Energy delivery systems for treatment of benign prostatic hyperplasia: an evidence-based analysis.
The Ontario Health Technology Advisory Committee asked the Medical Advisory Secretariat (MAS) to conduct a health technology assessment on energy delivery systems for the treatment of benign prostatic hyperplasia (BPH). TARGET POPULATION AND CONDITION BPH is a noncancerous enlargement of the prostate gland and the most common benign tumour in aging men. (1) It is the most common cause of lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) and is an important cause of diminished quality of life among aging men. (2) The primary goal in the management of BPH for most patients is a subjective improvement in urinary symptoms and quality of life. Until the 1930s, open prostatectomy, though invasive, was the most effective form of surgical treatment for BPH. Today, the benchmark surgical treatment for BPH is transurethral resection of the prostate (TURP), which produces significant changes of all subjective and objective outcome parameters. Complications after TURP include hemorrhage during or after the procedure, which often necessitates blood transfusion; transurethral resection (TUR) syndrome; urinary incontinence; bladder neck stricture; and sexual dysfunction. A retrospective review of 4,031 TURP procedures performed by one surgeon between 1979 and 2003 showed that the incidence of complications was 2.4% for blood transfusion, 0.3% for TUR syndrome, 1.5% for hemostatic procedures, 2.8% for bladder neck contracture, and 1% for urinary stricture. However, the incidence of blood transfusion and TUR syndrome decreased as the surgeon's skills improved. During the 1990s, a variety of endoscopic techniques using a range of energy sources have been developed as alternative treatments for BPH. These techniques include the use of light amplification by stimulated emission of radiation (laser), radiofrequency, microwave, and ultrasound, to heat prostate tissue and cause coagulation or vaporization. In addition, new electrosurgical techniques that use higher amounts of energy to cut, coagulate, and vaporize prostatic tissue have entered the market as competitors to TURP. The driving force behind these new treatment modalities is the potential of producing good hemostasis, thereby reducing catheterization time and length of hospital stay. Some have the potential to be used in an office environment and performed under local anesthesia. Therefore, these new procedures have the potential to rival TURP if their effectiveness is proven over the long term. The following energy-based techniques were considered for assessment: transurethral electrovaporization of the prostate (TUVP)transurethral electrovapor resection of the prostate (TUVRP)transurethral electrovaporization of the prostate using bipolar energy (plasmakinetic vaporization of the prostate [PKVP])visual laser ablation of the prostate (VLAP)transurethral ultrasound guided laser incision prostatectomy (TULIP)contact laser vaporization of the prostate (CLV)interstitial laser coagulation (ILC)holmium laser resection of the prostate (HoLRP)holmium laser enucleation of the prostate (HoLEP)holmium laser ablation of the prostate (HoLAP)potassium titanyl phosphate (KTP) lasertransurethral microwave thermotherapy (TUMT)transurethral needle ablation (TUNA) REVIEW STRATEGY: A search of electronic databases (OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library, and the International Agency for Health Technology Assessment [INAHTA] database) was undertaken to identify evidence published from January 1, 2000 to June 21, 2006. The search was limited to English-language articles and human studies. The literature search identified 284 citations, of which 38 randomized controlled trials (RCTs) met the inclusion criteria. Since the application of high-power (80 W) KTP laser (photoselective vaporization of the prostate [PVP]) has been supported in the United States and has resulted in a rapid diffusion of this technology in the absence of any RCTs, the MAS decided that any comparative studies on PVP should be identified and evaluated. Hence, the literature was searched and one prospective cohort study (3) was identified but evaluated separately. Meta-analysis of the results of RCTs shows that monopolar electrovaporization is as clinically effective as TURP for the relief of urinary symptoms caused by BPH (based on 5-year follow-up data). Meta-analysis of the results of RCTs shows that bipolar electrovaporization (PKVP) is clinically as effective as TURP for the relief of urinary symptoms caused by BPH (based on 1-year follow-up data). Two of the three RCTs on VLAP have shown that patients undergoing VLAP had a significantly lesser improvement in urinary symptom scores compared with patients undergoing TURP.RCTs showed that the time to catheter removal was significantly longer in patients undergoing VLAP compared with patients undergoing TURP.Meta-analysis of the rate of reoperation showed that patients undergoing VLAP had a significantly higher rate of reoperation compared with patients undergoing TURP.Meta-analysis showed that patients undergoing CLV had a significantly lesser improvement in urinary symptom scores compared with TURP at 2 years and at 3 or more years of follow-up.Two RCTs with 6-month and 2-year follow-up showed similar improvement in symptom scores for ILC and TURP.Time to catheter removal was significantly longer in patients undergoing ILC compared with patients undergoing TURP.The results of RCTs on HoLEP with 1-year follow-up showed excellent clinical outcomes with regard to the urinary symptom score and peak urinary flow.Meta-analysis showed that at 1-year follow-up, patients undergoing HoLEP had a significantly greater improvement in urinary symptom scores and peak flow rate compared with patients undergoing TURP.Procedural time is significantly longer in HoLEP compared with TURP.The results of one RCT with 4-year follow-up showed that HoLRP and TURP provided equivalent improvement in urinary symptom scores.The results of one RCT with 1-year follow-up showed that patients undergoing KTP had a lesser improvement in urinary symptom scores than did patients undergoing TURP. However, the results were not significant at longer-term follow-up periods.Two RCTs that provided 3-year follow-up data reported that patients undergoing TUMT had a significantly lesser improvement in symptom score compared with patients undergoing TURP.RCTs reported a longer duration of catheterization for TUMT compared with TURP (P values are not reported).The results of a large RCT with 5-year follow-up showed a significantly lesser improvement in symptom scores in patients undergoing TUNA compared with patients undergoing TURP.Meta-analysis of the rate of reoperation showed that patients undergoing TUNA had a significantly higher rate of reoperation compared with patients undergoing TURP.Based on the results of RCTs, TURP is associated with a 0.5% risk of TUR syndrome, while no cases of TUR syndrome have been reported in patients undergoing monopolar or bipolar electrovaporization, laser-based procedures, TUMT, or TUNA.Based on the results of RCTs, the rate of blood transfusion ranges from 0% to 8.3% in patients undergoing TURP. The rate is about 1.7% in monopolar electrovaporization, 1.4% in bipolar electrovaporization, and 0.4% in the VLAP procedure. No patients undergoing CLV, ILC, HoLEP, HoLRP, KTP, TUMT, and TUNA required blood transfusion.The mean length of hospital stay is between 2 and 5 days for patients undergoing TURP, about 3 days for electrovaporization, about 2 to 4 days for Nd:YAG laser procedures, and about 1 to 2 days for holmium laser procedures. TUMT and TUNA can each be performed as a day procedure in an outpatient setting (0.5 and 1 day respectively).Based on a prospective cohort study, PVP is clinically as effective as TURP for the relief of urinary symptoms caused by BPH (based on 6-month follow-up data). Time to catheter removal was significantly shorter in patients undergoing PVP than in those undergoing TURP. Operating room time was significantly longer in PVP than in TURP. PVP has the potential to reduce health care expenses due to shorter hospital stays. In the three most recent fiscal years (FY) reported, an average of approximately 5,000 TURP procedures per year were performed in Ontario. From FY 2002 to FY 2004, the total number of surgical interventions decreased by approximately 500 procedures. During this time, the increase in costs of drugs to the government was estimated at approximately $10 million (Cdn); however, there was a concurrent decrease in costs due to a decline in the total number of surgical procedures, estimated at approximately $1.9 million (Cdn). From FY 2002 to FY 2004, the increase in costs associated with the increase in utilization of drugs for the treatment of BPH translates into $353 (Cdn) per patient while the cost savings associated with a decrease in the total number of surgical procedures translates into a savings of $3,906 (Cdn) per patient. The following table summarizes the change in the current budget, depending on various estimates of the total percentage of the 5,000 TURP procedures that might be replaced by other energy-based interventions for the treatment of BPH in the future. Executive Summary Table 1:Budget Impact With Various Estimates of the Percentage of TURP Procedures Captured by Energy-based Interventions for the Treatment of BPHTechnologyCost perprocedure, $Budget Impact of 25% diffusion, $MBudget Impact of 50% diffusion, $MBudget Impact of 75% diffusion, $MBudget Impact of 100% diffusion, $MIncremental Budget Impact, $MTURP3,88719.4Bipolar Electrovaporization4,01119.619.719.920.00.6Monopolar Electrovaporization4,13019.720.020.320.61.2TUMT1,52916.513.510.67.6(11.8) TUNA4,80420.621.722.924.04.6PVP1,18416.012.79.35. (ABSTRACT TRUNCATED)


Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.
Warfarin is a commonly used anticoagulant that requires careful clinical management to balance the risks of overanticoagulation and bleeding with those of underanticoagulation and clotting. The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3. Patients with these genetic variants have been shown to require lower maintenance doses of warfarin, but a direct association between CYP2C9 genotype and anticoagulation status or bleeding risk has not been established. To determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation and bleeding events during warfarin therapy. Retrospective cohort study conducted at 2 anticoagulation clinics based in Seattle, Wash. Two hundred patients receiving long-term warfarin therapy for various indications during April 3, 1990, to May 31, 2001. Only patients with a complete history of warfarin exposure were included. Anticoagulation status, measured by time to therapeutic international normalized ratio (INR), rate of above-range INRs, and time to stable warfarin dosing; and time to serious or life-threatening bleeding events. Among 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype. Mean maintenance dose varied significantly among the 6 genotype groups (*1/*1 [n = 127], *1/*2 [n = 28], *1/*3 [n = 18], *2/*2 [n = 4], *2/*3 [n = 3], *3/*3 [n = 5]) (by Kruskall-Wallis test, chi(2)(5) = 37.348; P<.001). Compared with patients with the wild-type genotype, patients with at least 1 variant allele had an increased risk of above-range INRs (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.03-1.90). The variant group also required more time to achieve stable dosing (HR, 0.65; 95% CI, 0.45-0.94), with a median difference of 95 days (P =.004). In addition, although numbers were small for some genotypes, representing potentially unstable estimates, patients with a variant genotype had a significantly increased risk of a serious or life-threatening bleeding event (HR, 2.39; 95% CI, 1.18-4.86). The results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.


Universals and cultural diversity in the expression of gratitude.
Gratitude is argued to have evolved to motivate and maintain social reciprocity among people, and to be linked to a wide range of positive effects-social, psychological and even physical. But is socially reciprocal behaviour dependent on the expression of gratitude, for example by saying 'thank you' as in English? Current research has not included cross-cultural elements, and has tended to conflate gratitude as an emotion with gratitude as a linguistic practice, as might appear to be the case in English. Here, we ask to what extent people express gratitude in different societies by focusing on episodes of everyday life where someone seeks and obtains a good, service or support from another, comparing these episodes across eight languages from five continents. We find that expressions of gratitude in these episodes are remarkably rare, suggesting that social reciprocity in everyday life relies on tacit understandings of rights and duties surrounding mutual assistance and collaboration. At the same time, we also find minor cross-cultural variation, with slightly higher rates in Western European languages English and Italian, showing that universal tendencies of social reciprocity should not be equated with more culturally variable practices of expressing gratitude. Our study complements previous experimental and culture-specific research on gratitude with a systematic comparison of audiovisual corpora of naturally occurring social interaction from different cultures from around the world.


