Consultation on urological specimens from referred cancer patients using real-time digital microscopy: Optimizing the workflow.
Centralization of cancer treatment entails a reassessment of the diagnostic tissue specimens. Packaging and shipment of glass slides from the local to the central pathology unit means that the standard procedure is time-consuming and that it is difficult to comply with governmental requirements. The aim was to evaluate whether real-time digital microscopy for urological cancer specimens during the primary diagnostic process can replace subsequent physical slide referral and reassessment without compromising diagnostic safety. From May to October 2014, tissue specimens from 130 patients with urological cancer received at Næstved Hospital's Pathology Department, and expected to be referred for further treatment at cancer unit of a university hospital, were diagnosed using standard light microscopy. In the event of diagnostic uncertainty, the VisionTek digital microscope (Sakura Finetek) was employed. The Pathology Department at Næstved Hospital was equipped with a digital microscope and three consultant pathologists were stationed at Rigshospitalet with workstations optimized for digital microscopy. Representative slides for each case were selected for consultation and live digital consultation took place over the telephone using remote access software. Time of start and finish for each case was logged. For the physically referred cases, time from arrival to sign-out was logged in the national pathology information system, and time spent on microscopy and reporting was noted manually. Diagnosis, number of involved biopsies, grade, and stage were compared between digital microscopy and conventional microscopy. Complete data were available for all 130 cases. Standard procedure with referral of urological cancer specimens took a mean of 8 min 56 s for microscopy, reporting and sign-out per case. For live digital consultations, a mean of 18 min 37 s was spent on each consultation with 4 min 43 s for each case, depending on the number of digital slides included. Only in two cases could a consensus regarding the diagnosis not be reached during live consultation; this did not, it should be noted, affect patient treatment. Complete agreement between conventional and digital histopathology diagnosis was reached in all the 53 patients referred to central pathology units. The participating pathologists were in general comfortable using live digital microscopy, but they emphasized that a fast internet connection was essential for a smooth consultation. An almost perfect agreement between live digital and conventional microscopy was observed in this study. Live digital consultation allowed cases to be referred from local hospitals to central cancer units without the standard delay caused by shipment. Only a few preselected specimen slides for each patient were presented in live consultation, which reduced the time spent on diagnosis compared to using the conventional method. Implementation of real-time digital microscopy would result in quicker turnaround and patient referral time, and with careful selection of relevant specimen slides for consultation, diagnostic safety would not be compromised.


Host preferences in host-seeking and blood-fed mosquitoes in Switzerland.
The avian zoonotic agent for West Nile virus (WNV) can cause neuroinvasive disease in horses and humans and is expanding its range in Europe. Analyses of the risk for transmission to these hosts in non-endemic areas are necessary. Host preferences of mosquitoes (Diptera: Culicidae), the main vectors of WNV, were determined in Switzerland using animal-baited trap (horse, chickens) experiments at a natural and a periurban site. This was undertaken on four occasions during May-September 2014. In addition, the hosts of 505 blood-fed mosquitoes collected in a zoo and in the field were determined. Mosquito data obtained in the animal bait experiments were corrected for host weight and body surface area and by Kleiber's scaling factor. Collections of 11-14 different mosquito species were achieved with these approaches. Statistically significant host preferences were identified in three species in both approaches. The other species showed opportunistic feeding behaviours to varying extents. Specifically, the invasive species Hulecoeteomyia japonica (= Aedes japonicus) was identified for the first time as feeding on avians in nature. Abundance data, spatiotemporal activity and laboratory vector competence for WNV suggested that, in addition to the main WNV vector Culex pipiens, H. japonica and Aedimorphus vexans (= Aedes vexans) are the most likely candidate bridge vectors for WNV transmission in Switzerland.


Death Anxiety Associated With Coronavirus (COVID-19) Disease: A Systematic Review and Meta-Analysis.
Death anxiety is a feeling that exists since birth, continues throughout life, lies at the root of all fears, and develops after the awareness that people will no longer exist and that they can lose themselves and the world. It is associated with death-induced anxiety with many features of the COVID-19 pandemic, which can be seen as a threat to human existence. In this study, it is aimed to compile studies on death anxiety associated with coronavirus disease, list the general characteristics of these studies through descriptive summaries, and combine findings on the level of death anxiety associated with coronavirus disease through meta-analysis. The findings of this study suggest that COVID-19 pandemic process and is affected by socio-demographic factors such as fear of COVID-19, gender, and occupation. As a result of this study, it was determined that death anxiety was relatively high during the COVID-19 pandemic process.


Changes in pressure pain thresholds and Basal electromyographic activity after instrument-assisted spinal manipulative therapy in asymptomatic participants: a randomized, controlled trial.
The purpose of this study was to investigate the effects of instrument-assisted spinal manipulative therapy (SMT) targeted to the low-back region on changes in pressure pain thresholds (PPTs) and basal electromyographic activity (BEA) in asymptomatic participants. A repeated-measures, single-blind, randomized trial was conducted on 30 participants, 19 men and 11 women (mean age, 24.5±3.9 years), without a current history of low-back pain. Each participant attended all 2 treatment group sessions and received instrument-assisted SMT or a sham manipulation procedure. Instrument-assisted SMT was administered using the Activator Method protocol. Bilateral PPT levels over L5-S1 zygapophyseal joints, L5 dermatome, and first dorsal interossei in the hand and bilateral BEA of low back and neck region were assessed pre- and posttreatment by an assessor blinded to the treatment allocation of the participant. A 3-way analysis of variance with time (pre-post) and side (ipslateral, contralateral to the intervention) as within-group variable and intervention (manipulation or sham) as between-group variable was used to evaluate changes in PPT. A paired sample t test was used to analyze the differences between pre- and posttreatment in BEA. The group vs time interaction was statistically significant for PPT irrespective of the site tested or the side treated. Participants receiving the instrument-assisted SMT experienced greater improvement in PPT when compared with the control group. Paired sample t tests for BEA only show an immediate decrease in BEA of the paraspinal muscle on the pelvic deficiency side of the low-back region. The application of instrument-assisted SMT resulted in an immediate and widespread hypoalgesic effect with local muscle relaxation in asymptomatic participants. It is hypothesized that therapeutic mechanisms, either segmental or central, may be involved in the therapeutic effects of instrument-assisted SMT.


Newer agents for the management of overactive bladder.
The anticholinergics tolterodine and oxybutynin are well established in the management of overactive bladder. However, their activity at muscarinic receptors distant from the target site (i.e., bladder) produces anticholinergic side effects leading to poor tolerability. In 2004, trospium, solifenacin, and darifenacin were approved by the U.S. Food and Drug Administration for the treatment of overactive bladder. Trospium is water soluble and therefore is less likely to enter the central nervous system, and solifenacin and darifenacin are more selective for the bladder than older agents. Although these attributes could improve tolerability, clinical trials comparing relevant agents to validate this are lacking. Trials have shown that these newer agents decrease the frequency of incontinence episodes, the number of voids per day, and the number and severity of urgency episodes compared with placebo. These agents also have been shown to improve quality of life in women with overactive bladder and urinary incontinence. Head-to-head studies of the newer agents and immediate-release oxybutynin and tolterodine have suggested similar effectiveness across the class, although the newer agents are better tolerated. Trospium and darifenacin have not been compared with extended-release formulations of tolterodine or oxybutynin, which are better tolerated than the immediate-release versions. In one study, solifenacin produced a somewhat greater decrease in the number of incontinence episodes than extended-release tolterodine, with no difference in tolerability. In general, the newer agents appear to be at least as effective as their predecessors, although it is unclear whether they are better tolerated. Important pharmacokinetic differences among the agents (e.g., route of elimination) allow for selection of an appropriate agent based on individual factors such as cost and tolerability.


Outcomes of stroke patients in Medicare fee for service and managed care.
Increasing numbers of Medicare beneficiaries have been enrolling in health maintenance organizations (HMOs) because HMO participation reduces out-of-pocket expenses, and the federal government views HMOs as a way to contain Medicare costs. However, results comparing outcomes and quality of care in HMOs vs fee for service (FFS) have been mixed, and outcomes after stroke have not been adequately assessed. To compare discharge destinations and survival rates following stroke in Medicare HMOs with similar FFS settings. An observational study for 2 groups evaluating stroke patients' discharge destinations and survival times from the date of hospital admission. A total of 19 HMOs were selected from 12 states. The FFS sample was drawn from the same geographic areas. The sample included 402 HMO patients from 71 hospitals and 408 FFS patients from 60 hospitals. PROCESS AND OUTCOME MEASURES: Data were abstracted from medical records on demographics, clinical characteristics of stroke, comorbid illnesses, and discharge destinations following hospitalization. Data on survival were obtained from Medicare files and included 25 to 37 months of follow-up (median, 30.4 months, HMO; 31.1 months, FFS) from the date of hospital admission. There were 109 patients who died during the hospitalization (49 HMO, 12.2%; 60 FFS, 14.7%), and a total of 410 patients had died by the end of follow-up (191 HMO, 47.5%; 219 FFS, 53.7%). Approximately one fourth of both groups had do-not-resuscitate orders (HMO, 25.4%; FFS, 27.9%; P=.68). After controlling for age, marital status, and characteristics of dependency at discharge, HMO patients were more likely than FFS patients to be sent to nursing homes (HMO, 41.8%; FFS, 27.9%; P=.001) and less likely to be discharged to rehabilitation hospitals or units (HMO, 16.2%; FFS, 23.4%; P=.03). At follow-up, no significant differences in relative risk of dying were found between HMO and FFS groups (relative risk, 0.96; 95% confidence interval, 0.73-1.26; P=.77). Patients in Medicare HMOs who experience strokes are more likely to be discharged to nursing homes and less likely to go to rehabilitation facilities following the acute event. However, they have similar survival patterns compared with comparable patients in FFS settings after adjusting for other factors.


