Assessment of the morbidity and complications of total thyroidectomy.
To determine the incidence and predictive factors for complications after total thyroidectomy. Cross-sectional analysis of a national database on total thyroidectomy cases. The National Hospital Data Survey database was examined and all cases of total thyroidectomy performed during 1995 to 1999 were extracted. In addition to demographic information, postoperative complications including hypocalcemia, recurrent laryngeal nerve paralysis, wound complications, and medical morbidities were identified. Statistical analysis was conducted to determine potential predictive factors for postoperative complications. A total of 517 patients were identified (mean age, 48.3 years). The most common indications for total thyroidectomy were thyroid malignancy and goiter (73.9% of cases). Eighty-one patients (15.7%) underwent an associated nodal dissection along with total thyroidectomy, and 16 patients (3.1%) underwent parathyroid reimplantation. The mean length of stay was 2.5 days (95% confidence interval, 2.3-2.8 days). The incidence of postoperative wound hematoma was 1.0%, wound infection was 0.2%, and mortality rate was 0.2%. The incidence of postoperative hypocalcemia was 6.2%. Younger age was statistically associated with an increased incidence of hypocalcemia (P =.002, t test), whereas sex (P =.48), indication for surgery (P =.32), parathyroid reimplantation (P>.99), and associated neck dissection (P =.21) were not. The mean length of stay was 2.5 days and was unaffected by occurrence of postoperative hypocalcemia. The incidences of unilateral and bilateral vocal cord paralyses were 0.77% and 0.39%, respectively. Postoperative hypocalcemia is the most common immediate surgical complication of total thyroidectomy. Other complications, including recurrent laryngeal nerve paralysis, can be expected at rates approximating 1%.


Effects of hypoxia on the closing pressure of the canine systemic arterial circulation.
We studied the relationships among closing pressure (Pc) and indices of systemic arterial resistance (Ra) and compliance (Ca) during hypoxic hypoxia (HH) and carbon monoxide hypoxia (COH) in anesthetized dogs with cardiac bypass and constant ventilation. Closing pressure was measured as the lowest level to which arterial pressure (Pa) fell after inflow to the arterial bed was reduced suddenly to zero. Since the fall of Pa to Pc could be well-described as a single exponential function of time and since Pc was always greater than outflow (venous) pressure. Ra and CA were determined by applying a "vascular waterfall" model to the arterial bed. During HH, Pc increased while Ra and Ca decreased. During COH, Pc and Ra decreased, but Ca did not change. The Pc results indicate that during HH, but not COH, a large portion of the systemic arterial bed experienced a marked increase in vasomotor tone, a qualitative difference that would have been missed if Pc had not been measured. The relationship among Pc, Ra, and Ca during hypoxia suggest these indices may have been determined largely by different portions of the arterial bed in which tone changed independently.


The Effect of Chronic Opioid Use on End-Tidal Concentration of Sevoflurane Necessary to Maintain a Bispectral Index Below 50: A Prospective, Single-Blind Study.
Opioid analgesics decrease the minimum alveolar concentration of inhalation agents during the acute phase response. However, the effect of chronic opioid exposure on minimum alveolar concentration of inhalation agents remains unknown. This study aimed to determine the concentration of sevoflurane necessary to maintain a bispectral index (BIS) <50 (SEVOBIS50) in patients with chronic opioid use compared with those naïve to opioid use. We included chronic opioid users who received a stable dose of oral morphine of at least 60 mg/d according to the morphine equivalent daily dose for at least 4 weeks and opioid-naïve patients. General anesthesia that included thiopental, vecuronium, and sevoflurane in oxygen was administered to all patients. Anesthesia was maintained using predetermined end-tidal sevoflurane concentrations. Fifteen minutes after achieving the determined end-tidal sevoflurane concentration through closed circuit anesthesia, BIS was measured for 1 minute in both groups. SEVOBIS50 was determined using Dixon's up-down method and probit analysis. Nineteen and 18 patients from the chronic opioid and control groups, respectively, were included in the final analysis. SEVOBIS50values for the chronic opioid and control patients were 0.84 (95% confidence interval, 0.58-1.11) and 1.18 (95% confidence interval, 0.96-1.40), respectively (P = .0346). Our results suggest that the end-tidal concentration of sevoflurane necessary to maintain a BIS <50 is lower for chronic opioid users than for opioid-naïve patients.


[Clinical application of extracts of Echinacea purpurea or Echinacea pallida. Critical evaluation of controlled clinical studies].
The phytotherapy should be understood as being integrated into the rational pharmacotherapy. The modern phytotherapy tries hard to proof effects with pharmacological and clinical studies. The task force E of the federal bureau of health of Germany has made a statement regarding this problem. This article reviews only controlled clinical trials about the application of extracts of echinacea purpura or echinacea pallida.


Low prevalence of methicillin resistant Staphylococcus aureus as determined by an automated identification system in two private hospitals in Nairobi, Kenya: a cross sectional study.
Staphylococcus aureus (S.aureus) is a major cause of both healthcare and community acquired infections. In developing countries, manual phenotypic tests are the mainstay for the identification of staphylococci with the tube and slide coagulase tests being relied upon as confirmatory tests for S. aureus. The subjectivity associated with interpretation of these tests may result in misidentification of coagulase negative staphylococci as S.aureus. Given that antibiotic resistance is more prevalent in CONS, this may result in over estimation of methicillin resistant S.aureus (MRSA) prevalence. A review of susceptibility data from all non-duplicate S.aureus isolates generated between March 2011 and May 2013 by the Vitek-2 (bioMérieux) automated system was performed by the authors. The data was generated routinely from processed clinical specimens submitted to the microbiology laboratories for culture and sensitivity at the Aga Khan University Hospital and Gertrude's children's hospital both situated in Nairobi. Antimicrobial susceptibility data from a total of 731 non-duplicate S.aureus isolates was reviewed. Majority (79.2%) of the isolates were from pus swabs. Only 24 isolates were both cefoxitin and oxacillin resistant while 3 were resistant to oxacillin but susceptible to cefoxitin giving an overall MRSA prevalence of 3.7% (27/731). None of the isolates were resistant to mupirocin, linezolid, tigecycline, teicoplanin or vancomycin. The prevalence of MRSA in this study is much lower than what has been reported in most African countries. The significant change in antibiotic susceptibility compared to what has previously been reported in our hospital is most likely a consequence of the transition to an automated platform rather than a trend towards lower resistance rates.


Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis.
STAT3, an essential transcription factor with pleiotropic functions, plays critical roles in the pathogenesis of autoimmunity. Despite recent data linking STAT3 with inflammatory bowel disease, exactly how it contributes to chronic intestinal inflammation is not known. Using a T cell transfer model of colitis, we found that STAT3 expression in T cells was essential for the induction of both colitis and systemic inflammation. STAT3 was critical in modulating the balance of T helper 17 (Th17) and regulatory T (Treg) cells, as well as in promoting CD4(+) T cell proliferation. We used chromatin immunoprecipitation and massive parallel sequencing (ChIP-Seq) to define the genome-wide targets of STAT3 in CD4(+) T cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation, and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis.


Surveying treatment preferences in U.S. Iraq-Afghanistan Veterans with PTSD symptoms: a step toward veteran-centered care.
This study examined health care barriers and preferences among a self-selected sample of returning U.S. veterans drawn from a representative, randomly selected frame surveyed about posttraumatic stress disorder (PTSD) symptomatology and mental health utilization in the prior year. Comparisons between treated (n = 160) and untreated (n = 119) veterans reporting PTSD symptoms were conducted for measures of barriers and preferences, along with logistic models regressing mental health utilization on clusters derived from these measures. Reported barriers corroborated prior research findings as negative beliefs about treatment and stigma were strongly endorsed, but only privacy concerns were associated with lower service utilization (B = -0.408, SE = 0.142; p = .004). The most endorsed preference (91.0%) was for assistance with benefits, trailed by help for physical problems, and particular PTSD symptoms. Help-seeking veterans reported stronger preferences for multiple interventions, and desire for services for families (B = 0.468, SE = 0.219; p = .033) and specific PTSD symptoms (B = 0.659, SE = 0.302; p = .029) were associated with increased utilization. Outcomes of the study suggested PTSD severity drove help-seeking in this cohort. Results also support the integration of medical and mental health services, as well as coordination of health and benefits services. Finally, the study suggested that outreach about privacy protections and treatment options could well improve engagement in treatment.


Perceptuo-motor, cognitive, and description-based decision-making seem equally good.
Classical studies suggest that high-level cognitive decisions (e.g., choosing between financial options) are suboptimal. In contrast, low-level decisions (e.g., choosing where to put your feet on a rocky ridge) appear near-optimal: the perception-cognition gap. Moreover, in classical tasks, people appear to put too much weight on unlikely events. In contrast, when people can learn through experience, they appear to put too little weight on unlikely events: the description-experience gap. We eliminated confounding factors and, contrary to what is commonly believed, found results suggesting that (i) the perception-cognition gap is illusory and due to differences in the way performance is assessed; (ii) the description-experience gap arises from the assumption that objective probabilities match subjective ones; (iii) people's ability to make decisions is better than the classical literature suggests; and (iv) differences between decision-makers are more important for predicting peoples' choices than differences between choice tasks.


