Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: study protocol for a randomised controlled trial.
Constipation affects up to 20% of adults. Chronic constipation (CC) affects 1-2% of adults. Patient dissatisfaction is high; nearly 80% feel that laxative therapy is unsatisfactory and symptoms have significant impact on quality of life. There is uncertainty about the value of specialist investigations and whether equipment-intensive therapies using biofeedback confer additional benefit when compared with specialist conservative advice. A three-arm, parallel-group, multicentre randomised controlled trial. to determine whether standardised specialist-led habit training plus pelvic floor retraining using computerised biofeedback is more clinically effective than standardised specialist-led habit training alone; to determine whether outcomes are improved by stratification based on prior investigation of anorectal and colonic pathophysiology. Primary outcome measure is response to treatment, defined as a 0.4-point (10% of scale) or greater reduction in Patient Assessment of Constipation-Quality of Life (PAC-QOL) score 6 months after the end of treatment. Other outcomes up to 12 months include symptoms, quality of life, health economics, psychological health and qualitative experience. (1) habit training (HT) with computer-assisted direct visual biofeedback (HTBF) results in an average reduction in PAC-QOL score of 0.4 points at 6 months compared to HT alone in unselected adults with CC, (2) stratification to either HT or HTBF informed by pathophysiological investigation (INVEST) results in an average 0.4-point reduction in PAC-QOL score at 6 months compared with treatment not directed by investigations (No-INVEST). Inclusion: chronic constipation in adults (aged 18-70 years) defined by self-reported symptom duration of more than 6 months; failure of previous laxatives or prokinetics and diet and lifestyle modifications. Consenting participants (n = 394) will be randomised to one of three arms in an allocation ratio of 3:3:2: [1] habit training, [2] habit training and biofeedback or [3] investigation-led allocation to one of these arms. Analysis will be on an intention-to-treat basis. This trial has the potential to answer some of the major outstanding questions in the management of chronic constipation, including whether costly invasive tests are warranted and whether computer-assisted direct visual biofeedback confers additional benefit to well-managed specialist advice alone. International Standard Randomised Controlled Trial Number: ISRCTN11791740. Registered on 16 July 2015.


Magneto-elastic properties of a spin crossover membrane deposited on a deformable substrate.
Spin-crossover (SCO) solids have been studied for several years due to their fascinating physical properties and their potential applications as optical switches and reversible high-density memories for information storage. Through this article, we will examine in details the effects of substrate's lattice parameters, on a deformable spin crossover membrane, simulated using an electro-elastic model taking into account the volume change at the transition. The molecules of the membrane can be either in the low spin state (LS) or the high spin state (HS), while those of the substrate are electronically neutral. Magnetic properties of the SCO membrane and the pressure distribution as a function of the lattice parameter of the substrate have been investigated. We demonstrated that the thermally induced first-order spin transition is significantly affected by the structural properties of the substrate, where a rise in the lattice parameter of the latter lowers the transition temperature and reduces the width of the thermal hysteresis loop. The investigations on the spatiotemporal aspects of the spin transition in the membrane demonstrates that the nucleation and growth processes are sensitive to the structural properties of the elastic misfit between the substrate and the SCO membrane.


Prospective Association of Serum and Dietary Magnesium with Colorectal Cancer Incidence.
Laboratory and epidemiologic research suggests a protective role of magnesium in colorectal cancer development. We estimated the associations of serum and dietary magnesium with colorectal cancer incidence in the Atherosclerosis Risk in Communities (ARIC) study. Serum magnesium concentration was measured in blood collected twice (1987-1989 and 1990-1992) and averaged. Dietary magnesium was assessed by food-frequency questionnaire administered twice (1987-1989 and 1993-1995) and averaged. For both dietary and serum magnesium, the averaged measures were categorized into quintiles for analysis. Analyses included 315 colorectal cancer cases among 13,009 participants for serum magnesium (followed for a median of 20.4 years), and 256 cases among 10,971 participants for dietary magnesium (followed for a median of 17.5 years). Cox proportional hazards regression was used to calculate multivariable-adjusted HRs and 95% confidence intervals (CI). Multivariable-adjusted HRs (95% CI) of colorectal cancer for the highest four quintiles compared with the first quintile of serum magnesium were as follows: Q2: 0.70 (0.49-0.99); Q3: 0.68 (0.47-1.00); Q4: 0.87 (0.62-1.21); and Q5: 0.79 (0.57-1.11; P trend = 0.04). An inverse association was present in females (HR for Q5 vs. Q1: 0.59, 95% CI: 0.36-0.98, P trend = 0.01), but not males (HR for Q5 vs. Q1: 1.10, 95% CI: 0.67-1.79, P trend = 0.92; P interaction = 0.34). Dietary magnesium was not statistically significantly associated with colorectal cancer risk. Our study found a higher risk of colorectal cancer with lower serum magnesium among females, but not males. If our findings are confirmed, maintaining adequate serum magnesium levels may be important for colorectal cancer prevention.


Phylogenetic placement of the ectomycorrhizal genus Cenococcum in Gloniaceae (Dothideomycetes).
Cenococcum is a genus of ectomycorrhizal Ascomycota that has a broad host range and geographic distribution. It is not known to produce either meiotic or mitotic spores and is known to exist only in the form of hyphae, sclerotia and host-colonized ectomycorrhizal root tips. Due to its lack of sexual and asexual spores and reproductive structures, it has proven difficult to incorporate into traditional classification within Ascomycota. Molecular phylogenetic studies of ribosomal RNA placed Cenococcum in Dothideomycetes, but the definitive identification of closely related taxa remained elusive. Here we report a phylogenetic analysis of five nuclear loci (SSU, LSU, TEF1, RPB1, RPB2) of Dothideomycetes that placed Cenococcum as a close relative of the genus Glonium of Gloniaceae (Pleosporomycetidae incertae sedis) with strong statistical support. Glonium is a genus of saprobic Dothideomycetes that produces darkly pigmented, carbonaceous, hysteriate apothecia and is not known to be biotrophic. Evolution of ectomycorhizae, Cenococcum and Dothideomycetes is discussed.


Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation.
White matter hyperintensities (WMHs) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D convolutional neural network with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control, and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. Four hundred thirty-two subjects were recruited to train the CNNs from four multisite imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multisite study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 ± 0.08 and the lowest modified Hausdorff distance of 2.98 ± 4.40 mm. We further validated our models highlighting their robustness on "clinical adversarial cases" simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io.


Comparison between double-pigtail ureteral stents and ureteral bypass devices for treatment of ureterolithiasis in cats.
OBJECTIVE To compare the complication rates and outcomes in cats with ureteral obstruction treated by placement of double-pigtail ureteral stents or ureteral bypass (UB) devices. DESIGN Retrospective cohort study. ANIMALS Cats with unilateral or bilateral ureterolithiasis that received double-pigtail ureteral stents (30 stents in 27 cats; stent group) or UB devices (30 devices in 23 cats; UB group). PROCEDURES Medical records were reviewed to collect data on signalment, clinical signs, serum biochemical data, surgical procedure, duration of hospitalization, complications, and follow-up (≥ 6 months after placement) information. Outcomes were compared between device types. RESULTS Median durations of surgery and hospitalization were significantly longer in the stent versus UB group. Perioperative mortality rate was 18% (5/27) in the stent group and 13% (3/23) in the UB group. Median survival time was shorter in the stent versus UB group. Stent placement was associated with a greater risk of lower urinary tract-related signs, such as hematuria (52% [14/27]) and pollakiuria or stranguria (48% [13/27]). The risk of device occlusion was also greater in the stent (26% [7/27]) versus UB (4% [1/23]) group. The percentage of cats requiring additional procedures to treat complications was greater in the stent (44%; complications included uroabdomen, stent occlusion, and refractory cystitis) versus UB (9%; complications included UB occlusion and urethral obstruction) group. CONCLUSIONS AND CLINICAL RELEVANCE Although the benefits of stent placement in the treatment of ureteral obstruction in cats have been established, results suggested that cats treated with UB devices had a lower risk of complications and a longer survival time than those treated with double-pigtail ureteral stents.


Tinnitus distress: a paradoxical attention to the sound?
Tinnitus, the perception of sound in the absence of external stimuli, is often a disturbing symptom for which the underlying functional neuroanatomy still remains poorly understood. Most studies have focused solely on functional connectivity changes in the auditory cortex of tinnitus patients. The aim of this study was to investigate whether a correlation exists between tinnitus behavioural scores and functional brain connectivity of five resting-state networks comprising the auditory, the default mode, the external control left and right, and the salience network. For this purpose, a large sample of one hundred and thirty-five subjects underwent resting-state functional magnetic resonance imaging and their behavioural scores were obtained using clinical evaluations. Networks were extracted using independent component analysis, and functional connectivity patterns in the extracted networks were evaluated by a graph theoretical approach. The effects of tinnitus for each network were investigated by correlating the graph strength of all the regions with the tinnitus behavioural scores using stepwise fit regression analysis. Results indicated that alterations of functional interactions between key neural circuits of the brain are not limited to one single network. In particular, tinnitus distress showed a strong correlation with the connectivity pattern within and between the right executive control network and the other four resting-state networks, indicating that tinnitus distress is probably the consequence of a hyperactive attention condition. Among the behavioural scores, the strongest correlation was observed between age and hearing loss, while the tinnitus objective loudness was not correlated with any behavioural scores.


