Cerebral Oximetry During Cardiac Arrest: A Multicenter Study of Neurologic Outcomes and Survival.
Cardiac arrest is associated with morbidity and mortality because of cerebral ischemia. Therefore, we tested the hypothesis that higher regional cerebral oxygenation during resuscitation is associated with improved return of spontaneous circulation, survival, and neurologic outcomes at hospital discharge. We further examined the validity of regional cerebral oxygenation as a test to predict these outcomes. Multicenter prospective study of in-hospital cardiac arrest. Five medical centers in the United States and the United Kingdom. Inclusion criteria are as follows: in-hospital cardiac arrest, age 18 years old or older, and prolonged cardiopulmonary resuscitation greater than or equal to 5 minutes. Patients were recruited consecutively during working hours between August 2011 and September 2014. Survival with a favorable neurologic outcome was defined as a cerebral performance category 1-2. Cerebral oximetry monitoring. Among 504 in-hospital cardiac arrest events, 183 (36%) met inclusion criteria. Overall, 62 of 183 (33.9%) achieved return of spontaneous circulation, whereas 13 of 183 (7.1%) achieved cerebral performance category 1-2 at discharge. Higher mean ± SD regional cerebral oxygenation was associated with return of spontaneous circulation versus no return of spontaneous circulation (51.8% ± 11.2% vs 40.9% ± 12.3%) and cerebral performance category 1-2 versus cerebral performance category 3-5 (56.1% ± 10.0% vs 43.8% ± 12.8%) (both p < 0.001). Mean regional cerebral oxygenation during the last 5 minutes of cardiopulmonary resuscitation best predicted the return of spontaneous circulation (area under the curve, 0.76; 95% CI, 0.69-0.83); regional cerebral oxygenation greater than or equal to 25% provided 100% sensitivity (95% CI, 94-100) and 100% negative predictive value (95% CI, 79-100); regional cerebral oxygenation greater than or equal to 65% provided 99% specificity (95% CI, 95-100) and 93% positive predictive value (95% CI, 66-100) for return of spontaneous circulation. Time with regional cerebral oxygenation greater than 50% during cardiopulmonary resuscitation best predicted cerebral performance category 1-2 (area under the curve, 0.79; 95% CI, 0.70-0.88). Specifically, greater than or equal to 60% cardiopulmonary resuscitation time with regional cerebral oxygenation greater than 50% provided 77% sensitivity (95% CI,:46-95), 72% specificity (95% CI, 65-79), and 98% negative predictive value (95% CI, 93-100) for cerebral performance category 1-2. Cerebral oximetry allows real-time, noninvasive cerebral oxygenation monitoring during cardiopulmonary resuscitation. Higher cerebral oxygenation during cardiopulmonary resuscitation is associated with return of spontaneous circulation and neurologically favorable survival to hospital discharge. Achieving higher regional cerebral oxygenation during resuscitation may optimize the chances of cardiac arrest favorable outcomes.


A novel molecular pathway for Snail-dependent, SPARC-mediated invasion in non-small cell lung cancer pathogenesis.
Definition of the molecular pathogenesis of lung cancer allows investigators an enhanced understanding of the natural history of the disease, thus fostering development of new prevention strategies. In addition to regulating epithelial-to-mesenchymal transition (EMT), the transcription factor Snail exerts global effects on gene expression. Our recent studies reveal that Snail is upregulated in non-small cell lung cancer (NSCLC), is associated with poor prognosis, and promotes tumor progression in vivo. Herein, we demonstrate that overexpression of Snail leads to the upregulation of secreted protein, acidic and rich in cysteine (SPARC) in models of premalignancy and established disease, as well as in lung carcinoma tissues in situ. Snail overexpression leads to increased SPARC-dependent invasion in vitro, indicating that SPARC may play a role in lung cancer progression. Bioinformatic analysis implicates transforming growth factor beta (TGF-β), extracellular signal-regulated kinase (ERK)1/2, and miR-29b as potential intermediaries in Snail-mediated upregulation of SPARC. Both the TGF-β1 ligand and TGF-β receptor 2 (TGF-βR2) are upregulated following Snail overexpression. Treatment of human bronchial epithelial cell (HBEC) lines with TGF-β1 and inhibition of TGF-β1 mRNA expression modulates SPARC expression. Inhibition of MAP-ERK kinase (MEK) phosphorylation downregulates SPARC. MiR-29b is downregulated in Snail-overexpressing cell lines, whereas overexpression of miR-29b inhibits SPARC expression. In addition, miR-29b is upregulated following ERK inhibition, suggesting a Snail-dependent pathway by which Snail activation of TGF-β and ERK signaling results in downregulation of miR-29b and subsequent upregulation of SPARC. Our discovery of pathways responsible for Snail-induced SPARC expression contributes to the definition of NSCLC pathogenesis.


Interval Multiobjective Optimization With Memetic Algorithms.
One of the most important and widely faced optimization problems in real applications is the interval multiobjective optimization problems (IMOPs). The state-of-the-art evolutionary algorithms (EAs) for IMOPs (IMOEAs) need a great deal of objective function evaluations to find a final Pareto front with good convergence and even distribution. Further, the final Pareto front is of great uncertainty. In this paper, we incorporate several local searches into an existing IMOEA, and propose a memetic algorithm (MA) to tackle IMOPs. At the start, the existing IMOEA is utilized to explore the entire decision space; then, the increment of the hypervolume is employed to develop an activation strategy for every local search procedure; finally, the local search procedure is conducted by constituting its initial population, whose center is an individual with a small uncertainty and a big contribution to the hypervolume, taking the contribution of an individual to the hypervolume as its fitness function, and performing the conventional genetic operators. The proposed MA is empirically evaluated on ten benchmark IMOPs as well as an uncertain solar desalination optimization problem and compared with three state-of-the-art algorithms with no local search procedure. The experimental results demonstrate the applicability and effectiveness of the proposed MA.


An epidemiological case-control study of migraine and its associated comorbid conditions.
BACKGROUND: The economic impact of migraine to society has been well documented. However, few studies have identified the risk of migraine-specific comorbid conditions to explain the higher healthcare resource utilization by migraineurs. Because comorbidity has the potential to increase treatment costs, estimating its risks and its economc impact becomes imperative.OBJECTIVES: To estimate the risk for migraine by presence of a defined set of comorbidities, and to quantify the association of estimated healthcare costs between the case-control groups with and without comorbidity.METHODS: A matched case-control was designed using data from 1998 Idaho Medicaid claims. Cases were identified by physician-diagnoses and migraine-specific medication use. A 1:1 matching was performed on age, race, gender, and residence. Presence of comorbidity was determined by ICD-9 diagnostic categories. Total healthcare resource utilization was estimaed for all physician, hospital (inpatient and outpatient), and emergency services, including prescription medicines paid by Idaho Medicaid. Multivariate logistic regression was used to compute the odds ratio controlling for the matching variables. Multiple-regression models were used to quantify the association of total healthcare costs.RESULTS: Migraine patients were approximately five times more likely (Odds Ratio = 5.34; Confidence Interval(95%)-4.38 to 6.52) than their controls to be diagnosed with comorbid condition(s). A model with variables of age, gender, presence of comorbidity and migraine, explained approximately 21% of the variance in healthcare utilization (p < 0.05).CONCLUSIONS: Migraine patients are at a higher risk for defined comorbid conditions resulting in significantly higher healthcare costs as compared to non-migraine patients.


Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit.
Our previous studies of DARPP-32 in striatal slices have shown that activation of D1 receptors leads to cAMP-dependent dephosphorylation of Thr-75, the Cdk5 site in DARPP-32. In the current study, we have elucidated a mechanism whereby protein phosphatase 2A (PP2A) is activated by a cAMP/PKA-dependent pathway, leading to dephosphorylation of Thr-75. PP2A consists of a catalytic C subunit that associates with the scaffolding A subunit and a variety of B subunits. We have found that the A/C subunits of PP2A, in association with the B56delta (or PPP2R5D) regulatory subunit, is an active DARPP-32 phosphatase. The B56delta subunit expressed in HEK293 cells forms a heterotrimeric assembly that catalyzes PKA-mediated dephosphorylation at Thr-75 in DARPP-32 (also cotransfected into HEK293 cells). The B56delta subunit is phosphorylated by PKA, and this increases the overall activity of PP2A in vitro and in vivo. Among four PKA-phosphorylation sites identified in B56delta in vitro, Ser-566 was found to be critical for the regulation of PP2A activity. Moreover, Ser-566 was phosphorylated by PKA in response to activation of D1 receptors in striatal slices. Based on these studies, we propose that the B56delta/A/C PP2A complex regulates the dephosphorylation of DARPP-32 at Thr-75, thereby helping coordinate the efficacy of dopaminergic neurotransmission in striatal neurons. Moreover, stimulation of protein phosphatase activity by this mechanism may represent an important signaling pathway regulated by cAMP in neurons and other types of cell.


Angiotensin II type I receptor blocker and endothelial function in humans: role of nitric oxide and oxidative stress.
Recent large clinical trials have shown that angiotensin II type I receptor blockers (ARBs) reduce cardiovascular morbidity and mortality in patients with heart failure, acute myocardial infarction, and hypertension. However, the mechanism underlying antiatherogenic effects of ARBs remains unclear. The vascular endothelium is involved in the release of various vasodilators, including nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor as well as vasoconstrictors. NO plays an important role in the regulation of vascular tone, the inhibition of platelet aggregation, and the suppression of smooth muscle cell proliferation. Several investigators have reported impairment in endothelium-dependent vasodilation in the forearm, coronary, and renal vasculature in cardiovascular diseases, including hypertensive patients. Cardiovascular diseases are associated with alteration in endothelial function. Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis. Anti-renin-angiotensin system agents, angiotensin-converting enzyme (ACE) inhibitors improve endothelial function in patients with hypertension, diabetes mellitus, and coronary artery disease. It is well known that ACE inhibitors augment endothelium-dependent vasodilation through an increase in NO bioavailability, by an increase in NO production and a decrease in NO inactivation. ARBs are also thought to prevent cardiovascular complications through an augmentation of endothelial function. In this review, we focus on recent findings and putative mechanisms of the beneficial effects of ARBs on endothelial function.


