Functional Tricuspid Regurgitation Caused by Chronic Atrial Fibrillation: A Real-Time 3-Dimensional Transesophageal Echocardiography Study.
Functional tricuspid regurgitation (TR) with a structurally normal tricuspid valve (TV) may occur secondary to chronic atrial fibrillation (AF). However, the clinical and echocardiographic differences according to functional TR subtypes are unclear. Therefore, characterization of functional TR because of chronic AF (AF-TR) remains undetermined. To investigate the prevalence of AF-TR, 437 patients with moderate to severe TR underwent 3-dimensional (3D) transesophageal echocardiography. TR severity was determined by the averaged vena contracta width on apical and parasternal inflow views. The prevalence of AF-TR was 9.2%, whereas that of functional TR because of left-sided heart disease was 45.3%. Clinical features of AF-TR included advanced age, female sex, greater right atrial than left atrial enlargement and lower systolic pulmonary artery pressure compared with left-sided heart disease-TR with sinus rhythm (all P<0.05). In 3D TV assessment, patients with AF-TR had a larger TV annular area with weaker annular contraction (both P<0.001) but a smaller tethering angle (P<0.001) despite a similar leaflet coaptation status compared with patients with left-sided heart disease-TR with sinus rhythm. On multivariable analysis, only the TV annular area in midsystole (coefficient, 0.059; 95% confidence interval, 0.041-0.078 per 100 mm2; P<0.001) was associated with TR severity in AF-TR. The annular area was more closely correlated with the right atrial volume than right ventricular end-systolic volume in AF-TR (P<0.001). AF-TR is not rare and is associated with advanced age and right atrial enlargement. TV deformations and their association with right heart remodeling differ between AF-TR and left-sided heart disease-TR. Our results suggest that in patients with TR secondary to AF, TV annuloplasty should be effective because this entity has annular dilatation without leaflet deformation.


Association of pediatric obesity and asthma, pulmonary physiology, metabolic dysregulation, and atopy; and the role of weight management.
Introduction: Obesity affects about 40% of US adults and 18% of children. Its impact on the pulmonary system is best described for asthma. Areas covered: We reviewed the literature on PubMed and Google Scholar databases and summarize the effect of obesity, its associated metabolic dysregulation and altered systemic immune responses, and that of weight gain and loss on pulmonary mechanics, asthma inception, and disease burden. We include a distinct approach for diagnosing and managing the disease, including pulmonary function deficits inherent to obesity-related asthma, in light of its poor response to current asthma medications. Expert opinion: Given the projected increase in obesity, obesity-related asthma needs to be addressed now. Research on the contribution of metabolic abnormalities and systemic immune responses, intricately linked with truncal adiposity, and that of lack of atopy, to asthma disease burden, and pulmonary function deficits among obese children is fairly consistent. Since current asthma medications are more effective for atopic asthma, investigation for atopy will guide management by distinguishing asthma responsive to current medications from the non-responsive disease. Future research is needed to elucidate mechanisms by which obesity-mediated metabolic abnormalities and immune responses cause medication non-responsive asthma, which will inform repurposing of medications and drug discovery.


Specialising in radiology in Switzerland: still attractive for medical school graduates?
To gain insight into the professional characteristics of radiologists in Switzerland and to determine how to enhance the attractiveness of radiology to medical graduates as a specialty. Data from 262 members of the Swiss Society of Radiology (m:f = 76:24%) obtained in a questionnaire survey were analysed regarding socio-demographic variables, working status, specialty, main fields of interest, career success, mentoring and reasons for the shortage of radiologists. 35 (56.4%) female and 85 (45.5%) male radiologists were aged ≤ 45 years. 228 (87%) were board-certified; 44 (17.9%) had completed a sub-specialisation. Men worked part-time mostly just before retirement, while women worked part-time at a younger age. As reasons for specialty choice, the wide range of clinical work and the combination of technology and medicine were ranked highest. Women reported significantly less career success and support. To improve the attractiveness of radiology to graduates, radiology should be visible on medical school curricula. In Switzerland, more female radiologists work part-time than male ones, and there is less career success and support for women. In order to make radiology more attractive to medical graduates as a specialty, structured residency programmes and reliable gender-respecting career support are needed.


Outcomes of Gastric Cancer Resection in Octogenarians: A Multi-institutional Study of the U.S. Gastric Cancer Collaborative.
As the U.S. population ages, an increasing number of elderly patients with gastric adenocarcinoma are being evaluated for surgical resection. This study aimed to describe the short- and long-term outcomes after gastric cancer resection for patients 80 years of age or older. Patients who underwent gastrectomy for gastric adenocarcinoma from 2000 to 2012 at seven U.S. academic institutions were analyzed. The main outcome measures included postoperative morbidity, mortality, survival, and failure to rescue (defined as death after any complication). Of 953 patients who underwent distal or total gastrectomy during the 12-year study period, 127 (13 %) were 80 years of age or older. Although the type of postoperative complications did not differ between the two groups, octogenarians had a higher incidence of any (54 vs 41 %; p = 0.006) and of major (28 vs 17 %; p = 0.006) postoperative complications. This translated into higher 30-day (10.2 vs 3.6 %; p = 0.001) and 90-day mortality (19.7 vs 7.9 %; p = 0.001) rates, with correspondingly higher failure-to-rescue rates (17.4 vs 8 %; p = 0.015). However, disease-specific survival after resection was equivalent between the two groups (5-year survival: 46 vs 53 %; p = 0.676). In the multivariate analysis, age of 80 years or older, blood transfusion, and albumin and creatinine levels all were independent predictors of 90-day mortality. Stage, tumor grade, race, blood transfusion, and adjuvant therapy, but not age, were independently associated with disease-specific survival. Perioperative mortality and failure-to-rescue from complications is substantial for octogenarians undergoing gastric cancer resection. However, if the operation can be performed safely, the long-term cancer-specific outcome appears similar to that for younger patients.


Acute lower back pain mapped by dermatomal scarification in urban Malawi.
Lower back pain is a problem that affects many and generates an economic burden on the National Health Service. In modern days, although it is tempting to rely on specialist imaging for the initial investigation of back pain, it is often unnecessary. Comprehensive clinical examination is immediately available and should detect neurological impairments where they exist. A 32-year-old man from Malawi presented to clinic with lower back pain radiating to the right leg. Inspection revealed traditional scarification marks along the classical path of lumbar nerve root, which coincided with his L5 dermatomal pain. The distribution of his 'Mphini' along the typical path of lumbar nerve was identical to his myelography. This report strongly illustrates that in the Western medical setting, accurate history and examination would have allowed correct interpretation of these symptoms and correctly indicated the need for myelography.


Latissimus Dorsi Tendon Transfer With Acromial Osteotomy for Massive Irreparable Rotator Cuff Tear.
Latissimus dorsi tendon transfer is an effective option for young and active patients with massive irreparable posterosuperior rotator cuff tears and intact subscapularis tendon. This approach has been shown to relieve pain and improve shoulder function in both the short and long term. We describe a surgical technique using an acromial osteotomy to better expose the greater tuberosity for the tendon transfer without disrupting the deltoid muscle. The latissimus dorsi tendon is reinforced with a human dermal collagen matrix (GraftJacket; Wright Medical Group) for additional augmentation of the muscle to gain more excursion for the tendon transfer to the greater tuberosity. The transferred tendon is fixed to the supraspinatus and infraspinatus footprints on the greater tuberosity using suture anchors. The acromial osteotomy is repaired back anatomically with several No. 5 braided sutures (FiberWire; Arthrex).


Health communication, self-care, and treatment satisfaction among low-income diabetes patients in a public health setting.
Diabetes patients with limited resources often experience suboptimal care. Less is known about the role of effective health communication (HC) in caring for low income diabetes patients. Ten health department clinics in TN participated in a trial evaluating a literacy-sensitive communication intervention. We assessed the quality of baseline HC and measured associations with diabetes outcomes. Assessments included: demographics, measures of HC, health literacy, self-care behaviors, self-efficacy, medication non-adherence, treatment satisfaction, and A1C. Unadjusted and adjusted multivariable regression models were used to test associations. Participants (N=411) were 49.7±9.5 years, 61% female, uninsured (96%), with A1C 9.6±2.1. In unadjusted analyses, better communication, was associated with lower medication non-adherence (OR 0.40-0.68, all p<0.05), higher treatment satisfaction (OR 1.76-1.96, all p<0.01), portion size reduction (OR 1.43, p<0.05), diabetes self-efficacy (OR 1.41, p<0.05), and lower A1C (β=-0.06, p<0.01). In adjusted analyses, communication quality remained associated with lower medication non-adherence (AOR 0.39-0.68, all p<0.05), and higher treatment satisfaction (AOR 1.90-2.21, all p<0.001). Better communication between low-income patients and providers was independently associated with lower medication non-adherence and higher treatment satisfaction. Communication quality may be an important modifiable approach to improving diabetes care for vulnerable populations.