Predictors of response to acute treatment of chronic and double depression with sertraline or imipramine.
The literature on predictors of response to treatment of nonchronic major depression has identified shorter duration of illness, acute onset, and less severity of illness as positive predictors. Unfortunately, there are almost no data on predictors of response to treatment for chronic depression. This study examined predictors of response to pharmacotherapy (sertraline or imipramine) in the treatment of outpatients who had DSM-III-R-defined chronic major or double depression. The acute phase of the Chronic Major Depression and Double Depression Study is a double-blind, randomized, parallel-group 12-week comparison of sertraline and imipramine. Analyses are based on 623 patients who comprised the intent-to-treat sample, of whom 299 were nonresponders and 324 were responders, defined by a priori criteria as either remission or satisfactory therapeutic response. A stepwise logistic multiple regression analysis was performed on candidate clinical, psychosocial, and demographic variables previously identified as statistically significant in an attempt to develop a predictive model of positive antidepressant response. The sociodemographic variables that were predictive of positive response included living with spouse or partner or being at least a high school graduate. With regard to symptomatology and clinical history, responders had significantly lower baseline depression severity scores. In general, comorbid anxiety, substance abuse, and personality disorders did not influence rates of response. However, the presence of depressive personality traits was associated with a higher nonresponse rate. Among psychosocial variables, longer duration of personal relationships as well as higher baseline quality of life were associated with positive response. A stepwise logistic multiple regression identified 5 variables-living with spouse or partner, higher educational level, passive-aggressive personality, lower introverted-tense personality traits, and higher quality of life--that significantly and independently contributed to the predictive model. This model correctly classified 67% of patients. A higher baseline quality of life, living with spouse or partner, and having more education were the strongest predictors of response to acute pharmacotherapy among chronically depressed patients. Clinical variables and comorbidity were not identified as independent predictors, although personality traits did appear to influence treatment response. Overall, the predictive value of these baseline measures was modest, and therefore of limited clinical utility.


The CD46 transmembrane domain is required for efficient formation of measles-virus-mediated syncytium.
Two phosphatidylinositol (PI)-anchored versions of a measles virus (MV) receptor membrane cofactor protein (MCP; CD46) were generated by fusing the extracellular domain of MCP to the decay-accelerating factor (DAF; CD55) or its PI anchor. The PI-anchored forms of MCP expressed on Chinese hamster ovary cells, otherwise non-permissive to MV, conferred a smaller MV cytopathic effect than a wild-type MCP, a Ser/Thr-rich domain-deletion mutant and a cytoplasmic tail-deletion mutant of MCP. Therefore the differences in MV receptor properties between the two PI-anchored and three transmembrane forms were investigated. The PI-anchored forms were predominantly expressed on microvilli as in DAF, whereas the other transmembrane forms were found on intracellular membranes. The PI-anchored forms conferred high MV-binding capacity compared with the transmembrane versions. MV replication was, however, severely suppressed in cells expressing the PI-anchored forms, resulting in ineffective syncytium formation. In contrast, cell-to-cell fusion occurred efficiently after co-transfection of cDNA species encoding MV-H. MV-F and any version of MCP. Thus the PI-anchored forms, despite showing sufficient MV binding and cell-to-cell fusion competence together with MV-H and MV-F, mediate inefficient MV entry or replication, which causes severe suppression of the MV cytopathic effect. A biased receptor distribution on microvilli might participate in the selection of a low MV uptake pathway in the PI-anchored forms of MCP. Taken together, the transmembrane portion of MCP is a critical factor for effective virus-cell fusion and the subsequent MV replication.


Prevalence and risk factors of COPD among never-smokers in two areas of Sweden - Occupational exposure to gas, dust or fumes is an important risk factor.
Although active tobacco smoking is the main risk factor for COPD, COPD is not uncommon also among never-smokers. Different study locations along with different spirometric definitions of COPD have historically yielded different prevalence estimates of the disease. To study current prevalence and risk factors of COPD among never-smokers in two areas of Sweden. Data collected in 2008-2012 within the West Sweden Asthma Study and Obstructive Lung Disease in Northern Sweden Studies was pooled. The study population consisted of 1839 subjects who participated in spirometry and interviews. COPD was defined as post-bronchodilator a) FEV(1)/(F)VC < 0.7, b) FEV(1)/FVC < 0.7 and c) FEV(1)/FVC < lower limit of normal. Of the 1839 subjects, 967 (52.6%) were never-smokers. Among the never-smoking subjects, the prevalence of COPD according to definitions a-c was 7.7%, 4.9% and 3.0%, respectively. The corresponding prevalence of GOLD grade ≥2 was 2.0%, 1.4% and 1.3%. No significant difference in prevalence between the two study areas was observed. In never-smokers, occupational exposure to gas, dust or fumes (GDF) was significantly associated with both COPD (OR 1.85, 95% CI 1.03-3.33), and GOLD ≥2 (OR 4.51, 1.72-11.9) according to definition a), after adjusting for age, educational level and exposure to passive smoking at work. Depending on definition, prevalence of COPD among never-smokers was 3.0-7.7%, whereas GOLD ≥2 was present in 1.3-2.0%. Occupational exposure to GDF remained independently and significantly associated with COPD regardless of spirometric definition of the disease.


Epicardial progenitor cells in cardiac regeneration and neovascularisation.
While cardiovascular diseases remain the major worldwide cause of mortality and morbidity, there is an urgent need to tackle the clinical and economic burden of heart failure. Since the mammalian heart is unable to adequately regenerate beyond early postnatal stages, individuals surviving acute myocardial infarction are at risk of heart failure. Understanding the embryonic mechanisms of vasculogenesis and cardiogenesis, as well as the mechanisms retained for regeneration in species such as the zebrafish, will inform on strategies for human myocardial repair. Due to their fundamental role in heart development, epicardium-derived cells (EPDCs) have emerged as a population with potential to restore myocardium and coronary vasculature. The ability to revive ordinarily dormant EPDCs lies in the identification of key molecular cues used in the embryo to orchestrate cardiovascular development. One such stimulatory factor, Thymosin β4 (Tβ4), restores the quiescent adult epicardium to its pluripotent embryonic state. Tβ4 treatment of infarcted hearts induces dramatic EPDC proliferation and formation of a network of perfused, functional vessels to enhance blood flow to the ischaemic myocardium. Moreover, Tβ4 facilitates an epicardial contribution of mature de novo cardiomyocytes, structurally and functionally coupled with resident myocardium, which may contribute towards the functional improvement of Tβ4-treated hearts post-MI.


I recognize your face, but I can't remember your name: a question of expertise?
In four experiments on the identification of familiar faces we reassessed a robust performance pattern--namely, the temporal advantage for retrieving biographical facts as compared to recalling proper names, which has been interpreted as reflecting a serial ordering of the access to semantic and name information. Evidence for recent parallel accounts had been provided by Scanlan and Johnston (1997) who reported an advantage for name retrieval in children. Here we replicated the findings of Scanlan and Johnston but also showed that the naming advantage disappears, and performance is very similar to that of adults when stimuli and tasks are used that are familiar to children. Conversely, we also demonstrated an advantage for name retrieval in adults when highly unfamiliar semantic facts were associated with the faces. Together these findings suggest that there is no fundamental difference in the cognitive architectures of children and adults. The experiments indicate that the relative speed of naming and semantic fact retrieval depends on the expertise with the semantic facts to be retrieved. Implications for models of face identification and naming are discussed.


Performance-based incentive for improving quality of maternal health services in Bangladesh.
Poor motivation of providers, primarily caused by low remuneration and/or non-existence of financial incentives, has been a key challenge to improve the quality of maternal health services in the public sector health facilities in rural Bangladesh. An operations research study examined the impact of performance-based incentive for service providers at the institutional level to improve the quality of maternal health services. Quality of care was assessed through monitoring visits of professionals from higher-level health facilities, which contributed to improved service provision within the facilities. Quality scores of the facilities increased from 55% to 78% in 14 months of intervention with significant improvement in antenatal care, postnatal counseling, and institutional delivery (p < 0.01). Importantly, client satisfaction increased remarkably in the intervention facilities. Performance-based incentive has the potential for motivating service providers in improving the quality of maternal health services and for increasing the utilization of facilities for maternal health services in Bangladesh.


Large-Area Tunable Red/Green/Blue Tri-Stacked Quantum Dot Light-Emitting Diode Using Sandwich-Structured Transparent Silver Nanowires Electrodes.
Quantum dot light-emitting diodes (QLEDs), particularly those capable of emitting light with tunable colors, have attracted the attention of researchers for their variability in lighting and displays. So far, various color-tunable QLEDs have been developed using techniques of inkjet printing or white light combining with color filters (CFs), which however suffered from difficulties in mass production. Here, by inserting an insulating resin layer between two conductive silver nanowire (AgNW) layers, a unique AgNWs/resin/AgNWs (A/R/A) sandwich-structured electrode was developed, showing rather small sheet resistances at both sides and high transparency. The as-prepared A/R/A electrode is applicable for making a large-area transparent red QLED with an external quantum efficiency (EQE) of 11.42% and a transmittance of 72.5%. Furthermore, the A/R/A electrode can be used as intermediate connecting electrodes to stack three single-colored QLEDs, forming a novel structured R/G/B tri-stacked QLED, which enables emission not only of primary colors red, green, and blue independently with the maximum EQE of 8.22, 8.07, and 2.28%, respectively, but also arbitrary hybrid colors that cover a 107% National Television System Committee (NTSC) color triangle. Such large-area full-color-tunable tri-stacked QLED offers new perspectives for the next-generation solid-state scene lighting and full-color displays.