Surgical management of cerebellopontine angle epidermoid cysts: an institutional experience of 10 years.
Cerebellopontine angle (CPA) epidermoids, although of benign nature, are of considerable neurosurgical interest because of their close proximity and adherence to the cranial nerves and brain stem. In this paper, we describe our experience and attempt to correlate the final outcomes with the extent of surgical removal. The main objectives were to study various modes of surgical management of CPA epidermoids with regard to removal and preservation of the cranial nerves and also to evaluate the role of endoscopic assisted microsurgical excision thereby minimizing recurrences. This case series is one of the largest series reported so far worldwide. From 2006 to 2016, 139 patients with CPA epidermoids were operated at Grant Medical College and J. J. Hospital, Mumbai. All patients underwent detailed magnetic resonance imaging (MRI) of brain. Lesions were classified according Rogelio Revuelta-Gutiérrez et al. with respect to their anatomic extent: grade I- within the boundaries of the CPA, grade II- extension to the suprasellar and perimesencephalic cisterns, and grade III-parasellar and temporomesial region involvement. Retrosigmoidal and sub temporal approaches were taken to excise the lesions. Endoscopic assisted microsurgical excision was done in cases with extensions beyond the CPA. Patient follow-up was based on outpatient repeated brain MRI studies. The mean duration of symptoms before surgery was 42 months (range, 2 months to 6 years). The mean follow-up period was 27 months (range, 2-60 months). The main presenting sympt om was headache in 69% (96/139) of the cases and trigeminal neuralgia in 30% cases was the second most common cause of consultation. Seventy-five percent of patients had some degree of cranial nerve (CN) involvement. Retrosigmoid approach was taken in 92% patients and 7 patients with supratentorial extension were operated by combined retrosigmoidal and subtemporal approach. Endoscopic assisted microsurgical excision was done in 40% cases. Use of angled views by an endoscope helped to excise residual tumor in 47 (83%) patients. Complete excision was achieved in 67% of cases. In 33% patients, small capsular remnants could not be removed completely because of their adherence to vessels, brainstem and cranial nerves. Compared with their preoperative clinical status, 74% improved and 20% had persistent cranial nerve deficits in the first year of follow up. Epidermoid cysts are challenging entities in current neurosurgery practice due to tumor adhesions to neurovascular structures. Meticulous surgical technique with the aid of neurophysiological monitoring is crucial to achieve safe and effective total or subtotal removal of these lesions. A conservative approach is indicated for patients in whom the fragments of capsule is adhered closely to blood vessels, nerves, or the brainstem, in order to avoid risk of serious neurological deficits related to an inadvertent damage of these structures. Use of angled views by endoscope at the conclusion of the surgery may assure the surgeon of total removal of the tumor.


Relationships among Constitution, Stress, and Discomfort in the First Trimester.
The purpose of this study was to explore correlations among constitution, stress, and discomfort symptoms during the first trimester of pregnancy. We adopted a descriptive and correlational research design and collected data from 261 pregnant women during their first trimester in southern Taiwan using structured questionnaires. Results showed that (1) stress was significantly and positively correlated with Yang-Xu, Yin-Xu, and Tan-Shi-Yu-Zhi constitutions, respectively; (2) Yin-Xu and Tan-Shi-Yu-Zhi constitutions had significant correlations with all symptoms of discomfort, while Yang-Xu had significant correlations with all symptoms of discomfort except for "running nose"; (3) Tan-Shi-Yu-Zhi constitution and stress were two indicators for "fatigue"; Tan-Shi-Yu-Zhi was the indicator for "nausea"; Yang-Xu and Yin-Xu were indicators for "frequent urination." Our findings also indicate that stress level affects constitutional changes and that stress and constitutional change affect the incidence of discomfort. This research can help healthcare professionals observe these discomforts and provide individualized care for pregnant women, to nurture pregnant women into neutral-type constitution, minimize their levels of discomfort, and promote the health of the fetus and the mother.


Balance deficits after sports-related concussion in individuals reporting posttraumatic headache.
Posttraumatic headache (PTH) may affect neurocognition after sports-related concussion. To our knowledge, no studies have examined how PTH affects balance after concussion using dynamic posturography. The purpose of this study is to compare balance after concussion between athletes reporting PTH and athletes not reporting PTH. We conducted a retrospective, repeated-measures design with participants grouped by presence of postinjury report of headache. Balance testing was conducted on 108 concussed collegiate athletes (age, 18.83 +/- 1.27 yr; height, 180.92 +/- 10.01 cm; mass, 83.29 +/- 19.62 kg). Presence of PTH during the first postinjury test session (group) and test time (baseline, postinjury) served as the independent variables. The composite equilibrium score and the somatosensory, vestibular, and visual ratio scores served as dependent variables. A 2 x 2 mixed model analysis of variance was used to analyze each outcome measure. Significant decreases in all four measures assessed were noted after concussion compared with preseason baseline measures (P < 0.05). Significant group by test-time interactions were observed, suggesting that composite equilibrium (F1106 = 6.6089; P = 0.012) and vestibular ratio (F1106 = 7.156; P = 0.009) scores are affected by the presence of PTH. Athletes reporting PTH also demonstrated worse visual ratio scores compared with individuals not experiencing PTH (F1106 = 4.26; P = 0.041). No other significant findings were observed for the somatosensory ratio score. Current literature proposes that PTH is associated with cognitive deficits. Our study indicates that PTH may also contribute to increased balance deficits. We believe the deficits may be a result of increased sensory organization challenges after injury. Clinicians should be mindful of these findings when managing concussed athletes reporting headache.


Impact of iron-complex (Fe(III)-NTA) on photoinduced degradation of 4-chlorophenol in aqueous solution.
In this research work, the photochemical impact of Fe(III)-nitrilotriacetic acid complex (FeNTA) on the fate of an organic pollutant (4-chlorophenol (4-CP)) was investigated in natural waters. The quantum yields of the photodecomposition of the FeNTA complex and of Fe(II) formation, by an intra-molecular photoredox process (the first stage of the reaction) are high. This photoredox reaction represents the first step of the process leading to 4-CP disappearance. Whereas oxygen does not affect FeNTA photodegradation, 4-CP depletion requires the presence of oxygen. The radical species HO and CO3*- responsible of the degradation were identified by ESR spectroscopy under irradiation. Two different wavelength-dependent mechanisms of 4-chlorophenol degradation are proposed. It clearly appears that under solar irradiation, iron organic complexes like FeNTA can play a significant role on the fate of the organic compounds present in natural waters.


Electromagnetic navigation during flexible bronchoscopy.
Flexible bronchoscopy is routinely utilized in the diagnosis and treatment of various lung diseases. Nondiagnostic bronchoscopy leads to more invasive interventions, such as transthoracic needle aspiration, mediastinoscopy or even thoracotomy. Electromagnetic navigation is a novel technology that facilitates approaching peripheral lung lesions, which are difficult to sample by conventional means. The navigation system involves creating an electromagnetic field around the chest and localizing an endoscopic tool using a microsensor overlaid upon previously acquired CT images. To determine the practicality, accuracy and safety of real-time electromagnetic navigation, coupled with previously acquired 3D CT images, in locating artificially created peripheral lung lesions in a swine model. Peripheral lung lesions were created in four swine models by insertion of a metal tube (1 x 10 mm) via a transthoracic approach. An electromagnetic field was created by placing the animal on an electromagnetic location board. A position sensor incorporated into the distal tip of a dedicated tool was used to navigate to the various target lesions. Information gathered in real time during bronchoscopy was presented on a monitor simultaneously by displaying previously acquired CT images. Upon reaching the target lesion, biopsies were performed and the functionality and safety of the superDimension/Bronchus System was observed and documented. The registration accuracy expressed by the fiducial target registration error, expressing both the registration quality and the stability of fiducial (registration) points, was 4.5 mm on average. No adverse effects, such as pneumothorax or internal bleeding, were encountered in any of the animals in this study. Real-time electromagnetic positioning technology coupled with previously acquired CT images is an accurate technology added to standard bronchoscopy to assist in reaching peripheral lung lesions and performing biopsies.


Photosynthesis down-regulation precedes carbohydrate accumulation under sink limitation in Citrus.
Photosynthesis down-regulation due to an imbalance between sources and sinks in Citrus leaves could be mediated by excessive accumulation of carbohydrates. However, there is limited understanding of the physiological role of soluble and insoluble carbohydrates in photosynthesis regulation and the elements triggering the down-regulation process. In this work, the role of non-structural carbohydrates in the regulation of photosynthesis under a broad spectrum of source-sink relationships has been investigated in the Salustiana sweet orange. Soluble sugar and starch accumulation in leaves, induced by girdling experiments, did not induce down-regulation of the photosynthetic rate in the presence of sinks (fruits). The leaf-to-fruit ratio did not modulate photosynthesis but allocation of photoassimilates to the fruits. The lack of strong sink activity led to a decrease in the photosynthetic rate and starch accumulation in leaves. However, photosynthesis down-regulation due to an excess of total soluble sugars or starch was discarded because photosynthesis and stomatal conductance reduction occurred prior to any significant accumulation of these carbohydrates. Gas exchange and fluorescence parameters suggested biochemical limitations to photosynthesis. In addition, the expression of carbon metabolism-related genes was altered within 24 h when strong sinks were removed. Sucrose synthesis and export genes were inhibited, whereas the expression of ADP-glucose pyrophosphorylase was increased to cope with the excess of assimilates. In conclusion, changes in starch and soluble sugar turnover, but not sugar content per se, could provide the signal for photosynthesis regulation. In these conditions, non-stomatal limitations strongly inhibited the photosynthetic rate prior to any significant increase in carbohydrate levels.


