For diseases transmitted by non-sexual direct contacts, such as SARS or smallpox, individual variation is difficult to measure empirically, and thus its importance for outbreak dynamics has been unclear. Here we present an integrated theoretical and statistical analysis of the influence of individual variation in infectiousness on disease emergence. Using contact tracing data from eight directly transmitted diseases, we show that the distribution of individual infectiousness around R(0) is often highly skewed. Model predictions accounting for this variation differ sharply from average-based approaches, with disease extinction more likely and outbreaks rarer but more explosive. Using these models, we explore implications for outbreak control, showing that individual-specific control measures outperform population-wide measures. Moreover, the dramatic improvements achieved through targeted control policies emphasize the need to identify predictive correlates of higher infectiousness. Our findings indicate that superspreading is a normal feature of disease spread, and to frame ongoing discussion we propose a rigorous definition for superspreading events and a method to predict their frequency.


Cerebrospinal fluid disturbances after transcallosal surgery: incidence and predictive factors.
CSF dynamics after transcallosal resection of intraventricular lesions can be altered, and the need for shunt implantation complicates the management of these patients. Because the pathophysiological mechanism and contributing factors are poorly understood and the incidence has largely not been described, the authors conducted a study to elucidate these factors. The authors retrospectively reviewed data from patients who had been operated on at their institution via a transcallosal approach between March 2002 and December 2016. They evaluated the need for a shunt implantation up to 3 months after surgery by assessing clinical variables. These variables were age at surgery, the need for perioperative external CSF drainage, histology of the lesion, and the following radiological parameters: pre- and postoperative Evans index, maximal postoperative extension of subdural effusions (SDEs) measured on axial images, and maximal interhemispheric fissure (IHF) width measured on coronal images assessed at 4 different points in time (preoperatively, day 1, days 2-4, and days 4-8 after surgery). To identify potential risk factors, univariate and multivariate regression models were constructed. Receiver operating characteristic (ROC) curves for significant predictors, as well as the area under the curve (AUC), were calculated. Seventy-four patients (40 female and 34 male) were identified; their median age at surgery was 17.6 years (range 4 months to 76 years). Shunt implantation was necessary in 13 patients (ventriculoperitoneal [VP] shunt, n = 7; subdural peritoneal [SDP] shunt, n = 6) after a median interval of 24 days (range 10 days to 3 months). Univariate logistic regression models revealed a significant effect of IHF width on days 4-8 (OR 1.31, 95% CI 1.03-1.66; p = 0.027), extension of SDE on days 2-4 (OR 1.33, 95% CI 1.11-1 0.60; p = 0.003), and age (OR 0.932, 95% CI 0.88-0.99; p = 0.02). In the multiple regression model, the effect of the independent variable extension of the SDE remained significant. ROC curves for the predictors IHF width on days 4-8 and extension of SDE on days 2-4 revealed an AUC equal to 0.732 and 0.752, respectively. Before shunt implantation, the ventricles were smaller compared to the preoperative size in 9 of the 13 patients (SDP shunt, n = 5; VP shunt, n = 4). The rate of shunt-dependent hydrocephalus 3 months after surgery in this heterogeneous group of patients was 17.6% (95% CI 9.7%-28.2%). The authors identified as predictive factors the variables extension of the convexity space, IHF 1 week after surgery, and younger age.


The role of mitochondrial DNA copy number in mammalian fertility.
Mammalian mitochondrial DNA (mtDNA) is a small, maternally inherited genome that codes for 13 essential proteins in the respiratory chain. Mature oocytes contain more than 150 000 copies of mtDNA, at least an order of magnitude greater than the number in most somatic cells, but sperm contain only approximately 100 copies. Mitochondrial oxidative phosphorylation has been suggested to be an important determinant of oocyte quality and sperm motility; however, the functional significance of the high mtDNA copy number in oocytes, and of the low copy number in sperm, remains unclear. To investigate the effects of mtDNA copy number on fertility, we genetically manipulated mtDNA copy number in the mouse by deleting one copy of Tfam, an essential component of the mitochondrial nucleoid, at different stages of germline development. We show that males can tolerate at least a threefold reduction in mtDNA copy number in their sperm without impaired fertility, and in fact, they preferentially transmit a deleted Tfam allele. Surprisingly, oocytes with as few as 4000 copies of mtDNA can be fertilized and progress normally through preimplantation development to the blastocyst stage. The mature oocyte, however, has a critical postimplantation developmental threshold of 40 000-50 000 copies of mtDNA in the mature oocyte. These observations suggest that the high mtDNA copy number in the mature oocyte is a genetic device designed to distribute mitochondria and mtDNAs to the cells of the early postimplantation embryo before mitochondrial biogenesis and mtDNA replication resumes, whereas down-regulation of mtDNA copy number is important for normal sperm function.


Veal Calves Produce Less Antibodies against C. Perfringens Alpha Toxin Compared to Beef Calves.
Enterotoxaemia is a disease with a high associated mortality rate, affecting beef and veal calves worldwide, caused by C. perfringens alpha toxin and perfringolysin. A longitudinal study was conducted to determine the dynamics of antibodies against these toxins in 528 calves on 4 beef and 15 veal farms. The second study aimed to determine the effect of solid feed intake on the production of antibodies against alpha toxin and perfringolysin. The control group only received milk replacer, whereas in the test group solid feed was provided. Maternal antibodies for alpha toxin were present in 45% of the veal calves and 66% of the beef calves. In beef calves a fluent transition from maternal to active immunity was observed for alpha toxin, whereas almost no veal calves developed active immunity. Perfringolysin antibodies significantly declined both in veal and beef calves. In the second study all calves were seropositive for alpha toxin throughout the experiment and solid feed intake did not alter the dynamics of alpha and perfringolysin antibodies. In conclusion, the present study showed that veal calves on a traditional milk replacer diet had significantly lower alpha toxin antibodies compared to beef calves in the risk period for enterotoxaemia, whereas no differences were noticed for perfringolysin.


The impact of air pollution on deaths, disease burden, and life expectancy across the states of India: the Global Burden of Disease Study 2017.
Air pollution is a major planetary health risk, with India estimated to have some of the worst levels globally. To inform action at subnational levels in India, we estimated the exposure to air pollution and its impact on deaths, disease burden, and life expectancy in every state of India in 2017. We estimated exposure to air pollution, including ambient particulate matter pollution, defined as the annual average gridded concentration of PM2.5, and household air pollution, defined as percentage of households using solid cooking fuels and the corresponding exposure to PM2.5, across the states of India using accessible data from multiple sources as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. The states were categorised into three Socio-demographic Index (SDI) levels as calculated by GBD 2017 on the basis of lag-distributed per-capita income, mean education in people aged 15 years or older, and total fertility rate in people younger than 25 years. We estimated deaths and disability-adjusted life-years (DALYs) attributable to air pollution exposure, on the basis of exposure-response relationships from the published literature, as assessed in GBD 2017; the proportion of total global air pollution DALYs in India; and what the life expectancy would have been in each state of India if air pollution levels had been less than the minimum level causing health loss. The annual population-weighted mean exposure to ambient particulate matter PM2·5 in India was 89·9 μg/m3 (95% uncertainty interval [UI] 67·0-112·0) in 2017. Most states, and 76·8% of the population of India, were exposed to annual population-weighted mean PM2·5 greater than 40 μg/m3, which is the limit recommended by the National Ambient Air Quality Standards in India. Delhi had the highest annual population-weighted mean PM2·5 in 2017, followed by Uttar Pradesh, Bihar, and Haryana in north India, all with mean values greater than 125 μg/m3. The proportion of population using solid fuels in India was 55·5% (54·8-56·2) in 2017, which exceeded 75% in the low SDI states of Bihar, Jharkhand, and Odisha. 1·24 million (1·09-1·39) deaths in India in 2017, which were 12·5% of the total deaths, were attributable to air pollution, including 0·67 million (0·55-0·79) from ambient particulate matter pollution and 0·48 million (0·39-0·58) from household air pollution. Of these deaths attributable to air pollution, 51·4% were in people younger than 70 years. India contributed 18·1% of the global population but had 26·2% of the global air pollution DALYs in 2017. The ambient particulate matter pollution DALY rate was highest in the north Indian states of Uttar Pradesh, Haryana, Delhi, Punjab, and Rajasthan, spread across the three SDI state groups, and the household air pollution DALY rate was highest in the low SDI states of Chhattisgarh, Rajasthan, Madhya Pradesh, and Assam in north and northeast India. We estimated that if the air pollution level in India were less than the minimum causing health loss, the average life expectancy in 2017 would have been higher by 1·7 years (1·6-1·9), with this increase exceeding 2 years in the north Indian states of Rajasthan, Uttar Pradesh, and Haryana. India has disproportionately high mortality and disease burden due to air pollution. This burden is generally highest in the low SDI states of north India. Reducing the substantial avoidable deaths and disease burden from this major environmental risk is dependent on rapid deployment of effective multisectoral policies throughout India that are commensurate with the magnitude of air pollution in each state. Bill & Melinda Gates Foundation; and Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India.