Roles of glucocorticoids in human parturition: a controversial fact?
The pivotal role of glucocorticoids in the initiation of parturition has been very well documented in several domestic mammalian animal species. However the role of glucocorticoids in human parturition remains controversial mainly because of the absence of effect of synthetic glucocorticoids, given to promote fetal organ maturation in pregnant women with threatened preterm delivery, on the length of gestation. This article will review studies of glucocorticoids in human parturition and provide evidence for an important role of glucocorticoids in human parturition as well but a simultaneous high concentration of estrogen within the intrauterine tissues may be necessary for GCs to initiate parturition. The synthetic GCs dexamethasone and betamethasone pass through the placenta intact resulting in potent negative feedback on the fetal HPA axis and diminished production of DHEA from fetal adrenal glands for estrogen synthesis by the placenta. This may negate the effect of systemic administration of GCs on the induction of labor, especially in cases where the myometrium is not yet fully primed by estrogen. Endogenous glucocorticoids are inactivated by the placental 11β-HSD2 thus limiting the negative feedback of maternal cortisol on the fetal HPA axis and allowing the simultaneous rise of cortisol and estrogen levels towards the end of gestation. Therefore, endogenous glucocorticoids, particularly glucocorticoids produced locally in the intrauterine tissues may play an important role in parturition in humans by enhancing prostaglandin production in the fetal membranes and stimulating estrogen and CRH production in the placenta.


Uricosuric medications for chronic gout.
Uricosuric agents have long been used in the treatment of gout but there is little evidence regarding their benefit and safety in this condition. To assess the benefits and harms of uricosuric medications in the treatment of chronic gout. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2013), Ovid MEDLINE and Ovid EMBASE for studies to the 13 May 2013. We also searched the World Health Organization Clinical Trials Registry, ClinicalTrials.gov and the 2011 to 2012 American College of Rheumatology and European League against Rheumatism abstracts. WE considered black box warnings and searched drug safety databases to identify and describe rare adverse events. We considered all randomised controlled trials (RCTs) or quasi-randomised controlled trials (controlled clinical trials (CCTs)) that compared uricosuric medications (benzbromarone, probenecid or sulphinpyrazone) alone or in combination with another therapy (placebo or other active uric acid-lowering medication, or non-pharmacological treatment) in adults with chronic gout for inclusion. Two review authors independently selected the studies for inclusion, extracted data and performed a risk of bias assessment. Main outcomes were frequency of acute gout attacks, serum urate normalisation, study participant withdrawal due to adverse events, total adverse events, pain reduction, function and tophus regression. The search identified four RCTs and one CCT that evaluated the benefit and safety of uricosurics for gout. One study (65 participants) compared benzbromarone with allopurinol for a duration of four months; one compared benzbromarone with allopurinol (36 participants) for a duration of nine to 24 months; one study (62 participants) compared benzbromarone with probenecid for two months and one study (74 participants) compared benzbromarone with probenecid. One study (37 participants) compared allopurinol with probenecid. No study was completely free from bias.Low-quality evidence from one study (55 participants) comparing benzbromarone with allopurinol indicated uncertain effects in terms of frequency of acute gout attacks (4% with benzbromarone versus 0% with allopurinol; risk ratio (RR) 3.58, 95% confidence interval (CI) 0.15 to 84.13), while moderate-quality evidence from two studies (101 participants; treated for four to nine months) indicated similar proportions of participants achieving serum urate normalisation (73.9% with benzbromarone versus 60% with allopurinol; pooled RR 1.27, 95% CI 0.90 to 1.79). Low-quality evidence indicated uncertain differences in withdrawals due to adverse events (7.1% with benzbromarone versus 6.1% with allopurinol; pooled RR 1.25, 95% CI 0.28 to 5.62), and total adverse events (20% with benzbromarone versus 6.7% with allopurinol; RR 3.00, 95% CI 0.64 to 14.16). The study did not measure pain reduction, function and tophus regression.When comparing benzbromarone with probenecid, there was moderate-quality evidence based on one study (62 participants) that participants taking benzbromarone were more likely to achieve serum urate normalisation after two months (81.5% with benzbromarone versus 57.1% with probenecid; RR 1.43, 95% CI 1.02 to 2.00). This indicated that when compared with probenecid, five participants needed to be treated with benzbromarone in order to have one additional person achieve serum urate normalisation (number needed to treat for an additional beneficial outcome (NNTB) 5). However, the second study reported no difference in the absolute decrease in serum urate between these groups after 12 weeks. Low-quality evidence from two studies (129 participants) indicated uncertain differences between treatments in the frequency of acute gout attacks (6.3% with benzbromarone versus 10.6% with probenecid; pooled RR 0.73, 95% CI 0.09 to 5.83); fewer withdrawals due to adverse events with benzbromarone (2% with benzbromarone versus 17% with probenecid; pooled RR 0.15, 95% CI 0.03 to 0.79, NNTB 7) and fewer total adverse events (21% with benzbromarone versus 47% with probenecid; pooled RR 0.43, 95% CI 0.25 to 0.74; NNTB 4). The studies did not measure pain reduction, function and tophus regression.Low-quality evidence based on one small CCT (37 participants) indicated uncertainty around the difference in the incidence of acute gout attacks between probenecid and allopurinol after 18 to 20 months' treatment (53% with probenecid versus 55% with allopurinol; RR 0.96, 95% CI 0.53 to 1.75). The study did not measure or report the proportion achieving serum urate normalisation, pain reduction, function, tophus regression, withdrawal due to adverse events and total adverse events. There was moderate-quality evidence that there is probably no important difference between benzbromarone and allopurinol at achieving serum urate normalisation, but that benzbromarone is probably more successful than probenecid at achieving serum urate normalisation in people with gout. There is some uncertainty around the effect estimates, based on low-quality evidence from only one or two trials, on the number of acute gout attacks, the number of withdrawals due to adverse events or the total number of participants experiencing adverse events when comparing benzbromarone with allopurinol. However, when compared with probenecid, benzbromarone resulted in fewer withdrawals due to adverse events and fewer participants experiencing adverse events. Low-quality evidence from one small study indicated uncertain effects in the incidence of acute gout attacks when comparing probenecid with allopurinol therapy. We downgraded the evidence because of a possible risk of performance and other biases and imprecision.


A comparison of incest offenders based on victim age.
The purpose of the present study was to compare incest offenders (IOs) whose victims include infants or toddlers to IOs with adolescent victims on several variables commonly examined in the sexual offender literature. Participants were 48 men whose youngest victim was less than 6 years of age (younger-victim incest offenders; YVs); and 71 men whose youngest victim was 12 to 16 years of age (older-victim incest offenders (OVs). In general, YVs showed more emotional disturbance and pathology than OVs. Compared with OVs, YVs had a greater history of substance abuse and more current problems with alcohol. In addition, YVs reported significantly poorer sexual functioning and were significantly more psychiatrically disturbed. YVs were also more likely to have a male victim, to have victimized a nephew/niece or grandson/granddaughter, and to have denied their offense(s). It was evident that both the YVs and OVs demonstrated clinically significant difficulty with normal sexual functioning and exhibited deviant sexual arousal.


Multidisciplinary baseline assessment of homosexual men with and without human immunodeficiency virus infection. III. Neurologic and neuropsychological findings.
We explored the possibility that neurologic and neuropsychological changes constitute the earliest detectable manifestations of human immunodeficiency virus (HIV) infection. Without knowledge of HIV status, we assessed neurologic signs and symptoms and administered a battery of neuropsychological tests to 208 homosexual men, of whom 84 were HIV negative, 49 were HIV positive and asymptomatic, 29 were mildly symptomatic, and 46 had significant medical symptoms but not the acquired immunodeficiency syndrome. There was no difference between the HIV-negative and HIV-positive men in the frequency of neurologic signs or of defective or borderline performance on any neuropsychological test. However, HIV-positive men performed slightly but significantly worse than HIV-negative men on tests of verbal memory, executive function, and language. Similar results were obtained when comparisons were limited to HIV-positive medically asymptomatic and HIV-negative men. There was no degradation of neurologic status or neuropsychological performance across stages of HIV severity, but neurologic and neuropsychological summary scores correlated with CD4/CD8 ratios in the HIV-positive group. Ratings of neurologic signs and symptoms correlated with neuropsychological summary scores in the HIV-positive group only. Cognitive complaints were more frequent in the HIV-positive men; they correlated with actual test performance in the HIV-positive but not HIV-negative men. The constellation of subjective and objective neuropsychological and neurologic findings suggests the possibility of a definable syndrome associated with HIV infection in asymptomatic individuals.


Effect of curcumin on radiation-impaired healing of excisional wounds in mice.
To study the effect on wound contraction of pretreatment with various doses of curcumin (the most important active ingredient of the spice turmeric) in mice exposed to 6 Gy whole-body gamma radiation. A full-thickness skin wound was produced on the dorsum of Swiss albino mice treated with and without 25, 50, 100, 150 or 200 mg/kg body weight of curcumin before exposure to 6 Gy gamma radiation. Progression of wound contraction was monitored using video images of the wound at various days post-irradiation until full healing occurred. Mean wound healing times were also calculated. Irradiation caused significant delay in wound contraction and healing times. However, treatment with curcumin resulted in a dose-dependent increase in contraction when compared with a control. Greatest contraction was observed for 100 mg/kg curcumin, with statistically significant results at days three (p < 0.009), six (p < 0.05) and nine (p < 0.05) post-irradiation for this dose. Complete healing was achieved by day 23 post-irradiation in the curcumin-treated irradiation group. Pretreatment with curcumin has a conductive effect on irradiated wounds. It could be a substantial therapeutic agent for ameliorating radiation-induced delay in wound repair in cases of combined injuries.