Cardioprotective HIF-1α-frataxin signaling against ischemia-reperfusion injury.
Previous studies have demonstrated the protective signaling of hypoxia-inducible factor (HIF)-1 α against ischemia-reperfusion (I/R) injury in the heart. In the present study, we provide further evidence for a cardioprotective mechanism by HIF-1α against I/R injury exerted via the mitochondrial protein frataxin, which regulates mitochondrial Fe-S cluster formation. Disruption of frataxin has been found to induce mitochondrial iron overload and subsequent ROS production. We observed that frataxin expression was elevated in mice hearts subjected to I/R injury, and this response was blunted in cardiomyocyte-specific HIF-1α knockout (KO) mice. Furthermore, these HIF-1α KO mice sustained extensive cardiac damage from I/R injury compared with control mice. Similarly, reduction of HIF-1α by RNA inhibition resulted in an attenuation of frataxin expression in response to hypoxia in H9C2 cardiomyocytes. Therefore, we postulated that HIF-1α transcriptionally regulates frataxin expression in response to hypoxia and offers a cardioprotective mechanism against ischemic injury. Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. Our data also suggest that increased frataxin mitigated mitochondrial iron overload and subsequent ROS production, thus preserving mitochondrial membrane integrity and viability of cardiomyocytes. We postulate that frataxin may exert its beneficial effects by acting as an iron storage protein under hypoxia and subsequently facilitates the maintenance of mitochondrial membrane potential and promotes cell survival. The findings from our study revealed that HIF-1α-frataxin signaling promotes a protective mechanism against hypoxic/ischemic stress.


Immunopathogenesis of autoimmune tubulointerstitial nephritis. I. Demonstration of differential susceptibility in strain II and strain XIII guinea pigs.
Autoimmune tubulointerstitial nephritis (TN) was induced in strain XIII and Hartley but not strain II guinea pigs after immunization with rabbit tubular basement membranes (TBM) in CFA. Strain XIII guinea pigs developed extensive autoimmune TN associated with high anti-TBM (aTBM) antibody titers and linear deposits of IgG along renal cortical TBM after immunization with 10 mug to 10 mg of TBM. In addition, autoimmune TN was passively transferred to strain XIII animals by the i.p. injection of aTBM sera obtained from actively immunized Hartley guinea pigs. In contrast, strain II guinea pigs did not develop autoimmune TN after active immunization (10 mug to 10 mg) with rabbit TBM in CFA, and only produced high aTBM antibody titers with the highest immunnizing antigen dose. At this dose (10 mg) the strain II animals demonstrated linear deposits of IgG along renal cortical TBM but did not develop autoimmune TN. Further, recipient strain II guines pigs did not develop autoimmune TN after passive transfer of aTBM antisera despite renal cortical tubular deposition of aTBM antibodies. Both inbred guinea pig strains produced antibodies reactive with rabbit and rat renal basement membranes. No evidence for differences in nephritogenic TBM antigens could be demonstrated betweed strain XIII and strain II TBM. These observations indicate that 1) genetic factor(s) influence the production of antibodies reactive to autologous TBM, 2) after the deposition of antibodies on the TBM, additional or related genetic factor(s) determine the full expression of this autoimmune renal disease, and 3) aTBM antibody deposition on renal TBM is not sufficient to elicit autoimmune TN.


Comparison of Antioxidant Evaluation Assays for Investigating Antioxidative Activity of Gallic Acid and Its Alkyl Esters in Different Food Matrices.
The addition of antioxidants is one of the strategies to inhibit lipid oxidation, a major cause of lipid deterioration in foods leading to rancidity development and nutritional losses. However, several studies have been reported that conventional antioxidant assays, e.g., TPC, ABTS, FRAP, and ORAC could not predict antioxidant performance in several foods. This study aimed to investigate the performance of two recently developed assays, e.g., the conjugated autoxidizable triene (CAT) and the apolar radical-initiated conjugated autoxidizable triene (ApoCAT) assays to predict the antioxidant effectiveness of gallic acid and its esters in selected food models in comparison with the conventional antioxidant assays. The results indicated that the polarities of the antioxidants have a strong impact on antioxidant activities. In addition, different oxidant locations demonstrated by the CAT and ApoCAT assays influenced the overall antioxidant performances of the antioxidants with different polarities. To validate the predictability of the assays, the antioxidative performance of gallic acid and its alkyl esters was investigated in oil-in-water (O/W) emulsions, bulk soybean oils, and roasted peanuts as the lipid food models. The results showed that only the ApoCAT assay could be able to predict the antioxidative performances in O/W emulsions regardless of the antioxidant polarities. This study demonstrated that the relevance of antioxidant assays to food models was strongly dependent on physical similarities between the tested assays and the food structure matrices.


Kupffer cell inactivation delays repair in a rat model of reversible biliary obstruction.
During cholestatic liver injury, Kupffer cells (KC) and activated macrophages modulate cell proliferation and subsequent matrix deposition. The role of KC in the restoration of cell architecture and matrix metabolism during repair following chronic cholestatic liver injury is unknown. To determine the effect of KC inactivation, adult male Sprague-Dawley rats underwent bile duct suspension (BDS) for 5 days followed by reversal of the obstruction. Saline (control) and gadolinium chloride (10 mg/kg) were administered 1 day prior to BDS and 1 day prior to reversal, to inactivate KC during both injury and repair. Serum bilirubin and quantitative cell morphometry were compared to verify the reversibility of the model. Collagen content of the liver was measured in trichrome-stained paraffin sections using NIH imaging software. Reversibility of the obstruction was verified by normalization of direct serum bilirubin, which peaked at 8.42 +/- 0.76 mg/dL following 5 days of BDS and returned to sham-operated levels 2 days after reversal, 0.36 +/- 0.15 mg/dL. Hematoxylin and eosin (H&E)-stained paraffin-embedded liver sections from gadolinium-treated animals at 4 and 7 days after reversal exhibited persistent bile duct proliferation, matrix deposition, and inflammation. Gadolinium-treated animals had altered collagen metabolism compared to saline controls. Whereas the collagen content in the saline group slowly returned to sham-operated levels over time, the treatment group demonstrated progressive accumulation of collagen during repair which was statistically significant at 7 days following reversal (8.79%/mm(2) +/- 2.17 in gadolinium group vs 2. 33%/mm(2) +/- 0.34 in saline group, P = 0.0003). These results demonstrate that inactivation of resident hepatic macrophages during liver repair impairs collagen metabolism, inhibits the resolution of fibrosis, and allows the persistence of inflammatory cell infiltrates in the portal areas. This is the first evidence of profibrogenic responses in the absence of an intact KC compartment during repair after cholestatic injury.


Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers.
Alzheimer's disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure may be the invalidity of hypotheses focusing on amyloid to explain AD pathogenesis. Recently, hypotheses which are centered on synaptic and metabolic dysfunction are increasingly implicated in AD. Evaluate AD hypotheses by comparing neurotransmitter and metabolite marker concentrations in normal versus AD CSF. Meta-analysis allows for statistical comparison of pooled, existing cerebrospinal fluid (CSF) marker data extracted from multiple publications, to obtain a more reliable estimate of concentrations. This method also provides a unique opportunity to rapidly validate AD hypotheses using the resulting CSF concentration data. Hubmed, Pubmed and Google Scholar were comprehensively searched for published English articles, without date restrictions, for the keywords "AD", "CSF", and "human" plus markers selected for synaptic and metabolic pathways. Synaptic markers were acetylcholine, gamma-aminobutyric acid (GABA), glutamine, and glycine. Metabolic markers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured markers in AD and controls (Ctl), provided means, standard errors/deviation, and subject numbers were included. Data were extracted by six authors and reviewed by two others for accuracy. Data were pooled using ratio of means (RoM of AD/Ctl) and random effects meta-analysis using Cochrane Collaboration's Review Manager software. Of the 435 identified publications, after exclusion and removal of duplicates, 35 articles were included comprising a total of 605 AD patients and 585 controls. The following markers of synaptic and metabolic pathways were significantly changed in AD/controls: acetylcholine (RoM 0.36, 95% CI 0.24-0.53, p<0.00001), GABA (0.74, 0.58-0.94, p<0.01), pyruvate (0.48, 0.24-0.94, p=0.03), glutathione (1.11, 1.01- 1.21, p=0.03), alanine (1.10, 0.98-1.23, p=0.09), and lower levels of significance for lactate (1.2, 1.00-1.47, p=0.05). Of note, CSF glucose and glutamate levels in AD were not significantly different than that of the controls. This study provides proof of concept for the use of meta-analysis validation of AD hypotheses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity and GABAergic resistance to neurodegeneration, given observed unchanged glutamate levels and decreased GABA levels. With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and anaplerosis of the tricarboxylic acid cycle using glutamate. Future applications of meta-analysis indicate the possibility of further in silico evaluation and generation of novel hypotheses in the AD field.


The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation.
Autophagy is a fundamental adaptive response to amino acid starvation orchestrated by conserved gene products, the autophagy (ATG) proteins. However, the cellular cues that activate the function of ATG proteins during amino acid starvation are incompletely understood. Here we show that two related stress-responsive kinases, members of the p38 mitogen-activated protein kinase (MAPK) signaling pathway MAPKAPK2 (MK2) and MAPKAPK3 (MK3), positively regulate starvation-induced autophagy by phosphorylating an essential ATG protein, Beclin 1, at serine 90, and that this phosphorylation site is essential for the tumor suppressor function of Beclin 1. Moreover, MK2/MK3-dependent Beclin 1 phosphorylation (and starvation-induced autophagy) is blocked in vitro and in vivo by BCL2, a negative regulator of Beclin 1. Together, these findings reveal MK2/MK3 as crucial stress-responsive kinases that promote autophagy through Beclin 1 S90 phosphorylation, and identify the blockade of MK2/3-dependent Beclin 1 S90 phosphorylation as a mechanism by which BCL2 inhibits the autophagy function of Beclin 1.


[Epidemiology and health services]
The growing application of epidemiological investigation to the health and medical field has consolidated its various uses in health care services. Brazilian legislation now provides back-up for four different types of applications, although their implementation is still precarious: analysis of the health situation, epidemiological surveillance, etiological studies, and evaluation of health care services, programs, and technologies. Proper deployment of such epidemiological applications on both the political/institutional and operational levels will provide relevant subsidies for health services in conducting their activities.