Transforming Growth Factor Beta 1 Drives a Switch in Connexin Mediated Cell-to-Cell Communication in Tubular Cells of the Diabetic Kidney.
Changes in cell-to-cell communication have been linked to several secondary complications of diabetes, but the mechanism by which connexins affect disease progression in the kidney is poorly understood. This study examines a role for glucose-evoked changes in the beta1 isoform of transforming growth factor (TGFβ1), on connexin expression, gap-junction mediated intercellular communication (GJIC) and hemi-channel ATP release from tubular epithelial cells of the proximal renal nephron. Biopsy material from patients with and without diabetic nephropathy was stained for connexin-26 (CX26) and connexin-43 (CX43). Changes in expression were corroborated by immunoblot analysis in human primary proximal tubule epithelial cells (hPTECs) and model epithelial cells from human renal proximal tubules (HK2) cultured in either low glucose (5mmol/L) ± TGFβ1 (2-10ng/ml) or high glucose (25mmol/L) for 48h or 7days. Secretion of the cytokine was determined by ELISA. Paired whole cell patch clamp recordings were used to measure junctional conductance in control versus TGFβ1 treated (10ng/ml) HK2 cells, with carboxyfluorescein uptake and ATP-biosensing assessing hemi-channel function. A downstream role for ATP in mediating the effects of TGF-β1 on connexin mediated cell communication was assessed by incubating cells with ATPγS (1-100µM) or TGF-β1 +/- apyrase (5 Units/ml). Implications of ATP release were measured through immunoblot analysis of interleukin 6 (IL-6) and fibronectin expression. Biopsy material from patients with diabetic nephropathy exhibited increased tubular expression of CX26 and CX43 (P<0.01, n=10), data corroborated in HK2 and hPTEC cells cultured in TGFβ1 (10ng/ml) for 7days (P<0.001, n=3). High glucose significantly increased TGFβ1 secretion from tubular epithelial cells (P<0.001, n=3). The cytokine (10ng/ml) reduced junctional conductance between HK2 cells from 4.5±1.3nS in control to 1.15±0.9nS following 48h TGFβ1 and to 0.42±0.2nS after 7days TGFβ1 incubation (P<0.05, n=5). Acute (48h) and chronic (7day) challenge with TGFβ1 produced a carbenoxolone (200µM)-sensitive increase in carboxyfluorescein loading, matched by an increase in ATP release from 0.29±0.06μM in control to 1.99±0.47μM after 48hr incubation with TGFβ1 (10ng/ml; P<0.05, n=3). TGF-β1 (2-10ng/ml) and ATPγs (1-100µM) increased expression of IL-6 (P<0.001 n=3) and fibronectin (P<0.01 n=3). The effect of TGF-β1 on IL-6 and fibronectin expression was partially blunted when preincubated with apyrase (n=3). These data suggest that chronic exposure to glucose-evoked TGFβ1 induce an increase in CX26 and CX43 expression, consistent with changes observed in tubular epithelia from patients with diabetic nephropathy. Despite increased connexin expression, direct GJIC communication decreases, whilst hemichannel expression/function and paracrine release of ATP increases, changes that trigger increased levels of expression of interleukin 6 and fibronectin. Linked to inflammation and fibrosis, local increases in purinergic signals may exacerbate disease progression and highlight connexin mediated cell communication as a future therapeutic target for diabetic nephropathy.


Advanced Microbial Taxonomy Combined with Genome-Based-Approaches Reveals that Vibrio astriarenae sp. nov., an Agarolytic Marine Bacterium, Forms a New Clade in Vibrionaceae.
Advances in genomic microbial taxonomy have opened the way to create a more universal and transparent concept of species but is still in a transitional stage towards becoming a defining robust criteria for describing new microbial species with minimum features obtained using both genome and classical polyphasic taxonomies. Here we performed advanced microbial taxonomies combined with both genome-based and classical approaches for new agarolytic vibrio isolates to describe not only a novel Vibrio species but also a member of a new Vibrio clade. Two novel vibrio strains (Vibrio astriarenae sp. nov. C7T and C20) showing agarolytic, halophilic and fermentative metabolic activity were isolated from a seawater sample collected in a coral reef in Okinawa. Intraspecific similarities of the isolates were identical in both sequences on the 16S rRNA and pyrH genes, but the closest relatives on the molecular phylogenetic trees on the basis of 16S rRNA and pyrH gene sequences were V. hangzhouensis JCM 15146T (97.8% similarity) and V. agarivorans CECT 5085T (97.3% similarity), respectively. Further multilocus sequence analysis (MLSA) on the basis of 8 protein coding genes (ftsZ, gapA, gyrB, mreB, pyrH, recA, rpoA, and topA) obtained by the genome sequences clearly showed the V. astriarenae strain C7T and C20 formed a distinct new clade protruded next to V. agarivorans CECT 5085T. The singleton V. agarivorans has never been included in previous MLSA of Vibrionaceae due to the lack of some gene sequences. Now the gene sequences are completed and analysis of 100 taxa in total provided a clear picture describing the association of V. agarivorans into pre-existing concatenated network tree and concluded its relationship to our vibrio strains. Experimental DNA-DNA hybridization (DDH) data showed that the strains C7T and C20 were conspecific but were separated from all of the other Vibrio species related on the basis of both 16S rRNA and pyrH gene phylogenies (e.g., V. agarivorans CECT 5085T, V. hangzhouensis JCM 15146T V. maritimus LMG 25439T, and V. variabilis LMG 25438T). In silico DDH data also supported the genomic relationship. The strains C7T also had less than 95% average amino acid identity (AAI) and average nucleotide identity (ANI) towards V. maritimus C210, V. variabilis C206, and V. mediterranei AK1T, V. brasiliensis LMG 20546T, V. orientalis ATCC 33934T, and V. sinaloensis DSM 21326. The name Vibrio astriarenae sp. nov. is proposed with C7 as the type strains. Both V. agarivorans CECT 5058T and V. astriarenae C7T are members of the newest clade of Vibrionaceae named Agarivorans.


Comparing the quantity and quality of randomised placebo-controlled trials of antibiotics for acute respiratory, urinary, and skin and soft tissue infections: a scoping review.
The management of acute respiratory infections (ARIs), urinary tract infections (UTIs), and skin and soft tissue infections (SSTIs) should be guided by high quality evidence. To compare the quantity and quality of randomised placebo-controlled trials of antibiotics for ARIs, UTIs, and SSTIs. A scoping review of the literature was performed using comprehensive search strategies. PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for published studies from inception until 17 April 2019. Randomised controlled trials (RCTs) that compared participants in primary care or in the community who had uncomplicated acute ARI, UTI, or studies, and were randomised to antibiotic or placebo (or no active treatment), were eligible for inclusion. Two groups of researchers independently screened articles for inclusion, extracted data, and assessed the quality of included studies. A total of 108 eligible studies were identified: 80 on ARI, eight on UTI, and 20 on SSTI. The quality of studies varied with unclear risk of bias (RoB) prevalent in many domains. There was a gradual improvement in the quality of trials investigating ARIs over time, which could not be assessed in SSTI and UTI studies. This review highlights a sparsity of trials assessing the effectiveness of antibiotics in people with UTIs and SSTIs, compared to trials targeting ARIs. This gap in the evidence needs to be addressed by conducting further high quality trials on the effects of antibiotics in patients with UTI and SSTI.