[Effect of interleukin 2 on blast proliferative activity and expression of T-cell markers in patients with acute lymphoblastic leukemia].
The proliferative activity of blast cells from patients with acute lymphoblastic leukemia was compared with the activity of lymphoid cells of the thymus and blood of healthy subjects. The spontaneous proliferative activity in cells obtained extempore varied widely. On the basis of this index groups of patients with high proliferative activity (group 1) exceeding the level of thymocyte proliferation and with low proliferative activity (group 2) were distinguished. Direct correlation was revealed between the initial spontaneous proliferative activity and the number of leukocytes as well as with the absolute number of blasts in the blood. A decrease in the initial high proliferative activity in the time course of cultivation was noted in some patients of group 1 (group 1B). In the majority of these patients (91%) the administration of interleukin-2 into the cultural medium prevented a decrease in the proliferative activity. In the other patients of group 1 (group 1A) a high spontaneous proliferative activity was not decreased during cultivation. In group 1A a proliferative response to T-cell growth factor was observed in 36% of patients. The patients' blast cells in group 2 did not respond to this lymphokine. The expression de novo of T-cell markers was observed in some patients of group 1 as a result of interleukin-2 action. The role of interleukin-2 in the pathogenesis of acute lymphoblastic leukemia is discussed.


Chemoradiotherapy for locally advanced pancreatic cancer: a radiotherapy dose escalation and organ motion study.
To determine the efficacy of radiation dose escalation and to examine organ motion during conformal radiotherapy for locally advanced pancreatic cancer. Thirty-nine patients who were consecutively treated with chemoradiotherapy were studied. Fifteen patients, treated from 1993 to 1997, received 50 Gy in 20 fractions (group I). Twenty-four patients, treated from 1997 to 2003, received an escalated dose of 55 Gy in 25 fractions (group II). Intra-fraction pancreatic tumour motion was assessed in three patients using megavoltage movies during radiation delivery to track implanted radio-opaque markers. Improved survival rates were seen in latterly treated group II patients (P=0.083), who received escalated radiotherapy to smaller treatment volumes due to advances in verification. Worse toxicity effects (World Health Organization grade 3-4) were reported by some patients (<10%), but treatment compliance was similar in both groups, indicating equivalent tolerance. Substantial intra-fraction tumour displacement due to respiratory motion was observed: this was greatest in the superior/inferior (mean=6.6 mm) and anterior/posterior (mean=4.75 mm) directions. Lateral displacements were small (<2 mm). Dose escalation is feasible in pancreatic cancer, particularly when combined with a reduction in irradiated volume, and enhanced efficacy is indicated. Large, globally applied margins to compensate for pancreatic tumour motion during radiotherapy may be inappropriate. Strategies to reduce respiratory motion, and/or the application of image-guided techniques that incorporate individual patients' respiratory motion into radiotherapy planning and delivery, will probably improve pancreatic radiotherapy.


Day-to-day measurement of patient-reported outcomes in exacerbations of chronic obstructive pulmonary disease.
Exacerbations of chronic obstructive pulmonary disease (COPD) are a major burden to patients and to society. Little is known about the possible role of day-to-day patient-reported outcomes during an exacerbation. This study aims to describe the day-to-day course of patient-reported health status during exacerbations of COPD and to assess its value in predicting clinical outcomes. Data from two randomized controlled COPD exacerbation trials (n = 210 and n = 45 patients) were used to describe both the feasibility of daily collection of and the day-to-day course of patient-reported outcomes during outpatient treatment or admission to hospital. In addition to clinical parameters, the BORG dyspnea score, the Clinical COPD Questionnaire (CCQ), and the St George's Respiratory Questionnaire were used in Cox regression models to predict treatment failure, time to next exacerbation, and mortality in the hospital study. All patient-reported outcomes showed a distinct pattern of improvement. In the multivariate models, absence of improvement in CCQ symptom score and impaired lung function were independent predictors of treatment failure. Health status and gender predicted time to next exacerbation. Five-year mortality was predicted by age, forced expiratory flow in one second % predicted, smoking status, and CCQ score. In outpatient management of exacerbations, health status was found to be less impaired than in hospitalized patients, while the rate and pattern of recovery was remarkably similar. Daily health status measurements were found to predict treatment failure, which could help decision-making for patients hospitalized due to an exacerbation of COPD.


Effect of sucrose feeding on alpha 1-adrenergic responses in rat liver.
A sustained increase in sympathetic nervous system (SNS) activity was induced by substituting a 10% sucrose solution for the drinking water of rats fed laboratory chow ad libitum. The effects of increased SNS activity on alpha 1-adrenergic processes in liver were examined by evaluating three alpha 1-responses, namely, phenylephrine-stimulated ouabain-sensitive 86Rb+ uptake, 45Ca2+ efflux, and glucose release. Sucrose feeding abolished phenylephrine stimulation of ouabain-sensitive 86Rb+ uptake and 45Ca2+ efflux and induced a three- to fourfold reduction in the ability of phenylephrine to stimulate glucose release from liver slices. Pretreatment with 6-hydroxydopamine markedly reduced liver norepinephrine content. When 6-hydroxydopamine was used to prevent the sucrose-induced increase in SNS activity, the changes in 86Rb+ uptake, 45Ca2+ efflux, and glucose release that otherwise followed sucrose feeding were not observed. Sucrose feeding did not alter binding of the alpha 1-antagonist [3H]prazosin to liver cell membrane alpha 1-receptors or displacement of [3H]prazosin by the alpha-agonist epinephrine. These observations suggest that sustained increases in SNS activity may have profound effects on liver alpha 1-adrenergic events that occur subsequent to hormone-receptor interaction.


International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.
Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.


Associated factors and impact of myocarditis in patients with SLE from LUMINA, a multiethnic US cohort (LV). [corrected].
To examine the factors associated with myocarditis and its impact on disease outcomes in SLE patients. SLE patients aged > or = 16 yrs, disease duration < or = 5 yrs from LUMINA (LUpus in Minorities: NAture vs nurture), a multiethnic US cohort, were studied. Myocarditis was defined as per the category 3 of the pericarditis/myocarditis item of the SLAM-Revised (SLAM-R). Patients with concurrent pericardial involvement were excluded. Patients with myocarditis were compared with those without myocarditis or its sequelae in the preceding year. The association between myocarditis and baseline variables (T(0)) was first examined. The impact of myocarditis on disease activity over time (SLAM-R), damage accrual [SLICC Damage Index (SDI)] at last visit (T(L)) and mortality was evaluated. Fifty-three of the 496 patients studied had myocarditis. African American ethnicity [Odds ratio (OR) = 12.6; 95% CI 1.6, 97.8] and SLAM-R at diagnosis (OR = 1.1, 95% CI 1.0, 1.1) were significantly and independently associated with myocarditis. Myocarditis did not predict disease activity over time, but approached significance as a predictor of SDI at T(L) in multivariable analyses P = 0.051. Kaplan-Meier curves indicated that myocarditis was associated with shorter survival (log-rank = 4.87, P = 0.02), particularly in patients with > or = 5 yrs disease; however, myocarditis was not retained in the Cox proportional hazards regression model. Ethnicity and disease activity at diagnosis were associated with the occurrence of myocarditis in SLE. Myocarditis did not significantly impact on disease activity over time, but impacts some on damage accrual and survival, reflecting overall the more severe disease those patients experience.


Expected Monetary Impact of Oncotype DX Score-Concordant Systemic Breast Cancer Therapy Based on the TAILORx Trial.
TAILORx demonstrated that women with node-negative, hormone receptor-positive, HER2-negative breast cancers and Oncotype DX recurrence scores (RS) of 0-25 had similar 9-year outcomes with endocrine vs chemo-endocrine therapy; evidence for women aged 50 years and younger and RS 16-25 was less clear. We estimated how expected changes in practice following the trial might affect US costs in the initial 12 months of care (initial costs). Data from Surveillance, Epidemiology, and End Results (SEER), SEER-Medicare, and SEER-Genomic Health Inc datasets were used to estimate Oncotype DX testing and chemotherapy rates and mean initial costs pre- and post-TAILORx (in 2018 dollars), assuming all women received Oncotype DX testing and score-suggested therapy posttrial. Sensitivity analyses tested the impact on costs of assumptions about compliance with testing and score-suggested treatment and estimation methods. Pretrial mean initial costs were $2.816 billion. Posttrial, Oncotype DX testing costs were projected to increase from $115 to $231 million and chemotherapy use to decrease from 25% to 17%, resulting in initial care costs of $2.766 billion, or a net savings of $49 million (1.8% decrease). A small net savings was seen under most assumptions. The one exception was if all women aged 50 years and younger with tumors with RS 16-25 elected to receive chemotherapy, initial care costs could increase by $105 million (4% increase). Personalizing breast cancer treatment based on tumor genetic profiles could result in small cost decreases in the initial 12 months of care. Studies are needed to evaluate the long-term costs and nonmonetary benefits of personalized cancer care.


Coherent polarization transfer in chemically exchanging systems.
Signal Amplification by Reversible Exchange (SABRE) uses para-enriched dihydrogen, pH2, to boost the NMR signal by several orders of magnitude. Although the method was discovered more than a decade ago, the quest to optimize SABRE and to establish a complete description in silico is ever ongoing. The simulation of SABRE is exacerbated by a complex interplay of chemical exchange and coherent polarization transfer. Here, we compare two different simulation approaches, Markov chain Monte Carlo (MC) simulations and a modification of the Liouville von Neumann equation with superoperators of chemical exchange (SO). We apply these methods to simulate the fate of truncated and full, three and four spin-½ systems in two different experiments: continuous polarization at a constant or alternating B0 field. For all cases, MC and SO provided similar results, and previously reported experimental data were well reproduced. It appears that both methods are well suited to approach this matter, while SO was faster than MC by several orders of magnitude in the cases discussed.