Can an electronic device with a single cuff be accurate in a wide range of arm size? Validation of the Visomat Comfort 20/40 device for home blood pressure monitoring.
An appropriate cuff according to the individual's arm circumference is recommended with all blood pressure (BP) monitors. An electronic device for home monitoring has been developed (Visomat Comfort 20/40) that estimates the individual's arm circumference by measuring the cuff filing volume and makes an adjustment of measured BP taking into account the estimated arm circumference. Thus the manufacturer recommends the use of a single cuff for arm circumference 23-43 cm. The device accuracy was assessed using the European Society of Hypertension International Protocol. Simultaneous BP measurements were obtained in 33 adults by two observers (connected mercury sphygmomanometers) four times, sequentially with three measurements taken using the tested device. Absolute device-observer BP differences were classified into < or =5, < or =10 and < or =15 mm Hg zones. For each participant the number of measurements with a difference < or =5 mm Hg was calculated. The device produced 60/89/97 measurements within 5/10/15 mm Hg respectively for systolic BP, and 72/97/98 for diastolic. Twenty-three subjects had at least two of their systolic BP differences < or =5 mm Hg and three had no differences < or =5 mm Hg (for diastolic 27 and 1, respectively). Mean device-observer BP difference (systolic/diastolic) was 3.7 +/- 5.6/-1.5 +/- 4.7 mm Hg (4.7 +/- 4.9/ - 1.7 +/- 4.3 in arm circumference 23-29 cm [39 readings] and 3.1 +/- 5.9/-1.4 +/- 5.0 in arm 30-34 cm [60 readings], P=NS). In conclusion, the device fulfils the International Protocol requirements and can be recommended for clinical use. Interestingly, the device was accurate using a single cuff in a wide range of arm circumference (23-34 cm). This study provides no information about the device accuracy in larger arms.


Are psychosocial factors associated with low back pain and work absence for low back pain in an occupational cohort?
To examine the relationship between individual and work-related psychosocial factors and low back pain (LBP) and associated time off work in an occupational cohort. A self-administered questionnaire was completed by nurses working across 3 major public hospitals. Participants provided sociodemographic data and information on the occurrence of LBP, time off work, and psychosocial factors. One thousand one hundred eleven participants (response rate 38.6%) were included in the study. Fifty-six percent of participants reported LBP in the previous year. When individual psychosocial factors were examined in the same model, the relationship between somatization and LBP persisted (OR 1.64; 95% confidence interval [CI], 1.35, 2.01). Low job security was also significantly associated with LBP independent of the other work-related factors (OR 0.82; 95% CI, 0.69, 0.98). Of those participants with LBP, 30% reported absence from work due to LBP. When absence from work was examined, negative beliefs (OR 0.97; 95% CI, 0.94, 1.00) and pain catastrophizing (OR 1.33; 95% CI, 1.04, 1.71) were independently associated with time off work, along with low job satisfaction (OR 0.71; 95% CI, 0.51, 0.97) and high job support (OR 1.35; 95% CI, 1.04, 1.75). Somatization and low job security were found to be independently associated with occupational LBP, whereas negative beliefs, pain catastrophizing, reduced job satisfaction, and high job support were independently related to time off work. Longitudinal studies are needed to determine whether these individual and work-related psychosocial factors predict, or alternatively, are outcomes of pain and time off work associated with LBP.


Smokers with multiple behavioral risk factors: how are they different?
The first aim of the present investigation was to examine cross-sectional differences between smokers who engage in additional health risk behaviors (i.e., high-fat diets and low physical activity levels) and those who do not that could affect readiness for smoking cessation treatment and treatment prognosis. The second aim was to examine prospective associations between risk factor status and smoking outcomes (i.e., cessation and quit attempts). Data were derived from baseline and 1-year follow-up surveys for the SUCCESS project, a randomized trial of worksite smoking interventions conducted in 24 worksites in Minneapolis/St. Paul, Minnesota. Included in the analyses were 2,149 study participants who reported smoking at baseline. Current smokers were categorized into one of three "risk groups": the "1 additional risk factor" group (i.e., either low physical activity level or high dietary fat intake), the "2 additional risk factor" group (i.e., both low physical activity and high dietary fat intake), and the "smoker only" group (i.e., neither low physical activity nor high dietary fat intake). Mixed model regression analyses examined cross-sectional associations between risk group status and baseline demographic variables, smoking dependency, social environments for smoking, and health problems. Prospective associations between baseline risk group status and 1-year follow-up cessation attempts and quits were also examined. At baseline, risk factor status was associated with smoking dependency for both men and women. Women smokers with at least one additional risk factor reported a greater number of cigarettes smoked per day, higher Fagerstrom Nicotine Dependence scores, and lower self-efficacy for refraining from smoking in a variety of situations compared with smokers with no additional risk factors. Men smokers with at least one additional risk factor reported higher Fagerstrom Nicotine Dependence scores compared with smokers with no additional risk factors. Women smokers with at least one additional risk factor were more likely to report being encouraged to quit by co-workers compared with smokers with no other risk factors. No relationship between risk factor status and social pressure to quit was observed among men. Prospective analyses indicated that baseline risk factor status was marginally related to smoking outcome at 1-year follow-up; however, these relationships were attenuated considerably when controlling for smoking dependence. Relationships between risk factor status and smoking outcomes were stronger for men. Results indicated that the presence of multiple health risk behaviors was related to more serious problems with smoking. However, the presence of additional risk factors did not strongly affect prognosis for smoking cessation.


MR360: Mixed Reality Rendering for 360° Panoramic Videos.
This paper presents a novel immersive system called MR360 that provides interactive mixed reality (MR) experiences using a conventional low dynamic range (LDR) 360° panoramic video (360-video) shown in head mounted displays (HMDs). MR360 seamlessly composites 3D virtual objects into a live 360-video using the input panoramic video as the lighting source to illuminate the virtual objects. Image based lighting (IBL) is perceptually optimized to provide fast and believable results using the LDR 360-video as the lighting source. Regions of most salient lights in the input panoramic video are detected to optimize the number of lights used to cast perceptible shadows. Then, the areas of the detected lights adjust the penumbra of the shadow to provide realistic soft shadows. Finally, our real-time differential rendering synthesizes illumination of the virtual 3D objects into the 360-video. MR360 provides the illusion of interacting with objects in a video, which are actually 3D virtual objects seamlessly composited into the background of the 360-video. MR360 was implemented in a commercial game engine and tested using various 360-videos. Since our MR360 pipeline does not require any pre-computation, it can synthesize an interactive MR scene using a live 360-video stream while providing realistic high performance rendering suitable for HMDs.


Coordination chemistry with f-element complexes for an improved understanding of factors that contribute to extraction selectivity.
Here, we highlight some recent accomplishments in f-element coordination chemistry aimed at probing the fundamental chemical differences between the 4f elements, lanthanides, and the 5f elements, actinides. The studies of particular interest are those that target improving our knowledge of fundamental chemistry to aid in increased selectivity for extractions of actinides. Two components key to understanding the challenges of actinide separations are detailed here, namely, previously described separation methods and recent investigations into the fundamental coordination chemistry of actinides. Both are aimed at probing the critical features necessary for improved selectivity of separations. This is considered a critical goal in the safe remediation of contaminated sites and reprocessing of nuclear fuel sources used in either civilian and noncivilian energy production.


Evaluation of different dielectric barrier discharge plasma configurations as an alternative technology for green C1 chemistry in the carbon dioxide reforming of methane and the direct decomposition of methanol.
Carbon dioxide reforming of methane and direct decomposition of methanol have been investigated using dielectric barrier discharges (DBD) at atmospheric pressure and reduced working temperatures. Two different plasma reactor configurations are compared and special attention is paid to the influence of the surface roughness of the electrodes on the conversion yields in the first plasma device. The influence of different filling gap dielectric materials (i.e., Al(2)O(3) or BaTiO(3)) in the second packed configuration has been also evaluated. Depending on the experimental conditions of applied voltage, residence time of reactants, feed ratios, or reactor configuration, different conversion yields are achieved ranging from 20 to 80% in the case of methane and 7-45% for the carbon dioxide. The direct decomposition of methanol reaches 60-100% under similar experimental conditions. Interestingly, the selectivity toward the production of hydrogen and carbon monoxide is kept almost constant under all the experimental conditions, and the formation of longer hydrocarbon chains or coke as a byproduct is not detected. The maximum efficiency yields are observed for the packed-bed reactor configuration containing alumina for both reaction processes (approximately 1 mol H(2) per kilowatt hour for dry reforming of methane and approximately 4.5 mol H(2) per kilowatt hour for direct decomposition of methanol).


Adolescent Risk of Dating Violence and Electronic Dating Abuse: A Latent Class Analysis.
Electronic forms of dating violence among youth are common yet little is known about how these forms of violence overlap with the commonly studied domains of physical, sexual and verbal teen dating violence. Using factor analysis and latent class analysis, this study identifies patterns of electronic, verbal, physical and sexual dating violence victimization and perpetration in 9th and 12th graders. Data are from 470 9th (n = 190; 60.5% female; mean age = 12.0 years, age range: 11.3-13.8) and 12th graders (n = 280; 63.9% female; mean age = 14.9 years, age range: 14.0-16.6) from southeastern Michigan. A 5-class solution for 9th graders and a 6-class solution for 12th graders were selected given fit and interpretability. Classes were characterized by domain(s) of violence, as opposed to perpetration or victimization. Three domains of electronic dating aggression were identified: monitoring, harassment, and coercion. Electronic dating aggression was present in the majority of classes, and overlapped substantially with other domains of violence. The highest risk class had risk of victimization and perpetration for all types of dating violence (electronic monitoring, electronic harassment, electronic coercion, verbal violence, physical violence and sexual violence). Drug use and experiencing one or more adverse childhood experiences predicted membership in a higher risk group for the older cohort, while alcohol consumption predicted higher risk for the younger cohort. The findings from this study show overlap between dating violence domains and imply that domains of electronic dating violence are important to consider in conjunction with physical, sexual and verbal domains, to address teen dating violence.


Health status, diseases and vaccinations of the homeless in the city of Palermo, Italy.
In Italy, as in the rest of the world, the number of homeless people is increasing considerably. Many of them suffer from chronic conditions, mental health problems and addiction to alcohol, drugs or smoking, and need complex medical care. Their health status is often exacerbated by greater difficulty in accessing primary care. The aim of the present study was to assess health conditions of homeless people living in Palermo, Southern Italy, and to find ways to limit the spread of common infectious diseases that can be prevented by vaccination. A self-administered questionnaire was distributed. The questionnaire was structured into two parts including an introduction with socio-demographic information, and a second part investigating health status, chronic diseases and vaccinations. A multivariable logistic regression model was used and adjusted Odds Ratios (aOR) are presented. The sample consisted of 52 homeless, 35 (67.3%) of whom were male and the most represented age class (55.8%) was < 50 years of age. The average age of the sample was 49.6 years (SD ± 15.2) and 88.5% were born in Italy. A multivariable logistic regression model based on 52 observations was used. The analysis showed that the female gender was significantly associated with: not performing regular physical activity (aOR 4.14, 95% C.I. 1.20 - 14.32, p = 0.025), suffering from chronic diseases (aOR 3.52, 95% C.I. 1.02 - 12.11, p = 0.046) and taking medicines (aOR 3.95, 95% C.I. 1.14 - 13.64, p = 0.030). This particularly fragile population is exposed to diseases that are largely preventable or curable through a wider and more early access to care by local health facilities with a subsequent reduction in the worsening of clinical outcomes and related social costs.