Micro particle launcher/cleaner based on optical trapping technology.
Efficient and controllable launching function of an optical tweezers is a challenging task. We present and demonstrate a novel single fiber optical tweezers which can trap and launch (clean) a target polystyrene (PS) microsphere (diameter~10μm) with independent control by using two wavelengths beams: 980nm and 1480nm. We employ 980nm laser beam to trap the target PS microsphere by molding the fiber tip into a special tapered-shape; and we employ 1480nm laser beam to launch the trapped PS microsphere with a certain velocity by using the thermophoresis force generated from the thermal effect due to the high absorption of the 1480nm laser beams in water. When the launching force is smaller than the trapping force, the PS microsphere will be trapped near the fiber tip, and the launching force will blow away other PS microspheres in the workspace realizing the cleaning function; When the launching force is larger than the trapping force, the trapped PS microsphere will be launched away from the fiber tip with a certain velocity and towards a certain direction, realizing the launching function. The launching velocity, acceleration and the distance can be measured by detecting the interference signals generated from the PS microsphere surface and the fiber tip end-face. This PS microsphere launching and cleaning functions expanded new features of single fiber optical tweezers, providing for the possibility of more practical applications in the micro manipulation research fields.


OPTIMAL, an occupational therapy led self-management support programme for people with multimorbidity in primary care: a randomized controlled trial.
We investigated the effectiveness of an occupational therapy led self-management support programme, OPTIMAL, designed to address the challenges of living with multiple chronic conditions or multimorbidity in a primary care setting. Pragmatic feasibility randomised controlled trial including fifty participants with multimorbidity recruited from family practice and primary care settings. OPTIMAL is a six-week community-based programme, led by occupational therapy facilitators and focuses on problems associated with managing multimorbidity. The primary outcome was frequency of activity participation. Secondary outcomes included self-perception of, satisfaction with and ability to perform daily activities, independence in activities of daily living, anxiety and depression, self-efficacy, health-related quality of life, self-management support, healthcare utilisation and individualised goal attainment. Outcomes were collected within two weeks of intervention completion. There was a significant improvement in frequency of activity participation, measured using the Frenchay Activities Index, for the intervention group compared to the control group (Adjusted Mean Difference at follow up 4.22. 95% Confidence Interval 1.59-6.85). There were also significant improvements in perceptions of activity performance and satisfaction, self-efficacy, independence in daily activities and quality of life. Additionally, the intervention group demonstrated significantly higher levels of goal achievement, following the intervention. No significant differences were found between the two groups in anxiety, depression, self-management scores or healthcare utilisation. OPTIMAL significantly improved frequency of activity participation, self-efficacy and quality of life for patients with multimorbidity. Further work is required to test the sustainability of these effects over time but this study indicates that it is a promising intervention that can be delivered in primary care and community settings. ISRCTN67235963.


Determinants of neuropsychological and behavioural outcomes in early childhood survivors of congenital heart disease.
To evaluate the relative effect of cyanosis, surgical interventions and family processes on neuropsychological and behavioural outcomes in 4-year-old survivors of serious congenital heart disease (CHD). 90 children with a range of cyanotic and acyanotic conditions, who underwent either corrective or palliative surgery, completed a neuropsychological and behavioural evaluation. Families of participants were also profiled by evaluation of maternal mental health, worry, social support, parenting style and family functioning. Compromised neuropsychological outcomes were associated with a combination of cyanotic conditions and open-heart surgery, but this was not exacerbated by having a complex, palliative, status. Both cyanotic and acyanotic conditions were associated with specific sensorimotor delays, regardless of method of the correction. Only children with complex conditions and palliative interventions seemed at risk of poor behavioural outcomes; indeed, children with cyanosis with complete repair showed favourable behavioural outcomes compared with controls. Multivariate analyses highlighted the sometimes greater relevance of family processes (eg parenting style, maternal mental health and worry), rather than disease or surgical factors, in predicting especially behavioural outcomes. The findings (1) suggest a more complex relationship between cyanosis, surgical methods of correction, neuropsychological and behavioural outcomes than previously charted, (2) highlight that family processes may be aetiologically more important than disease and surgical factors, and (3) indicate specific targets for secondary prevention programmes for this at-risk population.


Electrophysiological mechanisms of atrial flutter.
Atrial flutter (AFL) is a common arrhythmia in clinical practice. Several experimental models such as tricuspid regurgitation model, tricuspid ring model, sterile pericarditis model and atrial crush injury model have provided important information about reentrant circuit and can test the effect of antiarrhythmic drugs. Human atrial flutter has typical and atypical forms. Typical atrial flutter rotates around tricuspid annulus and uses the crista terminalis and sometimes sinus venosa as the boundary. The IVC-tricuspid isthmus is a slow conduction zone and the target of radiofrequency ablation. Atypical atrial flutter may arise from the right or left atrium. Right atrial flutter includes upper loop reentry, free wall reentry and figure of eight reentry. Left atrial flutter includes mitral annular atrial flutter, pulmonary vein-related atrial flutter and left septal atrial flutter. Radiofrequency ablation of the isthmus between the boundaries can eliminate these arrhythmias.


Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.
Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.


Multiphoton fluorescence lifetime imaging microscopy reveals free-to-bound NADH ratio changes associated with metabolic inhibition.
Measurement of endogenous free and bound NAD(P)H relative concentrations in living cells isa useful method for monitoring aspects of cellular metabolism, because the NADH∕NAD⁺ reduction-oxidation pair is crucial for electron transfer through the mitochondrial electron transport chain. Variations of free and bound NAD(P)H ratio are also implicated in cellular bioenergetic and biosynthetic metabolic changes accompanying cancer. This study uses two-photon fluorescence lifetime imaging microscopy (FLIM) to investigate metabolic changes in MCF10A premalignant breast cancer cells treated with a range of glycolysis inhibitors: namely, 2 deoxy-D-glucose, oxythiamine, lonidamine, and 4-(chloromethyl) benzoyl chloride, as well as the mitochondrial membrane uncoupling agent carbonyl cyanide m-chlorophenylhydrazone. Through systematic analysis of FLIM data from control and treated cancer cells, we observed that all glycolytic inhibitors apart from lonidamine had a slightly decreased metabolic rate and that the presence of serum in the culture medium generally marginally protected cells from the effect of inhibitors. Direct production of glycolytic L-lactate was also measured in both treated and control cells. The combination of these two techniques gave valuable insights into cell metabolism and indicated that FLIM was more sensitive than traditional biochemical methods, as it directly measured metabolic changes within cells as compared to quantification of lactate secreted by metabolically active cells.


'The girl with her period is the one to hang her head' Reflections on menstrual management among schoolgirls in rural Kenya.
The onset of menstruation is a landmark event in the life of a young woman. Yet the complications and challenges that can accompany such an event have been understudied, specifically in resource-poor settings. As interventions aim to improve female attendance in schools, it is important to explore how menstruation is perceived and navigated by girls in the school setting. This research conveys rural Kenyan schoolgirls' perceptions and practices related to menstruation Data were collected at six rural schools in the Nyanza Province of Western Kenya. Using focus group discussions, in-depth interviews, and field notes from observations, researchers collected information from 48 primary schoolgirls and nine teachers. Systematic analysis began with a reading of transcripts and debriefing notes, followed by manual coding of the narratives. Focus group discussions became opportunities for girls to share thoughts on menstruation, instruct one another on management practices and advise one another on coping mechanisms. Girls expressed fear, shame, distraction and confusion as feelings associated with menstruation. These feelings are largely linked to a sense of embarrassment, concerns about being stigmatized by fellow students and, as teachers explained, a perception that the onset of menstruation signals the advent of a girl's sexual status. Among the many methods for managing their periods, girls most frequently said they folded, bunched up or sewed cloth, including cloth from shirts or dresses, scraps of old cloth, or strips of an old blanket. Cloth was reported to frequently leak and cause chafing, which made school attendance difficult particularly as the day progressed. Attitudes and practices of girls toward menstruation have been arranged into personal, environmental and behavioural factors. Further research on menstrual management options that are practical, sustainable and culturally acceptable must be conducted to inform future programs and policies that aim to empower young girls as they transition into womanhood. Stakeholders working within this and similar contexts must consider systematic mechanisms to explain to young girls what menstruation is and how to manage it. Providing sanitary supplies or guiding girls on how to create supplies serve as critical components for future interventions.


Lunar glasses and micro-breccias: properties and origin.
Impact has been an important rock-forming process on the moon. Electron- and ion-probe analyses of major and minor elements show that most glasses and chondrule-like particles formed by shock melting of various proportions of mainly pyroxene, plagioclase, and ilmenite. This is the first direct evidence that chondrule-like molten droplets can form in impact events. Welding and shock lithification resulted in rocks texturally similar to chondrites but composition rules out the moon as source for chondrites. Impact craters on a nickel-iron sample evidence the importance of secondary impacts by accelerated lunar matter.


Correlation between gliotoxin production and virulence of Aspergillus fumigatus in Galleria mellonella.
Aspergillus fumigatus is a pathogenic fungus capable of causing both allergic lung disease and invasive aspergillosis, a serious, life-threatening condition in neutropenic patients. Aspergilli express an array of mycotoxins and enzymes which may facilitate fungal colonisation of host tissue. In this study we investigated the possibility of using the insect, Galleria mellonella, for in vivo pathogenicity testing of Aspergillus species. Four clinical isolates of Aspergillus fumigatus and a single strain of Aspergillus niger were characterised for catalase and elastase activity and for the production of gliotoxin. Gliotoxin is an immunosuppressive agent previously implicated in assisting tissue penetration. Results illustrated a strain dependent difference in elastase activity but no significant difference in catalase activity. Gliotoxin production was detected in vitro and in vivo by Reversed Phase-High Performance Liquid Chromatography, with highest amounts being produced by A. fumigatus ATCC 26933 (350 ng/mg hyphae). Survival probability plots (Kaplan-Meier) of experimental groups infected with Aspergillus conidia indicate that G. mellonella is more susceptible to fungal infection by A. fumigatus ATCC 26933, implicating a critical role for gliotoxin production rather than growth rate or enzymatic activity in the virulence of A. fumigatus in this model.