Successful Trial of Practice Facilitation for Plan, Do, Study, Act Quality Improvement.
Practice facilitation (PF) is a promising but relatively new intervention supporting data-driven practice change. There is a need to better detail research-based facilitation methods, which must balance intervention fidelity and time restrictions with the flexibility required for the intervention. As part of a multi-level 4-armed cluster randomized clinical trial (RCT), 32 rural primary care practices received PF for 1 year. We evaluated the feasibility of having facilitators guide practices to perform 4 key driver domain activities, implemented as Plan-Do-Study-Act (PDSA) cycles, to better understand facilitation "exposure." We describe the intervention and activity length such that our experiences may be useful to other PF research efforts. Thirty-two practices serving rural patients involved in the Southeastern Collaboration to Improvement Blood Pressure Control engaged with a facilitator to develop and implement PDSAs nested within key drivers of change domains. Numbers of months practices worked on activities deemed most likely to be sustained were captured along with practice satisfaction data. All practices engaged in at least 4 domain-level activities, and 59% of the PDSAs were active for at least 3 months. There was variation by domain in the average length of the PDSA activities. Ninety-seven percent (31 of 32) of practices recommended similarly structured facilitation services to other primary care practices, and 84% (27 of 32) noted substantive changes in their care processes. In this trial, it was feasible for PFs to engage practices in at least 4 Key Driver quality improvement activities within 1 year, which will inform PF methods and protocol development in future trials.


Phenyl substituted indenylphosphine ruthenium complexes as catalysts for dehydrogenation of alcohols.
Thermal treatment of (1H-inden-3-yl)dicyclohexylphosphinium tetrafluoroborate (1) and (3-mesityl-1H-inden-3-yl)dicyclohexylphosphinium tetrafluoroborate (3) with tBuONa followed by [(η(6)-cymene)RuCl(2))](2) in methanol gave the adduct {(η(6)-cymene)RuCl(2)[(1H-inden-3-yl)PCy(2)]} (6) and {(η(6)-cymene)RuCl(2)[(3-mesityl-1H-inden-3-yl)PCy(2)]} (7), respectively. Thermal treatment of (2-phenyl-1H-inden-3-yl)dicyclohexylphosphinium tetrafluoroborate (4) with tBuONa followed by [(η(6)-cymene)RuCl(2))](2) or RuCl(3)·3H(2)O in methanol gave {Ru[κ(P):(η(6)-2-phenyl-1H-inden-3-yl)PCy(2)]Cl(2)} (8). Whereas (2-mesityl-1H-inden-3-yl)dicyclohexylphosphine (5) reacted with [(η(6)-cymene)RuCl(2))](2) (in toluene) or RuCl(3)·3H(2)O (in ethanol) to afford {Ru[κ(P):(η(6)-2-mesityl-1H-inden-3-yl)PCy(2)]Cl(2)} (9). The molecular structures of complexes 6, 8 and 9 have been determined by single-crystal X-ray diffraction analysis. In addition, complexes 8 and 9 have been found to catalyze the acceptorless dehydrogenation of alcohols in toluene. 9 displayed high activity and different substrates, including cyclic and linear alcohols, were efficiently oxidized to ketones by using 2.0 mol% of catalyst.


Characteristics of the amiodarone-warfarin interaction during long-term follow-up.
Characteristics of the amiodarone-warfarin interaction during long-term follow-up were studied. Medical records from patients seen in the anticoagulation clinic at the Hennepin County Medical Center between April 1998 and March 2003 were retrospectively reviewed. Patients were included if they were older than 18 years, used the anticoagulation clinic as their primary clinic for anticoagulation therapy, and were receiving combined amiodarone and warfarin therapy for at least one month. The primary study endpoint was the occurrence of International Normalized Ratios (INRs) of >5 at any time during combined warfarin-amiodarone therapy. The secondary endpoint was the frequency of warfarin dosage changes. A total of 70 patients met study inclusion criteria. Of these 70, 7 had amiodarone started before warfarin initiation. Of the 2434 INR values analyzed, 43% (n = 1043) were in the target therapeutic range, 34% (n = 820) were below target range, and 23% (n = 571) were above target range. A total of 102 INR values (4%) were above 5. The relative risk of having an INR of >5 for patients on concurrent warfarin and amiodarone versus those on warfarin alone was 1.366 (p = 0.005). INRs of >5 were most common during the first 12 weeks of combined therapy, with no subsequent large peaks evident. Among patients treated in an anticoagulation clinic, INR values of >5 were most common during the first 12 weeks of combined therapy with amiodarone and warfarin and necessitated reduction in warfarin dosage. No other notable changes in INR or amiodarone or warfarin dosage occurred throughout the remainder of the 80-week study period.


[Effect of testosterone and dihydrotestosterone on the sexual behavior of female rats].
Sexual behaviour was tested in female rats with ovariectomy treated with various sexual hormones and healthy male rats with sexual experience. There was a marked suppression of receptive behaviour in rats with ovariectomy but the proceptive one was preserved. A marked growth of lordosis, achieving the level of that in intact rats in estrus is observed after the administration of estradiol propionate (10 micrograms) and progesterone (500 micrograms). A single subcutaneous administration of testosterone dipropionate (100 micrograms) and dihydrotestosterone (DHT) with DHT-propionate (10 micrograms) to ovariectomized rats did not stimulate lordosis but preserved a high level of proceptive behaviour. Disconnections in the character of proceptive and mating behaviour show that different mechanisms are in the base of their regulation. No difference was noted in the effect of testosterone and DHT on sexual behaviour. The administration of DHT induced certain aggressiveness in the animals. No dynamics was observed in the character of the studied indicators for 3 days. The lack of differences in testosterone and DHT action on sexual behaviour of female rats shows that intracerebral aromatization is not obligatory for the manifestation of the effect.


Evolution of complex resistance transposons from an ancestral mercury transposon.
The molecular interrelationship of a transposon family which confers multiple antibiotic resistance and is assumed to have been generated from an ancestral mercury transposon was analyzed. Initially, the transposons Tn2613 (7.2 kilobases), encoding mercury resistance, and Tn2608 (13.5 kilobases), encoding mercury, streptomycin, and sulfonamide resistances, were isolated and their structures were analyzed. Next, the following transposons were compared with respect to their genetic and physical maps: Tn2613 and Tn501, encoding mercury resistance; Tn2608 and Tn21, encoding mercury, streptomycin, and sulfonamide resistance; Tn2607 and Tn4, encoding streptomycin, sulfonamide, and ampicillin resistance; and Tn2603, encoding mercury, streptomycin, sulfonamide, and ampicillin resistance. The results suggest that the transposons encoding multiple resistance were evolved from an ancestral mercury transposon.


The Care Team Visit: Approaching Interdisciplinary Rounds With Renewed Focus.
Interdisciplinary bedside rounds serve as a key mechanism to coordinate patient-centered care. With a focus on optimizing rounds, an interdisciplinary team developed an enhanced, structured process, coined the care team visit. Key findings included improved nurse participation, increased staff collaboration, and decreased Foley catheter days. The process outlined can be used by health care professionals to improve the effectiveness of interdisciplinary bedside rounds.


Thermal stability of amorphous nimesulide: from glass formation to crystal growth and thermal degradation.
Thermally induced physico-chemical transformations in amorphous nimesulide were studied by means of differential scanning calorimetry (DSC), thermogravimetry, and Raman microscopy. The equilibrium glass transition temperature was found to be Tg0 = 10-15 °C, and the relaxation motions were found to be temperature-dependent. Crystal growth from the amorphous phase was found to be crucially dependent on the presence of mechanical defects that serve as centers for heterogeneous nucleation. The large amounts of mechanical defects significantly decrease the activation energy of the macroscopic crystallization; the positions of the crystallization peaks and their asymmetry/shape remain however almost unchanged. At laboratory temperature, powdered nimesulide fully crystallizes within several hours, with an absolute majority of the crystalline phase being formed as the thermodynamically stable form I polymorph. Amorphous nimesulide does not crystallize from the free smooth surface (no trace of formed crystallites was found by optical microscopy after 30 days at laboratory temperature). Nimesulide was found to be very stable at temperatures above its melting point of 147.5 °C; thermal degradation starts to proceed slowly at 200 °C. Mutual correlations between the macroscopic and microscopic crystal growth processes and between the viscous flow and structural relaxation motions were discussed based on the values of the corresponding activation energies. A link between the cooperativity of structural domains, parameters of the Tool-Narayanaswamy-Moynihan relaxation model, and microscopic crystal growth was proposed.


Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models.
A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.


An automated pontine-wave detection system.
Pontine-waves (P-waves), the pontine component of ponto-geniculo-occipital waves, represent a close marker of brainstem phasic events and are associated with cardiorespiratory changes in sleep. Because visual scoring is subjective and cumbersome, we developed an automated P-wave analysis system, which could detect and classify P-waves as clusters or as isolated events in bipolar recordings of the pontine electroencephalogram (EEG) of conscious rats. A computer algorithm was developed to extract and normalize each half-wave of the pontine EEG according to the background noise level. Candidate events for different P-wave patterns (uniphasic, biphasic, and triphasic) were compared to a corresponding set of amplitude and duration thresholds to identify P-waves and to reject artifacts. Ten adult male Sprague-Dawley rats were instrumented for chronic polysomnography. Two human experts manually scored each recording, and their consensus score was used as the "gold standard" for algorithm optimization and validation. The algorithm's scoring thresholds were optimized on a training set of 5 six-hour polysomnographic records, yielding 96.8% accuracy and 97.7% sensitivity versus human consensus scoring. Validation of the algorithm, using the optimized threshold values, was conducted using a set of 5 independent recordings, resulting in 94.8% accuracy and 94.7% sensitivity versus human consensus scoring. We have developed and validated an automated system for detection and classification of P-waves in conscious rats with advantages over human scoring, including increased speed and perfect reliability.


Connecting for change: networks as a vehicle for regional health reform the early experiences of the Child Health Network for the Greater Toronto Area.
The Child Health Network (CHN) for the Greater Toronto Area (GTA) is a partnership of hospital, rehabilitation and community providers committed to developing a regional system to deliver high quality, accessible, family-centred care for mothers, newborns, children and youth. This article reviews the history and model of the CHN, assesses its achievements, and provides insights into the challenges and lessons learned by the network. Stemming from the CHN's commitment to quality, accessibility and efficiency, regionalization of maternal, newborn and children's services is emerging as a success story.