Obesity-Related Hormones and Metabolic Risk Factors: A Randomized Trial of Diet plus Either Strength or Aerobic Training versus Diet Alone in Overweight Participants.
There is debate about the additive effects of exercise in conjunction with diet to treat obesity, and not much is known about the differential effects of strength versus aerobic training. This randomized controlled trial examined the effects of diet plus strength training, diet plus aerobic training, or diet only on metabolic risk factors associated with obesity. Eighty-one overweight and obese participants completed the 8-week intervention. All participants received an energy-restrictive formula diet with an energy content based on 70% of measured resting metabolic rate (RMR). Participants assigned to an exercise group trained 3 days/week under supervision. Anthropometrics and fasting hormones were assessed pre- and post-intervention. Mean weight loss (8.5 ± 4.3kg SD) did not differ between groups nor did reductions in BMI or body fat, although the diet plus strength training group showed marginally greater lean mass retention. There were significant improvements in the values and number of metabolic syndrome risk factors, and decreases in insulin concentrations and insulin resistance, which did not vary between groups. For men, testosterone increased significantly more in the diet plus aerobic training as compared to the other groups. As compared to diet alone, the addition of strength or aerobic training did not improve changes in BMI, body fat or metabolic risk factors although the diet plus strength training group showed a trend toward preservation of lean mass, and the diet plus aerobic group in men resulted in increased testosterone concentrations.


Lack of evidence for qualitative treatment by disease severity interactions in clinical studies of severe sepsis.
The design of clinical trials of interventions aimed at reducing mortality in patients with severe sepsis assumes that the relative treatment effect of the intervention is independent of the patients' risk for death. We reviewed published data from phase III clinical studies of severe sepsis to determine whether a relationship exists between risk for death and the relative benefit of the investigational agent. Such an interaction might warrant a change in the assumptions that underlie current trial designs. We conducted a systematic review of published phase III, randomized, placebo-controlled trials in adult patients with sepsis, severe sepsis, or septic shock up to November 2004. All studies enrolled patients with known or suspected infection, evidence of a systemic response to the infection, and one or more organ dysfunctions resulting from the systemic response. Twenty-two publications, investigating 17 molecular entities, fulfilled criteria for phase III or equivalent studies aimed at reducing mortality in adult patients with severe sepsis or septic shock. Three studies achieved the prospectively defined primary end-point of a statistically significant reduction in 28-day all-cause mortality. The control group mortality rates for these studies were 31%, 43% and 61%, indicating that the beneficial effects of adjunct therapies could be demonstrated over a wide range of illness severity. Analysis of subgroup data from failed studies provided no evidence that the efficacy of the therapeutics being investigated varied by baseline placebo mortality rates. Among all studies, interventions with anticoagulant activity or anti-inflammatory activity did not appear to be harmful in patients with evidence of less coagulopathy or less inflammation. Our review of published clinical data does not support the hypothesis that mortality risk of the population studied alters the relative treatment effect associated with anti-inflammatory or other agents used to treat severe sepsis. Clinical studies in severe sepsis should continue to enroll patients over a wide range of disease severity, as long as patients enrolled have evidence of sepsis-induced organ dysfunction(s), patients are at an appreciable risk for death (e.g. as evidenced by admission to an intensive care unit), and the potential for benefit outweighs the potential for harm.


Using neurobiological measures to predict and assess treatment outcome of psychotherapy in posttraumatic stress disorder: systematic review.
Trauma-focused cognitive-behavioral therapy (TF-CBT) and eye movement desensitization and reprocessing (EMDR) are effective treatments for posttraumatic stress disorder. However, little is known about their neurobiological effects. The usefulness of neurobiological measures to predict the treatment outcome of psychotherapy also has yet to be determined. Systematic review of randomized controlled trials (RCTs) focused on neurobiological treatment effects of TF-CBT or EMDR and trials with neurobiological measures as predictors of treatment response. We included 23 publications reporting on 16 separate trials. TF-CBT was compared with a waitlist in most trials. TF-CBT was associated with a decrease in heart rate and blood pressure and changes in activity but not in volume of frontal brain structures and the amygdala. Neurobiological changes correlated with changes in symptom severity. EMDR was only tested against other active treatments in included trials. We did not find a difference in neurobiological treatment effects between EMDR and other treatments. Publications on neurobiological predictors of treatment response showed ambiguous results. TF-CBT was associated with a reduction of physiological reactivity. There is some preliminary evidence that TF-CBT influences brain regions involved in fear conditioning, extinction learning and possibly working memory and attention regulation; however, these effects could be nonspecific psychotherapeutic effects. Future trials should use paradigms aimed specifically at these brain regions and physiological reactivity. There are concerns regarding the risk of bias in some of the RCTs, indicating that methodologically more rigorous trials are required. Trials with neurobiological measures as predictors of treatment outcome render insufficient results to be useful in clinical practice.


Microbial shifts in the aging mouse gut.
The changes that occur in the microbiome of aging individuals are unclear, especially in light of the imperfect correlation of frailty with age. Studies in older human subjects have reported subtle effects, but these results may be confounded by other variables that often change with age such as diet and place of residence. To test these associations in a more controlled model system, we examined the relationship between age, frailty, and the gut microbiome of female C57BL/6 J mice. The frailty index, which is based on the evaluation of 31 clinical signs of deterioration in mice, showed a near-perfect correlation with age. We observed a statistically significant relationship between age and the taxonomic composition of the corresponding microbiome. Consistent with previous human studies, the Rikenellaceae family, which includes the Alistipes genus, was the most significantly overrepresented taxon within middle-aged and older mice. The functional profile of the mouse gut microbiome also varied with host age and frailty. Bacterial-encoded functions that were underrepresented in older mice included cobalamin (B12) and biotin (B7) biosynthesis, and bacterial SOS genes associated with DNA repair. Conversely, creatine degradation, associated with muscle wasting, was overrepresented within the gut microbiomes of the older mice, as were bacterial-encoded β-glucuronidases, which can influence drug-induced epithelial cell toxicity. Older mice also showed an overabundance of monosaccharide utilization genes relative to di-, oligo-, and polysaccharide utilization genes, which may have a substantial impact on gut homeostasis. We have identified taxonomic and functional patterns that correlate with age and frailty in the mouse microbiome. Differences in functions related to host nutrition and drug pharmacology vary in an age-dependent manner, suggesting that the availability and timing of essential functions may differ significantly with age and frailty. Future work with larger cohorts of mice will aim to separate the effects of age and frailty, and other factors.


Modal and polarization qubits in Ti:LiNbO3 photonic circuits for a universal quantum logic gate.
Lithium niobate photonic circuits have the salutary property of permitting the generation, transmission, and processing of photons to be accommodated on a single chip. Compact photonic circuits such as these, with multiple components integrated on a single chip, are crucial for efficiently implementing quantum information processing schemes.We present a set of basic transformations that are useful for manipulating modal qubits in Ti:LiNbO(3) photonic quantum circuits. These include the mode analyzer, a device that separates the even and odd components of a state into two separate spatial paths; the mode rotator, which rotates the state by an angle in mode space; and modal Pauli spin operators that effect related operations. We also describe the design of a deterministic, two-qubit, single-photon, CNOT gate, a key element in certain sets of universal quantum logic gates. It is implemented as a Ti:LiNbO(3) photonic quantum circuit in which the polarization and mode number of a single photon serve as the control and target qubits, respectively. It is shown that the effects of dispersion in the CNOT circuit can be mitigated by augmenting it with an additional path. The performance of all of these components are confirmed by numerical simulations. The implementation of these transformations relies on selective and controllable power coupling among single- and two-mode waveguides, as well as the polarization sensitivity of the Pockels coefficients in LiNbO(3).


Unexplained variation across US nursing homes in antipsychotic prescribing rates.
Serious safety concerns related to the use of antipsychotics have not decreased the prescribing of these agents to nursing home (NH) residents. We assessed the extent to which resident clinical characteristics and institutional prescribing practice were associated with antipsychotic prescribing. Antipsychotic prescribing was assessed for a nationwide, cross-sectional population of 16 586 newly admitted NH residents in 2006. We computed facility-level antipsychotic rates based on the previous year's (2005) prescribing patterns. Poisson regressions with generalized estimating equations were used to identify the likelihood of resident-level antipsychotic medication use in 2006, given 2005 facility-level prescribing pattern and NH resident indication for antipsychotic therapy (psychosis, dementia, and behavioral disturbance). More than 29% (n = 4818) of study residents received at least 1 antipsychotic medication in 2006. Of the antipsychotic medication users, 32% (n = 1545) had no identified clinical indication for this therapy. Residents entering NHs with the highest facility-level antipsychotic rates were 1.37 times more likely to receive antipsychotics relative to those entering the lowest prescribing rate NHs, after adjusting for potential clinical indications (risk ratio [RR], 1.37; 95% confidence interval [CI], 1.24-1.51). The elevated risk associated with facility-level prescribing rates was apparent for only NH residents with dementia but no psychosis (RR, 1.40; 95% CI, 1.23-1.59) and residents without dementia or psychosis (RR, 1.54; 95% CI, 1.24-1.91). The NH antipsychotic prescribing rate was independently associated with the use of antipsychotics in NH residents. Future research is needed to determine why such a prescribing culture exists and whether it could result in adverse health consequences.