Dietary meat and fat intake and prevalence of rhinoconjunctivitis in pregnant Japanese women: baseline data from the Kyushu Okinawa Maternal and Child Health Study.
Dietary fat exerts numerous complex effects on proinflammatory and immunologic pathways. Several epidemiological studies have examined the relationships between intake of fatty acids and/or foods high in fat and allergic rhinitis, but have provided conflicting findings. The current cross-sectional study investigated such relationships in Japan. Study subjects were 1745 pregnant women. The definition of rhinoconjunctivitis was based on criteria from the International Study of Asthma and Allergies in Childhood. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for age; gestation; region of residence; number of older siblings; number of children; smoking; secondhand smoke exposure at home and at work; family history of asthma, atopic eczema, and allergic rhinitis; household income; education; and body mass index. The prevalence of rhinoconjunctivitis in the past 12 months was 25.9%. Higher meat intake was significantly associated with an increased prevalence of rhinoconjunctivitis: the adjusted odds ratio between extreme quartiles was 1.71 (95% confidence interval: 1.25-2.35, P for trend = 0.002). No measurable association was found between fish intake and rhinoconjunctivitis. Intake of total fat, saturated fatty acids, monounsaturated fatty acids, n-3 polyunsaturated fatty acids, α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, n-6 polyunsaturated fatty acids, linoleic acid, arachidonic acid, and cholesterol and the ratio of n-3 to n-6 polyunsaturated fatty acid intake were not evidently related to the prevalence of rhinoconjunctivitis. The current results suggest that meat intake may be positively associated with the prevalence of rhinoconjunctivitis in young adult Japanese women.


The Effect of Rest Interval Length on Upper and Lower Body Exercises in Resistance-Trained Females.
The purpose of this study was to investigate the effects of SHORT (1 min) and LONG (3 min) rest intervals (RI) on total volume lifted (TVL), repetition performance, fatigue index (FI), and blood lactate [La] during upper body (chest press) and lower body (leg press) exercise with low-intensity (75% of a 10-RM) in trained female lifters. Fourteen females (mean ± SD, age = 22.9 ± 5.4 years, training experience = 5.2 ± 2.5 years, height = 166.1 ± 6.9 cm, weight = 61.3 ± 5.1 kg, body fat % = 21.7 ± 3.3%) participated in this randomized, repeated-measures, cross-over design study. They performed four sets to failure on chest press (CP) and leg press (LP) under two conditions (SHORT and LONG RIs) in a counterbalanced manner. Paired-samples t-tests were used to analyze mean differences for TVL in CP and LP, separately. A 2 (exercise) x 2 (rest interval) repeated measures ANOVA was used to analyze mean differences in FI and average [La] values. A 2 (rest interval) x 4 (sets) repeated measures ANOVA was used to analyze mean differences in repetitions completed for each exercise. TVL for SHORT was significantly less when compared to LONG for both exercises. There was no significant difference in average [La] between RIs despite a greater FI in SHORT compared to LONG for both exercises. Lastly, [La] was higher during LP compared to CP irrespective of RI length. These results suggest that longer RIs are better for female lifters who want to optimize TVL with low-intensity resistance training. Metabolic stress, as measured by blood lactate, was greater during lower-body exercise.


Is type A behavior really a trigger for coronary heart disease events?
The purpose of this study was to compare chronic with acute mechanisms by which Type A might predict incident coronary heart disease (CHD). The study included 2394 men aged 50 to 64 years who were assessed for CHD, Type A behavior, and CHD risk factors. Type A was assessed using the Jenkins Activity Survey (JAS), the Bortner scale, and the Framingham scale. Further examinations were completed at 5 and 9 years for incident CHD. After 9 years, there was no increased risk of CHD associated with any Type A score. Nevertheless, high Bortner scores were associated with increased risk of incident CHD at 5 years and high JAS and Bortner scores were associated with a decreased risk between 5 and 9 years. Further analysis of Type A scores on time to first coronary event found strong inverse associations for all type A scores (JAS = 205 -0.49 months to first event, 95% CI = -0.20, -0.78, p =.001) (Bortner = 176 -0.27 months; 95% CI = -0.10, -0.44; p =.002) (Framingham = 0.44 -0.0011 months; 95% CI = -0.0002, -0.0019; p =.01). The data show Type A is a strong predictor of when incident coronary heart disease (or coronary event) will occur rather than if it will occur. These findings suggest that Type A increases exposure to potential triggers, rather than materially affecting the process of atherosclerosis.


Effects of interleukin 3, interleukin 6, and granulocyte colony-stimulating factor on sorted murine splenic progenitor cells.
In order to examine the effect of recombinant growth factors on hemopoietic stem cells, these cells were enriched using wheat germ agglutinin (WGA) and monoclonal antibodies for lineage markers (Lin) such as B220, L3T4, Lyt-2, asialo GM1, Mac-1, and AL-21. Spleen colony-forming units (CFU-S) and in vitro colony-forming units were highly enriched in the fraction of WGA+Lin- spleen cells. To eliminate committed progenitor cells, spleen cells of 5-fluorouracil (5-FU)-treated mice were used. By this treatment, day-8 CFU-S disappeared but day-14 CFU-S were preserved. Day-14 CFU-S were also contained in the fraction of WGA+Lin- cells, which made up about 0.5% of total nucleated spleen cells. Moreover, this fraction contained primitive stem cells that could reconstitute the hemopoiesis of irradiated mice. Sorted WGA+Lin- spleen cells obtained from male 5-FU-treated mice were injected into lethally irradiated female mice. Southern hybridization using a mouse Y chromosome-specific probe showed that the bone marrow, spleen, and thymus of the recipients was reconstituted by male mouse-derived cells. When sorted WGA+Lin- spleen cells of the 5-FU-treated mice were cultured in vitro in the presence of recombinant interleukin 3 (IL-3), interleukin 6 (IL-6), and granulocyte colony-stimulating factor (G-CSF), colony formation was observed only in wells with IL-3, whereas unfractionated spleen cells formed colonies in the presence of IL-3, IL-6, or G-CSF. However, IL-6 but not G-CSF acted synergistically on enriched hemopoietic stem cells in the presence of IL-3. These data suggest that G-CSF or IL-6 did not affect primitive stem cells independently but showed the effect on these cells indirectly or synergistically with IL-3.


In vitro Fermentation Reveals Changes in Butyrate Production Dependent on Resistant Starch Source and Microbiome Composition.
One of the primary benefits associated with dietary resistant starch (RS) is the production of butyrate by the gut microbiome during fermentation of this fiber in the large intestine. The ability to degrade RS is a relatively rare trait among microbes in the gut, seemingly confined to only a few species, none of which are butyrate producing organisms. Thus, production of butyrate during RS fermentation requires a network of interactions between RS degraders and butyrate producers. This is further complicated by the fact that there are multiple types of RS that differ in their structural properties and impacts on the microbiome. Human dietary intervention trials with RS have shown increases in fecal butyrate levels at the population level but with individual to individual differences. This suggests that interindividual differences in microbiome composition dictate butyrate response, but the factors driving this are still unknown. Furthermore, it is unknown whether a lack of increase in butyrate production upon supplementation with one RS is indicative of a lack of butyrate production with any RS. To shed some light on these issues we have undertaken an in vitro fermentation approach in an attempt to mimic RS fermentation in the colon. Fecal samples from 10 individuals were used as the inoculum for fermentation with 10 different starch sources. Butyrate production was heterogeneous across both fecal inocula and starch source, suggesting that a given microbiome is best suited to produce butyrate only from a subset of RS sources that differs between individuals. Interestingly, neither the total amount of RS degraders nor butyrate producers seemed to be limiting for any individual, rather the membership of these sub-populations was more important. While none of the RS degrading organisms were correlated with butyrate levels, Ruminococcus bromii was strongly positively correlated with many of the most important butyrate producers in the gut, though total butyrate production was strongly influenced by factors such as pH and lactate levels. Together these results suggest that the membership of the RS degrader and butyrate producer communities rather than their abundances determine the RS sources that will increase butyrate levels for a given microbiome.


Repeatability of the Glaucoma Hemifield Test in automated perimetry.
To examine the concordance of the Glaucoma Hemifield Test and other global visual field indexes between two consecutive automated visual field tests. Normal subjects, subjects with ocular hypertension, and subjects with glaucoma had two automated visual field tests on the Humphrey Field Analyzer. The Glaucoma Hemifield Test results, mean deviation, and corrected pattern standard deviation of the two consecutive visual field tests were compared. Forty-one normal subjects were tested within 1 and 2 years of each other. Four hundred seven subjects with ocular hypertension and 95 subjects with glaucoma were tested 1 year apart. The proportion of normal subjects who met a criterion for abnormality on two consecutive tests was 2.4%. The proportion of subjects with glaucoma with normal results of two tests was 10.5%. The specificity of automated visual field testing was improved from 80.8% to 89.9%, with a modest loss of sensitivity if two rather than one abnormal test result was required for entry into a clinical trial enrolling patients with glaucomatous field loss. Similarly, specificity increased from 84.2% to 89.5% if two normal tests were required for entry into an ocular hypertensive clinical trial. Among subjects with more closely spaced tests, the agreement between consecutive tests was similar for tests spaced 4 versus 12 months apart. Although there is concordance of Glaucoma hemifield Test results on consecutive testing, there is enough disagreement to result in improved specificity from the use of a second test in a clinical trial setting.