Amelanotic conjunctival melanoma.
Conjunctival melanoma is a rare condition of the eye pigment predominantly affecting white adults. We describe a 32-year-old white man with an amelanotic malignant melanoma of the conjunctiva that is not associated with primary acquired melanosis (PAM) or melanocytic nevus. The patient presented with a 2-year history of nonpigmented vascularized nodules of the right eye. Results of hematoxylin and eosin (H and E) staining of the lesion showed an invasive nodule with vertical spreading, invasion of the substantia propria corneae, and ulceration. S100 protein was expressed in the cells of the invasive nodule. HMB45 protein was highly positive in the melanoma cells. The de novo amelanotic malignant melanoma of the conjunctiva we describe is an extremely uncommon tumor mainly affecting white adults.


Video-based evaluation system for tic action in Tourette syndrome: modeling, detection, and evaluation.
Behavioral ratings based on clinical observations are still the gold standard for screening, diagnosing, and assessing outcomes in Tourette syndrome. Detecting tic symptoms plays an important role in patient treatment and evaluation; accurate tic identification is the key to clinical diagnosis and evaluation. In this study, we proposed a tic action detection method using face video feature recognition for tic and control groups. Through facial ROI extraction, a 3D convolutional neural network was used to learn video feature representations, and multi-instance learning anomaly detection strategy was integrated to construct the tic action analysis and discrimination framework. We applied this tic recognition framework in our video dataset. The model evaluation results achieved average tic detection accuracy of 91.02%, precision of 77.07% and recall of 78.78%. And the tic score curve with postprocessing provided information of how the patient's twitches change over time. The detection results at the individual level indicated that our method can effectively detect tic actions in videos of Tourette patients without the need for fine labeling, which is significant for the long-term evaluation of patients with Tourette syndrome.


Sex Differences in Fractional Flow Reserve- or Intravascular Ultrasound-Guided Percutaneous Coronary Intervention.
A recent randomized trial reported fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) strategy was noninferior to the intracoronary ultrasound (IVUS)-guided PCI strategy with respect to clinical outcomes with fewer revascularizations. This study sought to investigate the sex differences in treatment and clinical outcomes according to physiology- or imaging-guided PCI strategies. In this secondary analysis of the FLAVOUR (Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI) trial, the impact of sex on procedural characteristics, PCI rate, and outcomes according to different strategies and treatment types (PCI vs deferral of PCI) was analyzed. The primary outcome was target vessel failure (TVF) at 24 months, defined as a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization. Of 1,619 patients, 30% were women. Compared with men, women had a smaller minimal lumen area, smaller plaque burden, and higher FFR. They had a lower PCI rate (40.8% vs 47.9%; P = 0.008), which was mainly contributed by FFR guidance. Overall, women showed a lower TVF rate (2.4% vs 4.5%). According to the treatment type, the cumulative incidence of TVF was lower in women than in men among those with the deferral of PCI (1.7% vs 5.2%). However, this trend was not observed in patients who underwent PCI. In both women and men, there were no differences in clinical outcomes between the FFR- and IVUS-guided strategies. In cases of intermediate stenosis, despite receiving fewer interventions, women had more favorable outcomes than men. The use of FFR led to a lower PCI rate but had a similar prognostic value compared with IVUS in both women and men.


The effects of a fungicide and chytrid fungus on anuran larvae in aquatic mesocosms.
The amphibian disease chytridiomycosis, caused by the pathogenic fungus Batrachochytrium dendrobatidis (Bd), has been linked to significant amphibian declines over the past three decades. The most severe effects of the pathogen have been primarily observed in relatively pristine areas that are not affected by many anthropogenic factors.One hypothesis concerning improved amphibian persistence with Bd in disturbed landscapes is that contaminants may abate the effects of Bd on amphibians. Recent laboratory studies have shown that pesticides, specifically the fungicide thiophanate-methyl (TM), can kill Bd outside of hosts and clear Bd infections within hosts. Using aquatic mesocosms, we tested the hypothesis that TM (0.43 mg/L) would alter growth and development of Lithobates sphenocephalus (southern leopard frog) tadpoles and Bd-infection loads in infected individuals. We hypothesized that the scope of such alterations and infection clearing would be affected by aquatic community variables, specifically zooplankton. TM altered zooplankton diversity (reduced cladoceran and increased copepod and ostracod abundances) and caused mortality to all tadpoles in TM-exposed tanks. In TM-free tanks, Bd-exposed tadpoles in high-density treatments metamorphosed smaller than Bd-unexposed, effects that were reversed in low-density treatments. Our study demonstrates the potential adverse effects of a fungicide and Bd on tadpoles and aquatic systems.


[Combined vision and hearing impairment: in an estimated 30,000-35,000 people aged 55 years or over in The Netherlands].
To determine the number of older people with acquired dual sensory impairment (DSI) in The Netherlands. Combination of studies in the general population and in relevant subpopulations. Eight databases derived from recent studies on older persons with vision and hearing data on Dutch subjects aged 55 years or over were selected for further analysis. The measurement methods included self-reports, clinical measurements and observations. The prevalences of DSI were calculated for the general population, the non-institutionalised population, and subgroups such as older people in nursing homes and homes for the elderly. The calculated prevalences were extrapolated to the overall Dutch population. For the non-institutionalised population of 55 years and older, the prevalences of acquired DSI in two different data sets were 0.4% (95% CI: 0.2-0.6) and 0.6% (95% CI: 0.3-0.8), respectively. Among the inhabitants of homes for the elderly these percentages were 5.4% (95% CI: 0.9-9.9) and 5.5% (95% CI: 3.8-7.2), and in nursing homes they were 12.7% (95% CI: 9.7-15.7) and 16.7% (95% CI: 14.6-18.8). Acquired DSI was most common in persons 85 years of age and older. It was estimated that the number of people aged 55 years and over with acquired DSI in The Netherlands is 30,000 to 35,000. DSI is particularly a problem of the oldest old. An integrated approach to the visual and hearing problems of these subjects is essential.


Systematic assessment of tolerance to pentobarbital by pellet implantation.
Rapid tolerance development to pentobarbital by pentobarbital pellet implantation was evidenced by a decrease in sleeping time after challenge with different doses of sodium pentobarbital ranging from 37.5 to 100 mg/kg i.p. or a fixed dose of 75 mg/kg i.p. of the drug. The sleeping time produced by sodium pentobarbital decreased by 50% after 1 day. After 2 or 3 days of implantation, the sleeping time was generally further decreased to 15 to 20% of the placebo control group. Tolerance to pentobarbital was still evident 72 hours after pellet removal. The tolerance development to pentobarbital by pentobarbital pellet implantation also was demonstrated by other pentobarbital-induced responses such as hypothermia and lethality. In mice implanted with a 75-mg pentobarbital pellet for 3 days, the degree and duration of pentobarbital-induced hypothermia by intraperitoneal or intracerebral administration of the drug was attenuated. The chronic administration of pentobarbital by three days of pellet implantation reduced the effect of sodium pentobarbital on lethality as evidenced by an increase in the LD50 of sodium pentobarbital after intraperitoneal or intracerebral administration of the drug.


Development and validation of the Decision-Specific Reinvestment Scale.
Items from the Reinvestment Scale were modified to create a decision-specific version of the scale. Principal components analysis of responses from 165 participants revealed one-, two-, three-, and four-factor solutions for the Decision-Specific Reinvestment Scale. Confirmatory factor analysis of responses from a second sample of 111 participants revealed that a 13-item two-factor solution showed the best fit. The first factor comprised six items referring to conscious monitoring of the process involved in making a decision, and was termed decision reinvestment. The second factor, decision rumination, comprised seven items related to focus on negative evaluations of previous poor decisions. In an initial assessment of predictive validity, Decision-Specific Reinvestment Scale scores of 59 skilled team sport players were found to be highly correlated with coaches' ratings of players' tendency to choke under pressure (r = 0.74), with high Decision-Specific Reinvestment Scale scores indicating greater susceptibility to poor decision-making under pressure. It was concluded that the Decision-Specific Reinvestment Scale highlights a performer's predisposition to engage in behaviours detrimental to performance under pressure, namely decision reinvestment and decision rumination.


Chaperone Mediated Autophagy Degrades TDP-43 Protein and Is Affected by TDP-43 Aggregation.
TAR DNA binding protein 43 kDa (TDP-43) is a ribonuclear protein regulating many aspects of RNA metabolism. Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) are fatal neurodegenerative diseases with the presence of TDP-43 aggregates in neuronal cells. Chaperone Mediated Autophagy (CMA) is a lysosomal degradation pathway participating in the proteostasis of several cytosolic proteins including neurodegenerative associated proteins. In addition, protein oligomers or aggregates can affect the status of CMA. In this work, we studied the relationship between CMA and the physiological and pathological forms of TDP-43. First, we found that recombinant TDP-43 was specifically degraded by rat liver's CMA+ lysosomes and that endogenous TDP-43 is localized in rat brain's CMA+ lysosomes, indicating that TDP-43 can be a CMA substrate in vivo. Next, by using a previously reported TDP-43 aggregation model, we have shown that wild-type and an aggregate-prone form of TDP-43 are detected in CMA+ lysosomes isolated from cell cultures. In addition, their protein levels increased in cells displaying CMA down-regulation, indicating that these two TDP-43 forms are CMA substrates in vitro. Finally, we observed that the aggregate-prone form of TDP-43 is able to interact with Hsc70, to co-localize with Lamp2A, and to up-regulate the levels of these molecular components of CMA. The latter was followed by an up-regulation of the CMA activity and lysosomal damage. Altogether our data shows that: (i) TDP-43 is a CMA substrate; (ii) CMA can contribute to control the turnover of physiological and pathological forms of TDP-43; and (iii) TDP-43 aggregation can affect CMA performance. Overall, this work contributes to understanding how a dysregulation between CMA and TDP-43 would participate in neuropathological mechanisms associated with TDP-43 aggregation.