Structure, photoluminescent and cathodoluminescent properties of a rare-earth free red emitting β-Zn3B2O6:Mn2+ phosphor.
A rare-earth free red emitting β-Zn3B2O6:Mn(2+) phosphor was prepared by a solid-state reaction method. The crystal structure, photoluminescent and cathodoluminescent properties of β-Zn3B2O6:Mn(2+) were systematically investigated. The absorption and photoluminescence excitation spectra confirm that β-Zn3B2O6:Mn(2+) matches the UV LED chip. Under UV light and low-voltage electron beam excitations, an interesting orange-red emission band centered at ∼600 nm of Mn(2+) at the tetrahedral Zn(2+) sites is observed. Besides, the unusual red shift with increasing Mn(2+) content is also found and contributed to an exchange interaction between Mn(2+). In addition, under low-voltage excitation, β-Zn3B2O6:Mn(2+) exhibits higher color purity of 98.1% than that of the commercial ZnS:Ag,Cd yellow phosphor and reported ZnGeN2:Mn(2+) orange phosphor, which indicated the β-Zn3B2O6:Mn(2+) has a patenting application in FEDs.


Predicting steep escalations in alcohol use over the teenage years: age-related variations in key social influences.
This study examined how family, peer and school factors are related to different trajectories of adolescent alcohol use at key developmental periods. Latent class growth analysis was used to identify trajectories based on five waves of data (from grade 6, age 12 to grade 11, age 17), with predictors at grades 5, 7 and 9 included as covariates. Adolescents completed surveys during school hours. A total of 808 students in Victoria, Australia. Alcohol use trajectories were based on self-reports of 30-day frequency of alcohol use. Predictors included sibling alcohol use, attachment to parents, parental supervision, parental attitudes favourable to adolescent alcohol use, peer alcohol use and school commitment. A total of 8.2% showed steep escalation in alcohol use. Relative to non-users, steep escalators were predicted by age-specific effects for low school commitment at grade 7 (P = 0.031) and parental attitudes at grade 5 (P = 0.003), and age-generalized effects for sibling alcohol use (Ps = 0.001, 0.012, 0.033 at grades 5, 7 and 9, respectively) and peer alcohol use (Ps = 0.041, < 0.001, < 0.001 at grades 5, 7 and 9, respectively). Poor parental supervision was associated with steep escalators at grade 9 (P < 0.001) but not the other grades. Attachment to parents was unrelated to alcohol trajectories. Parental disapproval of alcohol use before transition to high school, low school commitment at transition to high school, and sibling and peer alcohol use during adolescence are associated with a higher risk of steep escalations in alcohol use.


Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.
Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.


Molecules in a bose-einstein condensate
State-selected rubidium-87 molecules were created at rest in a dilute Bose-Einstein condensate of rubidium-87 atoms with coherent free-bound stimulated Raman transitions. The transition rate exhibited a resonance line shape with an extremely narrow width as small as 1.5 kilohertz. The precise shape and position of the resonance are sensitive to the mean-field interactions between the molecules and the atomic condensate. As a result, we were able to measure the molecule-condensate interactions. This method allows molecular binding energies to be determined with unprecedented accuracy and is of interest as a mechanism for the generation of a molecular Bose-Einstein condensate.


Increased CCN2, substance P and tissue fibrosis are associated with sensorimotor declines in a rat model of repetitive overuse injury.
Key clinical features of cumulative trauma disorders include pain, muscle weakness, and tissue fibrosis, although the etiology is still under investigation. Here, we characterized the temporal pattern of altered sensorimotor behaviors and inflammatory and fibrogenic processes occurring in forearm muscles and serum of young adult, female rats performing an operant, high repetition high force (HRHF) reaching and grasping task for 6, 12, or 18 weeks. Palmar mechanical sensitivity, cold temperature avoidance and spontaneous behavioral changes increased, while grip strength declined, in 18-week HRHF rats, compared to controls. Flexor digitorum muscles had increased MCP-1 levels after training and increased TNFalpha in 6-week HRHF rats. Serum had increased IL-1beta, IL-10 and IP-10 after training. Yet both muscle and serum inflammation resolved by week 18. In contrast, IFNγ increased at week 18 in both muscle and serum. Given the anti-fibrotic role of IFNγ, and to identify a mechanism for the continued grip strength losses and behavioral sensitivities, we evaluated the fibrogenic proteins CCN2, collagen type I and TGFB1, as well as the nociceptive/fibrogenic peptide substance P. Each increased in and around flexor digitorum muscles and extracellular matrix in the mid-forearm, and in nerves of the forepaw at 18 weeks. CCN2 was also increased in serum at week 18. At a time when inflammation had subsided, increases in fibrogenic proteins correlated with sensorimotor declines. Thus, muscle and nerve fibrosis may be critical components of chronic work-related musculoskeletal disorders. CCN2 and substance P may serve as potential targets for therapeutic intervention, and CCN2 as a serum biomarker of fibrosis progression.


Telomerase-immortalized sheep fibroblasts can be reprogrammed by nuclear transfer to undergo early development.
Telomere shortening and lack of telomerase activity have been implicated in cellular senescence in human fibroblasts. Expression of the human telomerase catalytic reverse transcriptase subunit (hTERT) in these cells reconstitutes telomerase activity and immortalizes the cells without tumor transformation. In this report, we show that sheep fibroblasts are similar to human cells. They do not have detectable telomerase activity and undergo only a finite numbers of cell divisions before replicative senescence. Telomere lengths in sheep fibroblasts are similar to those reported for human cells and shorten at a rate of 50-200 base pairs (bp) each cell division. Expression of the human telomerase catalytic subunit restored the telomerase activity in the sheep cells and extended their proliferative life span. None of the telomerase positive sheep fibroblasts exhibited a transformed phenotype after 200 days of continuous culture, and the higher hTERT expressing cells maintained their telomere lengths and normal cell characteristics for more than 500 days in culture. In cloning experiments using one of these cell lines as a nuclear donor, the reconstructed karyoplasts were reprogrammed and developed to the blastocyst stage at a similar frequency to that observed with the parental, telomerase negative cell line. After embryo transfer the blastocysts exhibited a relatively high frequency of implantation, early fetal development, and organogenesis. No fetuses survived beyond 40 days of development, however, showing that although these cells could be substantially reprogrammed, they were not fully competent for nuclear transfer.