Impact of the COVID-19 Pandemic on Loneliness and Social Isolation: A Multi-Country Study.
The COVID-19 global pandemic and subsequent public health social measures have challenged our social and economic life, with increasing concerns around potentially rising levels of social isolation and loneliness. This paper is based on cross-sectional online survey data (available in 10 languages, from 2 June to 16 November 2020) with 20,398 respondents from 101 different countries. It aims to help increase our understanding of the global risk factors that are associated with social isolation and loneliness, irrespective of culture or country, to support evidence-based policy, services and public health interventions. We found the prevalence of severe loneliness was 21% during COVID-19 with 6% retrospectively reporting severe loneliness prior to the pandemic. A fifth were defined as isolated based on their usual connections, with 13% reporting a substantial increase in isolation during COVID-19. Personal finances and mental health were overarching and consistently cross-cutting predictors of loneliness and social isolation, both before and during the pandemic. With the likelihood of future waves of COVID-19 and related restrictions, it must be a public health priority to address the root causes of loneliness and social isolation and, in particular, address the needs of specific groups such as carers or those living alone.


Co-ordinate induction of hepatic mitochondrial and peroxisomal carnitine acyltransferase synthesis by diet and drugs.
The present studies examined the effect of agents that induce peroxisomal and mitochondrial beta-oxidation on hepatic mitochondrial carnitine palmitoyltransferase (CPT) and peroxisomal carnitine acyltransferase [CPTs of Ramsay (1988) Biochem. J. 249, 239-245; COT of Farrell & Bieber (1983) Arch. Biochem. Biophys. 222, 123-132 and Miyazawa, Ozasa, Osumi & Hashimoto (1983) J. Biochem. 94, 529-542]. In the first studies, high fat diets containing corn oil or fish oil were used to induce peroxisomal and mitochondrial enzymes. Rats were fed one of three diets for 4 weeks: (1) low fat, with corn oil as 11% of energy (kJ); (2) high fat, with corn oil as 45% of kJ; (3) high fat, with fish oil as 45% of kJ. At the end of 4 weeks, both mitochondrial CPT and peroxisomal CPTs exhibited increases in activity, immunoreactive protein, mRNA levels and transcription rates in livers of rats fed either high-fat diet compared to the low fat diet. Riboflavin deficiency or starvation for 48 h also increased the peroxisomal CPTs mRNA. A second set of studies used the plasticizer 2-(diethylhexyl)phthalate (DEHP), 0.5% clofibrate or 1% acetylsalicylic acid (fed for 3 weeks) to alter peroxisomal and mitochondrial fatty acid oxidation. With DEHP, the mitochondrial CPT and peroxisomal CPTs activity, immunoreactive protein, mRNA levels and and transcription rate were all increased by 3-5-fold. The peroxisomal CPTs activity, immunoreactive protein, mRNA levels and transcription rate were increased 2-3-fold by clofibrate and acetylsalicylic acid, again similar to mitochondrial CPT. The results of the combined studies using both diet and drugs to cause enzyme induction suggest that the synthesis of the carnitine acyltransferases (mitochondrial CPT and peroxisomal CPTs) may be co-ordinated with each other; however, the co-ordinate regulatory factors have not yet been identified.


Idiopathic fibrotic lung disease at a university hospital setting: management and prognostic factors.
Idiopathic fibrosing interstitial pneumonia consists of many subtypes, most associated with a poor prognosis. The aim of the study was to evaluate diagnostic procedures and treatment as well as survival in patients with idiopathic fibrosing interstitial pneumonia. This study comprised 175 patients with idiopathic fibrosing interstitial pneumonia (ICD 10 code J84) that had been diagnosed at Uppsala University Hospital, during 2005 to 2012. Patient records were reviewed concerning: gender, age, smoking, occupational exposure, comorbidities, procedures, lung function, and treatment. Information on survival and cause of death was collected. A total of 98% had been examined with computed tomography, 93% with spirometry, 49% with measurement of diffusion capacity, 48% with bronchoalveolar lavage, and 23% with lung biopsy. Prednisolone had been prescribed to 74% while N-acetylcysteine (NAC) and omeprazole were prescribed to 54%, respectively. Five-year survival was 46%. Mortality was associated with high age, low diffusion capacity, and the use of NAC. High age and a low diffusion capacity are related to shorter survival in idiopathic fibrosing interstitial pneumonia. We also unexpectedly found that the use of NAC was related to shorter survival. A relatively low proportion of the patients were examined with diffusion capacity measurement. Thus, there is a possibility to improve diagnostic procedures and thereby improve estimation of prognosis in fibrotic lung disease.


Evaluation of a dedicated short-stay unit for acute medical admissions.
The number of acute medical admissions to hospital continues to rise although not all need a prolonged stay. At the Queen Elizabeth Hospital, Gateshead, a short-stay unit (SSU) was developed specifically for such patients. Admissions to SSU over the first three weeks of 2006 were assessed. A total of 209 patients were admitted to SSU (10 patients a day). This accounted for 35% of all admissions through the medical assessment unit (MAU). Of these, 149 (71%) went home within 48 hours and a further 14 (7%) went home from SSU within 72 hours. The mean length of stay was 33 hours and the overall length of stay across the MAU (4.6 days) was significantly lower than the corresponding period a year earlier (5.5 days) (p = 0.02). The mean daily number of medical patients staying on non-medical wards was also lower during the study period than in 2005 (11 v 38; p = 0.015). Readmission rates and percentage bed occupancy did not change. This paper shows that the introduction of an SSU helps to identify and treat those patients with more minor illness who can often be discharged home at an earlier stage.


Structural and functional analysis of the YAP-binding domain of human TEAD2.
The Hippo pathway controls organ size and suppresses tumorigenesis in metazoans by blocking cell proliferation and promoting apoptosis. The TEAD1-4 proteins (which contain a DNA-binding domain but lack an activation domain) interact with YAP (which lacks a DNA-binding domain but contains an activation domain) to form functional heterodimeric transcription factors that activate proliferative and prosurvival gene expression programs. The Hippo pathway inhibits the YAP-TEAD hybrid transcription factors by phosphorylating and promoting cytoplasmic retention of YAP. Here we report the crystal structure of the YAP-binding domain (YBD) of human TEAD2. TEAD2 YBD adopts an immunoglobulin-like beta-sandwich fold with two extra helix-turn-helix inserts. NMR studies reveal that the TEAD-binding domain of YAP is natively unfolded and that TEAD binding causes localized conformational changes in YAP. In vitro binding and in vivo functional assays define an extensive conserved surface of TEAD2 YBD as the YAP-binding site. Therefore, our studies suggest that a short segment of YAP adopts an extended conformation and forms extensive contacts with a rigid surface of TEAD. Targeting a surface-exposed pocket of TEAD might be an effective strategy to disrupt the YAP-TEAD interaction and to reduce the oncogenic potential of YAP.


Statistics of polymer extensions in turbulent channel flow.
We present direct numerical simulations of turbulent channel flow with passive Lagrangian polymers. To understand the polymer behavior we investigate the behavior of infinitesimal line elements and calculate the probability distribution function (PDF) of finite-time Lyapunov exponents and from them the corresponding Cramer's function for the channel flow. We study the statistics of polymer elongation for both the Oldroyd-B model (for Weissenberg number Wi<1) and the FENE model. We use the location of the minima of the Cramer's function to define the Weissenberg number precisely such that we observe coil-stretch transition at Wi ≈1. We find agreement with earlier analytical predictions for PDF of polymer extensions made by Balkovsky, Fouxon, and Lebedev [Phys. Rev. Lett. 84, 4765 (2000)] for linear polymers (Oldroyd-B model) with Wi <1 and by Chertkov [Phys. Rev. Lett. 84, 4761 (2000)] for nonlinear FENE-P model of polymers. For Wi >1 (FENE model) the polymer are significantly more stretched near the wall than at the center of the channel where the flow is closer to homogenous isotropic turbulence. Furthermore near the wall the polymers show a strong tendency to orient along the streamwise direction of the flow, but near the center line the statistics of orientation of the polymers is consistent with analogous results obtained recently in homogeneous and isotropic flows.


Health goals among American adults: Prevalence, characteristics, and barriers.
Although numerous factors have been demonstrated in laboratory settings to lead to more successful health goal attainment, their actual use in daily goal pursuit is unknown. This study examines spontaneously reported health goals and their characteristics in a sample of 557 American adults. Participants responded to questions about health and health goals, with items assessing motivation, social support, and implementation intentions. In all, 66 percent of respondents had a health goal, 26 percent of participants had implementation intentions, and 47 percent received support from close others. Results suggest that interventions should focus on encouraging goal setting, teaching implementation intentions, and educating close others in providing support.


Nurses' responses to ethical challenges in oncology practice: an ethnographic study.
Oncology nurses encounter increasingly complex ethical challenges in clinical practice. This ethnographic study explored 30 oncology nurses' descriptions of ethical situations and 12 key informants' perspectives on factors that influence the development of ethically difficult situations. Nurses described the goals of preventing patient suffering and injury, being honest with patients, and contributing meaningfully to patient improvement and stated goals. Nurses experienced six primary challenges in meeting their goals: being the eyes and arms of patient suffering, experiencing the precariousness of competing obligations, navigating the intricacies of hope and honesty, managing the urgency caused by waiting, straining to find time, and weighing risks of speaking up in hierarchal structures. Nurse actions included addressing concerns, creating other avenues, murmuring to one another, staying silent, and looking away. Several factors influenced nurses' responses to ethical challenges. Results imply a contextual model of moral action that reveals a need for altering practice environments in addition to improving nurses' ethics skills. Nurses are very aware of their moral responsibilities in ethically difficult situations and need work environments conducive to interprofessional collaboration and open dialogue.


Predicting the effects of supplemental EPA and DHA on the omega-3 index.
Supplemental long-chain omega-3 (n-3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear. The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I. Deidentified data from 1422 individuals from 14 published n-3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion. Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products. Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form.