A thyroid hormone receptor beta gene polymorphism associated with Graves' disease.
Autoimmune thyroid diseases (AITDs) are clustered in families, but the nature of this clustering is still poorly understood. One possible approach to the identification of genetic factors interacting with the AITDs is the study of the association between polymorphic markers and AITDs themselves. In the present study we have shown an association between an allele of a HindIII restriction fragment length polymorphism (EA beta H) intragenic to c-erbA beta, which codes for the thyroid hormone beta receptor, and Graves' disease. This polymorphism can be detected by PCR followed by digestion with the restriction enzyme HindIII. The allelic frequencies were analysed in a panel of DNAs extracted from a population of individuals affected by thyroid disease and originating from southern Italy. A control group (n = 120) from the same area was also analysed. The distribution of EA beta H alleles was significantly different (P < 0.001) in Graves' disease (n = 94) but not in autoimmune thyroiditis (n = 60), as compared with controls. Also the distribution of the EA beta H genotypes was significantly different in Graves' patients (P = 0.003), as compared with controls, the homozygous state EA beta H+/EA beta H+ being more frequent in Graves' patients than in all the other groups. We did not find any association between EA beta H genotypes and clinical parameters in Graves' patients, including eye signs, thyroid volume and level of TSH-binding inhibiting immunoglobulins. Our data support the idea that Graves' disease is a genetically distinct group within the AITDs.


Caring for migrant older Moroccans with dementia in Belgium as a complex and dynamic transnational network of informal and professional care: A qualitative study.
Due to its labour migration history, Belgium is confronted with an increasingly older population of people of Moroccan background who have been diagnosed with dementia. These migrants came to the country during the labour migration wave of the nineteen-sixties and seventies to work in mines and other industries and they are now ageing. Yet little is known about how dementia care is provided to this older population. This study explores how dementia care is provided to these Moroccan older people with dementia, and what challenges do caregivers face in providing care. A qualitative study including 31 informal caregivers of older Moroccan migrants with dementia and professional caregivers in the field of dementia care in several Belgian cities was conducted. After an initial focus group including 6 informal and professional caregivers, individual in-depth interviews were held with 12 informal caregivers of Moroccan decent and 13 professional caregivers. In order to be included in the study, informal caregivers had to have a recent experience in caring for an older family member with dementia. The professional caregivers had to be active in the field of dementia care (General Practitioners, nurses, psychologists,…) and have experience with older migrants with dementia. Analyses of the collected data reveal that current dementia care is a challenging, complex and dynamic search process. This process is shaped by (1) multiple factors reflecting the changing care needs of the care recipient during the course of the dementia, (2) the individual (transnational) recourses of the informal caregivers and the (3) current (lack of) accessibility of professional dementia care (driven by the absence of an accessible migration-, culture- and religion-sensitive professional care). The limited professional service-use is predominantly compensated through the search for transnational external helpers. The limited migration, cultural and religious sensitivity of current dementia care is often overlooked by professional caregivers. The study provides a better understanding of the complex reality of dementia care for older migrants in which these different aspects intersect. This understanding enable health professionals and policy makers to develop a better suited care for older migrants with dementia.


Altered oscillation patterns and connectivity during picture naming in autism.
Similar behavioral deficits are shared between individuals with autism spectrum disorders (ASD) and their first-degree relatives, such as impaired face memory, object recognition, and some language aspects. Functional neuroimaging studies have reported abnormalities in ASD in at least one brain area implicated in those functions, the fusiform gyrus (FG). High frequency oscillations have also been described as abnormal in ASD in a separate line of research. The present study examined whether low- and high-frequency oscillatory power, localized in part to FG and other language-related regions, differs in ASD subjects and first-degree relatives. Twelve individuals with ASD, 16 parents of children with ASD, and 35 healthy controls participated in a picture-naming task using magnetoencephalography (MEG) to assess oscillatory power and connectivity. Relative to controls, we observed reduced evoked high-gamma activity in the right superior temporal gyrus (STG) and reduced high-beta/low-gamma evoked power in the left inferior frontal gyrus (IFG) in the ASD group. Finally, reductions in phase-locked beta-band were also seen in the ASD group relative to controls, especially in the occipital lobes (OCC). First degree relatives, in contrast, exhibited higher high-gamma band power in the left STG compared with controls, as well as increased high-beta/low-gamma evoked power in the left FG. In the left hemisphere, beta- and gamma-band functional connectivity between the IFG and FG and between STG and OCC were higher in the autism group than in controls. This suggests that, contrary to what has been previously described, reduced connectivity is not observed across all scales of observation in autism. The lack of behavioral correlation for the findings warrants some caution in interpreting the relevance of such changes for language function in ASD. Our findings in parents implicates the gamma- and beta-band ranges as potential compensatory phenomena in autism relatives.


Recurrence of Atrial Fibrillation After Catheter Ablation or Antiarrhythmic Drug Therapy in the CABANA Trial.
The CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial randomized 2,204 patients with atrial fibrillation (AF) to catheter ablation or drug therapy. Analysis by intention-to-treat showed a nonsignificant 14% relative reduction in the primary outcome of death, disabling stroke, serious bleeding, or cardiac arrest. The purpose of this study was to assess recurrence of AF in the CABANA trial. The authors prospectively studied CABANA patients using a proprietary electrocardiogram recording monitor for symptom-activated and 24-h AF auto detection. The AF recurrence endpoint was any post-90-day blanking atrial tachyarrhythmias lasting 30 s or longer. Biannual 96-h Holter monitoring was used to assess AF burden. Patients who used the CABANA monitors and provided 90-day post-blanking recordings qualified for this analysis (n = 1,240; 56% of CABANA population). Treatment comparisons were performed using a modified intention-to-treat approach. Median age of the 1,240 patients was 68 years, 34.4% were women, and AF was paroxysmal in 43.0%. Over 60 months of follow-up, first recurrence of any symptomatic or asymptomatic AF (hazard ratio: 0.52; 95% confidence interval: 0.45 to 0.60; p < 0.001) or first symptomatic-only AF (hazard ratio: 0.49; 95% confidence interval: 0.39 to 0.61; p < 0.001) were both significantly reduced in the catheter ablation group. Baseline Holter AF burden in both treatment groups was 48%. At 12 months, AF burden in ablation patients averaged 6.3%, and in drug-therapy patients, 14.4%. AF burden was significantly less in catheter ablation compared with drug-therapy patients across the 5-year follow-up (p < 0.001). These findings were not sensitive to the baseline pattern of AF. Catheter ablation was effective in reducing recurrence of any AF by 48% and symptomatic AF by 51% compared with drug therapy over 5 years of follow-up. Furthermore, AF burden was also significantly reduced in catheter ablation patients, regardless of their baseline AF type. (Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial [CABANA]; NCT00911508).