Topical treatment of cutaneous vaccinia virus infections in immunosuppressed hairless mice with selected antiviral substances.
Certain nucleoside, nucleotide and pyrophosphate analogues may be useful for treating severe complications arising as a result of virus dissemination following smallpox (live vaccinia virus) vaccinations, especially in immunocompromised individuals. We used an immunosuppressed hairless mouse model to study the effects of 10 antiviral agents on progressive vaccinia infections. Hairless mice were immunosuppressed by treatment with cyclophosphamide (100 mg/kg) every 4 days starting 1 day prior to vaccinia virus (WR strain) infection of wounded skin. Topical treatments with antiviral agents were applied twice a day for 7 days starting 5 days after virus exposure. Topical 1% cidofovir cream treatment was effective in significantly reducing primary lesion severity and decreasing the number of satellite lesions. Topical 1% cyclic HPMPC and 1% phosphonoacetic acid were not quite as active as cidofovir. Ribavirin (5%) treatment reduced lesion severity and diminished the numbers of satellite lesions, but the mice died significantly sooner than placebos. 2-Amino-7-[(1,3,-dihydroxy-2-propoxy)methyl]purine (compound S2242; 1%) moderately reduced primary lesion sizes. Ineffective treatments included 5% arabinosyladenine, 1% arabinosylcytosine, 1% 5-chloro-arabinosylcytosine, 5% arabinosylhypoxanthine 5-monophosphate and 5% viramidine. Of the compounds tested, topically applied cidofovir was the most effective treatment of cutaneous vaccinia virus infections in immunosuppressed mice. Topical treatment with cidofovir could be considered as an adjunct to intravenous drug therapy for serious infections.


Quantitative Optical Coherence Tomography Angiography Biomarkers in a Treat-and-Extend Dosing Regimen in Neovascular Age-Related Macular Degeneration.
To evaluate the association between quantitative optical coherence tomography angiography (OCT-A) parameters and clinical outcomes in treatment-naïve neovascular age-related macular degeneration (nAMD) patients treated with a treat-and-extend dosing regimen on a 12-month follow-up interval. Observational, prospective study of consecutive patients. The treatment protocol was based on a loading dose of three anti-vascular endothelial growth factor (VEGF) intravitreal injections (IVI) followed by a treat-and-extend regimen. Eyes were evaluated by swept-source OCT-A at baseline, 1 month after the loading dose and at 12 months. A quantitative analysis was issued for fractal dimension (FD), lacunarity index (LAC), blood flow surface area (SA), and vessel density (VD). An association of these parameters with the anatomic response and functional responses, and IVI number at 12 months of follow-up was assessed. A level of significance α = 0.05 was considered. Sixty-four patients were included, 52 of whom (81%) completed the 12-month study protocol. The median number of injections at 12 months was 7 (P25-P75: 6-12). FD and SA were reduced 1 month after the loading dose of anti-VEGF (P < 0.001). The generalized linear models using baseline FD and baseline SA achieved the best performance in discriminating a lower treatment burden (area under the curve [AUC] = 0.78; 95% confidence interval [CI]: 0.64-0.91 and AUC = 0.76; 95% CI: 0.63-0.90, respectively). Baseline OCT-A may provide useful biomarkers for the treatment burden in nAMD. The application of fractal dimension and automatic blood flow area algorithms to OCT-A data can distinguish patients with distinct treatment burdens in the first year of nAMD.


Layer-resolved study of Mg atom incorporation at the MgO/Ag(001) buried interface.
By combining x-ray excited Auger electron diffraction experiments and multiple scattering calculations we reveal a layer-resolved shift for the Mg KL23L23 Auger transition in MgO ultrathin films (4-6 Å) on Ag(001). This resolution is exploited to demonstrate the possibility of controlling Mg atom incorporation at the MgO/Ag(001) interface by exposing the MgO films to a Mg flux. A substantial reduction of the MgO/Ag(001) work function is observed during the exposition phase and reflects both band-offset variations at the interface and band bending effects in the oxide film.


Classroom seating for children with attention deficit hyperactivity disorder: therapy balls versus chairs.
The purpose of this study was to investigate the effects of therapy balls as seating on in-seat behavior and legible word productivity of students with attention deficit hyperactivity disorder (ADHD). Additionally, social validity was assessed to evaluate teacher and student opinions regarding the intervention. A single subject, A-B-A-B interrupted time series design was employed across 3 students (2 males, 1 female) with ADHD. The study was conducted in a 4th grade inclusive classroom during daily language arts. During phases 1 and 3, the 3 participants and all other class members sat on chairs (in-seat on chair); during phases 2 and 4, everyone sat on therapy balls (in-seat on ball). Dependent variables were in-seat behavior and legible word productivity. Data were graphed and visually analyzed for differences between phases. Results demonstrated increases in in-seat behavior and legible word productivity for the students with ADHD when seated on therapy balls. Social validity findings indicated that generally the teacher and students preferred therapy balls. This study provides evidence that use of therapy balls for students with ADHD may facilitate in-seat behavior and legible word productivity.


Low and moderate-fat plant sterol fortified soymilk in modulation of plasma lipids and cholesterol kinetics in subjects with normal to high cholesterol concentrations: report on two randomized crossover studies.
Although consumption of various plant sterol (PS)-enriched beverages is effective in lowering plasma cholesterol, the lipid-lowering potential of PS in a soymilk format has not been investigated thoroughly. Therefore, to evaluate the efficacy of PS-enriched soy beverages on plasma lipids and cholesterol kinetics, we conducted two separate 28 d dietary controlled cross-over studies. In study 1, the cholesterol-lowering efficacy of a low-fat (2 g/serving) PS enriched soy beverage was examined in 33 normal cholesterolemic subjects in comparison with 1% dairy milk. In study 2, we investigated the efficacy of a moderate-fat (3.5 g/serving) PS-enriched soy beverage on plasma cholesterol concentrations and cholesterol kinetic responses in 23 hypercholesterolemic subjects compared with 1% dairy milk. Both the low and moderate-fat PS-enriched soymilk varieties provided 1.95 g PS/d. Endpoint plasma variables were analyzed by repeated-measures ANOVA using baseline values as covariates for plasma lipid measurements. In comparison with the 1% dairy milk control, the low-fat soy beverage reduced (P < 0.05) total and LDL-cholesterol by 10 and 13%, respectively. Consumption of the moderate-fat PS-enriched soy beverage reduced (P < 0.05) plasma total and LDL-cholesterol by 12 and 15% respectively. Fasting triglycerides were reduced by 9.4% following consumption of the moderate-fat soy beverage in comparison with the 1% dairy milk. Both low and moderate-fat PS-enriched soy varieties reduced (P < 0.05) LDL:HDL and TC:HDL ratios compared with the 1% dairy milk control. Consumption of the moderate-fat PS-enriched soymilk reduced (P < 0.05) cholesterol absorption by 27%, but did not alter cholesterol synthesis in comparison with 1% dairy milk. We conclude that, compared to 1% dairy milk, consumption of low and moderate-fat PS-enriched soy beverages represents an effective dietary strategy to reduce circulating lipid concentrations in normal to hypercholesterolemic individuals by reducing intestinal cholesterol absorption. TRIAL REGISTRATION (CLINICALTRIALS.GOV): NCT00923403 (Study 1), NCT00924391 (Study 2).


Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer.
Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles.