Comparison of Clinical Outcomes of Persons Living With HIV by Enrollment Status in Washington, DC: Evaluation of a Large Longitudinal HIV Cohort Study.
HIV cohort studies have been used to assess health outcomes and inform the care and treatment of people living with HIV disease. However, there may be similarities and differences between cohort participants and the general population from which they are drawn. The objective of this analysis was to compare people living with HIV who have and have not been enrolled in the DC Cohort study and assess whether participants are a representative citywide sample of people living with HIV in the District of Columbia (DC). Data from the DC Health (DCDOH) HIV surveillance system and the DC Cohort study were matched to identify people living with HIV who were DC residents and had consented for the study by the end of 2016. Analysis was performed to identify differences between DC Cohort and noncohort participants by demographics and comorbid conditions. HIV disease stage, receipt of care, and viral suppression were evaluated. Adjusted logistic regression assessed correlates of health outcomes between the two groups. There were 12,964 known people living with HIV in DC at the end of 2016, of which 40.1% were DC Cohort participants. Compared with nonparticipants, participants were less likely to be male (68.0% vs 74.9%, P<.001) but more likely to be black (82.3% vs 69.5%, P<.001) and have a heterosexual contact HIV transmission risk (30.3% vs 25.9%, P<.001). DC Cohort participants were also more likely to have ever been diagnosed with stage 3 HIV disease (59.6% vs 47.0%, P<.001), have a CD4 <200 cells/µL in 2017 (6.2% vs 4.6%, P<.001), be retained in any HIV care in 2017 (72.9% vs 59.4%, P<.001), and be virally suppressed in 2017. After adjusting for demographics, DC Cohort participants were significantly more likely to have received care in 2017 (adjusted odds ratio 1.8, 95% CI 1.70-2.00) and to have ever been virally suppressed (adjusted odds ratio 1.3, 95% CI 1.20-1.40). These data have important implications when assessing the representativeness of patients enrolled in clinic-based cohorts compared with the DC-area general HIV population. As participants continue to enroll in the DC Cohort study, ongoing assessment of representativeness will be required.


Signal-specific activation and regulation of human neutrophil Fc gamma receptors.
FcgammaRs with the ITIM domain have been shown to regulate the inflammatory signal delivered by the ITAM-containing FcgammaRs. In this study, we demonstrate that the function of human neutrophil FcgammaR type IIA (CD32A) is regulated in a distinct manner by different cell activation signals at the ligand-binding stage. Activation of neutrophils with fMLP up-regulated the ligand-binding function of CD32A, whereas PMA-mediated activation completely abolished ligand binding without altering CD32A expression. Furthermore, PMA treatment also abolished CD16B-dependent ligand binding irrespective of the level of expression. The effect of PMA was cell type specific, because the ligand-binding function of CD32A expressed on cultured cells such as K562 and CHO-CD32A transfectants was not affected by PMA. Interestingly, phorbol 12,13-dibutyrate, another phorbol ester, and IL-8 up-regulated CD32A-dependent ligand-binding function. These results demonstrate that regulation of CD32A-dependent ligand binding in human neutrophils is not only cell type specific but also activation signal specific. Moreover, these results suggest the possibility that signals delivered to neutrophils by various inflammatory stimuli can exert opposing effects on the function of human FcgammaRs, representing a novel inside-out regulatory mechanism of FcgammaR ligand binding.


Cost-effectiveness of out-of-hospital continuous positive airway pressure for acute respiratory failure: decision analytic modelling using data from a feasibility trial.
Standard prehospital management for Acute respiratory failure (ARF) involves controlled oxygen therapy. Continuous positive airway pressure (CPAP) is a potentially beneficial alternative treatment, however, it is uncertain whether this could improve outcomes and provide value for money. This study aimed to evaluate the cost-effectiveness of prehospital CPAP in ARF. A cost-utility economic evaluation was performed using a probabilistic decision tree model synthesising available evidence. The model consisted of a hypothetical cohort of patients in a representative ambulance service with undifferentiated ARF, receiving standard oxygen therapy or prehospital CPAP. Costs and quality adjusted life years (QALYs) were estimated using methods recommended by NICE. In the base case analysis, using CPAP effectiveness estimates form the ACUTE trial, the mean expected costs of standard care and prehospital CPAP were £15,201 and £14,850 respectively and the corresponding mean expected QALYs were 1.190 and 1.128, respectively. The mean ICER estimated as standard oxygen therapy compared to prehospital CPAP was £5685 per QALY which indicated that standard oxygen therapy strategy was likely to be cost-effective at a threshold of £20,000 per QALY (67% probability). The scenario analysis, using effectiveness estimates from an updated meta-analysis, suggested that prehospital CPAP was more effective (mean incremental QALYs of 0.157), but also more expensive (mean incremental costs of £1522), than standard care. The mean ICER, estimated as prehospital CPAP compared to standard care, was £9712 per QALY. At the £20,000 per QALY prehospital CPAP was highly likely to be the most cost-effective strategy (94%). Cost-effectiveness of prehospital CPAP depends upon the estimate of effectiveness. When based on a small pragmatic feasibility trial, standard oxygen therapy is cost-effective. When based on meta-analysis of heterogeneous trials, CPAP is cost-effective. Value of information analyses support commissioning of a large pragmatic effectiveness trial, providing feasibility and plausibility conditions are met.


[Mechanism of reaction catalyzed by RNA-ligase from bacteriophage T4].
The dissociation constants of the complexes of RNA-ligase with acceptors, donors and the adenylylated donor A(5')ppAp have been determined on the basis of the inhibition of ATP-pyrophosphate exchange reaction. The dissociation constants of the complexes of the enzyme with "poor" acceptors (oligouridilates) have been shown to be slightly different from those with "good" acceptors (oligoadenylates). The dependence of the reaction velocity of the formation of ligation products on the concentration of acceptors (pA)4, (pU)4 and the adenylylated donor A(5)ppAp has been studied. On the basis of the data obtained the conclusion about the random addition mechanism has been drawn. The reaction takes place in the steady-state conditions in the case of (pA)4 and in the equilibrium conditions--in the case of (pU)4.


Patterns of sedentary behavior and weight status among children.
To make robust conclusions regarding the association between accelerometer-measured sedentary time and overweight and obesity among children, several gaps in the literature must be addressed. The purpose of this study was to examine associations between sedentary time, weekday sedentary time, weekend sedentary time, sedentary bouts, sedentary breaks, and BMI z-score among children and by low (bottom 50%) and high (top 50%) moderate- to vigorous-intensity physical activity (MVPA) participation. Results are based on 787 children aged 11 years living in Toronto, Canada. Children's physical activity and sedentary time were objectively assessed using ActiGraph accelerometers in 2010/11. Height and weight were measured and BMI z-scores were calculated based on the World Health Organization growth standards. When participants were stratified into low and high MVPA groups, sedentary bouts of 5-9 (β = 0.22 [95% CI: 0.01, 0.43]) and 10-19 (0.30 [-0.05, 0.55]) minutes for total days were associated with BMI z-score in the low MVPA group only. Similar trends were observed with the weekday but not the weekend variables. Therefore, in addition to increasing MVPA, reducing time spent in 5- to 19-min sedentary bouts may have important implications for weight status particularly for children with lower MVPA participation during the week.


Design and rationale of an intelligent algorithm to detect BuRnoUt in HeaLthcare workers in COVID era using ECG and artificiaL intelligence: The BRUCEE-LI study.
There is no large contemporary data from India to see the prevalence of burnout in HCWs in covid era. Burnout and mental stress is associated with electrocardiographic changes detectable by artificial intelligence (AI). The present study aims to estimate the prevalence of burnout in HCWs in COVID-19 era using Mini Z-scale and to develop predictive AI model to detect burnout in HCWs in COVID-19 era. This is an observational and cross-sectional study to evaluate the presence of burnout in HCWs in academic tertiary care centres of North India in the COVID-19 era. At least 900 participants will be enrolled in this study from four leading premier government-funded/public-private centres of North India. Each study centre will be asked to recruit HCWs by approaching them through various listed ways for participation in the study. Interested participants after initial screening and meeting the eligibility criteria, will be asked to fill the questionnaire (having demographic and work related with Mini Z questionnaire) to assess burnout. The healthcare workers will include physicians at all levels of training, nursing staff and paramedical staff who are involved directly or indirectly in COVID-19 care. The analysis of the raw electrocardiogram (ECG) data and development of algorithm using convolutional neural networks (CNN) will be done by experts. In Summary, we propose that ECG data generated from the people with burnout can be utilized to develop AI-enabled model to predict the presence of stress and burnout in HCWs in COVID-19 era.


MLL fusion protein-driven AML is selectively inhibited by targeted disruption of the MLL-PAFc interaction.
MLL rearrangements are common in leukemia and considered an adverse risk factor. Through interactions with the polymerase-associated factor complex (PAFc), mixed lineage leukemia (MLL) fusion proteins activate genes critical for blocking differentiation, such as HOXA9. Here we investigate whether the MLL-PAFc interaction can be exploited therapeutically using both genetic and biochemical approaches. We tested the genetic requirement of the PAFc in acute myeloid leukemia (AML) using a conditional allele of the PAFc subunit, Cdc73. We show that the PAFc is indiscriminately necessary for the proliferation of AML cells through the epigenetic regulation of proleukemogenic target genes, such as MEIS1 and Bcl2. To investigate the therapeutic potential of targeting the MLL-PAFc interaction, we engineered a dominant negative fragment of MLL capable of binding to the PAFc. Disruption of the MLL-PAFc interaction selectively inhibits the proliferation of MLL leukemic cells without affecting cells transformed by an unrelated E2A-HLF fusion protein. Using in vivo hematopoietic reconstitution assays, we demonstrate that disruption of the MLL-PAFc does not alter normal hematopoietic stem cell function. Together, our data show a selective growth inhibition of MLL-associated leukemic cells and tolerance of normal hematopoiesis to disruption of the MLL-PAFc interaction establishing the MLL-PAFc interaction as an attractive therapeutic target.