Bone mineral density in relation to medical and lifestyle risk factors for osteoporosis in premenopausal, menopausal and postmenopausal women in general practice.
Interest in the prevention of osteoporosis is increasing and thus there is a need for an acceptable osteoporosis prevention programme in general practice. A study was undertaken to identify a cohort of middle-aged women attending a general practice who would be eligible for a longitudinal study looking at bone mineral density, osteoporosis and the effectiveness of hormone replacement therapy. This study aimed to describe the relationship between medical and lifestyle risk factors for osteoporosis and the initial bone density measurements in this group of women. A health visitor administered a questionnaire to women aged between 48 and 52 years registered with a Belfast general practice. The main outcome measures were menopausal status, presence of medical and lifestyle risk factors and bone mineral density measurements. A total of 358 women our of 472 (76%) took part in the study which was conducted in 1991 and 1992. A highly significant difference was found between the mean bone mineral density of premenopausal, menopausal and postmenopausal women within the narrow study age range, postmenopausal women having the lowest bone mineral density. A significant relationship was found between body mass index and bone mineral density, a greater bone mineral density being found among women with a higher body mass index. Risk factors such as smoking and sedentary lifestyle were common (reported by approximately one third of respondents) but a poor relationship was found between these two and all the other risk factors and bone mineral density in this age group. Risk of osteoporosis cannot be identified by the presence of risk factors in women aged between 48 and 52 years. In terms of a current prevention strategy for general practice it would be better to take a population-based approach except for those women known to be at high risk of osteoporosis: women with early menopause or those who have had an oophorectomy.


Age-specific determinants of stunting in Filipino children.
This study identifies age-specific factors related to new cases of stunting that develop in Filipino children from birth to 24 mo of age. Data come from nearly 3000 participants in the Cebu Longitudinal Health and Nutrition Survey, a community-based study conducted from 1983 to 1995. Length, morbidity, feeding and health-related data were collected bimonthly during home visits. Stunting (length >2 SD below the WHO age- and sex-specific medians) occurred in 69% of rural and 60% of urban children by 24 mo of age. We used a multivariate discrete time hazard model to estimate the likelihood of becoming stunted in each 2-mo interval. The likelihood of stunting was significantly increased by diarrhea, febrile respiratory infections, early supplemental feeding and low birth weight. The effect of birth weight was strongest in the first year. Breast-feeding, preventive health care and taller maternal stature significantly decreased the likelihood of stunting. Males were more likely to become stunted in the first year, whereas females were more likely to become stunted in the second year of life. Because stunting is strongly related to poor functional outcomes such as impaired intellectual development during childhood, and to short stature in adulthood, these results emphasize the need for prevention of growth retardation through promotion of prenatal care and breast-feeding, as well as control of infectious diseases.


Corneal abnormalities in incontinentia pigmenti: histopathological and confocal correlations.
To describe the clinical presentation and histopathologic and confocal correlations in a case of incontinentia pigmenti (IP)-associated whorllike corneal epitheliopathy. We describe the case report of a 22-year-old woman with IP and bilateral whorllike corneal epitheliopathy, with symptomatic dry eye complaints. Slit-lamp and confocal microscopic imaging confirmed that the pathology was restricted entirely within the epithelial layer. The cornea was debrided with the hopes of alleviating symptomatic eye complaints. The excised tissue was analyzed by standard light microscopy and transmission electron microscopy. In vivo confocal microscopic imaging (ConfoScan 3; Nidek, Fremont, CA) of both eyes showed the presence of multiple bright, round objects approximately 7-20 microm in diameter and located entirely within the epithelial layer. Hematoxylin-eosin-stained sections of the debrided tissue showed a mild disorganization of the overall epithelial architecture. Transmission electron microscopy noted various degrees of degenerating nuclei. The corneal epithelial defect of the patient's left eye healed by the fourth postoperative day. The new epithelium appeared normal, but at the 1-month examination, there was recurrence. Histomorphologic evaluation of the surgical specimen showed abnormal changes restricted to the epithelium in our patient. The observed changes are suggestive of a primary abnormality of cell maturation, which results in degeneration, and apoptosis as the epithelial cells migrate upward. The rapid recurrence of keratopathy clearly indicates that supportive treatment of blurred vision and secondary superficial punctate keratopathy with artificial tears, punctal plugs, and bandage contact lens are more likely to be beneficial.


Geology of the athabasca oil sands.
In-place bitumen resources in the Alberta oil sands are estimated at 1350 billion barrels. Open-pit mining and hot water extraction methods, which involve the handling of huge tonnages of earth materials, are being employed in the two commercial plants now operating. In situ recovery methods will be required to tap the 90 percent of reserves that are too deeply buried to be surface mined. Development of in situ technologies will be painstaking and expensive, and success will hinge on their compatibility with extremely complex geological conditions in the subsurface.


Age, trauma and the critical shoulder angle accurately predict supraspinatus tendon tears.
The pathogenesis of full-thickness tears of the rotator cuff remains unclear. Apart from age and trauma, distinct scapular morphologies have been found to be associated with rotator cuff disease. The purpose of the present study was to evaluate whether a score formed using these established risk factors was able to predict the presence of a rotator cuff tear reliably. We retrospectively assessed a consecutive series of patients with a minimal age of 40 years old, who had true antero-posterior (AP) radiographs of their shoulders, as well as a magnetic resonance (MR) gadolinium-arthrography, between January and December 2011. In all of these patients, the critical shoulder angle (CSA) was determined, and MR images were assessed for the presence of rotator cuff tears. Additionally, the patients' charts were reviewed to obtain details of symptom onset. Based on these factors, the so-called rotator cuff tear (RCT) score was calculated. Patients with full-thickness RCTs were significantly older and had significantly larger CSAs than patients with intact rotator cuffs. Multiple logistic regression, using trauma, age and CSA as independent variables, revealed areas under the curve (AUCs) for trauma of 0.55, for age of 0.65 and for CSA of 0.86. The combination of all three factors was the most powerful predictor, with an AUC of 0.92. Age, trauma and the CSA can accurately predict the presence of a posterosuperior RCT. Level IV. Case series with no comparison groups.