Endocrine and behavioural responses to acute central CRF challenge are antagonized in the periphery and CNS, respectively, in C57BL/6 mice.
Corticotropin releasing factor (CRF) is a major mediator of central and peripheral responses to environmental stressors, and antagonism of its receptors (CRF-R1, -R2) is an active area of pharmacotherapeutic research for stress-related disorders. Stress responses include CRF activation of the hypothalamus-pituitary-adrenal axis and behavioural inhibition. Valid in vivo models for the study of these neuro-endocrine and -behavioural CRF pathways and their central-peripheral antagonism are important. The aims of this study in C57BL/6 mice were to describe the acute effects of intracerebroventricular (ICV) CRF using plasma ACTH-CORT titres and locomotor activity as readouts, and to study the impact on these readouts of central versus peripheral pre-treatment with the CRF-R1/2 antagonist, astressin. The following experiments were performed: Effects of (i) serial blood sampling (SBS) per se, (ii) physical confinement+SBS, (iii) ICV saline infusion+SBS, on plasma titres of ACTH-CORT. (iv) Effects of ICV or IP CRF infusion on plasma ACTH-CORT. (v) Effects of ICV CRF on plasma CRF. (vi) Effects of ICV or IP astressin on ICV or IP CRF-stimulated plasma CORT. (vii) Effects of ICV or IP astressin on ICV CRF-induced locomotor inactivity. Main findings were: (i)-(ii) Serial blood sampling per se and physical confinement+SBS led to similar, mild increases in plasma ACTH-CORT. (iii) ICV saline infusion led to a marked increase in plasma ACTH, possibly due to assay crossreactivity with "washed out" pituitary peptides, and a mild increase in plasma CORT. (iv) ICV CRF (0.001-1μg) induced no further increase in plasma ACTH versus vehicle, and induced dose-dependent increased plasma CORT. 1μg ICV CRF also reduced locomotor activity. (v) ICV CRF-induced dose-dependent increased plasma CRF. (vi) ICV astressin failed to block ICV CRF-induced increased plasma CORT, whereas IP astressin did do so. (vii) ICV CRF-induced locomotor inactivity was blocked by ICV astressin, but not by IP astressin. Therefore, ICV CRF-induced a dose-dependent increase in plasma CORT via a peripheral pathway and a reduction in locomotion via a central pathway, indicated by the double dissociation in the ability of astressin to antagonize these effects relative to its route of administration, IP or ICV, respectively. The preparation described here could be readily used to provide initial indications on the central and peripheral activity of CRF-R antagonists, including pharmacokinetics following peripheral administration.


Importance of cell-matrix interactions in rat islet beta-cell secretion in vitro: role of alpha6beta1 integrin.
It has long been recognized that islet cell function is rapidly altered in vitro, but can be maintained, at least in part, when cells are layered on defined extracellular matrices. The present work addresses the influence of short-term cell-matrix interactions on islet beta-cell function and provides first insight into the molecular basis of these interactions. When primary rat beta-cells were allowed to attach to a matrix produced by a rat carcinoma cell line (804G), there was an increased insulin secretory response to secretagogues. This change was the result of an increase in the proportion of actively secreting beta-cells and in the amount of insulin secreted per active cell, as shown using the reverse hemolytic plaque assay. In turn, the spreading or flattening of beta-cells on this matrix was enhanced by secretagogues, and flattened cells secreted more insulin than rounded cells. Using indirect immunofluorescence, it was found that 1)alpha6beta1 integrins are present at the surface of islet cells in situ, 2) alpha6beta1 expression is heterogeneous among purified beta-cells and is upregulated by insulin secretagogues, 3) alpha6beta1 expression is higher in spreading cells, and 4) anti-alpha6beta1-specific antibodies decrease spreading. These observations demonstrate that islet cell-matrix interactions can improve the sensitivity of insulin cells to glucose and are mediated, at least in part, by alpha6beta1 integrins, suggesting that outside-in signaling through alpha6beta1 integrin plays a major role in the regulation of beta-cell function.


A Modest Increase in 11C-PK11195-Positron Emission Tomography TSPO Binding in Depression Is Not Associated With Serum C-Reactive Protein or Body Mass Index.
Immune mechanisms have been implicated in the pathogenesis of depression. Translocator protein (TSPO)-targeted positron emission tomography (PET) has been used to assess neuroinflammation in major depressive disorder. We aimed to 1) test the hypothesis of significant case-control differences in TSPO binding in the anterior cingulate cortex, prefrontal cortex, and insula regions; and 2) explore the relationship between cerebral TSPO binding and peripheral blood C-reactive protein (CRP) concentration. A total of 51 depressed subjects with Hamilton Depression Rating Scale score >13 (median 17; interquartile range, 16-22) and 25 healthy control subjects underwent dynamic brain 11C-PK11195 PET and peripheral blood immune marker characterization. Depressed subjects were divided into high CRP (>3 mg/L; n = 20) and low CRP (<3 mg/L; n = 31). Across the three regions, TSPO binding was significantly increased in depressed versus control subjects (η2p = .09; F1,71 = 6.97, p = .01), which was not influenced by body mass index. The case-control difference was greatest in the anterior cingulate cortex (d = 0.49; t74 = 2.00, p = .03) and not significant in the prefrontal cortex or insula (d = 0.27 and d = 0.36, respectively). Following CRP stratification, significantly higher TSPO binding was observed in low-CRP depression compared with controls (d = 0.53; t54 = 1.96, p = .03). These effect sizes are comparable to prior major depressive disorder case-control TSPO PET data. No significant correlations were observed between TSPO and CRP measures. Consistent with previous findings, there is a modest increase in TSPO binding in depressed patients compared with healthy control subjects. The lack of a significant correlation between brain TSPO binding and blood CRP concentration or body mass index poses questions about the interactions between central and peripheral immune responses in the pathogenesis of depression.


Clinico-microbiological profile and outcomes of nosocomial sepsis in an Indian tertiary care hospital--a prospective cohort study.
Nosocomial infections are linked to rising morbidity and mortality worldwide. We sought to investigate the pattern of nosocomial sepsis, device usage, risk factors for mortality and the antimicrobial resistance pattern of the causative organisms in medical intensive care units (ICUs) in an Indian tertiary care hospital. We conducted a single-centre based prospective cohort study in four medical ICUs and patients who developed features of sepsis 48 hours after admission to the ICUs were included. Patients' demographics, indwelling device usage, microbiological culture reports, drug resistance patterns and the outcomes were recorded. The Acute Physiology and Chronic Health Evaluation (APACHE) III score and the relative risk of variables contributing towards non recovery were calculated. Pneumonia (49%) was the commonest nosocomial infection resulting in sepsis, followed by urosepsis (21.8%), bloodstream infection (BSI) (10.3%) and catheter-related bloodstream infection (CRBSI) (5%). Sixty three percent of the Acinetobacter baumannii and 64.4% of the Pseudomonas aeruginosa were multidrug-resistant (MDR). Seventy percent of the Klebsiella pneumoniae were extended spectrum beta-lactamase producers and 7.4% were resistant to carbapenems. Forty three percent of the Staphylococcus aureus were methicillin-resistant S. aureus. Resistance to carbapenems was 35.2% in this study. High APACHE III scores (P = 0.006 by unpaired t-test) and chronic kidney disease (P = 0.023) were significantly associated with non-recovery. A high degree of multidrug resistance was observed among both Gram-positive and -negative organisms in nosocomial sepsis patients. Carbapenem resistance was a common occurrence. Chronic kidney disease and high APACHE III scores were significantly associated with non-recovery. Male gender and sepsis leading to cardiovascular failure were the independent predictors of mortality.


Cervical epidural analgesia in current anaesthesia practice: systematic review of its clinical utility and rationale, and technical considerations.
Cervical epidural analgesia (CEA) is an analgesic technique, potentially useful for surgeries involving the upper body. Despite the inherent technical risks and systemic changes, it has been used for various surgeries. There have been no previously published systematic reviews aimed at assessing its clinical utility. This systematic review was performed to explore the perioperative benefits of CEA. The review was also aimed at identifying the rationale of its use, reported surgical indications and the method of use. We performed a literature search involving PubMed and Embase databases, to identify studies using CEA for surgical indications. Out of 467 potentially relevant articles, 73 articles were selected. Two independent investigators extracted data involving 5 randomized controlled trials, 17 observational comparative trials, and 51 case reports (series). The outcomes studied in most comparative studies were on effects of local anaesthetics and other agents, systemic effects, and feasibility of CEA. In one randomized controlled study, CEA was observed to decrease the resting pain scores after pharyngo-laryngeal surgeries. In a retrospective study, CEA was shown to decrease the cancer recurrence after pharyngeal-hypopharyngeal surgeries. The limited evidence, small studies, and the chosen outcomes do not allow for any specific recommendations based on the relative benefit or harm of CEA. Considering the potential for significant harm, in the face of better alternatives, its use must have a strong rationale mostly supported by unique patient and surgical demands. Future studies must aim to assess analgesic comparator effectiveness for clinically relevant outcomes.


Canonical and non-canonical pathways of osteoclast formation.
Physiological and pathological bone resorption is mediated by osteoclasts, multinucleated cells which are formed by the fusion of monocyte / macrophage precursors. The canonical pathway of osteoclast formation requires the presence of the receptor activator for NFkappaB ligand (RANKL) and macrophage colony stimulating factor (M-CSF). Non-canonical pathways of osteoclast formation have been described in which cytokines / growth factors can substitute for RANKL or M-CSF to induce osteoclast formation. Substitutes for RANKL include LIGHT, TNFalpha and interleukins 6, 11 and 8. M-CSF substitutes include vascular endothelial growth factor (VEGF), placental growth factor (PlGF), FLt-3 ligand and hepatocyte growth factor (HGF). These growth factors can also influence canonical (RANKL / M-CSF-induced) osteoclast formation. Both canonical and non-canonical pathways of osteoclast formation play a role in the formation of osteolytic lesions where there is increased osteoclast formation and activity, such as in giant cell tumour of bone.