Molecular characterization of apocrine salivary duct carcinoma.
Contemporary classification and treatment of salivary duct carcinoma (SDC) require its thorough molecular characterization. Thirty apocrine SDCs were analyzed by the Ion Ampliseq Cancer HotSpot panel v2 for mutations in 50 cancer-related genes. Mutational findings were corroborated by immunohistochemistry (eg, TP53, BRAF, β-catenin, estrogen, and androgen receptors) or Sanger sequencing/SNaPshot polymerase chain reaction. ERBB2 (HER2), PTEN, FGFR1, CDKN2A/P16, CMET, EGFR, MDM2, and PIK3CA copy number changes were studied by fluorescence in situ hybridization. TP53 mutations (15/27, 56%), PTEN loss (11/29, 38%, including 2 cases with PTEN mutation), PIK3CA hotspot mutations (10/30, 33%), HRAS hotspot mutations (10/29; 34%), and ERBB2 amplification (9/29, 31%, including 1 case with mutation) represented the 5 most common abnormalities. There was no correlation between genetic changes and clinicopathologic parameters. There was substantial overlap between genetic changes: 8 of 9 cases with ERBB2 amplification also harbored a PIK3CA, HRAS, and TP53 mutation and/or PTEN loss. Six of 10 cases with PIK3CA mutation also had an HRAS mutation. These findings provide a molecular rationale for dual targeting of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways in SDC. FGFR1 amplification (3/29, 10%) represents a new potential target. On the basis of studies of breast carcinomas, the efficacy of anti-ERBB2 therapy will likely be decreased in SDC with ERBB2 amplification co-occurring with PIK3CA mutation or PTEN loss. Therefore, isolated ERBB2 testing is insufficient for theranostic stratification of apocrine SDC. On the basis of the prevalence and type of genetic changes, apocrine SDC appears to resemble one subtype of breast carcinoma-"luminal androgen receptor positive/molecular apocrine."


Challenges and opportunities for reinvigorating the physician-scientist pipeline.
Physician-scientists, with in-depth training in both medicine and research, are uniquely poised to address pressing challenges at the forefront of biomedicine. In recent years, a number of organizations have outlined obstacles to maintaining the pipeline of physician-scientists, classifying them as an endangered species. As in-training and early-career physician-scientists across the spectrum of the pipeline, we share here our perspective on the current challenges and available opportunities that might aid our generation in becoming independent physician-scientists. These challenges revolve around the difficulties in recruitment and retention of trainees, the length of training and lack of support at key training transition points, and the rapidly and independently changing worlds of medical and scientific training. In an era of health care reform and an environment of increasingly sparse NIH funding, these challenges are likely to become more pronounced and complex. As stakeholders, we need to coalesce behind core strategic points and regularly assess the impact and progress of our efforts with appropriate metrics. Here, we expand on the challenges that we foresee and offer potential opportunities to ensure a more sustainable physician-scientist workforce.


Anti-IgG combined with rate nephelometry for measuring polyethylene glycol-precipitated circulating immune complexes.
Immune complexes from serum were assayed for IgG by a simple rate-nephelometric method after extraction with polyethylene glycol that removes monomeric IgG. A 30-min preincubation of the extracted material in reaction buffer before the anti-IgG is introduced eliminates falsely increased values owing to precipitation that increased baseline light scatter in the reaction buffer. We found good parallelism in the reaction of anti-IgG with the IgG calibrator, aggregated human globulin, or endogenous immune complex. Thus IgG can be used for calibration in place of aggregated human globulin, greatly simplifying the assay. A good correlation was found between the present assay and the C1q-binding test (r = 0.83). The present assay is both sensitive and reproducible. The extraction and assay are straightforward and can be completed in a single morning after an overnight precipitation. The reagents for extraction are easily prepared and inexpensive, and the materials for assay are available in kit form. We believe this approach to be well suited for many clinical laboratories to measure circulating immune complexes.


Multidimensional flow cytometry immunophenotyping of hematologic malignancy.
Immunophenotyping of hematologic malignancies represents one of the most relevant clinical applications of flow cytometry. Classically, leukemic/lymphomatous cells have been considered to reflect the immunophenotypic characteristics of different precursors and mature healthy cells blocked at certain differentiation stages. Recently, accumulating evidence has shown that neoplastic cells display several aberrant phenotypic patterns. These aberrant phenotypes are believed to reflect genetic abnormalities present in pathologic cells, and recent data have shown that at least in acute leukemias, myelodysplastic syndromes, chronic lymphoproliferative disorders, and plasma cell dyscrasias, they may be present in almost all patients. The aim of this work is to review recent advances in flow cytometry and the role of gating strategies more useful in the identification and characterization of neoplastic cells of different hematologic malignancies.


Mueller matrix decomposition for determination of optical rotation of glucose molecules in turbid media.
The optical activity of glucose molecules is important for diagnosing and monitoring blood glucose of diabetes. In order to accurately detect the diabetes at an early stage, there is an urgent need to develop innovative detection methods. By use of Mueller matrix decomposition (MMD), we have studied the optical activity of glucose molecules in three types of turbid media--polystyrene (PST) sphere suspension, chicken blood, and the vein blood of diabetic patients. The experimental setup to obtain the Mueller matrix in the forward detection geometry has been used. The experimental results show that the rotation angle has linear relationship with the concentration of the glucose when the scattering coefficient of the PST sphere suspension remains unchanged, whereas the scattering effect enlarges the rotation angle. Furthermore, optical rotation abides by Drude's dispersion equation. The decomposition method has also been found useful applications in quantifying the optical rotations of blood glucose in diabetic patients. The diabetic severity status can be distinguished with the rotation angle of glucose and also is in accordance with the clinical diagnosis. Thus, the method of MMD has promising applications in diabetic diagnosis and monitoring.


Screening and Management of Delirium in Critically Ill Patients.
Delirium is highly prevalent in the critically ill population and has been associated with numerous negative outcomes including increased mortality. The presentation of a delirious patient in the intensive care unit (ICU) is characterized by a fluctuating cognitive status and inattention that varies dramatically among patients. Delirium can present in 3 different motoric subtypes: hyperactive, hypoactive, and mixed. Two tools, the Intensive Care Delirium Screening Checklist and Confusion Assessment ICU, are validated and recommended for the detection of delirium in critically ill patients. The identification of delirium in a critically ill patient should be facilitated using one of these tools. An intermediate form of delirium known as subsyndromal delirium also exists, although the significance of this syndrome is largely unknown. Another phenomenon known as sedation-related delirium has been recently described, although more research is needed to understand its significance. Patients in the ICU are exposed to many risk factors for developing delirium; controlling these risk factors is essential for preventing delirium development in critically ill patients. Nonpharmacologic interventions have been shown to prevent patients from developing delirium. Prevention is crucial because once delirium develops pharmacologic therapy is limited.


Modeling of friction force based on relative velocity between liver tissue and needle for needle insertion simulation.
Needle insertion treatments require accurate placement of the needle tip into the target cancer. However, it is difficult to insert the needle into the cancer because of cancer displacement due to the organ deformation. Then, a path planning using needle insertion simulation to analyze the deformation of the organ is important for the accurate needle insertion. A frictional model for needle insertion simulation is presented in this report. In particular, we focus on a model of frictional force based on the relative velocity between the needle and liver tissue ranging from hyper slow velocity. First, in vitro experiments using hog liver were performed at several relative velocities in order to measure the velocity dependence of the frictional force. Several needle insertion experiments were performed under identical conditions in order to deal with the variance of experimental data. The 60 frictional force data were used to obtain average data at each relative velocity. Second, the model of frictional force was developed using the averages of the experimental results. This model is defined according to the relative velocity ranging from hyper slow velocity. Finally, an evaluation experiment was carried out. The data obtained by the evaluation experiment reveals that the frictional force changes according to the relative velocity between the needle and liver tissue. The experimental results support the validity of proposed model of frictional force.


Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
In the recent outbreak of novel coronavirus infection in Wuhan, China, significantly abnormal coagulation parameters in severe novel coronavirus pneumonia (NCP) cases were a concern. To describe the coagulation feature of patients with NCP. Conventional coagulation results and outcomes of 183 consecutive patients with confirmed NCP in Tongji hospital were retrospectively analyzed. The overall mortality was 11.5%, the non-survivors revealed significantly higher D-dimer and fibrin degradation product (FDP) levels, longer prothrombin time and activated partial thromboplastin time compared to survivors on admission (P < .05); 71.4% of non-survivors and 0.6% survivors met the criteria of disseminated intravascular coagulation during their hospital stay. The present study shows that abnormal coagulation results, especially markedly elevated D-dimer and FDP are common in deaths with NCP.


Thoracic surgery training in Europe-the perspective of a trainee.
Duration and content of Thoracic surgery training differs considerably across Europe, leading to unequal levels of knowledge, skills and attitudes at the time of graduation as a specialist. The European Board of Thoracic Surgery examination strives to overcome these regional differences by offering a diploma to achieve harmonization and equal qualified certification. The HERMES initiative, driven by a joint task force from European Society of Thoracic Surgeons (ESTS) and European Respiratory Society (ERS) is currently establishing a consensual syllabus and curriculum for Thoracic Surgery to standardize content of training and achieve equal levels of qualification all-over Europe. In this context, new opportunities in teaching and learning have become available and should be considered to support and encourage for beneficial development in the future. International platforms are the key for connecting with experts and other trainees and are provided by annual meetings and within the ESTS School.


Congenital malformations in four siblings of a mother taking anticonvulsant drugs.
Four siblings have various congenital malformations attributable to the teratogenic effect of anticonvulsant drugs. Their mother has 23-year history of continuous medication for seizures. Since the malformations noted in her four offspring are more extensive and severe in each subsequent child, the question arises as to the possible cumulative effect of antiepileptic drugs in producing congenital malformations. The observations in this family strongly support the need to carefully evaluate all offspring of mothers receiving anticonvulsant drugs.