Linear quantification of lymphoid infiltration of the tumor margin: a reproducible method, developed with colorectal cancer tissues, for assessing a highly variable prognostic factor.
Lymphoid infiltration is a prognostic marker in solid tumors, such as colorectal, breast and lung carcinomas. However, lymphoid infiltration is heterogeneous and the reproducibility of quantification based on single counts within a tumor is very low. We aimed to develop a reproducible method for evaluating lymphoid infiltration in tumors. Virtual slides were obtained from tissue sections from the localized colorectal carcinomas of 117 patients, stained for CD3 and CD45R0. We assessed the variation of lymphoid cell density by automatic counts in 1 mm-wide, 5 μm-long segments of the invasive front, along an axis 4 mm in length running perpendicular to the invasive front of the tumor. We plotted curves of the variation of lymphocyte density across the tumor front. Three distinct patterns emerged from this linear quantification of lymphocyte (LQLI). In pattern 1, there was a high density of lymphocytes within the tumor. In pattern 2, lymphocyte density peaked close to the invasive margin. In pattern 3, lymphocytes were diffusely distributed, at low density. It was possible to classify all the tumors studied, and interobserver reproducibility was excellent (kappa =0.9). By contrast, single counts of CD3+ cells on tissue microarrays were highly variable for a given LQLI pattern, confirming the heterogeneity of lymphoid infiltration within individual tumors. In univariate analysis, all pathologic features (stage, metastatic lymph node ratio (LNR), vascular embolism, perineural invasion), CD3+ cell density, LQLI patterns for CD3+ and CD45R0+ cells) were found to have a significant effect on disease-free survival (DFS). In multivariate analysis, only the LQLI pattern for CD3+ cells (HR: 6.02; 95% CI: 2.74-13.18) and metastatic lymph node ratio (HR: 6.14; 95% CI: 2.32-16.2) were associated with DFS. LQLI is an automated, reproducible method for the assessment of lymphoid infiltration. However, validation of its prognostic value in larger series is required before its introduction into routine practice for prognostic evaluation in patients with colorectal carcinomas. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9861460717895880.


Survey data of finalists and winners in the search for outstanding teachers in the Philippines, 1988-2010.
The data derives from a survey of teachers who competed at the national level in the Metrobank Foundation, Inc. Search for Outstanding Teachers in the Philippines from 1988 to 2010. Conducted in March-September 2014, the survey has complete information from 252 national winners and finalists. The survey collected data on teachers' professional profile, socio-demographic characteristics, community involvement, socioeconomic characteristic of the teachers' household including income and expenditure, and their overall perception on the search process. It also collected information from school heads. The data collected by the survey from the school head include statistics on the educational profile of their teachers, performance indicators of the school, physical characteristics of the school, and school head's general assessment of colleagues and overall perception on the search process. The survey also includes information about the financial literacy of teachers. The dataset is in comma-separated values file (.csv) with accompanying data dictionary (.txt). The questionnaire is also included in data supplementary appendix. This data article is related to the research article, "Awards and Recognition: Do they Matter in Teachers' Income Trajectory?" Ravago and Mapa, 2020, where data interpretation and analysis can be found.


Macroscopic response to microscopic intrinsic noise in three-dimensional Fisher fronts.
We study the dynamics of three-dimensional Fisher fronts in the presence of density fluctuations. To this end we simulate the Fisher equation subject to stochastic internal noise, and study how the front moves and roughens as a function of the number of particles in the system, N. Our results suggest that the macroscopic behavior of the system is driven by the microscopic dynamics at its leading edge where number fluctuations are dominated by rare events. Contrary to naive expectations, the strength of front fluctuations decays extremely slowly as 1/logN, inducing large-scale fluctuations which we find belong to the one-dimensional Kardar-Parisi-Zhang universality class of kinetically rough interfaces. Hence, we find that there is no weak-noise regime for Fisher fronts, even for realistic numbers of particles in macroscopic systems.


Design, construction and validation of a computer controlled system for functional loading of soft tissue.
Osteoarthritis is a chronic degenerative disease affecting body joints. Abnormal mechanical loading could be an initiating factor of cartilage damage, by influencing chondrocytes activity. To date, devices performing mechanical studies of viable tissues are mostly uniaxial. In this work, we developed and validated a multi-axial device for static and dynamic mechanical testing of viable soft tissues. The system, named RPETS, is composed of a motor driven indenter, moving vertically and horizontally along the bottom of a tank containing tissue samples and it can apply combined compression, sliding, and rolling on viable samples. Validation studies were performed with standard rubber and bovine nasal cartilage tissue. Static tests demonstrated that the system is comparable to existing uniaxial devices, with a maximum force control error smaller than 0.5N and a positioning resolution of 5 μm. Dynamic tests performed with different motion profiles showed that the system can exert a load of 100N with a maximum velocity of 100mm/s maintaining the force control error within 10% of the desired value. Sinusoidal motion frequency can vary between 0.05 and 0.5Hz. In practical tests, viability staining of dynamically loaded cartilage slices showed extents of cell death to depend on the indenter velocity.


ASSIST applicability scoring of surgical trials. an investigator-reported assessment tool.
We aimed to develop a new tool for assessing and depicting the applicability of the results of surgical randomized controlled trials (RCTs) from the trial investigators' perspective. We identified all items related to applicability by a systematic methodological review, and then a sample of surgeons used these items in a web-based survey to evaluate the applicability of their own trial results. For each applicability item, participants had to indicate on a numerical scale that was simplified as a three-item scale: 1) items essential to consider, 2) items requiring attention, and 3) items inconsequential to the applicability of the results of their own RCT to clinical practice. For the final tool, we selected only items that were rated as being essential or requiring attention for at least 25% of the trials evaluated. We propose a specific process to construct the tool and to depict applicability in a graph. We identified all investigators of published and registered ongoing RCTs assessing surgery and invited them to participate in the web-based survey. 148 surgeons assessed applicability for their own trial and participated in the process of item selection. The final tool contains 22 items (4 dedicated to patients, 5 to centers, 5 to surgeons and 8 to the intervention). We proposed a straightforward process of constructing the graphical tool: 1) a multidisciplinary team of investigators or other care providers participating in the trial could independently assess each item, 2) a consensus method could be used, and 3) the investigators could depict their assessment of the applicability of the trial results in 4 graphs related to patients, centers, surgeons and the intervention. This investigator-reported assessment tool could help readers define under what conditions they could reasonably apply the results of a surgical RCT to their clinical practice.