Characterization of recombinant human liver thermolabile phenol sulfotransferase with minoxidil as the substrate.
Minoxidil, a potent antihypertensive agent and hair growth stimulator, is metabolized by phenol sulfotransferase to its activated form, minoxidil sulfate. The thermostable form of phenol sulfotransferase was reported to be the enzyme that catalyzed the reaction. Our previous findings with partially purified human platelet preparations indicated that the thermolabile form of phenol sulfotransferase also catalyzed the sulfation of minoxidil. To confirm and to characterize precisely the activity of thermolabile phenol sulfotransferase toward minoxidil, we investigated the ability of the enzyme expressed from a human liver cDNA clone to sulfate minoxidil during testing of thermal stability and of inhibition by 2,6-dichloro-4-nitrophenol and NaCl. The cDNA encoded thermolabile phenol sulfotransferase activity assayed with minoxidil behaved in the same fashion as the activity measured with dopamine, a finding that confirmed that this enzyme activity sulfated minoxidil. Thus, thermolabile phenol sulfotransferase must be taken into account with the thermostable enzyme when estimating the human tissue sulfotransferase contribution to minoxidil sulfation.


Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners.
Several recent reports have demonstrated that transplantation of bone marrow cells can result in the generation of functional hepatocytes. Cellular fusion between bone marrow-derived cells and host hepatocytes has been shown to be the mechanism of this phenomenon. However, the exact identity of the bone marrow cells that mediate cellular fusion has remained undetermined. Here we demonstrate that the hematopoietic progeny of a single hematopoietic stem cell (HSC) is sufficient to produce functional hepatic repopulation. Furthermore, transplantation of lymphocyte-deficient bone marrow cells and in vivo fate mapping of the myeloid lineage revealed that HSC-derived hepatocytes are primarily derived from mature myelomonocytic cells. In addition, using a Cre/lox-based strategy, we directly demonstrate that myeloid cells spontaneously fuse with host hepatocytes. Our findings raise the possibility that differentiated myeloid cells may be useful for future therapeutic applications of in vivo cellular fusion.


DNA barcoding in native plants of the Labiatae (Lamiaceae) family from Chios Island (Greece) and the adjacent Çeşme-Karaburun Peninsula (Turkey).
The plant family Labiatae (Lamiaceae) is known for its fine medicinal and aromatic herbs like lavender, mint, oregano, sage and thyme and is a rich source of essential oils for the food, pharmaceutical and cosmetic industry. Besides its great economic importance, the Labiatae family contributes significantly to the endemic flora of Greece and Turkey. Owing to its economic and biological significance and to the difficult identification based on morphological characters of several of its taxa, the Labiatae family is an ideal case for developing DNA barcodes. The purpose of this study is to evaluate the utility of DNA barcoding on a local scale in discriminating Labiatae species in Chios Island (Greece) and the adjacent Çeşme-Karaburun Peninsula (Turkey). We chose three cpDNA regions (matK, rbcL, trnH-psbA) that were proposed by previous studies and tested them either as single region or as multiregion barcodes based on the criteria determined by Consortium for the Barcode of Life (CBOL). Our results show that matK and trnH-psbA taken as useful in discriminating species of the Labiatae, for the species we examined, as any multiregion combination. matK and trnH-psbA could serve as single-region barcodes for Labiatae species contributing to the conservation and the trade control of valuable plant resources.


Examining variations of resting metabolic rate of adults: a public health perspective.
There has not been a recent comprehensive effort to examine existing studies on the resting metabolic rate (RMR) of adults to identify the effect of common population demographic and anthropometric characteristics. Thus, we reviewed the literature on RMR (kcal·kg(-1)·h(-1)) to determine the relationship of age, sex, and obesity status to RMR as compared with the commonly accepted value for the metabolic equivalent (MET; e.g., 1.0 kcal·kg(-1)·h(-1)). Using several databases, scientific articles published from 1980 to 2011 were identified that measured RMR, and from those, others dating back to 1920 were identified. One hundred and ninety-seven studies were identified, resulting in 397 publication estimates of RMR that could represent a population subgroup. Inverse variance weighting technique was applied to compute means and 95% confidence intervals (CI). The mean value for RMR was 0.863 kcal·kg(-1)·h(-1) (95% CI = 0.852-0.874), higher for men than women, decreasing with increasing age, and less in overweight than normal weight adults. Regardless of sex, adults with BMI ≥ 30 kg·m(-2) had the lowest RMR (<0.741 kcal·kg(-1)·h(-1)). No single value for RMR is appropriate for all adults. Adhering to the nearly universally accepted MET convention may lead to the overestimation of the RMR of approximately 10% for men and almost 15% for women and be as high as 20%-30% for some demographic and anthropometric combinations. These large errors raise questions about the longstanding adherence to the conventional MET value for RMR. Failure to recognize this discrepancy may result in important miscalculations of energy expended from interventions using physical activity for diabetes and other chronic disease prevention efforts.


Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain.
Multiple voltage-gated potassium (K) channel gene products are likely to be involved in regulating neuronal excitability of any single neuron in the mammalian brain. Here we show that two closely related voltage-gated K channel proteins, mKv1.1 and mKv1.2, are present in multiple subcellular locations including cell somata, juxta-paranodal regions of myelinated axons, synaptic terminals, unmyelinated axons, specialized junctions among axons, and proximal dendrites. Staining patterns of the two channel polypeptides overlap in some areas of the brain, yet each has a unique pattern of expression. For example, in the hippocampus, both mKv1.1 and mKv1.2 proteins are present in axons, often near or at synaptic terminals in the middle molecular layer of the dentate gyrus, while only mKv1.1 is detected in axons and synaptic terminals in the hilar/CA3 region. In the cerebellum, both channel proteins are localized to axon terminals and specialized junctions among axons in the plexus region of basket cells. Strong differential staining is observed in the olfactory bulb, where mKv1.2 is localized to cell somata and axons, as well as to proximal dendrites of the mitral cells. This overlapping yet differential pattern of expression and specific subcellular localization may contribute to the unique profile of excitability displayed by a particular neuron.


Low participation rates and disparities in participation in interventional clinical trials for myelodysplastic syndromes.
The development of novel therapies for the myelodysplastic syndromes (MDS) is hampered by inadequate trial recruitment. Factors contributing to low trial accrual are incompletely understood. This study analyzed a pooled patient database from institutions of the US MDS Clinical Research Consortium to compare the characteristics of participants in interventional trials with those of patients who did not enroll in a trial. Data were identified for 1919 patients with MDS, and 449 of these patients (23%) participated in an interventional clinical trial. The median age of all patients was 68 years, and 64% were male. Patients who participated in trials were significantly younger than nonparticipants (P = .014), and men were more likely to participate in a trial (71% of trial participants were male, whereas 61% of nonparticipants were; P < .001). Race and ethnicity were not associated with trial enrollment. Patients in more affluent ZIP codes had a higher participation rate (P < .001). Patients with intermediate- and high-risk disease according to the revised International Prognostic Scoring System were overrepresented (P = .004), and trial participants less frequently had treatment-related disease (P < .001). In multivariable analyses, participation in a clinical trial was associated with a reduced hazard of death (P = .004). Even at large referral centers, only a minority of patients with MDS enrolled in interventional trials. Restrictive trial eligibility criteria that exclude patients with MDS on account of age, comorbidities, or a history of another cancer are limit enrollment of MDS patients to clinical trials. Gaining insight into the barriers to trial accrual may help investigators and study sponsors to design trials that will accrue more rapidly and augment treatment options for patients with MDS.


Augmenting geovisual analytics of social media data with heterogeneous information network mining-Cognitive plausibility assessment.
This paper investigates the feasibility, from a user perspective, of integrating a heterogeneous information network mining (HINM) technique into SensePlace3 (SP3), a web-based geovisual analytics environment. The core contribution of this paper is a user study that determines whether an analyst with minimal background can comprehend the network data modeling metaphors employed by the resulting system, whether they can employ said metaphors to explore spatial data, and whether they can interpret the results of such spatial analysis correctly. This study confirms that all of the above is, indeed, possible, and provides empirical evidence about the importance of a hands-on tutorial and a graphical approach to explaining data modeling metaphors in the successful adoption of advanced data mining techniques. Analysis of outcomes of data exploration by the study participants also demonstrates the kinds of insights that a visual interface to HINM can enable. A second contribution is a realistic case study that demonstrates that our HINM approach (made accessible through a visual interface that provides immediate visual feedback for user queries), produces a clear and a positive difference in the outcome of spatial analysis. Although this study does not aim to validate HINM as a data modeling approach (there is considerable evidence for this in existing literature), the results of the case study suggest that HINM holds promise in the (geo)visual analytics domain as well, particularly when integrated into geovisual analytics applications. A third contribution is a user study protocol that is based on and improves upon the current methodological state of the art. This protocol includes a hands-on tutorial and a set of realistic data analysis tasks. Detailed evaluation protocols are rare in geovisual analytics (and in visual analytics more broadly), with most studies reviewed in this paper failing to provide sufficient details for study replication or comparison work.