The pupil can control an artificial lens intuitively.
After cataract surgery, the ability to accommodate is lost. For this reason, a mechatronic IOL is being developed at the moment: The Artificial Accommodation System. This device requires an easily measureable indicator of the distance of the observed object to determine the demand of accommodation. As the pupil constricts with near vision, pupil size might be such an indicator. Our research focused on whether the pupil can control an artificial lens. A study with 14 healthy subjects aged between 24 and 64 years was conducted. An artificial lens with variable refractive power was mounted in front of one eye. In this eye, natural accommodation was greatly reduced or absent due to presbyopia, pseudophakia, or iatrogenic cycloplegia. The lens' refractive power was changed in a computer-controlled manner depending on changes in the pupil diameter of the second eye, which could not see the fixation stimulus. The subject's task was to get a clear focused image of the target in different distances. The lens can be controlled by the pupil intuitively (P < 1.8 × 10(-18)). Without prior knowledge, 11/14 subjects passed the first trial, and 31/41 trials were successful. Only one subject was not able to control the lens at all. Most subjects comprehended instantly how to use the unfamiliar lens control to bring a target into focus. This study emphasizes the plasticity of the visual control system. Positioning accuracy was acceptable, but the control must be optimized to facilitate maintaining a defined refractive power.


Reducing interruptions during medication preparation and administration.
According to literature, interruptions during drug administration lead to a significant proportion of medication errors. Evidence on the effectiveness of interventions to reduce interruption is still limited. The purpose of this paper is to explore main reasons for interruptions during drug administration rounds in a geriatric ward of an Italian secondary hospital and test the effectiveness of a combined intervention. This is a pre and post-intervention observational study based on direct observation. All nurse staff (24) participated to the study that lead to observe a total of 44 drug dispensing rounds with 945 drugs administered to 491 patients in T0 and 994 drugs to 506 patients in T1. A significant reduction of raw number of interruptions (mean per round from 17.31 in T0 to 9.09 in T1, p<0.01), interruptions/patient rate (from 0.78 in T0 to 0.40 in T1, p<0.01) and interruptions/drugs rate (from 0.44 in T0 to 0.22 in T1, p<0.01) were observed. Needs for further improvements were elicited (e.g. a greater involvement of support staff). Nurse staff should be adequately trained on the risks related to interruptions during drug administration since routine activity is at high risk of distractions due to its repetitive and skill-based nature. A strong involvement of both MB and leadership, together with the frontline staff, helped to raise staff motivation and guide a bottom-up approach, able to identify tailored interventions and serve concurrently as training instrument tool.


EPIDEMIC TREMOR, AN ENCEPHALOMYELITIS AFFECTING YOUNG CHICKENS.
A new disease having a characteristic and well defined symptom complex is described as occurring in young chickens in four New England states. Tremor, principally of the head and neck, and progressive ataxia are the characteristic symptoms, either or both of which may be present in a single bird. Age at onset in field epidemics ranges from 3 days to 6 weeks, with a majority of cases reported at 3 weeks. Morbidity in commercial flocks ranges from 5 to 50 per cent; mortality in affected hatches may be 50 per cent. The disease may or may not recur in successive hatches, and in the same flock in successive years. Although birds may survive an attack of the disease, nervous symptoms persist in a majority of cases. There is no evidence that nutritional factors are involved. Normal chickens have not contracted the disease by contact with affected birds. The disease has been reproduced in normal chickens by intracerebral inoculation of brain and spinal cord from affected birds. Twenty brain-to-brain passages have been made up to the present time. The incubation period in laboratory passages ranges from 6 to 44 days with symptoms appearing usually between 21 and 28 days. The proportion of inoculated birds developing symptoms has increased with successive passages. The infective agent in the brain has survived in 50 per cent glycerine for 69 days. No organism has been cultivated. The disease has been reproduced after inoculation with bacteriologically sterile filtrates obtained with Seitz and Berkefeld N filters. Attempts to demonstrate the presence of the infective agent in the chicken embryo have been inconclusive. Chicks hatched from eggs laid by birds which had survived the disease were not infected, nor were they immune to inoculation at 6 weeks of age. The characteristic lesion of the disease consists of microscopic focal collections of glia cells, perivascular infiltration, degeneration of Purkinje's cells, and degeneration of nerve cells. Foci of infiltration are present throughout the brain and spinal cord. In the viscera of birds from field epidemics, microscopic focal infiltrations of cells of the lymphoid series are often found. Their presence is most notable in the pancreas and heart. No cell inclusions have been demonstrated.


The Effect of High Volume Power Training on Repeated High-Intensity Performance and the Assessment of Repeat Power Ability: A Systematic Review.
High volume power training (HVPT) involves high volumes of high-velocity resistance training, with the aim to improve repeated high-intensity efforts (RHIEs). Repeat power ability (RPA) is the ability to repeatedly produce maximal or near maximal efforts. Assessments of RPA using external loading may determine the ability to perform repeat RHIEs typical of many sports and, therefore, provide useful information on the effectiveness of training. (1) Identify the different HVPT protocols; (2) examine the acute responses and chronic adaptations to different HVPT protocols; (3) identify different lower body RPA assessment protocols and highlight similarities, differences and potential limitations between each protocol, and; (4) describe the reliability and validity of RPA assessments. An electronic search was performed using SPORTDiscus, PubMed, CINAHL and Embase for studies utilising HVPT protocols and assessments of RPA. Eligible studies included peer-reviewed journal articles published in English. Twenty studies met the inclusion criteria of the final review. Of the eight longitudinal studies, three were rated as fair and five were rated as poor methodological quality, respectively. In contrast, all 12 cross-sectional studies were considered to have a low risk of bias. Preliminary evidence suggests that HVPT can enhance RHIE, RPA, anaerobic capacity, anaerobic power and aerobic performance. HVPT generally consists of 2-3 sessions per week, utilising loads of 30-40% 1 repetition maximum (RM), for 3-5 sets of 10-20 repetitions, with inter-set rest periods of 2-3 min. RPA assessments can be valid and reliable and may provide useful information on an athlete's ability to perform RHIE and the success of HVPT programmes. HVPT can be used to improve a number of physical qualities including RPA and RHIE; while a variety of RPA assessments provide valid and reliable information regarding the athlete's ability to perform RHIEs. Considering the heterogeneity in the HVPT protocols currently used and the relatively low volume and quality of longitudinal publications in this area, further studies are needed to identify the effects of a variety of HVPT methods on RPA, RHIE and other performance outcomes and to identify the most valid and reliable RPA outcomes to use in such studies.


Validation of differential gene expression algorithms: application comparing fold-change estimation to hypothesis testing.
Sustained research on the problem of determining which genes are differentially expressed on the basis of microarray data has yielded a plethora of statistical algorithms, each justified by theory, simulation, or ad hoc validation and yet differing in practical results from equally justified algorithms. Recently, a concordance method that measures agreement among gene lists have been introduced to assess various aspects of differential gene expression detection. This method has the advantage of basing its assessment solely on the results of real data analyses, but as it requires examining gene lists of given sizes, it may be unstable. Two methodologies for assessing predictive error are described: a cross-validation method and a posterior predictive method. As a nonparametric method of estimating prediction error from observed expression levels, cross validation provides an empirical approach to assessing algorithms for detecting differential gene expression that is fully justified for large numbers of biological replicates. Because it leverages the knowledge that only a small portion of genes are differentially expressed, the posterior predictive method is expected to provide more reliable estimates of algorithm performance, allaying concerns about limited biological replication. In practice, the posterior predictive method can assess when its approximations are valid and when they are inaccurate. Under conditions in which its approximations are valid, it corroborates the results of cross validation. Both comparison methodologies are applicable to both single-channel and dual-channel microarrays. For the data sets considered, estimating prediction error by cross validation demonstrates that empirical Bayes methods based on hierarchical models tend to outperform algorithms based on selecting genes by their fold changes or by non-hierarchical model-selection criteria. (The latter two approaches have comparable performance.) The posterior predictive assessment corroborates these findings. Algorithms for detecting differential gene expression may be compared by estimating each algorithm's error in predicting expression ratios, whether such ratios are defined across microarray channels or between two independent groups.According to two distinct estimators of prediction error, algorithms using hierarchical models outperform the other algorithms of the study. The fact that fold-change shrinkage performed as well as conventional model selection criteria calls for investigating algorithms that combine the strengths of significance testing and fold-change estimation.