No change in developmental outcome with incubator covers and nesting for very preterm infants in a randomised controlled trial.
To investigate in a randomised controlled trial the effect of basic elements of developmental care (incubator covers and positioning aids) on growth and neurodevelopment in infants born at < 32 weeks. Infants were randomised within 48 h of birth to a developmental care (DC) or standard care (C) group. Outcome measures at 1 and 2 years corrected age were growth, standardised neurological examinations, and mental (MDI) and psychomotor (PDI) development (Dutch version of the Bayley Scales of Infant Development II). 192 infants were recruited (DC = 98; C = 94). Thirteen infants (DC = 7, C = 6) were excluded because they were admitted for <5 days or died within the first 5 days. In total, 179 infants met the inclusion criteria. In-hospital mortality was 12/91 (13.2%) in the DC group and 8/88 (9.1%) in the C group. Assessments were carried out on 147 children (DC = 74, C = 73) at 1 year and 142 children (DC = 72, C = 70) at 2 years. No significant difference in growth, neurological outcomes or MDI was found. A positive trend in PDI at 1 year (p = 0.05) did not continue once the children reached 2 years. There was no difference found when neurological and developmental scores were combined. Basic developmental care has no positive effect on neurological and mental development or growth at 1 and 2 years of age in infants born at <32 weeks. A positive effect on psychomotor development at 1 year did not continue at 2 years of age.


Study on skull asymmetry.
The aim of this study is to determine the type of skull as well as to examine its internal appearance and configuration of skull base. Special attention is given to the direction and position of the pyramid of the temporal bone, the volume and appearance of all the three cranial fossas, and the direction and appearance of crista alaris--all of those compared to the skull type. Considering the obtained results (specially for crista alaris and middle fossa) we can ascertain outstanding independence of sphenoid bone and its parts in the formation of cranial base. Located in the middle of the skull, in front of strong pyramids transversal axis and two vertical axis, frontal crest and internal occipital crest, it by itself with her lesser wing presents an important transversal axis of cranial base. Cases in which crista alaris with its position does not follow the type of skull (in 20 % cases crista alaris does not follow skull protuberances), may probably be explained by strong and independent development of this bone, which is placed among other bones of cranial base like a peg. It also, by itself dictates form and configuration of the middle part of skull. That is also confirmed by middle fossa which, according to its position in the middle of cranial base and relation with sphenoid bone, shows significant deviation with respect to posterior fossa (follows the type of skull in 47 % cases).


[A case of anti-myelin oligodendrocyte glycoprotein (MOG) and anti-N-methyl-D-aspartate (NMDA) receptor antibody-positive encephalitis with optic neuritis].
A 20-year-old female was hospitalized due to generalized seizure two weeks after an infection. She reported disorientation, neck stiffness and weakness in her legs. MRI FLAIR images and T2WI on her first visit to our hospital showed hyperintense lesions in the bilateral cingulate gyrus and the medial region of the superior frontal gyrus. Gadolinium (Gd)-enhanced T1WI showed enhancement in the upper part of the corpus callosum. Examination of her cerebrospinal fluid (CSF) revealed mildly elevated leucocytes. After the administration of high-dose intravenous methylprednisolone, her symptoms partially improved. However, MRI T2WI at 16 days after admission showed a lesion with a peripheral hypointense rim in the left side of the cingulate gyrus, which had ring enhancement on contrast CT. FLAIR images at 28 days after admission showed the hyperintense lesion spreading in the subcallosal area and the brainstem, and coronal short inversion time inversion recovery (STIR) images demonstrated bilateral optic neuritis. She was treated with steroid pulse therapy and plasma exchange. Thereafter her symptoms improved. The patient's CSF at 27 days after admission tested positive for anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies and anti-N-methyl-D-aspartate (anti-NMDA) receptor antibodies. Encephalitis with optic neuritis in a patient with both anti-MOG and anti-NMDA receptor antibodies is very rare. Coexistence of multiple antibodies in the same patient may contribute to the diversity of autoimmune diseases associated with anti-MOG antibodies or anti-NMDA receptor antibodies.


Lack of bladder tumor promoting activity in rats fed sodium saccharin in AIN-76A diet.
Sodium saccharin (NaSac) fed as 5% of Prolab diet promotes bladder tumor carcinogenesis in male F344 rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) fed as 0.2% of the diet for 4 weeks. NaSac also increases urothelial proliferation if fed for short periods in Prolab diet, but no increased proliferation is seen if it is fed for up to 10 weeks in AIN-76A semisynthetic diet, even at levels as high as 7.5% of the diet. To determine whether NaSac as part of an AIN-76A diet has promoting activity, groups of approximately 30 male, 5-week-old F344 rats were fed AIN-76A diet containing (a) 0.2% FANFT for 4 weeks followed by 5% NaSac for 100 weeks; (b) 0.2% FANFT followed by control diet; or (c) control diet followed by 5% NaSac. Bladder tumor incidences were 10, 23, and 0%, respectively. When fed in Prolab diet, 0.2% FANFT for 4 weeks followed by NaSac or control diet for 100 weeks resulted in bladder tumor incidences of 40 and 17%, respectively. Groups of rats fed 0.1 or 0.2% FANFT for 1 or 2 weeks followed by 5% NaSac or control diet for 100 weeks had bladder tumor incidences of 0 to 7%. These data demonstrate that NaSac does not promote bladder cancer in male rats if fed in AIN-76A diet. Other studies suggest that this is due to the low urinary pH in rats fed AIN-76A diet.


Ribosome rescue and translation termination at non-standard stop codons by ICT1 in mammalian mitochondria.
Release factors (RFs) govern the termination phase of protein synthesis. Human mitochondria harbor four different members of the class 1 RF family: RF1Lmt/mtRF1a, RF1mt, C12orf65 and ICT1. The homolog of the essential ICT1 factor is widely distributed in bacteria and organelles and has the peculiar feature in human mitochondria to be part of the ribosome as a ribosomal protein of the large subunit. The factor has been suggested to rescue stalled ribosomes in a codon-independent manner. The mechanism of action of this factor was obscure and is addressed here. Using a homologous mitochondria system of purified components, we demonstrate that the integrated ICT1 has no rescue activity. Rather, purified ICT1 binds stoichiometrically to mitochondrial ribosomes in addition to the integrated copy and functions as a general rescue factor, i.e. it releases the polypeptide from the peptidyl tRNA from ribosomes stalled at the end or in the middle of an mRNA or even from non-programmed ribosomes. The data suggest that the unusual termination at a sense codon (AGA/G) of the oxidative-phosphorylation enzymes CO1 and ND6 is also performed by ICT1 challenging a previous model, according to which RF1Lmt/mtRF1a is responsible for the translation termination at non-standard stop codons. We also demonstrate by mutational analyses that the unique insertion sequence present in the N-terminal domain of ICT1 is essential for peptide release rather than for ribosome binding. The function of RF1mt, another member of the class1 RFs in mammalian mitochondria, was also examined and is discussed.