Inositol 1,3,4-trisphosphate acts in vivo as a specific regulator of cellular signaling by inositol 3,4,5,6-tetrakisphosphate.
Ca2+-activated Cl- channels are inhibited by inositol 3,4,5, 6-tetrakisphosphate (Ins(3,4,5,6)P4) (Xie, W., Kaetzel, M. A., Bruzik, K. S., Dedman, J. R., Shears, S. B., and Nelson, D. J. (1996) J. Biol. Chem. 271, 14092-14097), a novel second messenger that is formed after stimulus-dependent activation of phospholipase C (PLC). In this study, we show that inositol 1,3,4-trisphosphate (Ins(1,3,4)P3) is the specific signal that ties increased cellular levels of Ins(3,4,5,6)P4 to changes in PLC activity. We first demonstrated that Ins(1,3,4)P3 inhibited Ins(3,4,5,6)P4 1-kinase activity that was either (i) in lysates of AR4-2J pancreatoma cells or (ii) purified 22,500-fold (yield = 13%) from bovine aorta. Next, we incubated [3H]inositol-labeled AR4-2J cells with cell permeant and non-radiolabeled 2,5,6-tri-O-butyryl-myo-inositol 1,3, 4-trisphosphate-hexakis(acetoxymethyl) ester. This treatment increased cellular levels of Ins(1,3,4)P3 2.7-fold, while [3H]Ins(3, 4,5,6)P4 levels increased 2-fold; there were no changes to levels of other 3H-labeled inositol phosphates. This experiment provides the first direct evidence that levels of Ins(3,4,5,6)P4 are regulated by Ins(1,3,4)P3 in vivo, independently of Ins(1,3,4)P3 being metabolized to Ins(3,4,5,6)P4. In addition, we found that the Ins(1, 3,4)P3 metabolites, namely Ins(1,3)P2 and Ins(3,4)P2, were >100-fold weaker inhibitors of the 1-kinase compared with Ins(1,3,4)P3 itself (IC50 = 0.17 microM). This result shows that dephosphorylation of Ins(1,3,4)P3 in vivo is an efficient mechanism to "switch-off" the cellular regulation of Ins(3,4,5,6)P4 levels that comes from Ins(1,3, 4)P3-mediated inhibition of the 1-kinase. We also found that Ins(1,3, 6)P3 and Ins(1,4,6)P3 were poor inhibitors of the 1-kinase (IC50 = 17 and >30 microM, respectively). The non-physiological trisphosphates, D/L-Ins(1,2,4)P3, inhibited 1-kinase relatively potently (IC50 = 0.7 microM), thereby suggesting a new strategy for the rational design of therapeutically useful kinase inhibitors. Overall, our data provide new information to support the idea that Ins(1,3,4)P3 acts in an important signaling cascade.


Individual differences in subconscious motor control predicted by GABA concentration in SMA.
Subliminal visual stimuli affect motor planning, but the size of such effects differs greatly between individuals. Here, we investigated whether such variation may be related to neurochemical differences between people. Cortical responsiveness is expected to be lower under the influence of more of the main inhibitory neurotransmitter, GABA. Thus, we hypothesized that, if an individual has more GABA in the supplementary motor area (SMA)--a region previously associated with automatic motor control--this would result in smaller subliminal effects. We measured the reversed masked prime--or negative compatibility--effect, and found that it correlated strongly with GABA concentration, measured with magnetic resonance spectroscopy. This occurred specifically in the SMA region, and not in other regions from which spectroscopy measurements were taken. We replicated these results in an independent cohort: more GABA in the SMA region is reliably associated with smaller effect size. These findings suggest that, across individuals, the responsiveness of subconscious motor mechanisms is related to GABA concentration in the SMA.


Acetylation of cyclophilin A is required for its secretion and vascular cell activation.
Cyclophilin A (CyPA) is a pro-inflammatory mediator involved in oxidative stress-related cardiovascular diseases. It is secreted from vascular smooth muscle cell (VSMC) in response to reactive oxygen species (ROS) in a highly regulated manner. Extracellular CyPA activates VSMCs and endothelial cells (ECs) promoting inflammation, cell growth, and cell death. Recently, it was shown that acetylated CyPA (AcK-CyPA) affects its function. We investigated the role of acetylation of CyPA for its secretion and signalling in vascular cells. We used angiotensin II (Ang II) to create sustained ROS and found significantly increased AcK-CyPA in VSMC. Site-directed mutagenesis showed that lysines K82 and K125 were the predominant CyPA residues acetylated in response to Ang II. Importantly, acetylation of K82 and K125 were required for Ang II-mediated CyPA secretion. ROS inhibitors, Tiron, and N-acetylcysteine inhibited Ang II-induced intracellular CyPA acetylation and also AcK-CyPA secretion. Using secreted CyPA from wild type and K82/125R mutants expressed in transduced VSMC or in vitro acetylated recombinant CyPA, we showed that extracellular AcK-CyPA significantly increased pERK1/2, matrix metalloproteinase-2 activation, and ROS production in VSMC compared with non-acetylated CyPA. Moreover, extracellular AcK-CyPA increased adhesion molecule expression (VCAM-1 and ICAM-1) in EC, which promoted monocyte adhesion. ROS-dependent acetylation of CyPA is required for the generation of extracellular CyPA. Acetylated extracellular CyPA regulates VSMC and EC activation, suggesting that inhibition of acetylation of CyPA may prevent the pathogenesis of oxidative stress-related cardiovascular diseases.


Method for recovery of heading from motion.
A new method for recovery of heading from motion is developed on the basis of Longuet-Higgins and Prazdny's algorithm [Proc. R. Soc. London Ser. B 208, 385 (1980)]. In the algorithm a radial virtual flow field is generated and the difference between the original velocity field and the virtual radial field is computed. The difference vectors, which are directed to the heading point in the projected plane, allow us to estimate the direction of heading. The simulations of the algorithm were performed, and it was shown that the method estimates the direction of heading accurately.


Afferent regulation of locus coeruleus neurons: anatomy, physiology and pharmacology.
Tract-tracing and electrophysiology studies have revealed that major inputs to the nucleus locus coeruleus (LC) are found in two structures, the nucleus paragigantocellularis (PGi) and the perifascicular area of the nucleus prepositus hypoglossi (PrH), both located in the rostral medulla. Minor afferents to LC were found in the dorsal cap of the paraventricular hypothalamus and spinal lamina X. Recent studies have also revealed limited inputs from two areas nearby the LC, the caudal midbrain periaqueductal gray (PAG) and the ventromedial pericoerulear region. The pericoeruleus may provide a local circuit interface to LC neurons. Recent electron microscopic analyses have revealed that LC dendrites extend preferentially into the rostromedial and caudal juxtaependymal pericoerulear regions. These extracoerulear LC dendrites may receive afferents in addition to those projecting to LC proper. However, single-pulse stimulation of inputs to such dendritic regions reveals little or no effect on LC neurons. Double-labeling studies have revealed that a variety of neurotransmitters impinging on LC neurons originate in its two major afferents, PGi and PrH. The LC is innervated by PGi neurons that stain for markers of adrenalin, enkephalin or corticotropin-releasing factor. Within PrH, large proportions of LC-projecting neurons stained for GABA or met-enkephalin. Finally, in contrast to previous conclusions, the dorsal raphe does not provide the robust 5-HT innervation found in the LC. We conclude that 5-HT inputs may derive from local 5-HT neurons in the pericoerulear area. Neuropharmacology experiments revealed that the PGi provides a potent excitatory amino acid (EAA) input to the LC, acting primarily at non-NMDA receptors in the LC. Other studies indicated that this pathway mediates certain sensory responses of LC neurons. NMDA-mediated sensory responses were also revealed during local infusion of magnesium-free solutions. Finally, adrenergic inhibition of LC from PGi could also be detected in nearly every LC neuron tested when the EAA-mediated excitation is first eliminated. In contrast to PGi, the PrH potently and consistently inhibited LC neurons via a GABAergic projection acting at GABAA receptors within LC. Such PrH stimulation also potently attenuated LC sensory responses. Finally, afferents to PGi areas that also contain LC-projecting neurons were identified. Major inputs were primarily autonomic in nature, and included the caudal medullary reticular formation, the parabrachial and Kölliker-Fuse nuclei, the PAG, NTS and certain hypothalamic areas.(ABSTRACT TRUNCATED AT 400 WORDS)


Children at Risk for Suicide Attempt and Attempt-related Injuries: Findings from the 2007 Youth Risk Behavior Survey.
The current study examines the associations between a range of risk factors and reports of suicide attempts and attempts requiring medical care in a nationally representative study of high school students. The goal is to examine sex differences in the risk factors associated with suicide attempts and attempt-related injuries requiring treatment by a health-care provider. We used data from the 2007 Youth Risk Behavior Survey for students in grades 9-12 to assess the prevalence and risk factors for suicidal behavior, as well as differences in these for boys and girls. Cross-sectional multivariate logistic regression analyses were computed to determine the most important risk factors for suicide attempts and for suicide attempts requiring medical care for the sample overall and also stratified for boys and for girls. Overall, 6.9% of adolescents attempted suicide (9.3% of girls versus 4.6% of boys). Girls were more likely than boys to report a suicide attempt in the past year (Adj.OR=2.89). Among girls, sadness (Adj.OR=5.74), weapon carrying (Adj.OR=1.48), dating violence (Adj.OR=1.60), forced sex (Adj.OR=1.72), and huffing glue (Adj.OR=2.04) were significantly associated with suicide attempts. Among boys, sadness (Adj.OR=10.96), weapon carrying (Adj.OR=1.66), forced sex (Adj.OR=2.60), huffing glue (OR=1.63), hard drug use (Adj.OR=2.18), and sports involvement (Adj.OR=1.52) were significantly associated with suicide attempts. These findings demonstrate similarities and differences in the modifiable risk factors that increase risk for suicide attempts among boys and girls. In terms of the differences between boys and girls, hard drug use and sports involvement may be important factors for suicide-prevention strategies directed specifically towards boys, while dating violence victimization may be an important risk factor to address for girls. Overall, these findings can help guide prevention, clinical practice, and intervention strategies to prevent suicidal behaviors among adolescents.


Acute sensorineural deafness in Lassa fever.
A prospective audiometric evaluation of 69 hospitalized febrile patients in Sierra Leone, West Africa, revealed a sensorineural hearing deficit (SNHD) in 14 (29%) of 49 confirmed cases of Lassa fever and in 0 of 20 febrile controls. An SNHD was present in nine (17.6%) of 51 people who had evidence of previous Lassa virus infection. Twenty-six of 32 local residents who had previously sustained a sudden deafness had antibody titers to Lassa virus of 16 or greater, compared with six of 32 matched controls. Lassa fever is associated with an incidence of SNHD, which considerably exceeds that previously reported with any other postnatally acquired infection, and accounts for a prevalence of virus-related hearing impairment in the eastern province of Sierra Leone that is greater than that reported from anywhere else in the world.