Fractionation of apple procyanidins according to their degree of polymerization by normal-phase high-performance liquid chromatography.
A new method was developed for the fractionation of procyanidin oligomers according to their degree of polymerization. Monomeric flavan-3-ols and low molecular mass procyanidins were selectively extracted from the lyophilized powder of apple condensed tannins (ACTs) by methyl acetate extraction. Sequentially, the separation of each oligomer from dimer to pentamer in this extract was carried out by normal-phase high-performance liquid chromatography using a silica-beads packed column. The best separation was achieved with a mobile phase system containing hexane; (1) hexane-methanol-ethyl acetate, (2) hexane-acetone. These sequential treatments can be easily adapted to large-scale fractionation.


Comparative profiling and comprehensive quantification of stratum corneum ceramides in humans and mice by LC/MS/MS.
Ceramides are the predominant lipids in the stratum corneum (SC) and are crucial components for normal skin barrier function. Although the composition of various ceramide classes in the human SC has been reported, that in mice is still unknown, despite mice being widely used as animal models of skin barrier function. Here, we performed LC/MS/MS analyses using recently available ceramide class standards to measure 25 classes of free ceramides and 5 classes of protein-bound ceramides from human and mouse SC. Phytosphingosine- and 6-hydroxy sphingosine-type ceramides, which both contain an additional hydroxyl group, were abundant in the human SC (35% and 45% of total ceramides, respectively). In contrast, in mice, phytosph-ingosine- and 6-hydroxy sphingosine-type ceramides were present at ∼1% and undetectable levels, respectively, and sphingosine-type ceramides accounted for ∼90%. In humans, ceramides containing α-hydroxy FA were abundant, whereas ceramides containing β-hydroxy or ω-hydroxy FA were abundant in mice. The hydroxylated β-carbon in β-hydroxy ceramides was in the (R) configuration. Genetic knockout of β-hydroxy acyl-CoA dehydratases in HAP1 cells increased β-hydroxy ceramide levels, suggesting that β-hydroxy acyl-CoA, an FA-elongation cycle intermediate in the ER, is a substrate for β-hydroxy ceramide synthesis. We anticipate that our methods and findings will help to elucidate the role of each ceramide class in skin barrier formation and in the pathogenesis of skin disorders.


The prefabricated temporal island flap for eyelid and eye socket reconstruction in total orbital exenteration patients: A new method.
Anophtalmic socket reconstruction is a challenging problem in plastic surgery. We had described a prefabricated superficial temporal fascia island flap and used this technique in >50 enucleation patients with severe socket contraction ending in excellent or good results for 28 years (Altindas- 1 procedure). However, the flap was not suitable for the exenteration patients with complete eyelid loss. The technique was modified and used in exenteration patients (Altindas-2 procedure). In this 2-staged procedure, the temporoparietal fascia is prefabricated with a full-thickness skin graft from the retroauricular area, and a strip of scalp is preserved at the middle of the flap. The flap is transferred to the orbit through a subcutaneous tunnel at the second stage. The prefabricated flap is used for the reconstruction of eyelids and periorbital skin; scalp island is used for the reconstruction of lid margins and eyelashes; and the neighboring bare temporoparietal fascia is used for the augmentation of the periorbital soft tissues. The orbital lining is elevated as a centrally based skin flap and used for the reconstruction of the eye socket, fornicles, and posterior lining of the eyelids. The technique was used successfully in 5 total exenteration patients with complete eyelid loss. In 1 patient, the ipsilateral temporal island flap was used previously, and the flap was prepared from the contralateral site and transferred to the anophtalmic orbit as a free flap 5 weeks later. By this procedure, it is possible to reconstruct a stable eye socket that is suitable for ocular prosthesis, upper and lower fornicles, periorbital skin with good color matching, naturally looking eyelids with eyelashes and lid margins, and medial and lateral canthal areas. It is also possible to improve periorbital soft tissue atrophy, which is an important problem in patients who had radiotherapy previously. Free transfer of the flap provides a new solution for the reconstruction of cases that were operated previously.


Whole organ cross-section chemical imaging using label-free mega-mosaic FTIR microscopy.
FTIR chemical imaging has been demonstrated as a promising technique to construct automated systems to complement histopathological evaluation of biomedical tissue samples. The rapid chemical imaging of large areas of tissue has previously been a limiting factor in this application. Consequently, smaller areas of tissue have previously had to be sampled, possibly introducing sampling bias and potentially missing diagnostically important areas. In this report a high spatial resolution chemical image of a whole prostate cross section is shown comprising 66 million pixels. Each pixel represents an area 5.5 × 5.5 μm(2) of tissue and contains a full infrared spectrum providing a chemical fingerprint. The data acquisition time was 14 hours, thus showing that a clinical time frame of hours rather than days has been achieved.


Reasons for failure to quit: a cross-sectional survey of tobacco use in major cities in Pakistan.
Tobacco dependence has been defined as a chronic relapsing disease. Around 5 million annual tobacco-related deaths have been reported worldwide. The majority of smokers want to quit but are not successful. To screen our population for tobacco use, gauge the baseline demographics of tobacco users and assess factors associated with failed attempts to quit. Free health camps supervised by a physician were held across two major cities of Pakistan. All consenting participants were administered a questionnaire and had their exhaled carbon monoxide (CO) levels measured. Of 12 969 participants successfully enrolled, the mean age was 31.4 ± 10.0 years. More than three quarters were aged 20-40 years (n = 10 168, 78.4%). The overall average CO level was 12.0 ± 8.0 ppm. The majority of the participants wanted to quit, and nearly everyone had received advice about quitting. The majority had tried smoking cessation pharmacotherapy. Friends/peer pressure (n = 1554, 12%), anxiety (n = 681, 5.3%), tobacco dependence (n = 1965, 15.2%) and stress/mood changes (n = 390, 3.0%) were the most widely observed reasons for failure to quit in study participants. The information provided by this study can guide the development of more targeted intervention programmes for smokers who wish to quit.


Developmental cell death in dopaminergic neurons of the substantia nigra of mice.
Dopaminergic neurons in the substantia nigra pars compacta (SNpc) undergo natural cell death during development in rats. Controversy exists as to the occurrence of this phenomenon in SNpc dopaminergic neurons in the developing mouse. Herein, by using an array of morphologic techniques, we show that many SNpc neurons fulfill the criteria for apoptosis and that the number of apoptotic neurons in the SNpc vary in a time-dependent manner from postnatal day 2 to 32. These dying neurons also show evidence of DNA fragmentation, of activated caspase-3, and of cleavage of beta-actin. Some, but not all of the SNpc apoptotic neurons still express their phenotypic marker tyrosine hydroxylase, confirming their dopaminergic nature. Consistent with the importance of target-derived trophic support in modulating developmental cell death, we demonstrate that destruction of intrinsic striatal neurons by a local injection of quinolinic acid (QA) dramatically enhances the magnitude of SNpc apoptosis and results in a lower number of adult SNpc dopaminergic neurons. Strengthening the apoptotic nature of the observed SNpc developmental cell death, we demonstrate that overexpression of the anti-apoptotic protein Bcl-2 attenuates both natural and QA-induced SNpc apoptosis. The present study provides compelling evidence that developmental neuronal death with a morphology of apoptosis does occur in the SNpc of mice and that this process plays a critical role in regulating the adult number of dopaminergic neurons in the SNpc.


Arteriovenous Fistula-A Rare Complication of IVC Filter Retrieval.
Inferior vena cava (IVC) filters are important devices for patients who are at high risk for developing thrombi and pulmonary embolism but have conditions that preclude the use of pharmacologic anticoagulants. IVC filter retrieval has become an important quality initiative backed by Food and Drug Administration guidelines for prompt removal after the filter is no longer indicated. Filter retrieval is a common procedure that usually has very few complications. However, when the filter is tilted or embedded in the caval wall, advanced techniques of retrieval may be necessary. These techniques have a higher rate of success but also a higher risk of complications such as injury to the IVC. Here, we describe a case of IVC filter retrieval resulting in formation of an arteriovenous fistula between the right renal artery and IVC and subsequent successful repair of this fistula using a vascular plug.


Improving Oral Cancer Outcomes with Imaging and Artificial Intelligence.
Early diagnosis is the most important determinant of oral and oropharyngeal squamous cell carcinoma (OPSCC) outcomes, yet most of these cancers are detected late, when outcomes are poor. Typically, nonspecialists such as dentists screen for oral cancer risk, and then they refer high-risk patients to specialists for biopsy-based diagnosis. Because the clinical appearance of oral mucosal lesions is not an adequate indicator of their diagnosis, status, or risk level, this initial triage process is inaccurate, with poor sensitivity and specificity. The objective of this study is to provide an overview of emerging optical imaging modalities and novel artificial intelligence-based approaches, as well as to evaluate their individual and combined utility and implications for improving oral cancer detection and outcomes. The principles of image-based approaches to detecting oral cancer are placed within the context of clinical needs and parameters. A brief overview of artificial intelligence approaches and algorithms is presented, and studies that use these 2 approaches singly and together are cited and evaluated. In recent years, a range of novel imaging modalities has been investigated for their applicability to improving oral cancer outcomes, yet none of them have found widespread adoption or significantly affected clinical practice or outcomes. Artificial intelligence approaches are beginning to have considerable impact in improving diagnostic accuracy in some fields of medicine, but to date, only limited studies apply to oral cancer. These studies demonstrate that artificial intelligence approaches combined with imaging can have considerable impact on oral cancer outcomes, with applications ranging from low-cost screening with smartphone-based probes to algorithm-guided detection of oral lesion heterogeneity and margins using optical coherence tomography. Combined imaging and artificial intelligence approaches can improve oral cancer outcomes through improved detection and diagnosis.