Obesity-related cardiovascular risk factors after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention.
Weight reduction improves several obesity-related health conditions. We aimed to compare the effect of bariatric surgery and comprehensive lifestyle intervention on type 2 diabetes and obesity-related cardiovascular risk factors. One-year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104). Morbidly obese subjects (19-66 years, mean (s.d.) body mass index 45.1 kg/m(2) (5.6), 103 women) were treated with either Roux-en-Y gastric bypass surgery (n=80) or intensive lifestyle intervention at a rehabilitation centre (n=66). The dropout rate within both groups was 5%. Among the 76 completers in the surgery group and the 63 completers in the lifestyle group, mean (s.d.) 1-year weight loss was 30% (8) and 8% (9) respectively. Beneficial effects on glucose metabolism, blood pressure, lipids and low-grade inflammation were observed in both groups. Remission rates of type 2 diabetes and hypertension were significantly higher in the surgery group than the lifestyle intervention group; 70 vs 33%, P=0.027, and 49 vs 23%, P=0.016. The improvements in glycaemic control and blood pressure were mediated by weight reduction. The surgery group experienced a significantly greater reduction in the prevalence of metabolic syndrome, albuminuria and electrocardiographic left ventricular hypertrophy than the lifestyle group. Gastrointestinal symptoms and symptomatic postprandial hypoglycaemia developed more frequently after gastric bypass surgery than after lifestyle intervention. There were no deaths. Type 2 diabetes and obesity-related cardiovascular risk factors were improved after both treatment strategies. However, the improvements were greatest in those patients treated with gastric bypass surgery.


Stark laws and fair market value exceptions: an introduction.
This article will focus on one aspect of complexity in modern healthcare, namely the implications of Stark laws and other fraud and abuse provisions, including anti-kickback statutes and HIPAA. Also, this article explores the prevalence of fair market value as an exception in the Stark laws and discusses the meanings of those exceptions. Finally, the article explores basic approaches to assessing fair market value, including cost, income, and marketing approaches.


Clustering earthquake signals and background noises in continuous seismic data with unsupervised deep learning.
The continuously growing amount of seismic data collected worldwide is outpacing our abilities for analysis, since to date, such datasets have been analyzed in a human-expert-intensive, supervised fashion. Moreover, analyses that are conducted can be strongly biased by the standard models employed by seismologists. In response to both of these challenges, we develop a new unsupervised machine learning framework for detecting and clustering seismic signals in continuous seismic records. Our approach combines a deep scattering network and a Gaussian mixture model to cluster seismic signal segments and detect novel structures. To illustrate the power of the framework, we analyze seismic data acquired during the June 2017 Nuugaatsiaq, Greenland landslide. We demonstrate the blind detection and recovery of the repeating precursory seismicity that was recorded before the main landslide rupture, which suggests that our approach could lead to more informative forecasting of the seismic activity in seismogenic areas.


Anti-Streptococcus mutans efficacy of Thai herbal formula used as a remedy for dental caries.
Traditional knowledge of herbal remedies plays an important role in the search for more effective alternative treatment of a variety of disorders. The ethnobotanical surveys in southern Thailand have revealed that 35 Thai herbal formulas have been used by Thai traditional healers against dental caries. However, the scientific evaluation to confirm their rational uses is scarce. To test in vitro anti-Streptococcus mutans activity of Thai herbal formulas used against dental caries (THF-DC). Ethanol extracts of Thai herbal formulas were evaluated for antibacterial activity against S. mutans. Agar disc diffusion was employed as a preliminary screening assay, followed by broth microdilution assay to assess minimum inhibitory concentration (MIC). Furthermore, medicinal plants contained in the most active THF-DC were investigated for their phytochemicals. Eleven THF-DC extracts exhibited clear inhibition zones of 7.0-22.5 mm against S. mutans. Subsequent determination of their MIC revealed that the formula containing Albizia myriophylla Benth. (Leguminosae), Alpinia galanga (L.) Willd. (Zingiberaceae), Avicennia marina (Forssk.) Vierh. (Acanthaceae), and Ocimum sanctum L. (Lamiaceae) was the most active, with MIC at 250 µg/mL. Among these medicinal plants, A. myriophylla gave the strongest activity with MIC at 3.9 µg/mL, followed by A. marina with MIC at 62.5 µg/mL. Various classes of bioactive phytochemicals including tannins, flavonoids, alkaloids, and terpenoids were found in these extracts. Anti-S. mutans activity of THF-DC extracts was established. Further investigations may be required for the isolation and chemical characterization of the active ingredients in A. myriophylla.


Hemoglobin A1c as a diagnostic tool: public health implications from an actor-network perspective.
Public health arguments for collecting hemoglobin A1c (HbA1c) data, particularly in clinical settings, should be reframed to place more emphasis on nonmedical determinants of population health. We compare individual- with population-level interpretations of HbA1c titers. This comparison reveals that public health researchers need to pay close attention to diagnostic tests and their uses, including rhetorical uses. We also synthesize historical and current evidence to map out 2 possible scenarios for the future. In the first scenario, prevention efforts emphasize primary care and focus almost entirely downstream. The second scenario anticipates downstream interventions but also upstream interventions targeting environments. Our analysis adapts actor-network theory to strategic planning and forecasting in public health.


Transoral endoscopic thyroidectomy using vestibular approach: updates and evidences.
Recently, natural orifice transluminal endoscopic surgery (NOTES) has been applied in thyroid surgery with transoral access. The benefit of transoral endoscopic thyroidectomy is the potential for scar-free surgery. However, there are many concerns over some aspects, such as infection, recurrent laryngeal nerve injury, and oncological outcome. In this paper, we have reviewed the development history and the current clinical evidence of this innovative surgery. We conclude that the transoral endoscopic thyroidectomy vestibular approach (TOETVA) is feasible and can be considered no longer an experimental operation.


Curcumin: updated molecular mechanisms and intervention targets in human lung cancer.
Curcumin, a yellow pigment derived from Curcuma longa Linn, has attracted great interest in the research of cancer during the past decades. Extensive studies documented that curcumin attenuates cancer cell proliferation and promotes apoptosis in vivo and in vitro. Curcumin has been demonstrated to interact with multiple molecules and signal pathways, which makes it a potential adjuvant anti-cancer agent to chemotherapy. Previous investigations focus on the mechanisms of action for curcumin, which is shown to manipulate transcription factors and induce apoptosis in various kinds of human cancer. Apart from transcription factors and apoptosis, emerging studies shed light on latent targets of curcumin against epidermal growth factor receptor (EGFR), microRNAs (miRNA), autophagy and cancer stem cell. The present review predominantly discusses significance of EGFR, miRNA, autophagy and cancer stem cell in lung cancer therapy. Curcumin as a natural phytochemicals could communicate with these novel targets and show synergism to chemotherapy. Additionally, curcumin is well tolerated in humans. Therefore, EGFR-, miRNA-, autophagy- and cancer stem cell-based therapy in the presence of curcumin might be promising mechanisms and targets in the therapeutic strategy of lung cancer.


High-pressure ruby and diamond fluorescence: observations at 0.21 to 0.55 terapascal.
A diamond-anvil, high-pressure apparatus was used to extend the upper pressure limit of static laboratory experiments. Shifts of the R(1) strong fluorescent line of ruby were observed that correspond to static pressures of 0.21 to 0.55 terapascal (2.1 to 5.5 megabars) at 25 degrees C. Sensitive spectroscopic techniques in the pressure range 0.15 to 0.28 terapascal were used to observe ruby and diamond fluorescence separately; these two fluorescent emissions overlap strongly at high pressures. At pressures greater than approximately 0.28 terapascal, the diamond fluorescence diminished and the ruby fluorescence reappeared strongly. Pressure was determined by extrapolation of the calibrated shift of the ruby R(1) line.


Adapting a Family-Focused Diabetes Prevention Program for a Federally Qualified Health Center: A Qualitative Report.
The purpose of the study was to explore the needs of high-risk Latinx/Hispanic women with a history of gestational diabetes who were patients at a Federally Qualified Health Center (FQHC) in anticipation of a future family-based program. Six focus group studies were conducted in partnership with El Rio Community Health Center, an FQHC in Tucson, Arizona. Thirty-nine women participated, each identified as Latinx/Hispanic, self-reported a history of gestational diabetes or prediabetes, and had at least 1 child aged 8 to 13. Three investigators independently reviewed transcripts from the focus groups to identify themes that reflected thematic saturation from participants' responses. Data coding and results were discussed as a group and any differences were collectively adjudicated. All participants had a family member with diabetes and worried about their and their immediate family members' risk for developing the disease. The possible benefits of participating in a lifestyle prevention program were universally recognized, but multiple barriers to participation were described, including scheduling conflicts, access to childcare, transportation, and the need to involve additional family members to reinforce program objectives. There is a strong willingness to participate in a diabetes prevention program among respondents, but to be successful, interventions must be tailored to specific needs and challenges. Trying to apply existing prevention curricula with low-income Latinx/Hispanic populations may not be successful without adaptations.


The regulation of apoptosis by activin and transforming growth factor-beta in early neoplastic and tumorigenic ovarian surface epithelium.
Most ovarian neoplasms arise from the ovarian surface epithelium (OSE), and multiple growth factors have been implicated to influence the transformation from OSE. The present study was performed to investigate the role of activin and transforming growth factor-beta (TGFbeta) in normal and neoplastic OSE cells. An immortalized OSE cell line (IOSE-29) was generated from normal OSE by transfecting simian virus 40 large T antigen and was rendered tumorigenic after subsequent transfection with the E-cadherin gene (IOSE-29EC). The activin/inhibin subunits and activin receptors were expressed at both messenger ribonucleic acids and protein levels in these cells, suggesting that activin may have an autocrine role in neoplastic OSE cells. Treatments with activin (1-100 ng/mL) resulted in a significant decrease in cell proliferation in both IOSE-29 and IOSE-29EC cells, although we have shown that it stimulated the growth of ovarian cancer cells and had no effect on normal OSE. This inhibitory effect was attenuated with cotreatment with follistatin. Treatment with TGFbeta (0.1-10 ng/mL) also significantly decreased the proliferation of normal, IOSE-29, and IOSE-29EC cells in a dose-dependent manner. In addition, treatments with both activin and TGFbeta resulted in an increase in DNA fragmentation in IOSE-29EC cells in a dose-dependent manner. This apoptotic effect of activin was attenuated by cotreatment with follistatin. Treatment with TGFbeta (1 and 10 ng/mL) resulted in a significant decrease in Bcl-2 protein (up to 50%) in IOSE-29EC, whereas no difference was observed in Bax protein levels. Therefore, down-regulated Bcl-2 by TGFbeta may eventually induce apoptosis in IOSE-29EC cells. In contrast, no difference was observed in Bax and Bcl-2 protein expression after treatment with activin. In conclusion, the present study indicates that activin and TGFbeta inhibited growth and induced apoptosis in early neoplastic (IOSE-29) and tumorigenic OSE (IOSE-29EC) cells. Furthermore, antiapoptotic Bcl-2 protein was down-regulated by TGFbeta, whereas no difference was produced in Bax protein by activin or TGFbeta treatment or in Bcl-2 protein by activin. These results suggest that activin and TGFbeta may play a role in growth inhibition and induction of apoptosis in early neoplastic and tumorigenic stage of ovarian cancer.