Brain volume, energy balance, and cardiovascular health in two nonindustrial South American populations.
Little is known about brain aging or dementia in nonindustrialized environments that are similar to how humans lived throughout evolutionary history. This paper examines brain volume (BV) in middle and old age among two indigenous South American populations, the Tsimane and Moseten, whose lifestyles and environments diverge from those in high-income nations. With a sample of 1,165 individuals aged 40 to 94, we analyze population differences in cross-sectional rates of decline in BV with age. We also assess the relationships of BV with energy biomarkers and arterial disease and compare them against findings in industrialized contexts. The analyses test three hypotheses derived from an evolutionary model of brain health, which we call the embarrassment of riches (EOR). The model hypothesizes that food energy was positively associated with late life BV in the physically active, food-limited past, but excess body mass and adiposity are now associated with reduced BV in industrialized societies in middle and older ages. We find that the relationship of BV with both non-HDL cholesterol and body mass index is curvilinear, positive from the lowest values to 1.4 to 1.6 SDs above the mean, and negative from that value to the highest values. The more acculturated Moseten exhibit a steeper decrease in BV with age than Tsimane, but still shallower than US and European populations. Lastly, aortic arteriosclerosis is associated with lower BV. Complemented by findings from the United States and Europe, our results are consistent with the EOR model, with implications for interventions to improve brain health.


Surfactant protein D decreases pollen-induced IgE-dependent mast cell degranulation.
Mast cells play a key role in allergy and asthma. They reside at the host-environment interface and are among the first cells to make contact with inhaled microorganisms and particulate antigens. Pulmonary surfactant proteins A and D (SP-A and SP-D) function in lung host defense by enhancing microbe phagocytosis and mediating other immune cell functions, but little is known about their effects on mast cells. We hypothesized that SP-A and/or SP-D modulate IgE-dependent mast cell functions. Pollen starch granules (PSG) extracted from Dactylis glomerata and coated with trinitrophenol (TNP) were used as a model of an inhaled organic particulate allergen. Our data revealed that SP-D inhibited by 50% the release of beta-hexosaminidase by peritoneal mast cells sensitized with IgE anti-TNP and stimulated with TNP-PSG. In contrast, SP-A had no effect. Furthermore, SP-D aggregated PSG in a dose-dependent manner, and this aggregation was mediated by SP-D's carbohydrate recognition domain. A single arm SP-D mutant (RrSP-Dser15,20) neither aggregated PSG nor inhibited degranulation, suggesting that multimerization of SP-D is required for maximal PSG aggregation and inhibition of PSG-induced mast cell degranulation. This study is the first to demonstrate that SP-D modulates IgE-mediated mast cell functions, which are important in asthma and allergic inflammation.


Oxygen pulse as a protective factor of insulin resistance in sedentary women with overweight or obesity.
obesity is associated with insulin resistance (IR). Through exercise, insulin resistant obese patients can effectively improve theircardiorespiratory fitness (CRF). The effect of exercise on patients CRF can be determined by oxygen pulse (PO2) analysis. Despite its usefulness, there is limited literature on PO2 analysis in patients with obesity and insulin resistance. the goal of the present study is to evaluate the relation between PO2 and IR in sedentary obese women. fifty-five women were submitted to a maximal exercise test for evaluation of maximal oxygen consumption and PO2. The subjects with a homeostatic model assessment of IR index greater or equal to 2.5 were considered as insulin-resistant (IR). Participants were divided into two groups, IR group (n = 35) and non-IR group (n = 20). the IR group had lower values of PO2 relative to body weight (11.0 ± 1.7 versus 12.6 ± 1.4 ml∙kg∙beats-1, p = 0.001) and relative to lean mass (21.7 ± 2.9 versus 23.2 ± 2.8 ml∙kg∙beats-1, p = 0.038) than non-IR group. No statistical differences were found in maximal oxygen consumption between the groups (non-IR = 1.53 ± 0.27 l∙min-1, IR = 1.51 ± 0.28 l∙min-1; p = 0.386). PO2 relative to body weight and HOMA-IR was inversely correlated (p < 0.001; r = -0.465). Logistic regression analysis showed an association between PO2 relative to weight (p = 0.001, OR = 0.47) and fat free mass (p = 0.01, OR = 0.73), both models adjusted by age. this study demonstrates a relation between HOMA-IR and PO2. Our results suggest that PO2 could be a protective factor against insulin resistance.


Comparison of the clinical manifestations of severe acute respiratory syndrome and Mycoplasma pneumoniae pneumonia.
The clinical manifestations of severe acute respiratory syndrome (SARS) and mycoplasma pneumonia are similar. However, administration of corticosteroid to Mycoplasma pneumoniae patients suspected of having SARS may unnecessarily increase the risk of opportunistic infection. We compared the clinical course of 13 SARS patients and 6 patients with mycoplasma pneumonia treated during the outbreak of SARS in Taiwan. Patients admitted due to suspicion of SARS with a subsequent diagnosis of SARS or Mycoplasma pneumoniae pneumonia were included. The initial clinical manifestations were similar in patients with SARS and those with M. pneumoniae infection. However, SARS patients had more severe lymphopenia (p = 0.013) and anemia (p = 0.007), and more persistent pulmonary infiltrates (p = 0.023). Respiratory failure developed in 15.4% of the SARS patients and in none of the M. pneumoniae patients. Recovery from thrombocytopenia was associated with defervescence in 12 SARS patients and radiographic improvement in 6 in the following 5 days. In those with unsatisfactory resolution of the pulmonary infiltrates, corticosteroid therapy was associated with rapid radiographic improvement. Because of similar initial presentations, differentiating SARS from M. pneumoniae pneumonia is very difficult based on symptomatology. In this series, lymphopenia and anemia were more severe in SARS than in M. pneumoniae infection, and SARS patients had more persistent and more new pulmonary infiltrates after hospitalization.


Measuring point defect density in individual carbon nanotubes using polarization-dependent X-ray microscopy.
The presence of defects in carbon nanotubes strongly modifies their electrical, mechanical, and chemical properties. It was long thought undesirable, but recent experiments have shown that introduction of structural defects using ion or electron irradiation can lead to novel nanodevices. We demonstrate a method for detecting and quantifying point defect density in individual carbon nanotubes (CNTs) based on measuring the polarization dependence (linear dichroism) of the C 1s --> pi* transition at specific locations along individual CNTs with a scanning transmission X-ray microscope (STXM). We show that STXM can be used to probe defect density in individual CNTs with high spatial resolution. The quantitative relationship between ion dose, nanotube diameter, and defect density was explored by purposely irradiating selected sections of nanotubes with kiloelectronvolt (keV) Ga(+) ions. Our results establish polarization-dependent X-ray microscopy as a new and very powerful characterization technique for carbon nanotubes and other anisotropic nanostructures.