Ultrasound elastography in children: establishing the normal range of muscle elasticity.
Ultrasound elastography allows assessment of tissue elasticity. To the best of our knowledge, the elastography appearance of muscles in normal children has not been described. To determine the US elasticity of muscles in children at rest and following exercise. Cine elastography of biceps brachii and rectus femoris muscles was obtained at rest and after exercise in 42 healthy children (23 males, 19 females; mean: 11.2 ± 4.4 years, range: 2-18 years). Elastography scores were assigned to each clip based on a five-point color scale. Mean elastography scores and standard deviations were calculated and resting and postexercise elastography scores were compared. Resting muscle elasticity was lower in the biceps brachii than in the rectus femoris (P = 0.008), and higher in the dominant than in the nondominant biceps brachii (P < 0.032). Rectus femoris elasticity was higher in males than females (P = 0.051). Postexercise muscle elasticity significantly increased in both the dominant and nondominant biceps brachii (P < 0.001) and in the rectus femoris (P < 0.001). There was no significant gender-related difference in postexercise muscle elasticity. Biceps brachii elasticity decreased and rectus femoris elasticity increased with increasing body mass index. Younger subjects had a greater change in muscle elasticity with exercise. Resting muscle elasticity in children is significantly lower in the biceps brachii than in the rectus femoris and in the nondominant biceps brachii than in the dominant biceps brachii. Elasticity significantly increases immediately postexercise in both muscle groups; resting differences between biceps brachii and rectus femoris elasticity, and dominant and nondominant biceps brachii elasticity, do not persist after exercise. The change in muscle elasticity with exercise is higher in younger children.


Vitamin D receptor activator selectivity in the treatment of secondary hyperparathyroidism: understanding the differences among therapies.
Secondary hyperparathyroidism (SHPT) is a common and serious consequence of chronic kidney disease (CKD). SHPT is a complex condition characterised by a decline in 1,25-dihydroxyvitamin D and consequent vitamin D receptor (VDR) activation, abnormalities in serum calcium and phosphorus levels, parathyroid gland hyperplasia, elevated parathyroid hormone (PTH) secretion, and systemic mineral and bone abnormalities. There are three classes of drugs used for treatment of SHPT: (i) nonselective VDR activators or agonists (VDRAs); (ii) selective VDRAs; and (iii) calcimimetics. The VDRAs act on the VDR, whereas the calcimimetics act on the calcium-sensing receptor. Calcimimetics are commonly used in conjunction with VDRA therapy. By virtue of the differences in their chemical structure, the nonselective and selective VDRAs differ in their effects on gene expression, and ultimately parathyroid gland, bone and intestine function. Medications in all three classes are effective in suppression of PTH; however, clinical studies show that calcimimetics are associated with an unfavourable tolerability profile and hypocalcaemia, whereas nonselective VDRAs, and to a lesser extent selective VDRAs, are associated with dose-limiting hypercalcaemia and hyperphosphataemia. Selective VDRAs also have minimal undesirable effects on calcium absorption in the intestine, and calcium and phosphorus mobilisation in the bone compared with nonselective VDRAs. Calcium load in patients with CKD can lead to vascular calcification, accelerated progression of cardiovascular disease and increased mortality. High serum phosphorus levels are also associated with adverse effects on cardiorenal function and survival. Recent evidence suggests that VDRAs are associated with a survival benefit in CKD patients, with a more favourable effect with selective VDRAs than nonselective VDRAs. Paricalcitol, a selective VDRA, is reported to exert specific effects on gene expression in various cell types that are involved in vascular calcification and the development of coronary artery disease. This article examines the molecular mechanisms that determine selectivity of VDRAs, and reviews the evidence for clinical efficacy, safety and survival associated with the three drug classes used for treatment of SHPT in CKD patients.


Changes in voltage activation, Cs+ sensitivity, and ion permeability in H5 mutants of the plant K+ channel KAT1.
KAT1 is a voltage-dependent inward rectifying K+ channel cloned from the higher plant Arabidopsis thaliana [Anderson, J. A., Huprikar, S. S., Kochian, L. V., Lucas, W. J. & Gaber, R. F. (1992) Proc. Natl. Acad. Sci. USA 89, 3736-3740]. It is related to the Shaker superfamily of K+ channels characterized by six transmembrane spanning domains (S1-S6) and a putative pore-forming region between S5 and S6 (H5). The 115 region between Pro-247 and Pro-271 in KAT1 contains 14 additional amino acids when compared with Shaker [Aldrich, R. W. (1993) Nature (London) 362, 107-108]. We studied various point mutations introduced into H5 to determine whether voltage-dependent plant and animal K+ channels share similar pore structures. Through heterologous expression in Xenopus oocytes and voltage-clamp analysis combined with phenotypic analysis involving a potassium transport-defective Saccharomyces cerevisiae strain, we investigated the selectivity filter of the mutants and their susceptibility toward inhibition by cesium and calcium ions. With respect to electrophysiological properties, KAT1 mutants segregated into three groups: (i) wild-type-like channels, (ii) channels modified in selectivity and Cs+ or Ca2+ sensitivity, and (iii) a group that was additionally affected in its voltage dependence. Despite the additional 14 amino acids in H5, this motif in KAT1 is also involved in the formation of the ion-conducting pore because amino acid substitutions at Leu-251, Thr-256, Thr-259, and Thr-260 resulted in functional channels with modified ionic selectivity and inhibition. Creation of Ca2+ sensitivity and an increased susceptibility to Cs+ block through mutations within the narrow pore might indicate that both blockers move deeply into the channel. Furthermore, mutations close to the rim of the pore affecting the half-activation potential (U1/2) indicate that amino acids within the pore either interact with the voltage sensor or ion permeation feeds back on gating.


Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs.
Many disease-causing missense mutations affect intrinsically disordered regions (IDRs) of proteins, but the molecular mechanism of their pathogenicity is enigmatic. Here, we employ a peptide-based proteomic screen to investigate the impact of mutations in IDRs on protein-protein interactions. We find that mutations in disordered cytosolic regions of three transmembrane proteins (GLUT1, ITPR1, and CACNA1H) lead to an increased clathrin binding. All three mutations create dileucine motifs known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), the glucose transporter causative of GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. Mutant GLUT1 interacts with adaptor proteins (APs) in vitro, and knocking down AP-2 reverts the cellular mislocalization and restores glucose transport. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in structurally disordered cytosolic domains of transmembrane proteins. Thus, several mutations in disordered regions appear to cause "dileucineopathies."


Separating arterial and venous-related components of photoplethysmographic signals for accurate extraction of oxygen saturation and respiratory rate.
We propose an algorithm for separating arterial and venous-related signals using second-order statistics of red and infrared signals in a blind source separation technique. The separated arterial signal is used to compute accurate arterial oxygen saturation. We have also introduced an algorithm for extracting the respiratory pattern from the extracted venous-related signal. In addition to real-time monitoring, respiratory rate is also extracted. Our experimental results from multiple subjects show that the proposed separation technique is extremely useful for extracting accurate arterial oxygen saturation and respiratory rate. Specifically, the breathing rate is extracted with average root mean square deviation of 1.89 and average mean difference of -0.69.


Antibiotic therapy success rate in pulmonary Mycobacterium avium complex: a systematic review and meta-analysis.
Objectives: The incidence of Mycobacterium avium complex (MAC) pulmonary disease is increasing worldwide. We conducted a systematic review and meta-analysis to determine the treatment success rate of antibiotic therapy in MAC pulmonary disease and evaluate the effectiveness of aminoglycoside-containing regimens.Methods: We searched literature between 1 January 1980 to 19 June 2019. Studies with diagnosis criteria based on the current guidelines that reported treatment outcomes were included. We defined treatment success as the achievement of culture conversion and completion of the planned treatment without relapse while on treatment.Results: We retrieved 45 studies including 3862 patients. The estimated pooled treatment success rate was 68.1% [95% confidence interval (CI) 64.7-71.4%]. Based on the Cochrane tool, the included studies had a low risk of bias. Forty-two studies reported macrolide-containing regimens, while 6 studies included aminoglycoside-containing regimens. Macrolide-containing regimens led to better treatment success rates comparing to non-macrolide-containing regimens; 69% vs 58.5%, respectively. Treatment duration of 12 months or more showed better results.Conclusion: Poor treatment success rate of MAC pulmonary disease calls for more randomized clinical trials designed based on consensus definitions of the disease diagnosis and treatment. New drugs with a better adherence rate need to be developed.Systematic Review Registration: PROSPERO (pending registration ID: 151674).


Comparison of sample preservation methods for clinical trace element analysis by inductively coupled plasma mass spectrometry.
The effects of chemical additives and storage temperatures on measurement of 16 trace elements in urine by inductively coupled plasma mass spectrometry (ICP-MS) were evaluated. A 24-hour urine specimen was supplemented with concentrations of the elements. Aliquots containing 1 of 4 chemical additives were stored at 3 different temperatures in sealed polypropylene containers. Elemental concentrations were determined by ICP-MS for the resulting samples after 1, 2, 8, and 65 days of storage. Initial element concentrations measured within 8 hours of specimen preparation were consistent with expected concentrations (except for aluminum). For most elements, preservation and storage conditions yielded consistent measured concentrations throughout the experiment. Notable exceptions were for aluminum (general rise over time) and mercury (general decrease over time). Adding boric acid and potassium pyrosulfate resulted in sample contamination; elemental contamination was concentration-dependent for both. Although little microbial contamination was observed during the experiment, refrigeration of samples is recommended to curtail bacterial growth in nonsterile specimens. In light of these results, refrigerated urine storage without the use of chemical additives is an effective preservation method for ICP-MS analysis of many trace elements.