The role of the locus coeruleus in mediating the attentional blink: a neurocomputational theory.
The attentional blink refers to the transient impairment in perceiving the 2nd of 2 targets presented in close temporal proximity. In this article, the authors propose a neurobiological mechanism for this effect. The authors extend a recently developed computational model of the potentiating influence of the locus coeruleus-norepinephrine system on information processing and hypothesize that a refractoriness in the function of this system may account for the attentional blink. The model accurately simulates the time course of the attentional blink, including Lag 1 sparing. The theory also offers an account of the close relationship of the attentional blink to the electrophysiological P3 component. The authors report results from two behavioral experiments that support a critical prediction of their theory regarding the time course of Lag 1 sparing. Finally, the relationship between the authors' neurocomputational theory and existing cognitive theories of the attentional blink is discussed.


A Portrait of the Human Organelle Proteome In Space and Time during Cytomegalovirus Infection.
The organelles within a eukaryotic host are manipulated by viruses to support successful virus replication and spread of infection, yet the global impact of viral infection on host organelles is poorly understood. Integrating microscopy, subcellular fractionation, mass spectrometry, and functional analyses, we conducted a cell-wide study of organelles in primary fibroblasts throughout the time course of human cytomegalovirus (HCMV) infection. We used label-free and isobaric-labeling proteomics to characterize nearly 4,000 host and 100 viral proteins, then classified their specific subcellular locations over time using machine learning. We observed a global reorganization of proteins across the secretory pathway, plasma membrane, and mitochondria, including reorganization and processing of lysosomal proteins into distinct subpopulations and translocations of individual proteins between organelles at specific time points. We also demonstrate that MYO18A, an unconventional myosin that translocates from the plasma membrane to the viral assembly complex, is necessary for efficient HCMV replication. This study provides a comprehensive resource for understanding host and virus biology during HCMV pathogenesis.


Autologous peripheral blood stem cell transplantation using simplified procedures for collection and freezing.
High-dose therapy with peripheral blood stem cell (PBSC) transplantation has been used increasingly for chemosensitive malignancies. The conventional procedures for collection and freezing of PBSCs are time-consuming and expensive. The optimal conditions for priming, collection and freezing of PBSCs have yet to be simplified. Simplified procedures for mobilization, collection and freezing were developed to provide PBSC transplantation. Twenty-two cancer patients were given intensive chemotherapy with a variety of regimens using granulocyte-colony stimulating factor (G-CSF, filgrastim) 300 micrograms/d subcutaneously to mobilize PBSCs. A rapidly rebounding white blood cell (WBC) count from nadir was used to predict the time of peak PBSC release and plan leukapheresis. Leukapheresis was performed, when the WBC count was greater than 1.0 x 10(9)/l. Leukapheresis was performed in all 22 patients on day 10 to 14 after completing intensive chemotherapy. G-CSF to mobilize PBSCs was administered for a median of 10 days (range, 7-12 days). Twenty-one of 22 patients achieved the target yield of greater than 2 x 10(6) CD34+ cells/kg of body weight (BW). This was achieved in a median of two harvests (range, 2-4), with a median processed blood volume of 10.2 l/apheresis. A median of 6.4 x 10(8) mononuclear cells/kg BW and 5.2 x 10(6) CD34+ cells/kg BW for each patient were obtained. After high-dose cancer chemotherapy and PBSC transplantation, rapid and sustained hematopoietic engraftment occurred in all but one patient who had an inadequate number of CD34+ cells. In patients with an adequate target yield of CD34+ cells, the median times to achieve an absolute neutrophil count of greater than 0.5 x 10(9)/l and a platelet count of greater than 20 x 10(9)/l were nine days (range, 7-12 days) and 12 days (range, 8-14 days), respectively. Adequate PBSCs can be achieved within a median of two aphereses in most eligible cancer patients. Apheresis should be performed on day 10 to 14 after completing intensive chemotherapy, followed by G-CSF 300 micrograms/d. This simple and effective approach makes PBSC transplantation more practicable for a wider range of malignant diseases.


Questionnaire instructions--does anybody read them?
In the absence of data useful to the design of instructions for self-administered questionnaires, a study was performed in a family practice clinic on people having their first complete physical there. Although 1,303 persons filled out a health questionnaire prior to their examination, only 36.5% gave evidence of having carefully read the brief instructions. Women did better than men and some occupational or educational subcategories were above this average, but no subgroup had a high enough response rate to warrant relying on the instructions for important information. In particular, there was no evidence that either those in poorer health or those completing a questionnaire for their young children were any more careful in reading the instructions. Those who design such self-administered questionnaires are advised to make the form completion self-evident, rather than to rely upon introductory instructions to convey this information.


The Daily Activity Report (DAR) a Novel Measure of Functional Outcome for Serious Mental Illness.
The assessment of real-world functional outcomes in clinical trials for medications targeting negative symptoms and cognitive impairment is extremely important. We tested the psychometric properties of the Daily Activity Report (DAR), a novel assessment of productive daily activity. We administered the DAR and additional assessments of functional outcome, functional capacity, cognition and symptomatology to 50 individuals with schizophrenia at 2 time points, 1 month apart and to 25 healthy controls. The DAR records a person's daily activity for 7 consecutive days based upon phone calls made 3 times a day. A total score and scores in 3 domains; instrumental activities (ie, independent living), social and work or school related activities are generated for the DAR. Inter-item consistency was high 0.89-0.94 for each domain and 0.88 overall. Test-retest reliability across 1 month for the total DAR score was 0.67,P< .0001. The total DAR score as well as scores for social activity and nondomestic work/school differed significantly between control and patient participants (P< .0001). DAR domain scores were associated with negative symptoms and functional outcomes, but the primary score related to these measures was the work/school dimension of the DAR. DAR scores were only weakly and nonsignificantly related to positive symptoms. This study provides preliminary support for the reliability and validity of the DAR using interviewer administration. The development of a patient reported version of the DAR using smart phone technology with automatic scoring is the next step.


Emerging Role of Vitamins D and K in Modulating Uremic Vascular Calcification: The Aspect of Passive Calcification.
Vascular calcification is a critical complication in patients with chronic kidney disease (CKD) because it is predictive of cardiovascular events and mortality. In addition to the traditional mechanisms associated with endothelial dysfunction and the osteoblastic transformation of vascular smooth muscle cells (VSMCs), the regulation of calcification inhibitors, such as calciprotein particles (CPPs) and matrix vesicles plays a vital role in uremic vascular calcification in CKD patients because of the high prevalence of vitamin K deficiency. Vitamin K governs the gamma-carboxylation of matrix Gla protein (MGP) for inhibiting vascular calcification, and the vitamin D binding protein receptor is related to vitamin K gene expression. For patients with chronic kidney disease, adequate use of vitamin D supplements may play a role in vascular calcification through modulation of the calciprotein particles and matrix vesicles (MVs).


Validation of Sentinel Lymph Node Biopsy in Robotic Endometrial Cancer Staging Surgery: Results From a High-Volume Center in India.
Lymph node involvement is one of the most important factors influencing recurrence and survival in patients with endometrial cancer (EC). However, the therapeutic role of lymphadenectomy in early-stage disease has been called into question. Sentinel lymph node (SLN) mapping may be an acceptable alternative to omitting lymphadenectomy or performing a complete lymphadenectomy in patients with EC. To validate SLN biopsy (SLNB) using indocyanine green (ICG) dye and near-infrared imaging in the background of comprehensive lymphadenectomy in patients with EC undergoing robotic staging surgery at Tata Medical Center. This was a single-center, prospective observational study involving patients with EC undergoing robotic staging. Patients received a standardized cervical injection of ICG at the 3- and 9-o'clock positions, with the dye reinjected if mapping failed. Depending on preoperative histology and radiological staging, patients had SLNB or comprehensive systematic lymphadenectomy in addition to SLNB. The study included 105 female patients, of whom 71 underwent SLN and full lymphadenectomy and 34 underwent only SLN. There was bilateral mapping in 92 (87.61%) patients, with no mapping in one patient. In 18 patients, ICG dye was reinjected. With the exception of one, the rest had successful mapping after reinjection. The sensitivity of the SLN-ICG algorithm was 92.3%, and the negative predictive value was 98.3%. Ultrastaging necessitated upstaging in 8.57% of patients. With a very high negative predictive value, SLN mapping with ICG dye has a high degree of diagnostic accuracy in detecting lymph node metastases in EC.


Cytomegalovirus immune plasma in bone marrow transplant recipients.
The effects of passive immunization on cytomegalovirus infection and interstitial pneumonia in marrow transplants were evaluated in a randomized, controlled trial. Twenty-four patients received cytomegalovirus immune plasma before and after transplantation, and 24 patients were controls. Although the incidence of cytomegalovirus infection was similar in the control and plasma groups, symptomatic infection (12 of 24 versus five of 24, p = 0.07) and interstitial pneumonia (11 of 24 versus five of 24, p = 0.12) occurred less frequently in the group receiving plasma. Cytomegalovirus infection occurred in 11 of 13 recipients of leukocyte transfusions and in 16 of 35 patients not given leukocyte transfusions (p = 0.02). Among patients not given leukocyte transfusions, the incidence of cytomegalovirus infection was similar in the control and plasma groups, but symptomatic infection (eight of 18 versus one of 17, p = 0.03) and interstitial pneumonia (nine of 18 versus one of 17, p = 0.01) were significantly less in the group receiving plasma. These results suggest that passive immunization modifies cytomegalovirus infection in humans and prevents interstitial pneumonia in marrow transplants especially when leukocyte transfusions are not used.