Spawning stock and recruitment in North Sea cod shaped by food and climate.
In order to provide better fisheries management and conservation decisions, there is a need to discern the underlying relationship between the spawning stock and recruitment of marine fishes, a relationship which is influenced by the environmental conditions. Here, we demonstrate how the environmental conditions (temperature and the food availability for fish larvae) influence the stock-recruitment relationship and indeed what kind of stock-recruitment relationship we might see under different environmental conditions. Using unique zooplankton data from the Continuous Plankton Recorder, we find that food availability (i.e. zooplankton) in essence determines which model applies for the once large North Sea cod (Gadus morhua) stock. Further, we show that recruitment is strengthened during cold years and weakened during warm years. Our combined model explained 45 per cent of the total variance in cod recruitment, while the traditional Ricker and Beverton-Holt models only explained about 10 per cent. Specifically, our approach predicts that a full recovery of the North Sea cod stock might not be expected until the environment becomes more favourable.


Patient-Centered Dentinal Hypersensitivity Treatment Outcomes: Results from the National Dental PBRN.
Dentinal hypersensitivity (DH) can have a significant impact on oral health and functioning, and it is a clinical symptom commonly managed by dentists during routine clinical practice. DH symptoms are typically elicited by otherwise innocuous, nonpainful stimuli applied to exposed dentin (e.g., tactile stimuli, warming or cooling temperatures or air puffs). Treatment approaches have sought to directly target the dentinal pulp tissues or close dentinal tubules via dental office care and treatment services (fluoride varnishes, glutaraldehydes, bonding agents, sealants, oxalates, or lasers) or home care services (toothpastes or dentifrices containing fluoride or potassium nitrate compounds). The purpose of this prospective multicenter cohort study was to assess how community-based dentists from the National Dental Practice-Based Research Network (National Dental PBRN) manage DH and whether the effectiveness of DH treatments can be assessed in those settings. A total of 171 dentists recruited 1862 subjects with DH from their existing patients. Dentists then recommended and provided DH treatment as appropriate. Treatment choice was at the discretion of the dentists. Patients rated their DH pain at baseline and 1, 4, and 8 wk during the course of their treatments. They used pain intensity and unpleasantness visual analog scales and 4 labeled magnitude scales and rated their satisfaction with treatment after 8 wk. Patients were provided reminders postbaseline via email, texting, or voice mail. These patient-centered outcomes served as the principal measures for the assessment of treatment because treatments sought to alleviate DH symptoms. The patients with DH who reported pain reduction from dentist-provided treatments (glutaraldehyde/HEMA [hydroxyethyl methacrylate] compounds, oxalates, and bonding agents), dentists' advice and counseling regarding oral habits and diet, and patient-applied fluoride toothpaste reported a concomitant positive rating of satisfaction with DH treatments. The results from this study support the feasibility of engaging network practices to assess the effectiveness of clinical DH treatments. Knowledge Transfer Statement: National Dental PBRN dentists provide a range of procedures to treat dentinal hypersensitivity. In this large nonrandomized study designed to assess clinical care and to capture patient-reported outcomes, about 60% of patients reported improvement in pain. This study demonstrated the feasibility of engaging network dentists and their patients to assess treatment effectiveness. Future studies will explore the feasibility of imposing randomization and measuring patient compliance with treatment in the manner that this treatment is provided.


A VH gene is located within 95 Kb of the human immunoglobulin heavy chain constant region genes.
Using cosmids covering about 117 Kb upstream of the human immunoglobulin chain C mu gene, we have identified a potentially functional VH gene, belonging to the VHVI subgroup. This VHVI gene is only about 95 Kb from the C mu gene and is probably the first functional VH segment of the Igh locus. These results illustrate the proximity of the human VH, DH and JH segments involved in creation of the complete heavy chain genes.


The God Allusion : Individual Variation in Agency Detection, Mentalizing and Schizotypy and Their Association with Religious Beliefs and Behaviors.
It has previously been suggested that the historically and geographically widespread persistence of religious beliefs occurs because it is a by-product of normal cognitive processes, ones which first evolved to confer survival advantages in the social domain. If this theory holds, then it is likely that inter-individual variation in the same biases may predict corresponding variation in religious thoughts and behaviors. Using an online questionnaire, 298 participants answered questions regarding their tendency to detect agency, the degree to which they displayed schizotypal traits, their ability to understand the emotions and motivations of others ("mentalizing"), and their religious beliefs and behaviors. Path analysis suggests that mentalizing, agency detection, and schizotypal thinking were each independently related to religiosity. Furthermore, schizotypal thinking and agency detection were highly interrelated with one another, whereas mentalizing was not. Although the degree to which an individual engages with religious or spiritual beliefs will be influenced by their cultural and historical context, this paper helps to elucidate the interplay between various cognitive processes that might predispose some individuals but not others toward holding such beliefs in the first place.


Hyper-recombination, diversity, and antibiotic resistance in pneumococcus.
Streptococcus pneumoniae is a pathogen of global importance that frequently transfers genetic material between strains and on occasion across species boundaries. In an analysis of 1930 pneumococcal genotypes from six housekeeping genes and 94 genotypes from related species, we identified mosaic genotypes representing admixture between populations and found that these were significantly associated with resistance to several classes of antibiotics. We hypothesize that these observations result from a history of hyper-recombination, which means that these strains are more likely to acquire both divergent genetic material and resistance determinants. This could have consequences for the reemergence of drug resistance after pneumococcal vaccination and also for our understanding of diversification and speciation in recombinogenic bacteria.


An Evaluation of Serum Procalcitonin and C-Reactive Protein Levels as Diagnostic and Prognostic Biomarkers of Severe Sepsis.
Recommendations have been made, following the multicenter Surviving Sepsis Campaign study, to standardize the definition of severe sepsis with reference to several parameters such as haemodynamic stability, acid-base balance, bilirubin, creatinine, International Normalized Ratio (INR), urine output and pulmonary functional value of the ratio between arterial oxigen partial pressure and inspiratory oxigen concentration. Procalcitonin (PCT) is considered to be a gold standard biomarker for the inflammatory response, and recent studies have shown that it may help to discover whether a seriously ill person is developing sepsis. C-reactive protein (CRP) is also used as a marker of inflammation in the body, as its blood levels increase if there is any inflammation in the body. The aim of this study was to evaluate serum procalcitonin and C-reactive protein levels as diagnostic and prognostic biomarkers of severe sepsis. Sixty patients, diagnosed as being "septic", were admitted to the intensive care unit (ICU). Based on laboratory results and clinical findings a diagnosis of "severe sepsis" was made, and correlated with PCT and CRP values. The APACHE II, SAPS II and SOFA severity scores were calculated, analyzed and correlated with PCT and CRP. Fifty two patients (86.67%) presented with criteria for severe sepsis. Multivariate correlation analysis indicated a significant positive association between procalcitonin and all severity scores (APACHEII p<0.0001, SOFA p<0.0001, SAPS II p<0.0001). CRP proved to be significantly correlated only with the SAPS II score (p=0.0145). Mortality rate was high, with 48 patients (80%) dying. There was no significant correlation between the levels of the PCT and CRP biomarkers and severe sepsis (p=0.2059 for PCT, p=0.6059 for CRP). The procalcitonin levels are highly correlated with the severity scores (APACHE II, SAPS II, SOFA) regularly used in ICUs and therefore can be used for determining the severity of the septic process. Quantitive procalcitonin and C-reactive protein analysis was not shown to be useful in diagnosing severe sepsis. However, PCT and CRP can be used to predict the fatal progression of the septic patient.


Impacted family equality, self-confidence and loneliness: a cross-sectional study of first-time and multi-time fathers' satisfaction with prenatal and postnatal father groups in Sweden.
Fathers often feel secondary or invisible in traditional parent groups. Gender-specific parent groups, referred to as father groups, may be inclusive spaces for fathers to discuss their transition into parenthood. To quantitatively assess fathers' perceptions and satisfaction of father groups in Sweden during the prenatal and postnatal periods. A cross-sectional quantitative study design was used to report fathers' satisfaction of father groups, including how the groups impacted their personal outcomes, as well as their relationship with their partner and child. Further analyses were completed on if their depressive symptoms, via EPDS, and/or parity affected their satisfaction and personal outcomes. Fathers were recruited through father group leaders, who then provided the researchers with their contact information. In total, 87 fathers were contacted via email and 67 fathers from two geographical areas, including urban and suburban settings, completed the survey. Most fathers had a university education, a good household economy and were married/cohabiting, while almost 60% were first-time fathers and almost 25% had depressive symptoms. Overall, fathers were generally satisfied with both the prenatal and postnatal father groups, although fathers attended prenatal father groups to a lesser extent. The participants rated the father groups as moderately impacting their equality in the family, self-confidence, feelings of loneliness, social network and being able to express their own opinions, as well as positively affected their relationship with their partner and child, respectively. While there were no differences based on fathers' parity, those who self-estimated depressive symptoms were less satisfied and rated the father groups less impactfully. Father groups may help encourage fathers to meet policy goals, such as childrearing equality, and can be an important arena for screening fathers for depression.