Computerization of workflows, guidelines, and care pathways: a review of implementation challenges for process-oriented health information systems.
There is a need to integrate the various theoretical frameworks and formalisms for modeling clinical guidelines, workflows, and pathways, in order to move beyond providing support for individual clinical decisions and toward the provision of process-oriented, patient-centered, health information systems (HIS). In this review, we analyze the challenges in developing process-oriented HIS that formally model guidelines, workflows, and care pathways. A qualitative meta-synthesis was performed on studies published in English between 1995 and 2010 that addressed the modeling process and reported the exposition of a new methodology, model, system implementation, or system architecture. Thematic analysis, principal component analysis (PCA) and data visualisation techniques were used to identify and cluster the underlying implementation 'challenge' themes. One hundred and eight relevant studies were selected for review. Twenty-five underlying 'challenge' themes were identified. These were clustered into 10 distinct groups, from which a conceptual model of the implementation process was developed. We found that the development of systems supporting individual clinical decisions is evolving toward the implementation of adaptable care pathways on the semantic web, incorporating formal, clinical, and organizational ontologies, and the use of workflow management systems. These architectures now need to be implemented and evaluated on a wider scale within clinical settings.


Head and neck cancer: changing epidemiology, diagnosis, and treatment.
Head and neck cancers account for less than 5% of all cancers and for less than 3% of all cancer deaths in the United States. The populations at risk for head and neck cancers are those who have a long-standing history of smoking and alcohol use. More recently, the incidence of oropharyngeal cancer in younger populations has been increasing and is associated with exposure to the human papillomavirus. This subset of patients appears to have a better overall prognosis and to respond better to treatment. This review is limited to head and neck cancers of squamous cell histology, which constitute more than 90% of head and neck cancers. Because treatment of head and neck cancers is complex and involves multiple modalities, a multidisciplinary approach is needed. This review focuses on the goal of organ preservation and postoperative treatment of high-risk patients with the concurrent use of chemotherapy and radiation therapy. This review also highlights recent advances in treatment using molecularly targeted therapies, specifically the role of inhibitors of the epidermal growth factor receptor in locally advanced and recurrent/metastatic squamous cell cancer of the head and neck. Studies in the English language were identified by searching the MEDLINE, EMBASE database (1980-2007) using the search terms head and neck, squamous cell, carcinoma, chemotherapy, radiation, human papillomavirus, epidermal growth factor receptor, and targeted therapy.


High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin's lymphoma.
No effective salvage regimen has been defined for patients with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) who do not respond to first-line chemotherapy that contains anthracycline. Combined dexamethasone, cytosine arabinoside, and cisplatin (DHAP) and etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) have shown good response rates in HIV-negative patients with relapsed lymphomas. We retrospectively analyzed patients with refractory or relapsed AIDS-NHL who had been treated with either DHAP or ESHAP to evaluate the feasibility and efficacy of these regimens. Twenty-six patients with refractory or relapsed AIDS-NHL were treated between 1990 and 1999 either with DHAP ( n = 13) or with ESHAP ( n = 13). Only 1 patient from each group (8%) had achieved complete remission with any previous therapy, and most had progressive disease after the regimen immediately preceding DHAP or ESHAP. In the ESHAP group, 4 patients (31%) achieved complete remission (CR) and 3 patients (23%) attained partial remission (PR) for an overall response rate of 54%. The median survival was 7.1 months (range, 1-58.9+ months) from the time ESHAP was begun. Among the 3 patients with primary refractory lymphoma, there was 1 CR, 1 PR, and one patient with stable disease. In contrast, only 1 PR (7%) was observed with DHAP; the median survival was 3 months. Myelosuppression was the most significant toxicity with grade 4 neutropenia occurring in all who received ESHAP and in 54% of patients treated with DHAP. Neutropenic fever occurred in 8 (62%) ESHAP-treated and 6 (46%) DHAP-treated patients. Although hematologic toxicity is profound, ESHAP appears to be an active salvage regimen for patients with relapsed or refractory AIDS-NHL.


Cooperation and the evolutionary ecology of bacterial virulence: the Bacillus cereus group as a novel study system.
How significant is social evolution theory for the maintenance of virulence in natural populations? We assume that secreted, distantly acting virulence factors are highly likely to be cooperative public goods. Using this assumption, we discuss and critically assess the potential importance of social interactions for understanding the evolution, diversity and distribution of virulence in the Bacillus cereus group, a novel study system for microbial social biology. We conclude that dynamic equilibria in Cry toxin production, as well as strong spatial structure and population bottlenecks in hosts are the main ecological factors maintaining the cooperative secretion of virulence factors and argue that collective action has contributed to the evolution of narrow host range. Non-linearities in the benefits associated with public goods, as well as the lack of private secretion systems in the Firmicutes may also explain the prevalence and importance of distantly acting virulence factors in B. cereus and its relatives.


Life cycle modelling of environmental impacts of application of processed organic municipal solid waste on agricultural land (EASEWASTE).
A model capable of quantifying the potential environmental impacts of agricultural application of composted or anaerobically digested source-separated organic municipal solid waste (MSW) is presented. In addition to the direct impacts, the model accounts for savings by avoiding the production and use of commercial fertilizers. The model is part of a larger model, Environmental Assessment of Solid Waste Systems and Technology (EASEWASTE), developed as a decision-support model, focusing on assessment of alternative waste management options. The environmental impacts of the land application of processed organic waste are quantified by emission coefficients referring to the composition of the processed waste and related to specific crop rotation as well as soil type. The model contains several default parameters based on literature data, field experiments and modelling by the agro-ecosystem model, Daisy. All data can be modified by the user allowing application of the model to other situations. A case study including four scenarios was performed to illustrate the use of the model. One tonne of nitrogen in composted and anaerobically digested MSW was applied as fertilizer to loamy and sandy soil at a plant farm in western Denmark. Application of the processed organic waste mainly affected the environmental impact categories global warming (0.4-0.7 PE), acidification (-0.06 (saving)-1.6 PE), nutrient enrichment (-1.0 (saving)-3.1 PE), and toxicity. The main contributors to these categories were nitrous oxide formation (global warming), ammonia volatilization (acidification and nutrient enrichment), nitrate losses (nutrient enrichment and groundwater contamination), and heavy metal input to soil (toxicity potentials). The local agricultural conditions as well as the composition of the processed MSW showed large influence on the environmental impacts. A range of benefits, mainly related to improved soil quality from long-term application of the processed organic waste, could not be generally quantified with respect to the chosen life cycle assessment impact categories and were therefore not included in the model. These effects should be considered in conjunction with the results of the life cycle assessment.


Comorbid psychopathology rates in children diagnosed with autism spectrum disorders according to the DSM-IV-TR and the proposed DSM-5.
To investigate differences in comorbid psychopathology rates between individuals who meet criteria of Autism Spectrum Disorders (ASDs) according to DSM-5 or the DSM-IV-TR. Comorbid psychopathology was measured using the Autism Spectrum Disorders- Comorbid for Children. 424 individuals between the ages of 2 and 18 years of age; including children who met criteria for an ASD according to the DSM-5, the DSM-IV-TR only, and a control group that did not meet either set of criteria. Of the ASD participants, 36% would no longer meet criteria according to proposed DSM-5. Comorbidity rates for the ASD groups were significantly different from the control group; however, ASD groups were not significantly different in terms of total comorbid psychopathology. The results elucidate the need for further research regarding services and treatments for those individuals that will no longer meet criteria for an ASD but still have significant rates of comorbid psychopathology.


Integrated care programmes for chronically ill patients: a review of systematic reviews.
To investigate effectiveness, definitions, and components of integrated care programmes for chronically ill patients on the basis of systematic reviews. Literature review from January 1996 to May 2004. Definitions and components of integrated care programmes and all effects reported on the quality of care. Searches in the Medline and Cochrane databases identified 13 systematic reviews of integrated care programmes for chronically ill patients. Despite considerable heterogeneity in interventions, patient populations, and processes and outcomes of care, integrated care programmes seemed to have positive effects on the quality of patient care. No consistent definitions were present for the management of patients with chronic illnesses. In all the reviews the aims of integrated care programmes were very similar, namely reducing fragmentation and improving continuity and coordination of care, but the focus and content of the programmes differed widely. The most common components of integrated care programmes were self-management support and patient education, often combined with structured clinical follow-up and case management; a multidisciplinary patient care team; multidisciplinary clinical pathways and feedback, reminders, and education for professionals. Integrated care programmes seemed to have positive effects on the quality of care. However, integrated care programmes have widely varying definitions and components and failure to recognize these variations leads to inappropriate conclusions about the effectiveness of these programmes and to inappropriate application of research results. To compare programmes and better understand the (cost) effectiveness of the programmes, consistent definitions must be used and component interventions must be well described.


Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity.
GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver-Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres.


Towards a better understanding of work participation among employees with common mental health problems: a systematic realist review.
Common mental health problems (CMHP) represent a major health issue and burden to employees and employers. Under certain conditions work contributes to wellbeing and participation of employees with CMHP. Promoting work participation is important, however the specific conditions in which work participation occurs is complex and largely unclear. This calls for a novel, realistic approach to unravel the complex relationship between outcomes, context and underlying mechanisms of work participation. In the present realist review, peer-reviewed studies conducted between 1995 and 2020 were systematically reviewed on the outcome measures `stay at work` (SAW) and `work performance` (WP). The database search from seven databases identified 2235 records, of which 61 studies met the selection criteria and methodological rigor. The synthesis demonstrates how work participation is promoted by the following mechanisms and contextual factors: (i) organizational climate and leadership, (ii) social support, (iii) perceived job characteristics, (iv) coping styles, (v) health symptoms and severity, (vi) personal characteristics, and (vii) features of interventions. An explanatory framework, based on the Capability-for-Work model, presents a new set of capabilities leading to SAW and WP. This systematic realist review revealed mechanisms and contextual factors that promote both SAW and WP among employees with CMHP. These show how the organizational climate, social support in the work context, job characteristics and certain capabilities enable employees with CMHP to participate at work. Our contributions and practical implications are discussed, providing valuable insights for employers, professionals and researchers in the development of evidence-based interventions.