Immunolocalization of Keratan Sulfate in Rat Spinal Tissues Using the Keratanase Generated BKS-1(+) Neoepitope: Correlation of Expression Patterns with the Class II SLRPs, Lumican and Keratocan.
This study has identified keratan sulfate in fetal and adult rat spinal cord and vertebral connective tissues using the antibody BKS-1(+) which recognizes a reducing terminal N-acetyl glucosamine-6-sulfate neo-epitope exposed by keratanase-I digestion. Labeling patterns were correlated with those of lumican and keratocan using core protein antibodies to these small leucine rich proteoglycan species. BKS-1(+) was not immunolocalized in fetal spinal cord but was apparent in adult cord and was also prominently immunolocalized to the nucleus pulposus and inner annulus fibrosus of the intervertebral disc. Interestingly, BKS-1(+) was also strongly associated with vertebral body ossification centers of the fetal spine. Immunolocalization of lumican and keratocan was faint within the vertebral body rudiments of the fetus and did not correlate with the BKS-1(+) localization indicating that this reactivity was due to another KS-proteoglycan, possibly osteoadherin (osteomodulin) which has known roles in endochondral ossification. Western blotting of adult rat spinal cord and intervertebral discs to identify proteoglycan core protein species decorated with the BKS-1(+) motif confirmed the identity of 37 and 51 kDa BKS-1(+) positive core protein species. Lumican and keratocan contain low sulfation KS-I glycoforms which have neuroregulatory and matrix organizational properties through their growth factor and morphogen interactive profiles and ability to influence neural cell migration. Furthermore, KS has interactive capability with a diverse range of neuroregulatory proteins that promote neural proliferation and direct neural pathway development, illustrating key roles for keratocan and lumican in spinal cord development.


MicroRNA expression profile during adipogenic differentiation in mouse embryonic stem cells.
Pluripotent embryonic stem cells (ESC) have the potential to differentiate into any cell type of the three germ layers. Differentiation processes depend on genetic and epigenetic factors. The guidance of cell fate determination by microRNAs (miRs) seems important for embryonic development and cell lineage decisions. MiRs are short, single-stranded, noncoding RNA molecules that regulate through posttranscriptional modulation, a subset of target genes involved in cell differentiation and specific cell function. We have used microarray profiling of miRs in the mouse embryonic stem cell line CGR8. Comparison of the miR profiles of undifferentiated stem cells with mesodermal progenitors cells (day 5), preadipocytes (day 10), and adipocytes (day 21) showed that the expression level of 129 miRs changed (twofold) during adipogenic differentiation. We identified 10 clusters of differentially expressed miRs, which contain putative markers and regulators of mesodermal differentiation and cell fate determination into adipocytes. Notably, the adipocyte-specific miRs 143 and 103 were upregulated from day 10 onward. We have therefore demonstrated and characterized the dynamic profile of miR expression during murine adipogenic differentiation in vitro, including the initial differentiation from ESC via mesenchymal progenitors up to adipocytes. Our findings and experimental approach provide a suitable system to directly interrogate the role of miRs during adipogenic differentiation of embryonic stem cells.


Selection of a CXCR4 antagonist from a human heavy chain CDR3-derived phage library.
Phage display technology is a powerful selection approach to identify strong and specific binders to a large variety of targets. In this study, we compared the efficacy of a phage library displaying human heavy chain complementarity determining region 3 (HCDR3) repertoires with a set of conventional random peptide libraries for the identification of CXCR4 antagonists using a peptide corresponding to the second extracellular loop of the receptor CXCR4 as target. A total of 11 selection campaigns on this target did not result in any specific ligand from the random peptide libraries. In contrast, a single selection campaign with an HCDR3 library derived from the IgM repertoire of a nonimmunized donor resulted in nine specific peptides with lengths ranging from 10 to 19 residues. Four of these HCDR3 sequences interacted with native receptor and the most frequently isolated peptide displayed an affinity of 5.6 μm and acted as a CXCR4 antagonist (IC(50) = 23 μm). To comprehend the basis of the highly efficient HCDR3 library selection, its biochemical properties were investigated. The HCDR3 length varied from 3 to 21 residues and displayed a biased amino acid content with a predominant proportion of Tyr, Gly, Ser and Asp. Repetitive and conserved motifs were observed in the majority of the HCDR3 sequences. The strength and efficacy of the HCDR3 libraries reside in the combination of multiple size peptides and a naturally biased sequence variation. Therefore, HCDR3 libraries represent a powerful and versatile alternative to fully randomized peptide libraries, in particular for difficult targets.


Hyperbaric oxygen therapy for laryngeal radionecrosis.
Radionecrosis of the larynx is a debilitating disease associated with pain, dysphagia, respiratory obstruction, and, in some cases, the need for laryngectomy. Persistent poor wound healing can lead to death. A series of eight patients with advanced (grades III and IV, Chandler classification) radionecrosis of the larynx treated with adjunctive hyperbaric oxygen therapy is presented. Signs and symptoms of radionecrosis were dramatically ameliorated in seven of eight patients, while one patient, despite subjective improvement, eventually required laryngectomy. There were no deaths. These results are compared to previous series on radionecrosis of the larynx in which hyperbaric oxygen was not used. This series indicates that hyperbaric oxygen therapy is a useful and effective adjunctive treatment modality in the management of laryngeal radionecrosis.


Cross-clade recognition of p55 by cytotoxic T lymphocytes in HIV-1 infection.
To evaluate cross-clade recognition of p55 antigen by cytotoxic T lymphocytes (CTL) in persons infected with diverse clades of HIV-1; to facilitate the development of a CTL-inducing vaccine to prevent transmission of multiple clades of HIV-1. Experiments were designed to evaluate whether persons in Uganda and the United Kingdom, infected with diverse clades of HIV-1, have CTL capable of recognizing and killing autologous target cells infected with recombinant vaccinia viruses (rVV) expressing the Gag protein from A, B, C and D clade HIV-1. The extent of cross-reactivity within such individuals, each infected with characterized virus, might reflect the type of cross-reactive immune response inducible by a monovalent vaccine. Asymptomatic HIV-positive individuals were fully tissue-typed by ARMS (amplification of refractory mutation system) polymerase chain reaction. rVV expressing the Gag protein from identified A, B, C and D viruses were prepared. CTL were cultured and tested for cytolytic activity on autologous rVV-infected or peptide-pulsed B cells. Ugandan patients had inducible CTL responses recognizing A, B, C and D clade HIV-1 Gag. The majority of UK patients had inducible CTL responses that recognized two or more clades. No patient showed any HIV-2 cross-reactivity. Cross-reactive responses were characterized in three Ugandan patients. Most patients tested mounted cross-reactive CTL responses that recognized Gag proteins from clades of HIV-1 other than those with which they were infected.


Multiwavelength super-structured Bragg grating laser for tunable repetition rate mode-locked operation.
A multiwavelength laser based on a super-structured Bragg grating is designed and fabricated on multiquantum well AlGaInAs-InP. This laser exhibits phase locking via mutual injection of the neighboring cavities assisted by four wave mixing. We present optical and electrical characterization of its emission regimes showing a complex dynamic behavior. More specifically, this paper focuses on a pulsed regime with a quasi-continuous tunable repetition rate from 32 GHz to 49 GHz.


Establishment and characterization of a canine keratinocyte organoid culture system.
Perturbations of epidermal and follicular homeostasis have been attributed to a variety of skin diseases affecting dogs. The availability of an in vitro system to investigate these diseases is important to understand underlying pathomechanisms. To establish an accurate and reliable in vitro 3D system of canine keratinocyte organoids to lay the basis for studying functional defects in interfollicular epidermis (IFE) and hair follicle (HF) morphogenesis, reconstitution and differentiation that lead to alopecic and epidermal diseases. Skin biopsies were obtained from freshly euthanized dogs of different breeds with no skin abnormalities. Cells derived from microdissected IFE and HFs were seeded in Matrigel and keratinocyte organoids were grown and characterized using immunohistochemistry, RT-qPCR and RNA sequencing. Both organoid lines develop into a basal IFE-like cell type. Gene and protein expression analysis revealed high mRNA and protein levels of keratins 5 and 14, IFE differentiation markers and intercellular molecules. Key markers of HF stem cells were lacking. Withdrawal of growth factors resulted in upregulation of markers such as KRT16, Involucrin, KRT17 and SOX9, showing the potential of the organoids to develop towards more differentiated tissue. Our 3D in vitro culture system provides the basis to explore epidermal function, to investigate the culture conditions necessary for the development of organoids with a HF signature and to address cutaneous disorders in dogs. However, for induction of HF signatures or hair growth, addition of different growth factors or co-culture with dermal papilla will be required.