Internally sensed optical phased array.
Extending phased array techniques to optical frequencies is challenging because of the considerably smaller wavelengths and the difficulty of stabilizing the optical path lengths of multiple emitters to this level of precision. This is especially true under real-world conditions where thermal and vibrational disturbances cause path length variations that are considerable in relation to the wavelength. Earlier attempts have relied on an external mechanism to sense and compensate for any unwanted variations in the outgoing beams. Here we propose and demonstrate a method that does not rely on any external components. The method combines a pseudo-random noise phase modulation scheme together with conventional heterodyne interferometry to simultaneously measure phase variations between emitters. This information is then used to control the relative phases between the emitters and compensate for any unwanted disturbance. Experimental results are presented that support the viability of this design.


The transcriptional activation program of human neutrophils in skin lesions supports their important role in wound healing.
To investigate the cellular fate and function of polymorphonuclear neutrophilic granulocytes (PMNs) attracted to skin wounds, we used a human skin-wounding model and microarray technology to define differentially expressed genes in PMNs from peripheral blood, and PMNs that had transmigrated to skin lesions. After migration to skin lesions, PMNs demonstrated a significant transcriptional response including genes from several different functional categories. The up-regulation of anti-apoptotic genes concomitant with the down-regulation of proapoptotic genes suggested a transient anti-apoptotic priming of PMNs. Among the up-regulated genes were cytokines and chemokines critical for chemotaxis of macrophages, T cells, and PMNs, and for the modulation of their inflammatory responses. PMNs in skin lesions down-regulated receptors mediating chemotaxis and anti-microbial activity, but up-regulated other receptors involved in inflammatory responses. These findings indicate a change of responsiveness to chemotactic and immunoregulatory mediators once PMNs have migrated to skin lesions and have been activated. Other effects of the up-regulated cytokines/chemokines/enzymes were critical for wound healing. These included the breakdown of fibrin clots and degradation of extracellular matrix, the promotion of angiogenesis, the migration and proliferation of keratinocytes and fibroblasts, the adhesion of keratinocytes to the dermal layer, and finally, the induction of anti-microbial gene expression in keratinocytes. Notably, the up-regulation of genes, which activate lysosomal proteases, indicate a priming of skin lesion-PMNs for degradation of phagocytosed material. These findings demonstrate that migration of PMNs to skin lesions induces a transcriptional activation program, which regulates cellular fate and function, and promotes wound healing.


The evolution of ultraconserved elements with different phylogenetic origins.
Ultraconserved elements of DNA have been identified in vertebrate and invertebrate genomes. These elements have been found to have diverse functions, including enhancer activities in developmental processes. The evolutionary origins and functional roles of these elements in cellular systems, however, have not yet been determined. Here, we identified a wide range of ultraconserved elements common to distant species, from primitive aquatic organisms to terrestrial species with complicated body systems, including some novel elements conserved in fruit fly and human. In addition to a well-known association with developmental genes, these DNA elements have a strong association with genes implicated in essential cell functions, such as epigenetic regulation, apoptosis, detoxification, innate immunity, and sensory reception. Interestingly, we observed that ultraconserved elements clustered by sequence similarity. Furthermore, species composition and flanking genes of clusters showed lineage-specific patterns. Ultraconserved elements are highly enriched with binding sites to developmental transcription factors regardless of how they cluster. We identified large numbers of ultraconserved elements across distant species. Specific classes of these conserved elements seem to have been generated before the divergence of taxa and fixed during the process of evolution. Our findings indicate that these ultraconserved elements are not the exclusive property of higher modern eukaryotes, but rather transmitted from their metazoan ancestors.


Elements Involved in the Rsv3-Mediated Extreme Resistance against an Avirulent Strain of Soybean Mosaic Virus.
Extreme resistance (ER) is a type of R-gene-mediated resistance that rapidly induces a symptomless resistance phenotype, which is different from the phenotypical R-resistance manifested by the programmed cell death, accumulation of reactive oxygen species, and hypersensitive response. The Rsv3 gene in soybean cultivar L29 is responsible for ER against the avirulent strain G5H of soybean mosaic virus (SMV), but is ineffective against the virulent strain G7H. Rsv3-mediated ER is achieved through the rapid accumulation of callose, which arrests SMV-G5H at the point of infection. Callose accumulation, however, may not be the lone mechanism of this ER. Analyses of RNA-seq data obtained from infected soybean plants revealed a rapid induction of the abscisic acid pathway at 8 h post infection (hpi) in response to G5H but not to G7H, which resulted in the down-regulation of transcripts encoding β-1,3 glucanases that degrade callose in G5H-infected but not G7H-infected plants. In addition, parts of the autophagy and the small interfering (si) RNA pathways were temporally up-regulated at 24 hpi in response to G5H but not in response to G7H. The jasmonic acid (JA) pathway and many WRKY factors were clearly up-regulated only in G7H-infected plants. These results suggest that ER against SMV-G5H is achieved through the quick and temporary induction of ABA, autophagy, and the siRNA pathways, which rapidly eliminate G5H. The results also suggest that suppression of the JA pathway in the case of G5H is important for the Rsv3-mediated ER.


Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis.
Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP) induction was favored over long-term depression (LTD) in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β) perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS.


Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial.
This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed. This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms. Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC.


Generation of DC from mouse spleen cell cultures in response to GM-CSF: immunophenotypic and functional analyses.
In all tissues that have been studied to date, dendritic leucocytes constitute only a small proportion of total cells and are difficult both to isolate and purify. This study reports on a method for the propagation of large numbers of dendritic cells (DC) from mouse spleen using granulocyte-macrophage colony-stimulating factor (GM-CSF) and their characteristics. Within a few days of liquid culture in GM-CSF, B10 BR (H-2k, I-E+) mouse splenocytes formed loosely adherent myeloid cell clusters. Mononuclear progeny released from these clusters at and beyond 4 days exhibited distinct dendritic morphology and strongly expressed leucocyte common antigen (CD45), CD11b, heat-stable antigen, Pgp-1 (CD44) and intercellular adhesion molecule-1 (ICAM-1; CD54). The intensity of expression of the DC-restricted markers NLDC 145 and 33D1, the macrophage marker F4/80, and Fc gamma RII (CDw32) was low to moderate, whereas the cells were negative for CD3, CD45RA and NK1.1. High and moderate levels, respectively, of cell surface staining for major histocompatibility complex (MHC) class II (I-Ek) and the B7 antigens (counter-receptors of CTLA4, a structural homologue of CD28) were associated with potent stimulation of unprimed, allogeneic T cells (B10; H-2b, I-E-). DC propagated in a similar fashion from DBA/2 mouse spleen proved to be strong antigen-presenting cells (APC) for MHC-restricted, syngeneic T-helper type 2 (Th2) cell clones specifically responsive to sperm whale myoglobin. Footpad or intravenous injection of GM-CSF-stimulated B10.BR spleen-derived DC into B10 (H-2b, I-E-) recipients resulted in homing of the allogeneic cells to T-cell-dependent areas of lymph nodes and spleen, where they strongly expressed donor MHC class II antigen 1-2 days later. These findings indicate that cells can be propagated from fresh splenocyte suspensions that exhibit distinctive features of DC, namely morphology, motility, cell-surface phenotype, potent allogeneic and syngeneic APC function and in vivo homing ability. Propagation of DC in this manner from progenitors present in lymphoid tissue provides an alternative and relatively convenient source of high numbers of these otherwise difficult to isolate but functionally important APC.


A critical discussion of intraclass correlation coefficients.
In general, intraclass correlation coefficients (ICC's) are designed to assess consistency or conformity between two or more quantitative measurements. They are claimed to handle a wide range of problems, including questions of reliability, reproducibility and validity. It is shown that care must be taken in choosing a suitable ICC with respect to the underlying sampling theory. For this purpose a decision tree is developed. It may be used to choose a coefficient which is appropriate for a specific study setting. We demonstrate that different ICC's may result in quite different values for the same data set, even under the same sampling theory. Other general limitations of ICC's are also addressed. Potential alternatives are presented and discussed, and some recommendations are given for the use of an appropriate method.


Statistical analysis of clinical trials.
The randomized clinical trial is widely viewed to be the gold standard for evaluation of treatments, diagnostic procedures, or disease screening. The proper design and analysis of a clinical trial requires careful consideration of the study objectives (eg, whether to demonstrate treatment superiority or noninferiority) and the nature of the primary end point. Different statistical methods apply when the end point variable is discrete (counts), continuous (measurements), or time to event (survival analysis). Other complicating factors include patient noncompliance, loss to follow-up, missing data, and multiple comparisons when more than 2 treatments are evaluated in the same study. This article provides an overview of the basic statistical approaches for analyzing clinical trials with binary, continuous or time-to-event outcomes as well as methods for handling protocol deviations due to noncompliance and early drop-out. Issues surrounding the determination of sample size and power of clinical trials are also discussed.