When wanting to change is not enough: automatic appetitive processes moderate the effects of a brief alcohol intervention in hazardous-drinking college students.
Research indicates that brief motivational interventions are efficacious treatments for hazardous drinking. Little is known, however, about the psychological processes that may moderate intervention success. Based on growing evidence that drinking behavior may be influenced by automatic (nonvolitional) mental processes, the current study examined whether automatic alcohol-approach associations moderated the effect of a brief motivational intervention. Specifically, we examined whether the efficacy of a single-session intervention designed to increase motivation to reduce alcohol consumption would be moderated by the strength of participants' automatic alcohol-approach associations. Eighty-seven undergraduate hazardous drinkers participated for course credit. Participants completed an Implicit Association Test to measure automatic alcohol-approach associations, a baseline measure of readiness to change drinking behavior, and measures of alcohol involvement. Participants were then randomly assigned to either a brief (15-minute) motivational intervention or a control condition. Participants completed a measure of readiness to change drinking at the end of the first session and returned for a follow-up session six weeks later in which they reported on their drinking over the previous month. Compared with the control group, those in the intervention condition showed higher readiness to change drinking at the end of the baseline session but did not show decreased drinking quantity at follow-up. Automatic alcohol-approach associations moderated the effects of the intervention on change in drinking quantity. Among participants in the intervention group, those with weak automatic alcohol-approach associations showed greater reductions in the amount of alcohol consumed per occasion at follow-up compared with those with strong automatic alcohol-approach associations. Automatic appetitive associations with alcohol were not related with change in amount of alcohol consumed per occasion in control participants. Furthermore, among participants who showed higher readiness to change, those who exhibited weaker alcohol-approach associations showed greater reductions in drinking quantity compared with those who exhibited stronger alcohol-approach associations. The results support the idea that automatic mental processes may moderate the influence of brief motivational interventions on quantity of alcohol consumed per drinking occasion. The findings suggest that intervention efficacy may be improved by utilizing implicit measures to identify those who may be responsive to brief interventions and by developing intervention elements to address the influence of automatic processes on drinking behavior.


Allostatic gene regulation of inhibitory synaptic factors in the rat ventral hippocampus in a juvenile/adult stress model of psychopathology.
Early life stress is an important vulnerability factor for the development of anxiety disorders, depression and late-onset cognitive decline. Recently, we demonstrated that juvenile stress (JS) lastingly enhanced long-term potentiation via reduction of steady-state glutamine synthetase mRNA expression and the associated dysregulation of the astrocytic glutamate-glutamine cycle in the rat ventral CA1. We now investigated the regulation of steady-state mRNA expression of neuronal gene products that determine GABAergic and glutamatergic neurotransmission in layers of the ventral and dorsal CA1 after JS. We further studied their interaction with stress in young adult age (AS) to address their putative role in psychopathology development. Strikingly, mRNA levels of the glutamic acid decarboxylase (GAD) isoforms GAD65 and of the GABA-A receptor α2 (Gabra2) were increased after single JS or AS, but not after combined JS/AS stress experience. In fact, JS/AS resulted in layer-specific reduction of Gabra2 and also of Gabra1 mRNA levels in the ventral CA1. Furthermore, GAD65 and Gabra2 mRNAs were correlated with glutamatergic AMPA and NMDA receptor subunit mRNAs after single JS and AS, but not after combined JS/AS. Together, these data indicate a loss of allostatic regulation of steady-state mRNA levels of key GABAergic components that may result in a dysregulation of excitation/ inhibition balance in the ventral CA1 upon dual stress exposure. Finally, individual differences in local glucocorticoid receptor mRNA expression may contribute to this regulation.


Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop.
Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have recently been characterized in a subset of patients with advanced non-small cell lung cancer (NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The EGFR-TKI gefitinib has been approved in Europe for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of the EGFR TK. Because EGFR mutation testing is not yet well established across Europe, biomarker-directed therapy only slowly emerges for the subset of NSCLC patients most likely to benefit: those with EGFR mutations. The "EGFR testing in NSCLC: from biology to clinical practice" International Association for the Study of Lung Cancer-European Thoracic Oncology Platform multidisciplinary workshop aimed at facilitating the implementation of EGFR mutation testing. Recommendations for high-quality EGFR mutation testing were formulated based on the opinion of the workshop expert group. Co-operation and communication flow between the various disciplines was considered to be of most importance. Participants agreed that the decision to request EGFR mutation testing should be made by the treating physician, and results should be available within 7 working days. There was agreement on the importance of appropriate sampling techniques and the necessity for the standardization of tumor specimen handling including fixation. Although there was no consensus on which laboratory test should be preferred for clinical decision making, all stressed the importance of standardization and validation of these tests. The recommendations of the workshop will help implement EGFR mutation testing in Europe and, thereby, optimize the use of EGFR-TKIs in clinical practice.


Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling.
Mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that relays nutrient availability signals to control numerous cellular functions including autophagy, a process of cellular self-eating activated by nutrient depletion. Addressing the therapeutic potential of modulating mTORC1 signaling and autophagy in human disease requires active chemicals with pharmacologically desirable properties. Using an automated cell-based assay, we screened a collection of >3,500 chemicals and identified three approved drugs (perhexiline, niclosamide, amiodarone) and one pharmacological reagent (rottlerin) capable of rapidly increasing autophagosome content. Biochemical assays showed that the four compounds stimulate autophagy and inhibit mTORC1 signaling in cells maintained in nutrient-rich conditions. The compounds did not inhibit mTORC2, which also contains mTOR as a catalytic subunit, suggesting that they do not inhibit mTOR catalytic activity but rather inhibit signaling to mTORC1. mTORC1 inhibition and autophagosome accumulation induced by perhexiline, niclosamide or rottlerin were rapidly reversed upon drug withdrawal whereas amiodarone inhibited mTORC1 essentially irreversibly. TSC2, a negative regulator of mTORC1, was required for inhibition of mTORC1 signaling by rottlerin but not for mTORC1 inhibition by perhexiline, niclosamide and amiodarone. Transient exposure of immortalized mouse embryo fibroblasts to these drugs was not toxic in nutrient-rich conditions but led to rapid cell death by apoptosis in starvation conditions, by a mechanism determined in large part by the tuberous sclerosis complex protein TSC2, an upstream regulator of mTORC1. By contrast, transient exposure to the mTORC1 inhibitor rapamycin caused essentially irreversible mTORC1 inhibition, sustained inhibition of cell growth and no selective cell killing in starvation. The observation that drugs already approved for human use can reversibly inhibit mTORC1 and stimulate autophagy should greatly facilitate the preclinical and clinical testing of mTORC1 inhibition for indications such as tuberous sclerosis, diabetes, cardiovascular disease and cancer.


Major transcriptome re-organisation and abrupt changes in signalling, cell cycle and chromatin regulation at neural differentiation in vivo.
Here, we exploit the spatial separation of temporal events of neural differentiation in the elongating chick body axis to provide the first analysis of transcriptome change in progressively more differentiated neural cell populations in vivo. Microarray data, validated against direct RNA sequencing, identified: (1) a gene cohort characteristic of the multi-potent stem zone epiblast, which contains neuro-mesodermal progenitors that progressively generate the spinal cord; (2) a major transcriptome re-organisation as cells then adopt a neural fate; and (3) increasing diversity as neural patterning and neuron production begin. Focussing on the transition from multi-potent to neural state cells, we capture changes in major signalling pathways, uncover novel Wnt and Notch signalling dynamics, and implicate new pathways (mevalonate pathway/steroid biogenesis and TGFβ). This analysis further predicts changes in cellular processes, cell cycle, RNA-processing and protein turnover as cells acquire neural fate. We show that these changes are conserved across species and provide biological evidence for reduced proteasome efficiency and a novel lengthening of S phase. This latter step may provide time for epigenetic events to mediate large-scale transcriptome re-organisation; consistent with this, we uncover simultaneous downregulation of major chromatin modifiers as the neural programme is established. We further demonstrate that transcription of one such gene, HDAC1, is dependent on FGF signalling, making a novel link between signals that control neural differentiation and transcription of a core regulator of chromatin organisation. Our work implicates new signalling pathways and dynamics, cellular processes and epigenetic modifiers in neural differentiation in vivo, identifying multiple new potential cellular and molecular mechanisms that direct differentiation.


Novel therapies targeting endometriosis.
Endometriosis is an often painful disorder in which the endometrial glands and stroma grow outside the uterus. The disease affects women's quality of life and is a common cause of infertility. In this review, we describe promising new developments in the field based on in vitro assays and rodent models, each of which has the potential to be beneficial in the treatment of this disease. We will specifically describe the role of anti-inflammatory drugs, selective estrogen, or progesterone modulators, statins, antiangiogenic agents, and the potential for targeting stem cells as likely methods to hone in and eliminate endometriosis. The most promising of these potential therapies are currently slated for further testing in both rodent and nonhuman primate trials.


Modulation of brain insulin signaling in Alzheimer's disease: New insight on the protective role of green coffee bean extract.
Objective: Alzheimer's disease (AD), a neurodegenerative disorder, involves brain insulin signaling cascades and insulin resistance (IR). Because of limited treatment options, new treatment strategies are mandatory. Green coffee bean extract (GCBE) was reported to attenuate IR and improve brain energy metabolism. We aimed to investigate the possible use of GCBE as a prophylactic strategy to delay the onset of AD or combined with pioglitazone (PIO) as a strategy to retard the progression of AD.Methods: Rats received 10% fructose in drinking water for 18 weeks to induce AD. GCBE-prophylactic group received GCBE for 22 weeks started 4 weeks prior to fructose administration. The PIO group treated with PIO for 6 weeks started on week 12 of fructose administration. The GCBE+PIO group received GCBE for 22 weeks started 4 weeks prior to fructose administration and treated with PIO for the last 6 weeks of fructose administration.Results: Pretreatment with GCBE, either alone or combined with PIO, alleviated IR-induced AD changes. GCBE improved cognition, decreased serine phosphorylation of insulin receptor substrate, increased phosphoinositol-3 kinase (PI3K) activity and protein kinase B (Akt) gene expression, decreased glycogen synthase kinase-3β (GS3Kβ) gene expression and Tau hyperphosphorylation.Discussion: GCBE exerted neuroprotective effects against IR-induced AD mediated by alleviating IR and modulating brain insulin signaling cascade.