Serum 25-hydroxyvitamin D, vitamin D binding protein and risk of colorectal cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.
The potential role of vitamin D in cancer prevention has generated substantial interest, and laboratory experiments indicate several anti-cancer properties for vitamin D compounds. Prospective studies of circulating 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, suggest an inverse association with colorectal cancer risk, but with some inconsistencies. Furthermore, the direct or indirect impact of the key transport protein, vitamin D binding protein (DBP), has not been examined. We conducted a prospective study of serum 25(OH)D and DBP concentrations and colorectal cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, based on 476 colorectal cancer cases and 476 controls, matched on age, sex, race and date of serum collection. All subjects underwent sigmoidoscopic screening at baseline and once during follow-up. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Circulating 25(OH)D was inversely associated with colorectal cancer (OR = 0.60, 95% CI 0.38-0.94 for highest versus lowest quintile, p trend 0.01). Adjusting for recognized colorectal cancer risk factors and accounting for seasonal vitamin D variation did not alter the findings. Neither circulating DBP nor the 25(OH)D:DBP molar ratio, a proxy for free circulating 25(OH)D, was associated with risk (OR = 0.82, 95% CI 0.54-1.26, and OR = 0.79, 95% CI 0.52-1.21, respectively), and DBP did not modify the 25(OH)D association. The current study eliminated confounding by colorectal cancer screening behavior, and supports an association between higher vitamin D status and substantially lower colorectal cancer risk, but does not indicate a direct or modifying role for DBP.


Adolescents' Perspectives on Atopic Dermatitis Treatment-Experiences, Preferences, and Beliefs.
For a considerable proportion of pediatric patients, atopic dermatitis symptoms persist into adolescence. Previous studies have focused mainly on (parents of) children, whereas little is known about adolescents with atopic dermatitis. To explore the beliefs, experiences, and preferences of adolescents with atopic dermatitis toward their treatment. We conducted a qualitative study employing focus group interviews of 15 adolescents (aged 12-18 years) who collected at least 1 prescription for topical corticosteroids in class 2 (moderately potent) or 3 (potent) in the preceding year. The study included 9 community pharmacies in 3 different regions in the Netherlands. Data were collected from November to December 2016, until data saturation was reached. Focus groups were recorded, transcribed verbatim, and data were analyzed by 2 researchers. Adolescents' beliefs, experiences, and preferences toward their atopic dermatitis treatment were explored during focus groups. We used a thick analysis approach to analyze the transcripts; both deductive and inductive coding were used to analyze the transcripts. Three focus groups including 15 adolescents (8 male) with a mean age of 15.3 (range, 12-18) years were conducted. Adolescents were in general satisfied with the efficacy of the treatment; however, they prefer a faster and more persistent effect. Most adolescents had little contact with their physicians and did not completely adhere to the prescribed medication regimen; they developed their own routine of using topical corticosteroids in combination with emollients and moisturizers. They also seemed to have incorrect beliefs about the mechanism of action. Adolescents developed their own way of using topical treatment for atopic dermatitis. Some practical suggestions were mentioned to improve medication use. Health care providers should devote special attention to adolescents with atopic dermatitis to make them more aware of the principles of topical treatment and ensure proper use.


Secondary myelodysplastic syndromes and leukaemias.
Secondary MDS, or AL induced by the treatment of another primary disease, occurs at an average of 48-71 months after that treatment. A high percentage of the 2 MDS convert to AL. Survival of either is less than 1 year. A constellation of morphological abnormalities from all three cell lines produces a unique appearance. The 2 AL are difficult to classify by the FAB system. With the exception of cytogenetic analysis, the biology of 2 MDS/AL remains largely unexplored. Alterations of chromosomes 5 and 7 predominate, but other associated cytogenetical abnormalities are increasingly being recognized. A review of the development of 2 MDS/AL in a variety of primary diseases generates the following tentative conclusions: many of the commonly used alkylating agents, and the non-classical alkylating agent procarbazine, are leukaemogens; procarbazine is probably the important leukaemogen in the MOPP programme; cyclophosphamide appears to be a less potent leukaemogen than other alkylating agents; the method in which a drug is administered probably influences its leukaemogenic potential; the duration of therapy with a drug, or the total amount of drug delivered, is probably an important factor in leukaemogenesis; irradiation alone appears to be a weak leukaemogen; irradiation has little or no synergism with chemotherapy in leukaemogenesis; the older patient treated with leukaemogenic drugs is at substantial risk to develop a 2 MDS/AL; most studies show no plateau in the actuarial incidence of developing a 2 MDS/AL, despite lengthy follow-up. Benzene is the only chemical agent for which strong evidence of leukaemogenesis exists. Nonetheless, the similarities in the karyotypic alterations of leukaemic cells between those whose occupations expose them to chemical hazard and those who are exposed to cytotoxic agents lend support to the idea that more environmental leukaemogens have yet to be discovered. Aggressive therapy should be considered for a patient of any age with an adequate performance status and a diagnosis of secondary AL, especially if the karyotype in the malignant cell is predictive of a high response rate. The therapy of 2 MDS remains investigational. To mitigate the development of a leukaemic complication, maintenance therapy should be restricted to diseases in which its efficacy is established or to an investigational setting, and consideration of the leukaemogenic potential of equally effective regimens should be part of the therapeutic planning in the older patient.


Left-right asymmetric morphogenesis of the anterior midgut depends on the activation of a non-muscle myosin II in Drosophila.
Many animals exhibit stereotypical left-right (LR) asymmetry in their internal organs. The mechanisms of LR axis formation required for the subsequent LR asymmetric development are well understood, especially in some vertebrates. However, the molecular mechanisms underlying LR asymmetric morphogenesis, particularly how mechanical force is integrated into the LR asymmetric morphogenesis of organs, are poorly understood. Here, we identified zipper (zip), encoding a Drosophila non-muscle myosin II (myosin II) heavy chain, as a gene required for LR asymmetric development of the embryonic anterior midgut (AMG). Myosin II is known to directly generate mechanical force in various types of cells during morphogenesis and cell migration. We found that myosin II was involved in two events in the LR asymmetric development of the AMG. First, it introduced an LR bias to the directional position of circular visceral muscle (CVMU) cells, which externally cover the midgut epithelium. Second, it was required for the LR-biased rotation of the AMG. Our results suggest that myosin II in CVMU cells plays a crucial role in generating the force leading to LR asymmetric morphogenesis. Taken together with previous studies in vertebrates, the involvement of myosin II in LR asymmetric morphogenesis might be conserved evolutionarily.


The influence of anatomical boundaries, age, and sex on the assessment of abdominal visceral fat.
Single-slice abdominal computed tomography (CT) scanning has been used extensively for the measurement of abdominal visceral fat (AVF). Optimal anatomical scan location and pixel density ranges have been proposed and are specifically reported to allow for the replication and standardization of AVF measurements. Standardization of the anatomical boundaries for CT measurement of AVF and the influence of age and gender on results obtained with different boundary locations have received much less attention. To determine the influence of three boundary analysis methods (AVF-1, AVF-2, and AVF-3) on the measurement of AVF by CT, 54 older (60 years to 79 years) and 37 younger (20 years to 29 years) healthy men and women were examined. The measurement boundary for AVF-1 was the internal most aspect of the abdominal and oblique muscle walls, and the posterior aspect of the vertebral body. AVF-2 used fat measurements enclosed in a boundary formed by the midpoint of the abdominal and oblique muscle walls, and the most posterior aspect of the spinous process. AVF-3 used fat measurements enclosed in a boundary formed by the external border of the abdominal and oblique muscle walls, and the external border of the erector spinae. Greater AVF measures were obtained with AVF-2 and AVF-3 compared with AVF-1 (p < 0.0001). These differences were greater in older compared with younger subjects (p < 0.0001) and greater in women compared with men (p < 0.02). The significantly greater AVF measurements obtained with AVF-2 and AVF-3 resulted from the inclusion of larger amounts of fat that are not drained by the portal circulation. This included retroperitoneal, intermuscular, and intramuscular lipid droplets, which increase with aging. On the basis of these results, we recommend the AVF-1 anatomical boundaries for the measurement of AVF in clinical investigations, particularly with older subjects. These data demonstrate the importance of precise and reproducible anatomical boundaries for the measurement of AVF, particularly in longitudinal studies.


Beyond building back better: imagining a future for human and planetary health.
COVID-19 is disrupting and transforming the world. We argue that transformations catalysed by this pandemic should be used to improve human and planetary health and wellbeing. This paradigm shift requires decision makers and policy makers to go beyond building back better, by nesting the economic domain of sustainable development within social and environmental domains. Drawing on the engage, assess, align, accelerate, and account (E4As) approach to implementing the 2030 Agenda for Sustainable Development, we explore the implications of this kind of radical transformative change, focusing particularly on the role of the health sector. We conclude that a recovery and transition from the COVID-19 pandemic that delivers the future humanity wants and needs requires more than a technical understanding of the transformation at hand. It also requires commitment and courage from leaders and policy makers to challenge dominant constructs and to work towards a truly thriving, equitable, and sustainable future to create a world where economic development is not an end goal itself, but a means to secure the health and wellbeing of people and the planet.


Estimating sampling error of evolutionary statistics based on genetic covariance matrices using maximum likelihood.
We explore the estimation of uncertainty in evolutionary parameters using a recently devised approach for resampling entire additive genetic variance-covariance matrices (G). Large-sample theory shows that maximum-likelihood estimates (including restricted maximum likelihood, REML) asymptotically have a multivariate normal distribution, with covariance matrix derived from the inverse of the information matrix, and mean equal to the estimated G. This suggests that sampling estimates of G from this distribution can be used to assess the variability of estimates of G, and of functions of G. We refer to this as the REML-MVN method. This has been implemented in the mixed-model program WOMBAT. Estimates of sampling variances from REML-MVN were compared to those from the parametric bootstrap and from a Bayesian Markov chain Monte Carlo (MCMC) approach (implemented in the R package MCMCglmm). We apply each approach to evolvability statistics previously estimated for a large, 20-dimensional data set for Drosophila wings. REML-MVN and MCMC sampling variances are close to those estimated with the parametric bootstrap. Both slightly underestimate the error in the best-estimated aspects of the G matrix. REML analysis supports the previous conclusion that the G matrix for this population is full rank. REML-MVN is computationally very efficient, making it an attractive alternative to both data resampling and MCMC approaches to assessing confidence in parameters of evolutionary interest.