Status of forest onchocerciasis in the Lower Cross River basin, Nigeria: entomologic profile after five years of ivermectin intervention.
In the Lower Cross River basin in Nigeria, no pre-control entomologic profile of Onchocerca volvulus infection in the local Simulium damnosum population was available prior to the initiation of an ivermectin control program in 1995. A longitudinal entomologic study was therefore carried out over a 12-month period (January-December 2001) at the Agbokim waterfalls and Afi River, which are breeding sites of S. damnosum in the river basin. A total of 9,287 adult S. damnosum were caught on human bait; 9,048 (97.43%) were dissected, of which 313 (3.46%) were infected. Annual biting rates (ABRs) of 42,419 and 28,346 bites per persons per year were recorded at the Agbokim Waterfalls and Afi River, respectively. The annual transmission potential (ATP) was 419 infective larvae per person per year at the Agbokim Waterfalls and 427 at the Afi River. Monthly biting rate and monthly transmission potential varied significantly (P < 0.05) at the two sites. Transmission was highly seasonal from April to September, corresponding to the peak biting period of the vector. The high ATP and ABR values are a measure of the mesoendemicity of onchocerciasis in the river basin. There was a significant F(0).05 (1, 10) (P < 0.05) variation in the relative fly abundance from both sites. It was observed that human activities such as farming, fishing, timber cutting, and hunting are done in the early morning and late afternoon, which corresponds to the peak diurnal biting period of the vector. Changes in these practices and attitudes may markedly affect the disease intensity and transmission.


Mobile learning app: A novel method to teach clinical decision making in prosthodontics.
Prosthodontics involves replacing lost dentofacial structures using artificial substitutes. Due to availability of many materials and techniques, clinician's clinical decision-making regarding appropriate selection of prosthesis requires critical thinking abilities and is demanding. Especially during graduate training years, learners do not receive the exposure to a variety of cases, thus their clinical reasoning skills are not developed optimally. Therefore, using the trend of incorporating technology in education, we developed a mobile learning app for this purpose. The aim of this study was to evaluate learners' perceptions of this app's utility and impact on their clinical decision-making skills. After taking informed consent, interns of the Department of Prosthodontics of VSPM Dental College, Nagpur, India, during the academic year May 2015-May 2016 were sent the link for the app to be installed in their Android smartphones. Their perceptions were recorded on a feedback questionnaire using 5-point Likert scale. The script concordance test (SCT) was used to check for changes in clinical reasoning abilities. Out of 120 students who were sent the link, 102 downloaded the link and 92 completed the feedback questionnaire and appeared for the SCT (response rate: 76%). The overall response to the app was positive for more than two-thirds of interns, who reported a greater confidence in their clinical decision-making around prostheses through this app and 94% of the students felt that this app should be regularly used along with conventional teaching techniques. Mean SCT scores were pretest 41.5 (±1.7) and posttest 63 (±2.4) (P < 0.005). Clinical decision-making in prosthodontics, a mobile learning app, is an effective way to improve clinical reasoning skills for planning prosthodontic rehabilitation. It is well received by students.


A Rapid Resazurin-Based Microtiter Assay to Evaluate QoI Sensitivity for Alternaria alternata Isolates and Their Molecular Characterization.
Chemical management of Alternaria brown spot of citrus is based upon the timely application of site-specific fungicides, many of which are vulnerable to the development of fungicide resistance. A rapid microtiter bioassay based on the colorimetric changes of resazurin (RZ) dye was developed to evaluate the sensitivity of Alternaria alternata to quinone outside inhibitor (QoI) fungicides. Four liquid media (complete medium, minimal medium, potato dextrose broth, and yeast peptone dextrose broth), five conidia concentrations (from 101 to 105 conidia/ ml), and five RZ concentrations (10, 20, 30, 40, and 50 μM) were evaluated. Complete medium at 105 conidia/ml and 40 μM RZ were identified as optimal for measuring RZ reduction. The effective concentration of two QoI fungicides (azoxystrobin and pyraclostrobin) needed to reduce RZ by 50% (EC50) was calculated and compared with those obtained from conidia germination tests on fungicide-amended media. Concordant EC50 values were observed (R2 = 0.923; P < 0.0001) from both methods. Resistant phenotypes were further characterized by the partial sequencing of the cytochrome b gene. Genetic variability associated with the presence or absence of two introns was observed among isolates. The identified resistant isolates had the amino acid substitution G143A, typical of QoI resistance in other fungi.


The presentation of depression in the British Army.
The British Army is predominately composed of young men, often from disadvantaged backgrounds, in which Depression is a common mental health disorder. To construct a predictive model detailing the presentation of depression in the army that could be utilised as an educational and clinical guideline for Army clinical personnel. Utilising a Constructivist Grounded Theory, phase 1 consisted of 19 interviews with experienced Army mental health clinicians. Phase 2 was a validation exercise conducted with 3 general practitioners. Depression in the Army correlates poorly with civilian definitions, and has a unique interpretation. Young soldiers presented with symptoms not in the International Classification of Disorders and older soldiers who feared being medically downgraded, sought help outside the Army Medical Services. Women found it easier to seek support, but many were inappropriately labelled as depressed. Implications include a need to address the poor understanding of military stressors; their relationships to depressive symptoms and raise higher awareness of gender imbalances with regard to access and treatment. The results have international implications for other Armed forces, and those employed in Young Men's Mental Health. The results are presented as a simple predictive model and aide memoire that can be utilised as an educational and clinical guideline. There is scope to adapt this model to international civilian healthcare practice.


Sulfate radical oxidation of aromatic contaminants: a detailed assessment of density functional theory and high-level quantum chemical methods.
Advanced oxidation processes that utilize highly oxidative radicals are widely used in water reuse treatment. In recent years, the application of sulfate radical (SO4˙-) as a promising oxidant for water treatment has gained increasing attention. To understand the efficiency of SO4˙- in the degradation of organic contaminants in wastewater effluent, it is important to be able to predict the reaction kinetics of various SO4˙--driven oxidation reactions. In this study, we utilize density functional theory (DFT) and high-level wavefunction-based methods (including computationally-intensive coupled cluster methods), to explore the activation energies of SO4˙--driven oxidation reactions on a series of benzene-derived contaminants. These high-level calculations encompass a wide set of reactions including 110 forward/reverse reactions and 5 different computational methods in total. Based on the high-level coupled-cluster quantum calculations, we find that the popular M06-2X DFT functional is significantly more accurate for OH- additions than for SO4˙- reactions. Most importantly, we highlight some of the limitations and deficiencies of other computational methods, and we recommend the use of high-level quantum calculations to spot-check environmental chemistry reactions that may lie outside the training set of the M06-2X functional, particularly for water oxidation reactions that involve SO4˙- and other inorganic species.


Prediction of carcinogenicity from two versus four sex-species groups in the carcinogenic potency database.
Prediction of a positive result in rodent carcinogenesis bioassays using two instead of four sex-species groups is examined for the subset of chemicals in the Carcinogenic Potency Database that have been tested in four sex-species groups and are positive in at least one (n = 212). Under the conditions of these bioassays, a very high proportion of rodent carcinogens that are identified as positive by tests in four groups is also identified by results from one sex of each species (86-92%). Additionally, chemicals that are classified as "two-species carcinogens" or "multiple-site carcinogens" on the basis of results from four sex-species groups are also identified as two-species or multiple-site carcinogens on the basis of two sex-species groups. Carcinogenic potency (TD50) values for the most potent target site are similar when based on results from two compared to four sex-species groups. Eighty-five percent of the potency values are within a factor of 2 of those obtained from tests in 4 sex-species groups, 94% are within a factor of 4, and 98% are within a factor of 10. This result is expected because carcinogenic potency values are constrained to a narrow range about the maximum dose tested in a bioassay, and the maximum doses administered to rats and mice are highly correlated and similar in dose level. Information that can be known in advance of a 2-yr bioassay (mutagenicity, class, route, and maximum dose to test) does not identify groups of rodent carcinogens for which four sex-species groups are required to identify carcinogenicity. The range of accurate prediction of carcinogenicity using only male rats and female mice is 93% among mutagens and 88% among nonmutagens; for various routes of administration, 88-100%; for various chemical classes, 75-100%; and for various levels of the maximum dose tested, 81-100%. Results are similar for the pair male rats and male mice. Using a strength of evidence approach, weaker carcinogens are somewhat less likely than stronger carcinogens to be identified by two sex-species groups. Strength of evidence is measured using the proportion of experiments on a chemical that are positive, the extent to which tumors occur in animals that die before terminal sacrifice, and whether the chemical induces tumors at more than one site and in more than one species.


Removal of phenol and chlorophenols from water with reusable dye-affinity hollow fibers.
Reactive Green HE 4BD carrying polyamide hollow fibers were investigated as dye-affinity adsorbents for removal of chlorophenols (i.e., phenol, o-chlorophenol, p-chlorophenol and 2,4,6-trichlorophenol). Adsorption rates of chlorophenols were very high. Equilibrium was achieved in about 30 min. The applicability of two kinetic models including pseudo-first order and pseudo-second order model was estimated on the basis of comparative analysis of the corresponding rate parameters, equilibrium capacity and correlation coefficients. Results suggest that chemisorption process could be the rate-limiting step in the adsorption process. The maximum adsorption values of chlorophenols onto the Reactive Green HE 4BD carrying hollow fibers were 145.9 micromol/g for phenol, 179.2 micromol/g for 2,4,6-trichlorophenol, 194.5 micromol/g for p-chlorophenol and 202.8 micromol/g for o-chlorophenol. The affinity order was as follows: o-chlorophenol>p-chlorophenol>2,4,6-trichlorophenol>phenol. The adsorption capacity of chlorophenols decreased with increasing pH. Desorption of chlorophenols was achieved using methanol solution (30%, v/v). The Reactive Green HE 4BD-carrying hollow fibers are suitable for repeated use for more than 10 cycles without noticeable loss of adsorption capacity.