Partial Transphyseal Anterior Cruciate Ligament Reconstruction: Clinical, Functional, and Radiographic Outcomes.
With a steadily increasing rate of anterior cruciate ligament (ACL) injury and reconstruction in the pediatric population, disagreement remains regarding the optimal reconstruction technique for patients with ACL injury and ≥2 years of growth remaining. This study aims to quantify the incidence of linear and angular growth disturbance of adolescents undergoing partial transphyseal ACL reconstruction (ACLR) while assessing graft failure rates, reoperation rates, and functional outcomes in the population. Case series; Level of evidence, 4. Consecutive patients undergoing partial transphyseal ACLR by 2 surgeons were retrospectively reviewed. Radiographic outcomes, including bilateral limb length, mechanical axis deviation (MAD), mechanical lateral distal femoral angle (MLDFA), and medial proximal tibial angle (MPTA), were measured on long standing anterior-posterior view radiographs postoperatively. Growth disturbance was defined as ≥1-cm leg length discrepancy, ≥1-cm difference in MAD, or 5° difference in MLDFA or MPTA as compared with the nonoperative side and as MAD, MLDFA, or MPTA outside the established range of reference values. Clinical outcomes, including graft failure and reoperation, were recorded at each follow-up visit. Pediatric International Knee Documentation Committee (Pedi-IKDC) scores were collected electronically after last follow-up. Twenty-four patients (mean ± SD age, 12.3 ± 0.9 years; 79.2% male) with a mean follow-up of 31.5 ± 17.1 months met inclusion criteria for the study. Overall postoperative growth disturbance incidence was 16.7% (4 of 24), but the incidence of growth disturbance was 66.7% (2 of 3) for those patients with >5 years of growth remaining. Seven patients (29.2%) required reoperation, most frequently for hardware removal. Two patients (8.3%) had graft failure with subsequent revision ACL reconstruction. One patient underwent bilateral medial distal femur hemiepiphysiodesis for genu valgum that was present before ACLR, but no other patients required guided growth procedures. In the subset of patients who completed a Pedi-IKDC questionnaire, the mean score was 94.8 ± 5.3. Overall, partial transphyseal ACLR has good functional outcomes and graft failure and reoperation rates, comparable with those seen with transphyseal and all-epiphyseal techniques. While postoperative growth disturbance occurred in 16.7% of the cohort, the severity was mild and well tolerated without necessitating secondary procedures. There is a high rate of growth disturbance of patients with >5 years of growth remaining (66.7%). Partial transphyseal ACLR represents a valid recommendation for adolescent patients with ACL injury and ≤5 years of growth remaining.


A model for structure-based comparison of many categories in small-multiple displays.
Many application domains deal with multi-variate data that consist of both categorical and numerical information. Smallmultiple displays are a powerful concept for comparing such data by juxtaposition. For comparison by overlay or by explicit encoding of computed differences, however, a specification of references is necessary. In this paper, we present a formal model for defining semantically meaningful comparisons between many categories in a small-multiple display. Based on pivotized data that are hierarchically partitioned by the categories assigned to the x and y axis of the display, we propose two alternatives for structure-based comparison within this hierarchy. With an absolute reference specification, categories are compared to a fixed reference category. With a relative reference specification, in contrast, a semantic ordering of the categories is considered when comparing them either to the previous or subsequent category each. Both reference specifications can be defined at multiple levels of the hierarchy (including aggregated summaries), enabling a multitude of useful comparisons. We demonstrate the general applicability of our model in several application examples using different visualizations that compare data by overlay or explicit encoding of differences.


Energy Landscape Mapping and Replica Exchange Molecular Dynamics of an Adsorbed Peptide.
Adsorption of peptides at the interface between a fluid and a solid occurs widely in both nature and applications. Knowing the dominant conformations of adsorbed peptides and the energy barriers between them is of interest for a variety of reasons. Molecular dynamics (MD) simulation is a widely used technique that can yield such understanding. However, the complexity of the energy landscapes of adsorbed peptides means that comprehensive exploration of the energy landscape by MD simulation is challenging. An alternative approach is energy landscape mapping (ELM), which involves the location of stationary points on the potential energy surface, and its analysis to determine, for example, the pathways and energy barriers between them. In the study reported here, a comparison is made between this technique and replica exchange molecular dynamics (REMD) for met-enkephalin adsorbed at the interface between graphite and the gas phase: the first ever direct comparison of these techniques for adsorbed peptides. Both methods yield the dominant adsorbed peptide conformations. Unlike REMD, however, ELM readily allows the identification of the connectivity and energy barriers between the favored conformations, transition paths, and structures between these conformations and the impact of entropy. It also permits the calculation of the constant volume heat capacity although the accuracy of this is limited by the sampling of high-energy minima. Overall, compared to REMD, ELM provides additional insights into the adsorbed peptide system provided sufficient care is taken to ensure that key parts of the landscape are adequately sampled.


A CRISPR/Cas9 genetically engineered organoid biobank reveals essential host factors for coronaviruses.
Rapid identification of host genes essential for virus replication may expedite the generation of therapeutic interventions. Genetic screens are often performed in transformed cell lines that poorly represent viral target cells in vivo, leading to discoveries that may not be translated to the clinic. Intestinal organoids are increasingly used to model human disease and are amenable to genetic engineering. To discern which host factors are reliable anti-coronavirus therapeutic targets, we generate mutant clonal IOs for 19 host genes previously implicated in coronavirus biology. We verify ACE2 and DPP4 as entry receptors for SARS-CoV/SARS-CoV-2 and MERS-CoV respectively. SARS-CoV-2 replication in IOs does not require the endosomal Cathepsin B/L proteases, but specifically depends on the cell surface protease TMPRSS2. Other TMPRSS family members were not essential. The newly emerging coronavirus variant B.1.1.7, as well as SARS-CoV and MERS-CoV similarly depended on TMPRSS2. These findings underscore the relevance of non-transformed human models for coronavirus research, identify TMPRSS2 as an attractive pan-coronavirus therapeutic target, and demonstrate that an organoid knockout biobank is a valuable tool to investigate the biology of current and future emerging coronaviruses.


Fractionation of fiber and crude protein in fresh forages during the spring growth.
The composition of the fiber and CP of alfalfa, bromegrass, and endophyte-free and -infected tall fescue forages was compared during the spring growth from vegetative to reproductive stages. Forages were sampled from April 27 to June 6 in 1994, and from April 27 to June 11 in 1995, with 11 and 12 harvest dates, respectively. Total dietary fiber (TDF) was fractionated into insoluble and soluble fiber (SF). The CP of the forages was fractionated into nonprotein N (A), soluble CP (B1), insoluble CP that was soluble in neutral detergent (B2), CP insoluble in neutral detergent but soluble in acid detergent (B3), and CP insoluble in acid detergent (C). Effects of year, forage species, and harvest dates (day as a covariable) were included in the model. Across harvest dates, alfalfa (A) had lower (P < .01) TDF and higher (P < .01) SF concentrations than grasses (GR) (A: 49.9 and 14.4% and GR: 60.4 and 4.5% [OM basis] for TDF and SF, respectively). Alfalfa had higher (P < .01) CP (20.6% DM) than GR (15.3%). The rate of decrease in CP (% DM) across days was higher (P < .01) for bromegrass (-.4%/d) than for the other forages (-.29%/d). Fraction A (% of CP) was not different (P = .24) among forages (22.5%), but B1 was higher (P < .01) in A (17.1%) than in GR (13.2%). The B2 fraction (% of CP) was higher (P < .01) in A compared with GR (51.6 vs 45.9%, respectively). Alfalfa had lower (P < .01) B3 (3.0% of CP) than bromegrass (18.6%) and tall fescue (13.2%). Fraction C was not different (P = .23) among forages (3.8%). Fractions A, B1, and C (% of CP) did not change (P > .05) across days for all forages. Fraction B2 (% of CP) decreased across days in A (-.21%/d) but was not affected in GR. Fraction B3 (% of CP) increased (P < .05) in A (.1%/d), decreased in endophyte-infected tall fescue (-.20%/d), and did not change (P > .05) in the other forages. Crude protein and fiber composition were affected more by forage species than by maturity. The CP and NDF concentrations were more affected by maturity. Insoluble fractions but not soluble fractions of CP were affected by maturity.


Optimized breath detection algorithm in electrical impedance tomography.
This paper defines a method for optimizing the breath delineation algorithms used in electrical impedance tomography (EIT). In lung EIT the identification of the breath phases is central for generating tidal impedance variation images, subsequent data analysis and clinical evaluation. The optimisation of these algorithms is particularly important in neonatal care since the existing breath detectors developed for adults may give insufficient reliability in neonates due to their very irregular breathing pattern. Our approach is generic in the sense that it relies on the definition of a gold standard and the associated definition of detector sensitivity and specificity, an optimisation criterion and a set of detector parameters to be investigated. The gold standard has been defined by 11 clinicians with previous experience with EIT and the performance of our approach is described and validated using a neonatal EIT dataset acquired within the EU-funded CRADL project. Three different algorithms are proposed that improve the breath detector performance by adding conditions on (1) maximum tidal breath rate obtained from zero-crossings of the EIT breathing signal, (2) minimum tidal impedance amplitude and (3) minimum tidal breath rate obtained from time-frequency analysis. As a baseline a zero-crossing algorithm has been used with some default parameters based on the Swisstom EIT device. Based on the gold standard, the most crucial parameters of the proposed algorithms are optimised by using a simple exhaustive search and a weighted metric defined in connection with the receiver operating characterics. This provides a practical way to achieve any desirable trade-off between the sensitivity and the specificity of the detectors.