Responding to epidemics in large-scale humanitarian crises: a case study of the cholera response in Yemen, 2016-2018.
Large epidemics frequently emerge in conflict-affected states. We examined the cholera response during the humanitarian crisis in Yemen to inform control strategies. We conducted interviews with practitioners and advisors on preparedness; surveillance; laboratory; case management; malnutrition; water, sanitation and hygiene (WASH); vaccination; coordination and insecurity. We undertook a literature review of global and Yemen-specific cholera guidance, examined surveillance data from the first and second waves (28 September 2016-12 March 2018) and reviewed reports on airstrikes on water systems and health facilities (April 2015-December 2017). We used the Global Task Force on Cholera Control's framework to examine intervention strategies and thematic analysis to understand decision making. Yemen is water scarce, and repeated airstrikes damaged water systems, risking widespread infection. Since a cholera preparedness and response plan was absent, on detection, the humanitarian cluster system rapidly developed response plans. The initial plans did not prioritise key actions including community-directed WASH to reduce transmission, epidemiological analysis and laboratory monitoring. Coordination was not harmonised across the crisis-focused clusters and epidemic-focused incident management system. The health strategy was crisis focused and was centralised on functional health facilities, underemphasising less accessible areas. As vaccination was not incorporated into preparedness, consensus on its use remained slow. At the second wave peak, key actions including data management, community-directed WASH and oral rehydration and vaccination were scaled-up. Despite endemicity and conflict, Yemen was not prepared for the epidemic. To contain outbreaks, conflict-affected states, humanitarian agencies, and donors must emphasise preparedness planning and community-directed responses.


An ortholog of the Leptospira interrogans lipoprotein LipL32 aids in the colonization of Pseudoalteromonas tunicata to host surfaces.
The bacterium Pseudoalteromonas tunicata is a common surface colonizer of marine eukaryotes, including the macroalga Ulva australis.Genomic analysis of P. tunicata identified genes potentially involved in surface colonization, including genes with homology to bacterial virulence factors that mediate attachment. Of particular interest is the presence of a gene, designated ptlL32, encoding an ortholog to the Leptospira lipoprotein LipL32, which has been shown to facilitate the interaction of Leptospira sp. with host extracellular matrix (ECM) structures and is thought to be an important virulence trait for pathogenic Leptospira. To investigate the role of PtlL32 in the colonization by P. tunicata we constructed and characterized a ΔptlL32 mutant strain. Whilst P. tunicata ΔptlL32 bound to an abiotic surface with the same capacity as the wild type strain, it had a marked effect on the ability of P. tunicata to bind to ECM, suggesting a specific role in attachment to biological surfaces. Loss of PtlL32 also significantly reduced the capacity for P. tunciata to colonize the host algal surface demonstrating a clear role for this protein as a host-colonization factor. PtlL32 appears to have a patchy distribution across specific groups of environmental bacteria and phylogenetic analysis of PtlL32 orthologous proteins from non-Leptospira species suggests it may have been acquired via horizontal gene transfer between distantly related lineages. This study provides the first evidence for an attachment function for a LipL32-like protein outside the Leptospira and thereby contributes to the understanding of host colonization in ecologically distinct bacterial species.


Italian Survey on adjuvant treatment of non-small cell lung cancer (ISA).
A recent pooled analysis of randomized trials indicated significant improvement in overall survival from cisplatin-based adjuvant chemotherapy for non-small cell lung cancer (NSCLC), depending on disease stage (only in stages II and III) and PS (≤ 1). Post-operative radiotherapy (RT) is optional for pN2 tumours. To evaluate opinions and daily clinical practice of Italian Oncologists about adjuvant treatment of NSCLC, a 46-item questionnaire was delivered via e-mail. Seventy-eight physicians from 68 Centers (out of 98 contacted) returned their questionnaire. Seventy-four, 86, 94, and 78% of them give the indication for adjuvant chemotherapy for stage IIA, IIB, IIIA, and IIIB disease, respectively and 14% in stage IB disease. Stage, PS, and age are taken into consideration evaluating adjuvant approach by 97, 95 and 73%, respectively. Cisplatin-vinorelbine (64%) and cisplatin-gemcitabine (33%), for 4 cycles (81%), are the preferred regimens, while 32% use different regimens. Ninety-two percent indicate RT in pN2 disease and/or positive resection margins. Real Number of patients Needed to Treat (NNT) is probably not completely known/understood and/or used by physicians. A substantial adherence between clinical daily practice in Italy and scientific progresses is described in this paper, even with some discordances regarding the most appropriate adjuvant chemotherapy regimen.


The Effects of Videogaming with a Brain-Computer Interface on Mood and Physiological Arousal.
Objective: In recent years, immersive videogame technologies such as virtual reality have been shown to affect psychological welfare in such way that they can be applied to clinical psychology treatments. However, the effects of videogaming with other immersive gaming apparatuses such as commercial electroencephalography (EEG)-based brain-computer interfaces (BCIs) on psychological welfare have not been extensively researched. Thus, we aimed at providing early insights into some of these effects by looking at how videogaming with a commercial EEG-based BCI would impact mood and physiological arousal. Materials and Methods: A total of 26 participants were sampled. Participants were randomly assigned to either a BCI condition or a traditional condition wherein they played an action videogame with a commercial EEG-based BCI or a standard keyboard and mouse interface for 20 minutes. In both conditions, participants filled out the profile of mood states to assess mood and the perceived stress scale to control for stress. We also measured heart rate, heart rate variability as measured by the root mean square of successive differences, and galvanic skin response (GSR) amplitude differences. Results: Participants in the BCI condition overall reported a significantly higher total mood disturbance (P < 0.05), tension (P < 0.05), confusion (P < 0.05), and significantly less vigor (P < 0.05). We also found that participants in the BCI condition had significantly lower GSR amplitude differences between gaming and baseline (P < 0.05). Conclusion: The results suggest that the use of commercial EEG-based BCIs for playing with videogames can induce greater frustration and negative moods than playing with a traditional keyboard and mouse interface, possibly limiting their use in clinical psychology settings.


Generating political priority for newborn survival in three low-income countries.
Deaths to babies in their first 28 days of life now account for more than 40% of global under-5 child mortality. High neonatal mortality poses a significant barrier to achieving the child survival Millennium Development Goal. Surmounting the problem requires national-level political commitment, yet only a few nation-states have prioritised this issue. We compare Bolivia, Malawi and Nepal, three low-income countries with high neonatal mortality, with a view to understanding why countries prioritise or neglect the issue. The three have had markedly different trajectories since 2000: attention grew steadily in Nepal, stagnated then grew in Malawi and grew then stagnated in Bolivia. The comparison suggests three implications for proponents seeking to advance attention to neglected health issues in low-income countries: the value of (1) advancing solutions with demonstrated efficacy in low-resource settings, (2) building on existing and emerging national priorities and (3) developing a strong network of domestic and international allies. Such actions help policy communities to weather political storms and take advantage of policy windows.


A protein quality control pathway at the mitochondrial outer membrane.
Maintaining the essential functions of mitochondria requires mechanisms to recognize and remove misfolded proteins. However, quality control (QC) pathways for misfolded mitochondrial proteins remain poorly defined. Here, we establish temperature-sensitive (ts-) peripheral mitochondrial outer membrane (MOM) proteins as novel model QC substrates in Saccharomyces cerevisiae. The ts- proteins sen2-1HAts and sam35-2HAts are degraded from the MOM by the ubiquitin-proteasome system. Ubiquitination of sen2-1HAts is mediated by the ubiquitin ligase (E3) Ubr1, while sam35-2HAts is ubiquitinated primarily by San1. Mitochondria-associated degradation (MAD) of both substrates requires the SSA family of Hsp70s and the Hsp40 Sis1, providing the first evidence for chaperone involvement in MAD. In addition to a role for the Cdc48-Npl4-Ufd1 AAA-ATPase complex, Doa1 and a mitochondrial pool of the transmembrane Cdc48 adaptor, Ubx2, are implicated in their degradation. This study reveals a unique QC pathway comprised of a combination of cytosolic and mitochondrial factors that distinguish it from other cellular QC pathways.


Magnetic resonance myelography in early postoperative lumbar discectomy: An efficient and cost effective modality.
Magnetic resonance myelography (MRM) after lumbar discectomy is all too often an unrewarding challenge. A constellation of findings are inevitable, and determining their significance is often difficult. MRM is a noninvasive technique that can provide anatomical information about the subarachnoid space. Until now, there is no study reported in literature showing any clinico-radiological correlation of post operative MRM. The objective of this study was to prospectively evaluate the diagnostic effectiveness of MRM for the demonstration of decompression in operated discectomy patients and its correlation with subjective and objective outcome (pain and SLR) in immediate postoperative period. Fifty three patients of single level lumbar disc herniation (LDH) justifying the inclusion criteria were operated for discectomy. All patients underwent MRM on second/third postoperative day. The pain relief and straight leg raise sign improvement was correlated with the postoperative MRM images to group the patients into: A- Subjective Pain relief, SLR improved and MRM image showing myelo regression; B- Subjective Pain relief, SLR improved and MRM image showing no myelo regression; C- No Subjective Pain relief, no SLR improved and MRM image showing myelo regression and; D- No Subjective Pain relief, no SLR improved and MRM image showing no myelo regression. The result showed that Group A had 46 while Group B, C and Group D had 4, 2 and one patients respectively. Clinico-radiological correlation (Clinically diagnosed patient and findings with MRM correlation) was present in 47 patients (88.68%) which includes both A and D groups. The MRM specificity and sensitivity were 92% and 33.33% respectively. MRM is a non-invasive, efficient and reliable tool in confirming postoperative decompression in lumbar discectomy patients, especially when economic factors are to be considered and the required expertise to reliably read a complex confusing post-operative MRI is not available readily. Further, controlled double blinded multicentric study in operated and non operated LDH, with MRI comparison would give better evidence to justify its use in screening to detect persisting compression and to document decompression.