Classification and clinical anatomy of the first spinal nerve: surgical implications.
Data regarding the first cervical nerve are scanty and conflicting, however this nerve may need to be identified for neurosurgical procedures such as rhizotomy for torticollis and suboccipital pain syndromes. The authors performed the present study to elucidate further the detailed anatomy of the first cervical nerve and review its clinical relevance. Forty adult cadavers (80 sides) were used in this study. Dissection was performed at the craniocervical junction with special attention to the formation and presence of the components of the C-1 spinal nerve. Additionally, connections between the C-1 nerve and the spinal accessory nerves were recorded. The authors classified the C-1 nerves into Types Ia, Ib, and II, in 34, 9, and 37 sides, respectively. Type Ia was composed of ventral and dorsal roots with a dorsal root ganglion, Type Ib was composed of ventral and dorsal roots and no dorsal root ganglion, and Type II was composed of only ventral roots. All types contained both dorsal and ventral rami. Mackenzie's nerve was identified on 2 left sides (2.5%). On 48 sides (60%), the C-1 nerve received a mean of 2.5 dorsal rootlets. In the remaining specimens, C-1 did not receive any dorsal rootlets. On the sides found to receive C-1 dorsal rootlets, 14 (30%) were found to have a distinct dorsal root ganglion present, and in 21 (44%) the spinal accessory nerve joined with the dorsal rootlets. The first cervical vertebra in these cases did not possess a dorsal root ganglion. A dorsal ramus of the C-1 spinal nerve was identified on all sides. Communication between the dorsal rami of C-1 and C-2 near their posterior elements was found on 12 sides (15%). A detailed knowledge of C-1 nerve anatomy may be of use to the surgeon operating in the vicinity. Specifically, this knowledge may be helpful in procedures involving C-1 rhizotomy, including peripheral denervation procedures for cervical dystonia and occipital neuralgia.


Kinetics of enzyme-catalyzed cross-linking of feruloylated arabinan from sugar beet.
Ferulic acid (FA) groups esterified to the arabinan side chains of pectic polysaccharides can be oxidatively cross-linked in vitro by horseradish peroxidase (HRP) catalysis in the presence of hydrogen peroxide (H(2)O(2)) to form ferulic acid dehydrodimers (diFAs). The present work investigated whether the kinetics of HRP catalyzed cross-linking of FA esterified to α-(1,5)-linked arabinans are affected by the length of the arabinan chains carrying the feruloyl substitutions. The kinetics of the HRP-catalyzed cross-linking of four sets of arabinan samples from sugar beet pulp, having different molecular weights and hence different degrees of polymerization, were monitored by the disappearance of FA absorbance at 316 nm. MALDI-TOF/TOF-MS analysis confirmed that the sugar beet arabinans were feruloyl-substituted, and HPLC analysis verified that the amounts of diFAs increased when FA levels decreased as a result of the enzymatic oxidation treatment with HRP and H(2)O(2). At equimolar levels of FA (0.0025-0.05 mM) in the arabinan samples, the initial rates of the HRP-catalyzed cross-linking of the longer chain arabinans were slower than those of the shorter chain arabinans. The lower initial rates may be the result of the slower movement of larger molecules coupled with steric phenomena, making the required initial reaction of two FAs on longer chain arabinans slower than on shorter arabinans.


Cerebral venous thrombosis.
Cerebral venous thrombosis (CVT) is an uncommon cause of stroke that mainly affects young adults and children. In contrast to venous thromboembolism, women are affected three times more often than men. Baseline symptoms can vary considerably between patients, but most present with headache, seizures, or focal neurological deficits. Patients can be diagnosed with magnetic resonance imaging, computerized tomography-venography, or catheter angiography, although the latter is rarely required anymore. Approximately 30-50% of patients have an intracerebral hemorrhage, which can range from a small juxtacortical hemorrhage to large space-occupying lesions. Based on limited evidence from clinical trials, the primary therapy for CVT is anticoagulation with heparin. Uncontrolled studies have shown promising results for the use of endovascular treatment in severely affected patients, but these studies require confirmation in prospective clinical trials. In patients who develop clinical and radiological signs of impending herniation decompressive surgery can be both life saving and result in a good functional outcome.


Priority Outcomes in Critically Ill Children: A Patient and Parent Perspective.
Outcomes in pediatric critical care research are typically selected by the researcher. (1) To identify outcomes prioritized by patients and their families following a critical illness and (2) to determine the overlap between patient-centered and researcher-selected study outcomes. An exploratory descriptive qualitative study nested within a longitudinal cohort study conducted in 2 pediatric intensive care units (PICUs). Participants were purposively sampled from the primary cohort to ensure adequate demographic representation. Qualitative descriptive approaches based on naturalistic observation were used to collect data and analyze results. Data were coded by using the International Classification of Functioning, Disability, and Health Children and Youth (ICF-CY) framework. Twenty-one participants were interviewed a mean of 5.1 months after PICU discharge. Outcomes fell into 2 categories: patient-centered and family-centered. In the former, diagnosis, survival, and prognosis were key priorities during the acute critical illness. Once survival appears possible, functioning (physical, cognitive, and emotional), and factors that influence recovery (ie, rehabilitation, environment, and quality of life) are prioritized. Family-centered outcomes consisted of parents' psychosocial functioning and experience of care. Patient-centered outcomes were covered well by the selected study measures of functioning, but not by the clinical outcome measures. Functioning and quality of life are key patient-centered outcomes during recovery from critical illness. These are not well captured by end points typically used in PICU studies. These results justify the importance of patient- and family-centered outcomes in PICU research and a need to determine how these outcomes can be comprehensively measured.


Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer.
Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene expression. Androgen levels and androgen-regulated gene expression (by microarray profiling, quantitative reverse transcription-PCR, and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the gonadotropin-releasing hormone antagonist, Acyline, versus placebo in healthy men. To assess the effects of long-term ADT, gene expression measurements were evaluated at baseline and after 3, 6, and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized prostate cancer. Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, and TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and prostate-specific antigen (PSA), were not suppressed after short-term castration or after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in prostate cancer samples at each time point of ADT. Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing prostate cancer cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment.


Generalized models as a universal approach to the analysis of nonlinear dynamical systems.
We present a universal approach to the investigation of the dynamics in generalized models. In these models the processes that are taken into account are not restricted to specific functional forms. Therefore a single generalized models can describe a class of systems which share a similar structure. Despite this generality, the proposed approach allows us to study the dynamical properties of generalized models efficiently in the framework of local bifurcation theory. The approach is based on a normalization procedure that is used to identify natural parameters of the system. The Jacobian in a steady state is then derived as a function of these parameters. The analytical computation of local bifurcations using computer algebra reveals conditions for the local asymptotic stability of steady states and provides certain insights on the global dynamics of the system. The proposed approach yields a close connection between modelling and nonlinear dynamics. We illustrate the investigation of generalized models by considering examples from three different disciplines of science: a socioeconomic model of dynastic cycles in china, a model for a coupled laser system and a general ecological food web.


Effects of an acute bout of aerobic exercise on immediate and subsequent three-day food intake and energy expenditure in active and inactive men.
This study examined the effects of an acute bout of low-intensity cycling on food intake and energy expenditure over four days. Thirty healthy, active (n=15) and inactive (n=15) men completed two conditions (exercise and control), in a randomised crossover fashion. The exercise experimental day involved cycling for one hour at an intensity equivalent to 50% of maximum oxygen uptake and two hours of rest. The control condition comprised three hours of rest. Participants arrived at the laboratory fasted overnight; breakfast was standardised and an ad libitum pasta lunch was consumed on each experimental day. Participants kept a food diary and wore an Actiheart to estimate energy intake and expenditure for the remainder of the experimental days and over the subsequent 3 days. Ad libitum lunch energy intake did not differ between conditions (p=0.32, d=0.18) or groups (p=0.43, d=0.27). Energy intake in the active group was greater on the exercise experimental day than on the control experimental day (mean difference=2070 kJ; 95% CI 397 to 3743 kJ, p=0.024, d=0.56) while in the inactive group it was increased on only the third day after exercise (mean difference=2225 kJ; 95% CI 414 to 4036 kJ, p=0.024, d=0.80). There was only a group effect (p=0.032, d=0.89) for free-living energy expenditure, indicating that active participants expended more energy than inactive over this period. Acute low-intensity exercise did not affect energy intake at the meal immediately after exercise, but induces an acute (within the experimental day) and delayed (third day after the experimental day) increase in energy intake in active and inactive participants, respectively with no compensatory changes to daily energy expenditure. These results suggest that active individuals compensate for an acute exercise-induced energy deficit quicker than inactive individuals.


Two faces of high-molecular-weight kininogen (HK) in angiogenesis: bradykinin turns it on and cleaved HK (HKa) turns it off.
High-molecular-weight kininogen (HK) is a plasma protein that possesses multiple physiological functions. Originally identified as a precursor of bradykinin, a bioactive peptide that regulates many cardiovascular processes, it is now recognized that HK plays important roles in fibrinolysis, thrombosis, and inflammation. HK binds to endothelial cells where it can be cleaved by plasma kallikrein to release bradykinin (BK). The remaining portion of the molecule, cleaved HK, is designated cleaved high-molecular-weight kininogen or HKa. While BK has been intensively studied, the physiological implication of the generation of HKa is not clear. Recent studies have revealed that HKa inhibits angiogenesis while BK promotes angiogenesis. These findings represent novel functions of the kallikrein-kinin system that have not yet been fully appreciated. In this review, we will briefly discuss the recent progress in the studies of the molecular mechanisms that mediate the antiangiogenic effect of HKa and the proangiogenic activity of BK.