The effect of mountain bike wheel size on cross-country performance.
The purpose of this study was to determine the influence of different wheel size diameters on indicators of cross-country mountain bike time trial performance. Nine competitive male mountain bikers (age 34.7 ± 10.7 years; stature 177.7 ± 5.6 cm; body mass 73.2 ± 8.6 kg) performed 1 lap of a 3.48 km mountain bike (MTB) course as fast as possible on 26″, 27.5″ and 29″ wheeled MTB. Time (s), mean power (W), cadence (revs · min-1) and velocity (km · h-1) were recorded for the whole lap and during ascent and descent sections. One-way repeated measure ANOVA was used to determine significant differences. Results revealed no significant main effects for any variables by wheel size during all trials, with the exception of cadence during the descent (F(2, 16) = 8.96; P = .002; P2 = .53). Post hoc comparisons revealed differences lay between the 26″ and 29″ wheels (P = .02). The findings indicate that wheel size does not significantly influence performance during cross-country when ridden by trained mountain bikers, and that wheel choice is likely due to personal choice or sponsorship commitments.


Building a better neonatal mouse model to understand infant respiratory syncytial virus disease.
Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract infection in infants; and severe RSV infection in infants is associated with asthma development. Today, there are still no vaccines or specific antiviral therapies against RSV. The mechanisms of RSV pathogenesis in infants remain elusive. This is partly due to the fact that the largely-used mouse model is semi-permissive for RSV. The present study sought to determine if a better neonatal mouse model of RSV infection could be obtained using a chimeric virus in which the F protein of A2 strain was replaced with the F protein from the line 19 clinical isolate (rA2-19F). Five-day-old pups were infected with the standard laboratory strain A2 or rA2-19F and various immunological and pathophysiological parameters were measured at different time points post infection, including lung histology, bronchoalveolar lavage fluid (BALF) cellularity and cytokines, pulmonary T cell profile, and lung viral load. A cohort of infected neonates were allowed to mature to adulthood and reinfected. Pulmonary function, BALF cellularity and cytokines, and T cell profiles were measured at 6 days post reinfection. The rA2-19F strain in neonatal mice caused substantial lung pathology including interstitial inflammation and airway mucus production, while A2 caused minimal inflammation and mucus production. Pulmonary inflammation was characterized by enhanced Th2 and reduced Th1 and effector CD8(+) T cells compared to A2. As with primary infection, reinfection with rA2-19F induced similar but exaggerated Th2 and reduced Th1 and effector CD8(+) T cell responses. These immune responses were associated with increased airway hyperreactivity, mucus hyperproduction and eosinophilia that was greater than that observed with A2 reinfection. Pulmonary viral load during primary infection was higher with rA2-19F than A2. Therefore, rA2-19F caused enhanced lung pathology and Th2 and reduced effector CD8(+) T cell responses compared to A2 during initial infection in neonatal mice and these responses were exacerbated upon reinfection. The exact mechanism is unknown but appears to be associated with increased pulmonary viral load in rA2-19F vs. A2 infected neonatal lungs. The rA2-19F strain represents a better neonatal mouse model of RSV infection.


Identifying electrochemical effects in a thermal-electrochemical co-driven system for CO2 capture.
Currently, the most promising amine absorption system for CO2 capture still faces the challenges of heavy steam consumption and a high energy penalty. Thus, a new thermal-electrochemical co-driven system (TECS) for CO2 capture was developed to resolve these problems. In the TECS, unknown electrochemical behaviors are quite essential to assess the CO2 capture performance. Electrochemical experiments were designed using response surface methodology (RSM) to identify electrochemical effects. The results show that the cathode process is slow and difficult, which is the main limitation in improving the performance of the TECS. Forced convection is necessary to improve the diffusion-controlled process and accelerate desorption. Four factors (Cu(ii) molality, CO2 loading, temperature, KNO3 molality) play an auxo-action role in determining anode and cathode reaction rates. A regression model is developed based on the experimental data, and optimum operating conditions are obtained. Regeneration energy consumption reaches about 1.3 GJ per t CO2, a decline of up to 70% compared with the traditional process. In addition, preliminary CO2 desorption experiments suggest that the mass transfer ascribed to the electrochemical process accounts for over 50% of the overall mass transfer coefficient in the CO2 desorption process.


Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders.
Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss-Durkee Hostility Inventory and the Beck Depression Inventory. No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed.


The conundrum of functional brain networks: small-world efficiency or fractal modularity.
The human brain has been studied at multiple scales, from neurons, circuits, areas with well-defined anatomical and functional boundaries, to large-scale functional networks which mediate coherent cognition. In a recent work, we addressed the problem of the hierarchical organization in the brain through network analysis. Our analysis identified functional brain modules of fractal structure that were inter-connected in a small-world topology. Here, we provide more details on the use of network science tools to elaborate on this behavior. We indicate the importance of using percolation theory to highlight the modular character of the functional brain network. These modules present a fractal, self-similar topology, identified through fractal network methods. When we lower the threshold of correlations to include weaker ties, the network as a whole assumes a small-world character. These weak ties are organized precisely as predicted by theory maximizing information transfer with minimal wiring costs.


Band reporting rates of waterfowl: does individual heterogeneity bias estimated survival rates?
In capture-recapture studies, the estimation accuracy of demographic parameters is essential to the efficacy of management of hunted animal populations. Dead recovery models based upon the reporting of rings or bands are often used for estimating survival of waterfowl and other harvested species. However, distance from the ringing site or condition of the bird may introduce substantial individual heterogeneity in the conditional band reporting rates (r), which could cause bias in estimated survival rates (S) or suggest nonexistent individual heterogeneity in S. To explore these hypotheses, we ran two sets of simulations (n = 1000) in MARK using Seber's dead recovery model, allowing time variation on both S and r. This included a series of heterogeneity models, allowing substantial variation on logit(r), and control models with no heterogeneity. We conducted simulations using two different values of S: S = 0.60, which would be typical of dabbling ducks such as mallards (Anas platyrhynchos), and S = 0.80, which would be more typical of sea ducks or geese. We chose a mean reporting rate on the logit scale of -1.9459 with SD = 1.5 for the heterogeneity models (producing a back-transformed mean of 0.196 with SD = 0.196, median = 0.125) and a constant reporting rate for the control models of 0.196. Within these sets of simulations, estimation models where σS = 0 and σS > 0 (σS is SD of individual survival rates on the logit scale) were incorporated to investigate whether real heterogeneity in r would induce apparent individual heterogeneity in S. Models where σS = 0 were selected approximately 91% of the time over models where σS > 0. Simulation results showed < 0.05% relative bias in estimating survival rates except for models estimating σS > 0 when true S = 0.8, where relative bias was a modest 0.5%. These results indicate that considerable variation in reporting rates does not cause major bias in estimated survival rates of waterfowl, further highlighting the robust nature of dead recovery models that are being used for the management of harvested species.