An efficient method for cloning human autoantigen-specific T cells.
T-cell clones are valuable tools for investigating T-cell specificity in infectious, autoimmune and malignant diseases. T cells specific for clinically-relevant autoantigens are difficult to clone using traditional methods. Here we describe an efficient method for cloning human autoantigen-specific CD4+ T cells pre-labelled with CFSE. Proliferating, antigen-responsive CD4+ cells were identified flow cytometrically by their reduction in CFSE staining and single cells were sorted into separate wells. The conditions (cytokines, mitogens and tissue culture plates) for raising T-cell clones were optimised. Media supplemented with IL-2+IL-4 supported growth of the largest number of antigen-specific clones. Three mitogens, PHA, anti-CD3 and anti-CD3+anti-CD28, each stimulated the growth of similar numbers of antigen-specific clones. Cloning efficiency was similar in flat- and round-bottom plates. Based on these findings, IL-2+IL-4, anti-CD3 and round-bottom plates were used to clone FACS-sorted autoantigen-specific CFSE-labelled CD4+ T cells. Sixty proinsulin- and 47 glutamic acid decarboxylase-specific clones were obtained from six and two donors, respectively. In conclusion, the CFSE-based method is ideal for cloning rare, autoantigen-specific, human CD4+ T cells.


Stress, mental health, and burnout in national humanitarian aid workers in Gulu, northern Uganda.
This study examined the mental health of national humanitarian aid workers in northern Uganda and contextual and organizational factors predicting well-being. A cross-sectional survey was conducted among 376 national staff working for 21 humanitarian aid agencies. Over 50% of workers experienced 5 or more categories of traumatic events. Although, in the absence of clinical interviews, no clinical diagnoses were able to be confirmed, 68%, 53%, and 26% of respondents reported symptom levels associated with high risk for depression, anxiety disorders, and posttraumatic stress disorder (PTSD), respectively. Between one quarter and one half of respondents reported symptom levels associated with high risk regarding measured dimensions of burnout. Female workers reported significantly more symptoms of anxiety, depression, PTSD, and emotional exhaustion than males. Workers with the United Nations and related agencies reported fewest symptoms. Higher levels of social support, stronger team cohesion, and reduced exposure to chronic stressors were associated with improved mental health. National humanitarian staff members in Gulu have high exposure to chronic and traumatic stress and high risk of a range of poor mental health outcomes. Given that work-related factors appear to influence the relationship between the two strategies are suggested to support the well-being of national staff working in such contexts.


Network analysis of EtOH-related candidate genes.
Recently, we collected many large-scale datasets for alcohol dependence and EtOH response in five organisms and deposited them in our EtOH-related gene resource database (ERGR, http://bioinfo.mc.vanderbilt.edu/ERGR/). Based on multidimensional evidence among these datasets, we prioritized 57 EtOH-related candidate genes. To explore their biological roles, and the molecular mechanisms of EtOH response and alcohol dependence, we examined the features of these genes by the Gene Ontology (GO) term-enrichment test and network/pathway analysis. Our analysis revealed that these candidate genes were highly enriched in alcohol dependence/alcoholism and highly expressed in brain or liver tissues. All the significantly enriched GO terms were related to neurotransmitter systems or EtOH metabolic processes. Using the Ingenuity Pathway Analysis system, we found that these genes were involved in networks of neurological disease, cardiovascular disease, inflammatory response, and small molecular metabolism. Many key genes in signaling pathways were in the central position of these networks. Furthermore, our protein-protein interaction (PPI) network analysis suggested some novel candidate genes which also had evidence in the ERGR database. This study demonstrated that our candidate gene selection is effective and our network/pathway analysis is useful for uncovering the molecular mechanisms of EtOH response and alcohol dependence. This approach can be applied to study the features of candidate genes of other complex traits/phenotypes.


Surveillance imaging in pediatric lymphoma.
Current therapies used in treating children with Hodgkin lymphoma and many histological subtypes of non-Hodgkin lymphoma have resulted in overall survival rates exceeding 90% in many instances. With increasing concerns related to the cost of radiologic imaging, exposure to ionizing radiation, and potential false-positive results, the role of routine off-therapy surveillance imaging has been called into question. Although radiologic imaging plays an important role in diagnosing and assessing treatment response, in these children - the majority of whom have an excellent outcome following completion of therapy - there is an opportunity to dramatically reduce the number of off-therapy imaging evaluations. This review summarizes several recent studies in both Hodgkin and non-Hodgkin lymphoma providing evidence to support these efforts. In addition, we propose a surveillance imaging strategy that uses a novel risk-adapted and response-based approach to determine which children would most benefit from off-therapy imaging surveillance.


Introducing mother's curse: low male fertility associated with an imported mtDNA haplotype in a captive colony of brown hares.
Mitochondrial DNA mutations create variation in the efficiency of the oxidative phosphorylation pathway and therefore cellular energy production. Mildly deleterious mutations may reduce the performance of sperm cells in particular, due to their high energy requirements and low number of mitochondria, yet have little or no effect on the viability of somatic cells or ova. Mutations will be maintained in the population, despite the fitness cost for males, because mtDNA is passed down the female line. We looked for this so-called mother's curse effect in our captive colony of European brown hares. Significantly reduced male reproductive success was detected for a divergent haplotype that could be traced back to hares imported from a remote population. Median reproductive success for these hares was 0.17 compared to 0.49 for the indigenous haplotypes (Wilcoxon rank-sum, P = 0.002). No difference was detected for female reproductive success, nor were we able to find a nuclear DNA component to variation in male fertility. Our data are strong evidence for a mother's curse effect persisting despite multiple crossings over seven generations. These data raise important issues relating to the reproductive fitness of small or intermixing populations and have particular implications for the management of populations for conservation.


Pilot evaluation of a novel clinical test of reaction time in national collegiate athletic association division I football players.
Evidence suggests that concussion prolongs reaction time (RT). We have developed a simple, reliable clinical tool for measuring reaction time that may be of value in the assessment of concussion in athletes. To compare baseline values of clinical RT (RT(clin)) obtained using the new clinical reaction time apparatus with computerized RT (RT(comp)) obtained using a validated computerized neuropsychological test battery. Cross-sectional study. Data were collected during a National Collegiate Athletic Association Division I collegiate football team's preparticipation physical examination session. Ninety-four Division I collegiate football players. The RT(clin) was measured using a 1.3-m measuring stick embedded in a weighted rubber disk that was released and caught as quickly as possible. The RT(comp) was measured using the simple RT component of CogState Sport. For the 68 athletes whose CogState Sport tests passed the program's integrity check, RT(clin) and RT(comp) were correlated (r = 0.445, P < .001). Overall, mean RT(clin) was shorter and less variable than mean RT(comp) (203 +/- 20 milliseconds versus 268 +/- 44 milliseconds; P < .001). When RT(clin) and RT(comp) were compared between those athletes with (n = 68) and those without (n = 26) valid CogState Sport test sessions, mean RT(clin) was similar (202 +/- 19 milliseconds versus 207 +/- 23 milliseconds; P = .390), but mean RT(comp) was different (258 +/- 35 milliseconds versus 290 +/- 55 milliseconds; P = .009). The RT(clin) was positively correlated with RT(comp) and yielded more consistent reaction time values during baseline testing. Given that RT(clin) is easy to measure using simple, inexpensive equipment, further prospective study is warranted to determine its clinical utility in the assessment of concussion in athletes.


Impact of a combined diet and progressive exercise intervention for overweight and obese children: the B.E. H.I.P. study.
The Biochemical Evaluation of a Health Intervention Programme (B.E. H.I.P.) investigated the impact of progressive exercise intensity in overweight and obese children. A 5-month prospective randomized crossover design (X(A), immediate intervention; O(B), control group; X(B), delayed intervention, O(A), postintervention follow-up) with a 10-week health intervention programme was employed. The intervention utilized a progressive increase in high-intensity exercise (≥ 75% maximum heart rate) and included 3 nutrition and 2 parent education sessions. Primary analysis was completed with (i) X(A) versus O(B) and (ii) all intervention participants (collapsed X(A) and X(B) = X(A)X(B)). Prepubertal overweight and obese male and female children (n = 27) between 5 and 10 years of age were randomly allocated to X(A) (n = 16; 11 females; waist circumference = 80.0 ± 10.6 cm) or O(B) (n = 11; 3 females; waist circumference = 76.6 ± 7.5 cm). The primary variables were heart rate and percent fat mass. All variables, including body composition, habitual activity, and serum lipids, were repeatedly measured for up to a maximum of 7 time points. Energy expenditure was quantitatively measured throughout each exercise class (n = 20). A significantly longer time in the exercise sessions was spent in high-intensity (35.1%-60.0%) versus low- to moderate-intensity (64.9%-40.0%) exercise as the intervention progressed from the first to the last attended exercise class (Fisher exact test, p < 0.0001). The percent fat mass decreased in all intervention participants (-2.2%, p < 0.0001). X(A) had a greater slope decrease than O(B) for percent fat mass (p = 0.00051) and triglycerides (p = 0.0467). In conclusion, high-intensity exercise, within a comprehensive health programme that includes nutrition education, improved the lipid and physiological health profiles of obese children.


Using an Educational Multimedia Application to Prepare Children for Outpatient Surgeries.
Surgery is a highly stressful event for children and caregivers. Extensive effort has been made to improve preoperative care in order to alleviate worry about the surgical procedure itself. This study tested the impact of an educational multimedia intervention on the cognitive, emotional, and physiological responses of children undergoing surgery, as well as on parental state anxiety. Children (n = 90) were assigned to three different groups: an educational multimedia intervention (experimental group), an entertainment video game intervention (comparison group), and a control group (no intervention). Children who received the educational multimedia intervention reported lower level of worries about hospitalization, medical procedures, illness, and negative consequences than those in the control and in the comparison groups. Parental state anxiety was also lower in the both the educational and the entertainment video game interventions compared to the control group. These findings suggest that providing information to children regarding medical procedures and hospital rules and routines is important to reduce their preoperative worries, and also relevant for parental anxiety.