Proteomic, biomechanical and functional analyses define neutrophil heterogeneity in systemic lupus erythematosus.
Low-density granulocytes (LDGs) are a distinct subset of proinflammatory and vasculopathic neutrophils expanded in systemic lupus erythematosus (SLE). Neutrophil trafficking and immune function are intimately linked to cellular biophysical properties. This study used proteomic, biomechanical and functional analyses to further define neutrophil heterogeneity in the context of SLE. Proteomic/phosphoproteomic analyses were performed in healthy control (HC) normal density neutrophils (NDNs), SLE NDNs and autologous SLE LDGs. The biophysical properties of these neutrophil subsets were analysed by real-time deformability cytometry and lattice light-sheet microscopy. A two-dimensional endothelial flow system and a three-dimensional microfluidic microvasculature mimetic (MMM) were used to decouple the contributions of cell surface mediators and biophysical properties to neutrophil trafficking, respectively. Proteomic and phosphoproteomic differences were detected between HC and SLE neutrophils and between SLE NDNs and LDGs. Increased abundance of type 1 interferon-regulated proteins and differential phosphorylation of proteins associated with cytoskeletal organisation were identified in SLE LDGs relative to SLE NDNs. The cell surface of SLE LDGs was rougher than in SLE and HC NDNs, suggesting membrane perturbances. While SLE LDGs did not display increased binding to endothelial cells in the two-dimensional assay, they were increasingly retained/trapped in the narrow channels of the lung MMM. Modulation of the neutrophil proteome and distinct changes in biophysical properties are observed alongside differences in neutrophil trafficking. SLE LDGs may be increasingly retained in microvasculature networks, which has important pathogenic implications in the context of lupus organ damage and small vessel vasculopathy.


Effective use of forensic science in volume crime investigations: identifying recurring themes in the literature.
New scientific, technological and legal developments, particularly the introduction of national databases for DNA and fingerprints, have led to increased use of forensic science in the investigation of crime. There is an assumption, and in some instances specific assertions, that such developments bring improvements either in broad criminal justice terms or more narrowly in terms of economic or practical efficiencies. The underlying presumption is that the new technological opportunities will be understood and effectively implemented. This research investigates whether such increases in activity have also been accompanied by improvements in the effective use of forensic science. A systematic review of thirty-six reports published (predominantly in England and Wales) since the 1980s, which have considered the use of forensic science in the investigation of volume crimes, was carried out. These reports have identified a number of recurrent themes that influenced how effectively forensic science was used in investigations. The themes identified included forensic knowledge and training of investigators, communication and information exchange between specialists and investigators, timeliness of forensic results, interagency relationships and deployment of crime scene examiner resources. The research findings suggest that these factors continue to hinder the effective use of forensic science despite technological advances and this paper considers their potential causes.


Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic.
The COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19. To facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS). The present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research - with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics. A model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described. There is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.


Binocular single vision and perceptual processing.
Stimuli with small binocular disparities are seen as single, despite their differing visual directions for the two eyes. Such stimuli also yield stereopsis, but stereopsis and single vision can be dissociated. The occurrence of binocular single vision depends not only on the disparities of individual stimulus elements, but also on the geometrical relation of different parts of the pattern presented to each eye. A pair of vertical bars with opposite binocular disparities is seen as single if the pair is moderately widely spaced but not if it is narrow. Vertical alignment and identity in length of such bars also increase the occurrence of double vision. It is argued that these effects reflect the extraction of features of the monocular patterns, with these detected monocular features determining the binocular percept. Single and double vision of bars differing in orientation can be similarly analysed. The occurrence of relatively elaborate processing of monocular signals does not exclude the possibility that binocular interaction can occur between signals that have not been so processed. Multiple sites or types of binocular interaction are likely.


Establishment of a two-dimensional chiral HPLC system for the simultaneous detection of lactate and 3-hydroxybutyrate enantiomers in human clinical samples.
A two-dimensional chiral high-performance liquid chromatography system was established for simultaneous detection of lactate (LA) and 3-hydroxybutyrate (3HB) enantiomers in human clinical samples. d-LA is increased upon kidney damage but 3HB protected against kidney injury. Therefore, determining the concentrations of D,L-LA and D,L-3HB simultaneously would be useful for evaluating pathological conditions. LA and 3HB were pre-column-derivatized with the fluorescent reagent 4-(N-chloroformylmethyl-N-methylamino)-7-nitro-2,1,3-benzoxadiazole (NBD-COCl) at 60 °C for 15 min and separated in the first dimension with a capillary monolithic octadecylsilane column. The mobile phase consisted of 13% acetonitrile and 0.05% tirfluoroacetic acid in water. Chiralpak QD-AX and KSAACSP-001S enantioselective columns were used in the second dimension to separate LA and 3HB enantiomers, respectively. Mobile phases were mixed solutions of methanol and acetonitrile containing formic acid. The separation factors were 1.14 and 1.08, respectively. The detection limit of LA and 3HB enantiomers was 10 fmol/injection. This method was applied to human clinical samples; intra- and inter-day relative standard deviations of LA and 3HB enantiomers were, respectively, 1.04-3.25% and 1.61-5.12% in plasma, 9.19-11.2% and 4.60-5.89% in urine, and 7.12-8.90% and 2.86-6.97% in saliva. This novel analytical method is a powerful tool for investigating variations in LA and 3HB enantiomers under disease conditions.


Association of Expanded VA Hospice Care With Aggressive Care and Cost for Veterans With Advanced Lung Cancer.
Medicare hospice beneficiaries discontinue disease-modifying treatments because the hospice benefit limits access. While veterans have concurrent access to hospice care and Veterans Affairs (VA) Medical Center (VAMC)-provided treatments, the association of this with changes in treatment and costs of veterans' end-of-life care is unknown. To determine whether increasing availability of hospice care, without restrictions on disease-modifying treatments, is associated with reduced aggressive treatments and medical care costs at the end of life. A modified difference-in-differences study design, using facility fixed effects, compared patient outcomes during years with relatively high vs lower hospice use. This study evaluated 13 085 veterans newly diagnosed with stage IV non-small cell lung cancer (NSCLC) from 113 VAMCs with a minimum of 5 veterans diagnosed with stage IV NSCLC per year, between 2006 and 2012. Data analyses were conducted between January 2017 and July 2018. Using VA inpatient, outpatient, pharmacy claims, and similar Medicare data, we created VAMC-level annual aggregates of all patients who died of cancer for hospice use, cancer treatment, and/or concurrent receipt of both in the last month of life, dividing all VAMC years into quintiles of exposure to hospice availability. Receipt of aggressive treatments (2 or more hospital admissions within 30 days, tube feeding, mechanical ventilation, intensive care unit [ICU] admission) and total costs in the first 6 months after diagnosis. Of the 13 085 veterans included in the study, 12 858 (98%) were men; 10 531 (81%) were white, and 5949 (46%) were older than 65 years. Veterans with NSCLC treated in a VAMC in the top hospice quintile (79% hospice users), relative to the bottom quintile (55% hospice users), were more than twice as likely to have concurrent cancer treatment after initiating hospice care (adjusted odds ratio [AOR], 2.28; 95% CI, 1.67-3.31). Nonetheless, for veterans with NSCLC seen in VAMCs in the top hospice quintile, the AOR of receiving aggressive treatment in the 6 months after diagnosis was 0.66 (95% CI, 0.53-0.81), and the AOR of ICU use was 0.78 (95% CI, 0.62-0.99) relative to patients seen in VAMCs in the bottom hospice quintile. The 6-month costs were lower by an estimated $266 (95% CI, -$358 to -$164) per day for the high-quintile group vs the low-quintile group. There was no survival difference. Increasing the availability of hospice care without restricting treatment access for veterans with advanced lung cancer was associated with less aggressive medical treatment and significantly lower costs while still providing cancer treatment.


Differential microvascular response to cyclooxygenase blockade in the rat small intestine during acute bacteremia.
To determine whether arachidonic acid metabolites are mediators of regional blood flow changes during sepsis, we examined the effects of cyclooxygenase blockade on intestinal microvascular diameters and blood flow during acute bacteremia, induced in the rat by the intravenous injection of 10(9) live Escherichia coli. Mean arterial pressure, cardiac output, intestinal microvascular diameters, and blood flow were measured in the presence or absence of a topically applied selective cyclooxygenase inhibitor (mefenamate). Bacteremia caused a diffuse constriction of both arterioles and venules and a concomitant 50% decrease in blood flow. Treatment with mefenamate did not affect baseline intestinal microvascular tone or bacteremia-induced arteriolar constriction and hypoperfusion, but did reverse an intense venular constriction. Our results suggest that the small intestinal microcirculation has a differential response to cyclooxygenase products of arachidonic acid metabolism during acute bacteremia. They appear not to be mediators of the intestinal arteriolar constriction and hypoperfusion observed during acute E. coli bacteremia, but profoundly influence the mesenteric venular constriction. These observations support the concept that microvascular control mechanisms are different not only between but within organ specific vascular beds.