Default settings of computerized physician order entry system order sets drive ordering habits.
Computerized physician order entry (CPOE) systems are quickly becoming ubiquitous, and groups of orders ("order sets") to allow for easy order input are a common feature. This provides a streamlined mechanism to view, modify, and place groups of related orders. This often serves as an electronic equivalent of a specialty requisition. A characteristic, of these order sets is that specific orders can be predetermined to be "preselected" or "defaulted-on" whenever the order set is used while others are "optional" or "defaulted-off" (though there is typically the option is to "deselect" defaulted-on tests in a given situation). While it seems intuitive that the defaults in an order set are often accepted, additional study is required to understand the impact of these "default" settings in an order set on ordering habits. This study set out to quantify the effect of changing the default settings of an order set. For quality improvement purposes, order sets dealing with transfusions were recently reviewed and modified to improve monitoring of outcome. Initially, the order for posttransfusion hematocrits and platelet count had the default setting changed from "optional" to "preselected." The default settings for platelet count was later changed back to "optional," allowing for a natural experiment to study the effect of the default selections of an order set on clinician ordering habits. Posttransfusion hematocrit values were ordered for 8.3% of red cell transfusions when the default order set selection was "off" and for 57.4% of transfusions when the default selection was "preselected" (P < 0.0001). Posttransfusion platelet counts were ordered for 7.0% of platelet transfusions when the initial default order set selection was "optional," increased to 59.4% when the default was changed to "preselected" (P < 0.0001), and then decreased to 7.5% when the default selection was returned to "optional." The posttransfusion platelet count rates during the two "optional" periods: 7.0% versus 7.5% - were not statistically different (P = 0.620). Default settings in CPOE order sets can significantly influence physician selection of laboratory tests. Careful consideration by all stakeholders, including clinicians and pathologists, should be obtained when establishing default settings in order sets.


5-oxoproline-induced anion gap metabolic acidosis after an acute acetaminophen overdose.
Metabolic acidosis after acute acetaminophen overdose is typically attributed to either transient lactic acidosis without evidence of hepatic injury or hepatic failure. High levels of the organic acid 5-oxoprolinuria are usually reported in patients with predisposing conditions, such as sepsis, who are treated in a subacute or chronic fashion with acetaminophen. The authors report a case of a 40-year-old woman who developed anion gap metabolic acidosis and somnolence after an acute acetaminophen overdose. Substantial hepatic damage did not occur, which ruled out acetaminophen-induced hepatic insufficiency as a cause of the patient's acidosis or altered mental status. Urinalysis revealed elevated levels of 5-oxoproline, suggesting that the patient's acute acetaminophen overdose was associated with marked anion gap metabolic acidosis due solely to 5-oxoproline without hepatic complications. The acidosis fully resolved with N-acetylcysteine treatment and supportive care including hydration.


Agglutination of Plasmodium falciparum-infected erythrocytes from east and west African isolates by human sera from distant geographic regions.
Plasmodium falciparum-infected erythrocytes (PfE) were collected from acutely infected children in The Gambia and Tanzania and cultured for more than 30 hr until the parasites were mature trophozoites. Sera collected from these countries, other African countries, Asia, and South America were used in the PfE microagglutination test to determine whether PfE from East and West Africa share surface antigens. From the patterns of agglutination reactivity, we identified extensive antigenic diversity in surface antigens, but obtained no evidence for greater differences between isolates from East or West Africa and those within one region. The majority of sera from immune adults from The Gambia, Tanzania, Sudan, Nigeria, or Ghana were pan-agglutinating, and agglutinated all PfE isolates from The Gambia and Tanzania. Some sera from immune adults of Irian Jaya also agglutinated each of the seven African isolates, while others agglutinated many but not all of the isolates, similar to sera from immune adults of Flores, Indonesia. In contrast, sera from nonimmune adults from Colombia agglutinated few of the African isolates. It was remarkable, however, that sera from nonimmune Colombians agglutinated any African isolates. Our results are consistent with the following conclusions: some PfE surface antigen(s) are very diverse; this diversity is a feature of the parasite worldwide; the repertoire of isolate-specific surface antigens, although large, includes antigens that are either identical or antigenically cross-reactive in geographically very distant parasite populations; and African adults have pan-agglutinating antibodies that may contribute to protective immunity. Such pan-agglutinating antibodies could reflect the accumulation of a large repertoire of isolate-specific antibodies. The contribution of antibody against any shared PfE surface antigen to the pan-agglutinating reactivities is unknown and awaits development of the appropriate reagents.


The neovessel occlusion efficacy of 15-hydroxypurpurin-7-lactone dimethyl ester induced with photodynamic therapy.
In this study, the photodynamic therapy (PDT) induced efficacy of a semi-synthesized analogue 15(1)-hydroxypurpurin-7-lactone dimethyl ester or G2, in terms of chick chorioallantoic membrane blood vessel occlusion was evaluated in reference to verteporfin. Early formulation studies showed that G2 prepared in a system of cremophor EL 2.5% and ethanol 2.5% in saline was biocompatible up to 20 microL volume of injection. Following injection, G2 accumulation peaked within the first minute and its extravasation from intra- to extra-vascular occurred somewhat slower as compared with verteporfin. In the PDT study, closure of capillaries and small neovessels was observed with 4 microg per embryo of G2 and a light dose of 20 J cm(-2) at a fluence rate of 40 mW cm(-2) filtered at 400-440 nm-a result that may be considered optimum for the treatment of age-related macular degeneration (AMD). Also, partial occlusion of the large vessels was observed using the same dose of G2 and light-an effect which is desirable for cancer treatment. From this study, we conclude that G2 has the potential to be developed as a therapeutic agent for photodynamic treatment for AMD and cancer.


Why Chemotherapy Should be Given Early for Men with Metastatic Prostate Cancer.
Metastatic hormone-sensitive prostate cancer (mHSPC) is an incurable disease, and despite a high response rate to androgen-deprivation therapy (ADT), outcomes have not significantly changed for many decades. Earlier attempts at multitargeted strategies with the addition of cytotoxic chemotherapy to ADT did not affect survival. As more effective therapies are emerging, including cytotoxic therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC), there is increasing interest for testing these drugs earlier in the disease course. The premise is that agents with clinical benefit in advanced mCRPC may have a better effect if used preemptively before the development of significant resistance and to attack earlier de novo androgen resistant/independent clones. The recent results of the phase III clinical trial E3805 investigating ADT with or without docetaxel in mHSPC provide compelling support for this strategy. Docetaxel combined with ADT significantly improved overall survival from 44 to 57.6 months (p=0.0003), particularly in patients with high-volume disease (from 32.2 to 49.2 months; p=0.0006). Longer follow-up is needed to assess the effect on patients with low disease burden. Further studies are needed to further maximize the antitumor effect in patients with mHSPC and to investigate the effects of advancing therapy to this disease setting on the efficacy of respective agents in the castration-resistant setting.


Genome-wide association reveals genetic effects on human Aβ42 and τ protein levels in cerebrospinal fluids: a case control study.
Alzheimer's disease (AD) is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE ε2/ε3/ε4. However, the genetic backgrounds for normal cognition, mild cognitive impairment (MCI) and AD in terms of changes in cerebrospinal fluid (CSF) levels of Aβ1-42, T-tau, and P-tau181P, have not been clearly delineated. We carried out a genome-wide association study (GWAS) in order to better define the genetic backgrounds to these three states in relation to CSF levels. Subjects were participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The GWAS dataset consisted of 818 participants (mainly Caucasian) genotyped using the Illumina Human Genome 610 Quad BeadChips. This sample included 410 subjects (119 Normal, 115 MCI and 176 AD) with measurements of CSF Aβ1-42, T-tau, and P-tau181P Levels. We used PLINK to find genetic associations with the three CSF biomarker levels. Association of each of the 498,205 SNPs was tested using additive, dominant, and general association models while considering APOE genotype and age. Finally, an effort was made to better identify relevant biochemical pathways for associated genes using the ALIGATOR software. We found that there were some associations with APOE genotype although CSF levels were about the same for each subject group; CSF Aβ1-42 levels decreased with APOE gene dose for each subject group. T-tau levels tended to be higher among AD cases than among normal subjects. From adjusted result using APOE genotype and age as covariates, no SNP was associated with CSF levels among AD subjects. CYP19A1 'aromatase' (rs2899472), NCAM2, and multiple SNPs located on chromosome 10 near the ARL5B gene demonstrated the strongest associations with Aβ1-42 in normal subjects. Two genes found to be near the top SNPs, CYP19A1 (rs2899472, p = 1.90 × 10(-7)) and NCAM2 (rs1022442, p = 2.75 × 10(-7)) have been reported as genetic factors related to the progression of AD from previous studies. In AD subjects, APOE ε2/ε3 and ε2/ε4 genotypes were associated with elevated T-tau levels and ε4/ε4 genotype was associated with elevated T-tau and P-tau181P levels. Pathway analysis detected several biological pathways implicated in Normal with CSF β-amyloid peptide (Aβ1-42). Our genome-wide association analysis identified several SNPs as important factors for CSF biomarker. We also provide new evidence for additional candidate genetic risk factors from pathway analysis that can be tested in further studies.