An epigenetic mechanism for cavefish eye degeneration.
Coding and non-coding mutations in DNA contribute significantly to phenotypic variability during evolution. However, less is known about the role of epigenetics in this process. Although previous studies have identified eye development genes associated with the loss-of-eyes phenotype in the Pachón blind cave morph of the Mexican tetra Astyanax mexicanus, no inactivating mutations have been found in any of these genes. Here, we show that excess DNA methylation-based epigenetic silencing promotes eye degeneration in blind cave A. mexicanus. By performing parallel analyses in A. mexicanus cave and surface morphs, and in the zebrafish Danio rerio, we have discovered that DNA methylation mediates eye-specific gene repression and globally regulates early eye development. The most significantly hypermethylated and downregulated genes in the cave morph are also linked to human eye disorders, suggesting that the function of these genes is conserved across vertebrates. Our results show that changes in DNA methylation-based gene repression can serve as an important molecular mechanism generating phenotypic diversity during development and evolution.


Chronic meningitis with multiple cranial neuropathies: A rare initial presentation of Wegener's granulomatosis.
Wegener's granulomatosis (WG) is a systemic necrotizing vasculitis that affects the small blood vessels. It mainly affects the upper and lower respiratory tract and kidneys. Central nervous system (CNS) involvement is rare, and has been reported only in about 8% of cases during the course of illness. Initial presentation with neurologic affection, particularly chronic hypertrophic meningitis is very unusual. We report the case of a 34 year old male who presented with chronic hypertrophic meningitis and multiple cranial nerve involvement as the initial manifestation, without respiratory and renal symptoms. This case highlights the difficulties in diagnosing a rare disease with rarer presentation, and at the same time illustrates that Wegener's granulomatosis should be considered in the differential diagnosis of chronic meningitis.


Bacterial adhesion force quantification by fluidic force microscopy.
Quantification of detachment forces between bacteria and substrates facilitates the understanding of the bacterial adhesion process that affects cell physiology and survival. Here, we present a method that allows for serial, single bacterial cell force spectroscopy by combining the force control of atomic force microscopy with microfluidics. Reversible bacterial cell immobilization under physiological conditions on the pyramidal tip of a microchanneled cantilever is achieved by underpressure. Using the fluidic force microscopy technology (FluidFM), we achieve immobilization forces greater than those of state-of-the-art cell-cantilever binding as demonstrated by the detachment of Escherichia coli from polydopamine with recorded forces between 4 and 8 nN for many cells. The contact time and setpoint dependence of the adhesion forces of E. coli and Streptococcus pyogenes, as well as the sequential detachment of bacteria out of a chain, are shown, revealing distinct force patterns in the detachment curves. This study demonstrates the potential of the FluidFM technology for quantitative bacterial adhesion measurements of cell-substrate and cell-cell interactions that are relevant in biofilms and infection biology.


Modeling Rett Syndrome With Human Patient-Specific Forebrain Organoids.
Engineering brain organoids from human induced pluripotent stem cells (hiPSCs) is a powerful tool for modeling brain development and neurological disorders. Rett syndrome (RTT), a rare neurodevelopmental disorder, can greatly benefit from this technology, since it affects multiple neuronal subtypes in forebrain sub-regions. We have established dorsal and ventral forebrain organoids from control and RTT patient-specific hiPSCs recapitulating 3D organization and functional network complexity. Our data revealed a premature development of the deep-cortical layer, associated to the formation of TBR1 and CTIP2 neurons, and a lower expression of neural progenitor/proliferative cells in female RTT dorsal organoids. Moreover, calcium imaging and electrophysiology analysis demonstrated functional defects of RTT neurons. Additionally, assembly of RTT dorsal and ventral organoids revealed impairments of interneuron's migration. Overall, our models provide a better understanding of RTT during early stages of neural development, demonstrating a great potential for personalized diagnosis and drug screening.


Measuring teacher practices and student academic engagement: A convergent validity study.
We examined the convergent validity of observer ratings of teachers' use of evidence-based instructional and behavior management practices using the Classroom Strategies Assessment System (CSAS; Reddy & Dudek, 2014) with student academic engagement as measured by the Cooperative Learning Observational Code for Kids (CLOCK; Volpe & DiPerna, 2010). This study was conducted with a sample of 107 teachers and 2,000 students in 11 urban elementary schools serving students in a community with high concentrations of poverty. Correlational and multiple linear regression analyses examined whether CSAS instructional and behavior management scores predicted classwide academic engagement. Results provide initial evidence of the relationship between observer ratings of teacher practices and student engagement. Specifically, CSAS scores indicating higher quality instruction and behavior management were associated with higher student engagement. Multiple linear regression revealed that instructional practice scores (as measured by the CSAS) uniquely predicted student academic engagement (i.e., attention and participation during instruction) while behavior management practice scores did not. Implications for future research and practice are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Radical C-N Borylation of Aromatic Amines Enabled by a Pyrylium Reagent.
Herein, we report a radical borylation of aromatic amines through a homolytic C(sp2 )-N bond cleavage. This method capitalizes on a simple and mild activation via a pyrylium reagent (Sc Pyry-OTf) thus priming the amino group for reactivity. The combination of terpyridine and a diboron reagent triggers a radical reaction which cleaves the C(sp2 )-N bond and forges a new C(sp2 )-B bond. The unique non-planar structure of the pyridinium intermediate, provides the necessary driving force for the aryl radical formation. The method permits borylation of a wide variety of aromatic amines indistinctively of the electronic environment.


Angiographic evaluation of brain infarction limited to the anterior cerebral artery territory.
Brain infarction localized in the anterior cerebral artery territory is rather uncommon, and its etiology has not yet been fully elucidated. Based on computed tomographic findings, 17 patients with solitary anterior cerebral artery territory infarction were selected from among 3,619 patients admitted consecutively to our institute. Patients without angiographic examinations were excluded. The angiographic findings and clinical category of stroke were analyzed in each patient. Angiographic abnormalities were revealed in all patients. These consisted of occlusive changes (n = 10) or reversible segmental dilatation (n = 3) of the anterior cerebral artery, A1 hypoplasia (n = 5), and occlusive changes of the carotid artery (n = 3). In one patient with anterior cerebral artery occlusion, the occluded artery was reopened and subsequently became reoccluded. The clinical category of stroke was classified as atherothrombotic in 10 patients, cardioembolic in three, and undetermined in the remaining four. In eight of the 10 patients with atherothrombotic infarction, the anterior cerebral artery was narrowed or occluded. In all patients with cardioembolic infarction, the A1 segment contralateral to the infarction was hypoplastic. In our series, solitary anterior cerebral artery territory infarction was attributable most commonly to local atherothrombosis and occasionally to cardiogenic embolism. A hypoplastic A1 segment may facilitate the occurrence of embolism in the anterior cerebral artery. Reversible dilatatory and occlusive changes of this artery may be another important cause of infarction.


Murine interstitial nephritis. I. Analysis of disease susceptibility and its relationship of pleiomorphic gene products defining both immune-response genes and a restrictive requirement for cytotoxic T cells at H-2K.
Anti-tubular basement membrance (alpha TBM) disease-producing interstitial nephritis in mice is not dependent on the generation of alpha TBM antibodies. Susceptibility seems to be defined by very private specificities in H-2K. These specificities are pleiomorphic, providing both immune-response genes and identity restrictions for cytotoxic effector functions expressed by a Thy-1.2+, Lyt-2,3+ T cell. These studies establish a role for T cells in the pathogenesis in interstitial nephritis as well as providing further evidence for the role of H-2K in the expression of an autoimmune disease.


Resonant-tunnelling-assisted crossing for subwavelength plasmonic slot waveguides.
We theoretically investigate properties of crossing for two perpendicular subwavelength plasmonic slot waveguides. In terms of symmetry consideration and resonant-tunnelling effect, we design compact cavity-based crossing structures for nanoplasmonic waveguides. Our results show that the crosstalk is practically eliminated and the throughput reaches the unity on resonance. Simulation results are in agreement with those from coupled-mode theory. Taking the material loss into account, the symmetry properties of the modes are preserved and the crosstalk remains suppressed, while the throughput is naturally lowered. Our results may open a way to construct nanoscale crossings for high-density nanoplasmonic integration circuits.


Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline.
The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer's disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer's disease pathology and cognitive deficits.


Predictive validity of kindergarten assessments on handwriting readiness.
We investigated the predictive value of a new kindergarten assessment of handwriting readiness on handwriting performance in first grade as evaluated by the Systematic Screening for Handwriting Difficulties (Dutch abbreviation: SOS). The kindergarten assessment consisted of the Writing Readiness Inventory Tool In Context (WRITIC), the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery™VMI) and the Nine-Hole Peg Test (9-HPT). The WRITIC evaluates in kindergarten children (aged 5-6 years) prewriting skills, the Beery™VMI and 9-HPT evaluate visual motor integration and fine-motor coordination, all elements important for handwriting readiness. In kindergarten, 109 children (55 boys; mean age 70 months, SD 4.8 months) were tested with the WRITIC, Beery™VMI and 9-HPT and one year later in first grade (mean age 85 months, SD 4.5 months) with the SOS. A multivariable linear mixed model was used to identify variables that independently predict outcomes in first grade (SOS): baseline scores on WRITIC-TP, Beery™VMI, 9-HPT, 'sustained attention,' 'gender,' 'age' and 'intervention' in the intermediate period. The results showed that WRITIC-TP, Beery™VMI, and 9-HPT, 'sustained attention,' 'gender' and 'intervention' had all predictive value on the handwriting outcome. Thereby WRITIC-TP was the main predictor for outcome of SOS-Quality, and Beery™VMI and 9-HPT were the main predictors of SOS-Speed. This kindergarten assessment of WRITIC-TP, Beery™VMI, and 9-HPT contributes to the detection of children at risk for developing handwriting problems.