Effect of Low-Frequency Electro-Acupuncture in Unmarried Women With Polycystic Ovary Syndrome: A Randomized Controlled Study.
We aimed to evaluate the effect of low-frequency electro-acupuncture (EA) in unmarried women with polycystic ovary syndrome (PCOS). A total of 54 women with PCOS were randomly assigned to either the acupuncture group (n=27) or the sham acupuncture group (control, n=27) for a total of 32 treatments over 16 weeks. In the acupuncture group 26 patients and in the control group 20 patients completed the trial. Main measures were androgen levels including 17-α-hydroxyprogesterone (17-α-OHP), androstenedione (A2), testosterone (T) and dehydroepiandrosterone (DHEA) at 0, 24 and 48 hours after stimulation with a dose of human chorionic gonadotropin (HCG). Other measures included body mass index, waist-to-hip ratio, sex hormone levels, etc. After treatment, there was no significant difference in the main measures between the 2 groups (P > .05), except for the DHEA level at 0 h of HCG stimulation (P = .024) and acne score (P < .05). Comparison within the acupuncture group found that 17-α-OHP and A2 levels at 0 h and DHEA levels at 24 h of HCG stimulation after treatment were significantly decreased (P < .05), whereas T levels at 24 h were significantly increased (P < .05). Comparison within the control group showed 17-α-OHP level at 0 h and 17-α-OHP and A2 and DHEA levels at 24 h after treatment were significantly lower (P < .05). In addition, weight, BMI, HCG and Ferriman-Gallwey score in the acupuncture group and LH/FSH ratio was significantly reduced in the control group. Traditional EA is slightly more effective than sham acupuncture in reducing DHEA secretion and the acne score. Meanwhile, sham acupuncture is not completely ineffective. The specific mechanism of the two may be different.


The effect of biomicroscope illumination system on grading anterior chamber inflammation.
To determine how a biomicroscope illumination system affects the grading of anterior chamber (AC) inflammation. Laboratory investigation. An artificial AC was designed to replicate optically a human AC and was filled with 5-mum polystyrene beads suspended in ethanol. A high-definition video eyepiece camera recorded the moving beads. Using image processing software, the main outcomes measures determined were the average number of beads in a 1 x 1-mm field at varying widths of the slit-beam. The volume of light and number of beads observed increased significantly as the slit-beam widened. Additionally, 3 separate biomicroscopes of identical make and model were found to produce different levels of luminance at the same aperture dial settings, influencing the number of beads observed, with the brighter biomicroscope yielding higher bead counts. Ability to count beads and perhaps the ability to count inflammatory cells in an inflamed eye depend on a number of factors, including the level of illumination and width of the slit-beam. This study demonstrated that the brighter the illumination and the wider the beam, the more beads were observed. This illustrates the importance of standardizing biomicroscopy, particularly where consecutive observations are used to make clinical decisions and in cases of multicenter clinical trials where clinical data are evaluated across different facilities.


Phylogeny and evolution of Planomonadida (Sulcozoa): eight new species and new genera Fabomonas and Nutomonas.
Planomonads are widespread gliding zooflagellates from marine and freshwater sediments with seven species. We cultured 13 new strains; morphology and 18S and ITS2 rDNA sequences show that 11 represent eight new species described here. The 15 species form four robust clades, corresponding to revised Planomonas and Ancyromonas and new genera Fabomonas (marine) and Nutomonas (freshwater). Fabomonas tropica differs in shape and is genetically very distant from previously known planomonads, yet ultrastructurally similar. Anterior cilium morphology maps simply onto the rDNA tree forming the basis for two revised families: Ancyromonadidae (Ancyromonas, Nutomonas) have a uniformly thin, entirely acronematic anterior cilium; Planomonadidae (Fabomonas, Planomonas micra, and new species Planomonas elongata, bulbosa, and brevis) have a more conspicuous emergent basal region of the anterior cilium of normal thickness. ITS2 secondary structure is clade-specific, differing most sharply in the main Nutomonas subclade from all marine species, being exceptionally short compared with earlier-diverging marine clades. Nutomonas longa is very distant but Nutomonas howeae subsp. lacustris differs from Nutomonas (Planomonas) howeae and limna (new combinations) mainly by ITS2 compensatory and/or hemi-compensatory mutations. Ancyromonas indica, atlantica, and kenti are genetically more distinct from Ancyromonas sigmoides (=Planomonas mylnikovi). The first soil planomonad (new Nutomonas limna subspecies) was isolated.


What is boredom proneness? A comparison of three characterizations.
Boredom proneness is associated with various problematic behaviors and mental health issues. Despite its wide-ranging implication, boredom proneness as a trait-like construct suffers from conceptual ambiguity and measurement issues. We examined whether boredom proneness represents individual differences in (a) the frequency of getting bored, (b) the intensity of boredom, and/or (c) a holistic perception of life being boring (perceived life boredom). Across Study 1 (U.S. Sample, N = 495; HK Sample, N = 231) and Study 2 (N = 608), we tested the construct validity of boredom proneness by estimating its association with measures of the three possible characterizations (convergent validity), and examined to what extent associations between boredom proneness and variables relevant to well-being (e.g., life satisfaction, psychological distress) could be reproduced with the three potential characterizations (concurrent validity). Results suggest that each of the three characterizations represents some aspect of boredom proneness, and they generally reproduced boredom proneness' associations with other variables. Among them, perceived life boredom had the strongest convergent and concurrent validity. Our findings provide novel insights into the characterization of boredom proneness and its hitherto poorly understood relationship with psychological well-being.


Consistency conditions and linear reconstruction methods in diffraction tomography.
Because an image can be reconstructed from knowledge of its Radon transform (RT), the task of reconstructing an image is tantamount to that of estimating its RT. Based upon the Fourier diffraction projection (FDP) theorem, from the statistical perspective of unbiased reduction of image variance, we previously proposed an infinite family of estimation methods for obtaining the RT from the scattered data in diffraction tomography (DT). In this work, using the FDP theorem, we define the diffraction Radon transform (DRT), which can be treated as the data function in DT. Subsequently, using strategies similar to those that analyze the consistency conditions on the exponential Radon transform in two-dimensional (2-D) single-photon emission computed tomography with uniform attenuation, we studied the consistency condition on the DRT and we show that there is a hierarchy of estimation methods that actually project the noisy data function onto its consistency space in different ways. In terms of a weighted inner product of the consistency and inconsistency parts of a noisy data function, we further demonstrate that a subset of the family of estimation methods can be interpreted as orthogonal projections onto the consistency space of the DRT. In particular, the statistically suboptimal estimation method in the family corresponds to an orthogonal projection associated with an ordinary inner product of the consistency and inconsistency parts of a noisy data function.


SIRT2 overexpression decreases remifentanil-stimulated post-surgical hyperalgesia via microglia.
Remifentanil (Remi)-induced hyperalgesia is a serious but common postoperative clinical problem. Sirtuin 2 (SIRT2) is essential in the pathogenetic mechanisms of several neurological disorders. However, whether SIRT2 contributes to the modulation of Remi-induced postsurgical hyperalgesia (POH) is unknown. Here, we investigated the regulatory potential of SIRT2 in Remi-stimulated POH. A rat Remi-stimulated POH model was built by infusing Remi in the surgical incision. Mechanical allodynia and thermal hyperalgesia were separately assessed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) measurements. SIRT2 and binding adaptor molecule 1 (Iba1) protein expressions and localization in spinal cord samples were detected by western blot and immunofluorescence. The results revealed SIRT2 downregulation in the spinal cord of rats with Remi-stimulated POH. Intrathecal administration of the overexpression plasmid harboring SIRT2 remarkably relieved mechanical allodynia, along with thermal hyperalgesia in the model animals. Iba1 amounts were increased upon intraoperative incision or Remi infusion, and this effect was more pronounced upon combining both treatments. Furthermore, SIRT2 overexpression suppressed microglia activation in the spinal cord of model animals, and starkly relieved incision- and/or Remi-associated pronociceptive processes as well as spinal microglia activation. SIRT2 elevation relieved Remi-associated POH, likely by suppressing spinal microglia activation. Thus, SIRT2 could be a potent target for treating neuropathic pain.


Cross-modal integration of simple auditory and visual events.
Responses are typically faster and more accurate when both auditory and visual modalities are stimulated than when only one is. This bimodal advantage is generally attributed to a speeding of responding on bimodal trials, relative to unimodal trials. It remains possible that this effect might be due to a performance decrement on unimodal ones. To investigate this, two levels of auditory and visual signal intensities were combined in a double-factorial paradigm. Responses to the onset of the imperative signal were measured under go/no-go conditions. Mean reaction times to the four types of bimodal stimuli exhibited a superadditive interaction. This is evidence for the parallel self-terminating processing of the two signal components. Violations of the race model inequality also occurred, and measures of processing capacity showed that efficiency was greater on the bimodal than on the unimodal trials. These data are discussed in terms of a possible underlying neural substrate.


Insulin-like growth factor-2 regulation of conceptus composition: effects of the trophectoderm and inner cell mass genotypes in the mouse.
The purpose of this study was to measure the effect of insulin-like growth factor-2 deficiency on the growth of the mouse conceptus. Initial observations on normal development in the 129J/Sv strain established that wet and dry weights were reduced by 35% when the insulin-like growth factor-2 gene was inactive. The DNA contents were reduced by only 15%. We exchanged the inner cell mass and trophectoderm between mouse blastocysts that had or lacked an active insulin-like growth factor-2 gene. At embryonic Day 16.5, lack of this gene's activity in the derivatives of either tissue decreased the fluid volumes of the exocelomic and amniotic cavities. The wet weights of the "fetal placentas," the yolk sacs, and the fetuses were also decreased. However, the tissue wet weight decrease could not be accounted for by the change in DNA content, indicating that cell-associated biomass had changed. The conclusions are 1) that insulin-like growth factor-2 levels regulate the composition of the fetus and extra-embryonic tissues and 2) that trophectoderm and inner cell mass derivatives cooperate to control extra-cellular fluid volume in the conceptus.


Being baby friendly: evidence-based breastfeeding support.
Breast feeding improves important outcomes for mothers and infants. In the UK, breastfeeding rates have historically been low, particularly among socially disadvantaged young women. Although there have been gradual increases in breastfeeding initiation rates since 2000, rates of exclusive breast feeding and continuation until 6 months remain lower than those in similar countries. This review summarises the evidence for effective and cost-effective strategies to help women, particularly those in low income groups, make informed choices, overcome barriers and establish and maintain breast feeding. We describe the development and impact of the Unicef Baby Friendly Initiative, and the roles and responsibilities, and challenges and opportunities that clinicians have in promoting breast feeding and maintaining a baby-friendly culture and environment.