Preoperative Expectations Associated With Postoperative Dissatisfaction After Total Knee Arthroplasty: A Cohort Study.
Unfulfilled expectations, assessed postoperatively, have been consistently associated with dissatisfaction after total knee arthroplasty (TKA). However, identifying these expectations preoperatively has been a challenge. We aimed at identifying specific expectations that are most likely to affect postoperative dissatisfaction. We included all patients in our institutional registry with a body mass index of <40 kg/m who underwent primary unilateral TKA and had a minimum 2-year follow-up. Preoperatively, patients completed the 19-item Hospital for Special Surgery Expectations Survey, Short Form-12, Knee Injury and Osteoarthritis Outcomes Score and EuroQol 5-D. Two years postoperatively, patients reported their dissatisfaction on five domains. We estimated logistic regression models to identify the expectation items associated with each domain. A total of 2,279 TKA patients (mean age: 65.3 ± 9.2 years; mean body mass index: 30.2 ± 5.9 kg/m) met our inclusion/exclusion criteria. The association between expectations and dissatisfaction was domain specific, that is, subsets of 4 to 5 items were markedly associated with each dissatisfaction domain, and these expectations differed depending on the dissatisfaction domain examined. Of those, expectations predicting dissatisfaction on multiple domains included kneeling ability and leg straightening and participation in recreation and sports. We identified a subset of expectations most likely to affect dissatisfaction after TKA. Our findings should inform preoperative patient education approaches on those expectations to realistically orient patient expectations and increase satisfaction. Level II.


Healthy Children, Strong Families 2: A randomized controlled trial of a healthy lifestyle intervention for American Indian families designed using community-based approaches.
Background/Aims Few obesity prevention trials have focused on young children and their families in the home environment, particularly in underserved communities. Healthy Children, Strong Families 2 is a randomized controlled trial of a healthy lifestyle intervention for American Indian children and their families, a group at very high risk of obesity. The study design resulted from our long-standing engagement with American Indian communities, and few collaborations of this type resulting in the development and implementation of a randomized clinical trial have been described. Methods Healthy Children, Strong Families 2 is a lifestyle intervention targeting increased fruit and vegetable intake, decreased sugar intake, increased physical activity, decreased TV/screen time, and two less-studied risk factors: stress and sleep. Families with young children from five American Indian communities nationwide were randomly assigned to a healthy lifestyle intervention ( Wellness Journey) augmented with social support (Facebook and text messaging) or a child safety control group ( Safety Journey) for 1 year. After Year 1, families in the Safety Journey receive the Wellness Journey, and families in the Wellness Journey start the Safety Journey with continued wellness-focused social support based on communities' request that all families receive the intervention. Primary (adult body mass index and child body mass index z-score) and secondary (health behaviors) outcomes are assessed after Year 1 with additional analyses planned after Year 2. Results To date, 450 adult/child dyads have been enrolled (100% target enrollment). Statistical analyses await trial completion in 2017. Lessons learned Conducting a community-partnered randomized controlled trial requires significant formative work, relationship building, and ongoing flexibility. At the communities' request, the study involved minimal exclusion criteria, focused on wellness rather than obesity, and included an active control group and a design allowing all families to receive the intervention. This collective effort took additional time but was critical to secure community engagement. Hiring and retaining qualified local site coordinators was a challenge but was strongly related to successful recruitment and retention of study families. Local infrastructure has also been critical to project success. Other challenges included geographic dispersion of study communities and providing appropriate incentives to retain families in a 2-year study. Conclusion This multisite intervention addresses key gaps regarding family/home-based approaches for obesity prevention in American Indian communities. Healthy Children, Strong Families 2's innovative aspects include substantial community input, inclusion of both traditional (diet/activity) and less-studied obesity risk factors (stress/sleep), measurement of both adult and child outcomes, social networking support for geographically dispersed households, and a community selected active control group. Our data will address a literature gap regarding multiple risk factors and their relationship to health outcomes in American Indian families.


A unique case of vision loss in a patient with hypotrichosis and juvenile macular dystrophy and primary ciliary dyskinesia.
We describe a unique case of CDH3-related hypotrichosis with juvenile macular dystrophy (HJMD) and DNAH5-related primary ciliary dyskinesia (PCD) with progressive vision loss in a young Indian female without positive family history. Both mutations in this patient have not been previously described in the literature. An 11-year-old girl of Indian descent from a consanguineous family presented to our clinic with poor central visual acuity, recurrent sinopulmonary infections, hypotrichosis, and gradual hearing loss. Fundus examination was significant for atrophic retinal pigmented epithelial (RPE) changes involving both the macula and periphery of both eyes with central foveal hypoautofluorescence. Optical coherence tomography (OCT) demonstrated RPE loss and significant disruption of the ellipsoid layer in both eyes. Full-field electrophysiology tests on initial presentation demonstrated low cone amplitude reduced to <70% of normal range without prolongation. OCT angiography of the RPE and choriocapillaris demonstrated possible flow voids in the central macular region of both eyes. Genetic testing showed that the proband was homozygous for variants CDH3 c.1660A > C; p. Thr554Pro and DNAH5 c.6688-1G>T. and Importance: We report two novel variants in the CDH3 and DNAH5 genes that are important for future mutational analysis of both HJMD and PCD respectively. A relationship between the cadherin protein dysfunction in CDH3 mutations and the ciliopathy of DNAH5 mutations has not been established. HJMD is known to cause a longitudinal deterioration of cone and rod mediated function, therefore recognizing the symptoms, visual impairment, physical examination, and photographic and electrophysiological findings is crucial in counseling the patient, the family, and fellow clinicians.


Extracellular and intracellular regulation of calcium homeostasis.
An organism with an internal skeleton must accumulate calcium while maintaining body fluids at a well-regulated, constant calcium concentration. Neither calcium absorption nor excretion plays a significant regulatory role. Instead, isoionic calcium uptake and release by bone surfaces causes plasma calcium to be well regulated. Very rapid shape changes of osteoblasts and osteoclasts, in response to hormonal signals, modulate the available bone surfaces so that plasma calcium can increase when more low-affinity bone calcium binding sites are made available and can decrease when more high-affinity binding sites are exposed. The intracellular free calcium concentration of body cells is also regulated, but because cells are bathed by fluids with vastly higher calcium concentration, their major regulatory mechanism is severe entry restriction. All cells have a calcium-sensing receptor that modulates cell function via its response to extracellular calcium. In duodenal cells, the apical calcium entry structure functions as both transporter and a vitamin D--responsive channel. The channel upregulates calcium entry, with intracellular transport mediated by the mobile, vitamin D-dependent buffer, calbindin D9K, which binds and transports more than 90% of the transcellular calcium flux. Fixed intracellular calcium binding sites can, like the body's skeleton, take up and release calcium that has entered the cell, but the principal regulatory tool of the cell is restricted entry.