Human Metapneumovirus Is Capable of Entering Cells by Fusion with Endosomal Membranes.
Human metapneumovirus (HMPV), a member of the Paramyxoviridae family, is a leading cause of lower respiratory illness. Although receptor binding is thought to initiate fusion at the plasma membrane for paramyxoviruses, the entry mechanism for HMPV is largely uncharacterized. Here we sought to determine whether HMPV initiates fusion at the plasma membrane or following internalization. To study the HMPV entry process in human bronchial epithelial (BEAS-2B) cells, we used fluorescence microscopy, an R18-dequenching fusion assay, and developed a quantitative, fluorescence microscopy assay to follow virus binding, internalization, membrane fusion, and visualize the cellular site of HMPV fusion. We found that HMPV particles are internalized into human bronchial epithelial cells before fusing with endosomes. Using chemical inhibitors and RNA interference, we determined that HMPV particles are internalized via clathrin-mediated endocytosis in a dynamin-dependent manner. HMPV fusion and productive infection are promoted by RGD-binding integrin engagement, internalization, actin polymerization, and dynamin. Further, HMPV fusion is pH-independent, although infection with rare strains is modestly inhibited by RNA interference or chemical inhibition of endosomal acidification. Thus, HMPV can enter via endocytosis, but the viral fusion machinery is not triggered by low pH. Together, our results indicate that HMPV is capable of entering host cells by multiple pathways, including membrane fusion from endosomal compartments.


Delayed onset muscle soreness : treatment strategies and performance factors.
Delayed onset muscle soreness (DOMS) is a familiar experience for the elite or novice athlete. Symptoms can range from muscle tenderness to severe debilitating pain. The mechanisms, treatment strategies, and impact on athletic performance remain uncertain, despite the high incidence of DOMS. DOMS is most prevalent at the beginning of the sporting season when athletes are returning to training following a period of reduced activity. DOMS is also common when athletes are first introduced to certain types of activities regardless of the time of year. Eccentric activities induce micro-injury at a greater frequency and severity than other types of muscle actions. The intensity and duration of exercise are also important factors in DOMS onset. Up to six hypothesised theories have been proposed for the mechanism of DOMS, namely: lactic acid, muscle spasm, connective tissue damage, muscle damage, inflammation and the enzyme efflux theories. However, an integration of two or more theories is likely to explain muscle soreness. DOMS can affect athletic performance by causing a reduction in joint range of motion, shock attenuation and peak torque. Alterations in muscle sequencing and recruitment patterns may also occur, causing unaccustomed stress to be placed on muscle ligaments and tendons. These compensatory mechanisms may increase the risk of further injury if a premature return to sport is attempted.A number of treatment strategies have been introduced to help alleviate the severity of DOMS and to restore the maximal function of the muscles as rapidly as possible. Nonsteroidal anti-inflammatory drugs have demonstrated dosage-dependent effects that may also be influenced by the time of administration. Similarly, massage has shown varying results that may be attributed to the time of massage application and the type of massage technique used. Cryotherapy, stretching, homeopathy, ultrasound and electrical current modalities have demonstrated no effect on the alleviation of muscle soreness or other DOMS symptoms. Exercise is the most effective means of alleviating pain during DOMS, however the analgesic effect is also temporary. Athletes who must train on a daily basis should be encouraged to reduce the intensity and duration of exercise for 1-2 days following intense DOMS-inducing exercise. Alternatively, exercises targeting less affected body parts should be encouraged in order to allow the most affected muscle groups to recover. Eccentric exercises or novel activities should be introduced progressively over a period of 1 or 2 weeks at the beginning of, or during, the sporting season in order to reduce the level of physical impairment and/or training disruption. There are still many unanswered questions relating to DOMS, and many potential areas for future research.


Bioinspired multilayer membranes as potential adhesive patches for skin wound healing.
Bioinspired and adhesive multilayer membranes are produced using the layer-by-layer (LbL) assembly of chitosan (CHT), alginate (ALG) and hyaluronic acid modified with dopamine (HA-DN). Freestanding multilayer membranes without DN are also produced as a control. The success of the synthesis of HA-DN was confirmed using UV-visible spectroscopy. Scanning electron microscopy images indicate that the surface of the DN-containing membranes is more porous than the control ones; they also present a higher average thickness value for the same number of CHT/ALG/CHT/HA(-DN) tetralayers (n = 100). Also, water uptake, mechanical strength and adhesion are enhanced with the introduction of DN moieties along the nano-layers. Besides, human dermal fibroblast viability, enhanced adhesion and proliferation were confirmed by immunofluorescence assays and by measuring both the metabolic activity and DNA content. Moreover, in vivo assays with such kinds of DN-containing multilayer membranes were performed; the application of these membranes in the treatment of dermal wounds induced in Wistar rats results in the highest decrease of inflammation of rat skin, compared with the control conditions. Overall, this investigation suggests that these mussel-inspired freestanding multilayer membranes may enhance either their mechanical performance or cellular adhesion and proliferation, leading to an improved wound healing process, being a promising material to restore the structural and functional properties of wounded skin.


Hyperpolarized [1,(13)C]pyruvate in lysed human erythrocytes: effects of co-substrate supply on reaction time courses.
Hyperpolarized [1,(13)C]pyruvate was injected rapidly into haemolysates in which hydrolysis of nicotinamide adenine dinucleotide (phosphate) (NAD(P))/NAD(P)H had been inhibited with nicotinamide. Haemolysates provide a stable glycolytic system in which membrane permeability is not a flux-controlling step, and they enable the concentration of NADH to be adjusted experimentally while keeping the rest of the sample with the same composition as that of the cytoplasm of the cell (albeit diluted twofold at the time of injection of the [1,(13)C]pyruvate). We showed that the maximum amplitude of the (13)C NMR signal from the [1,(13)C]L-lactate, produced from [1,(13)C]pyruvate, and the time at which it occurred was dependent on NADH concentration, as predicted by enzyme-kinetic analysis. The main feature of such curves was dictated by the immediacy of the supply of the co-substrate of lactate dehydrogenase (LDH, EC 126.96.36.199), and we posit that this also pertains in vivo in various tissues including neoplasms. By constructing an appropriate mathematical model and by using a Markov-chain Monte Carlo approach, we fitted experimental data to estimate LDH and NADH concentrations. Experiments carried out with only endogenous NADH present enabled the estimation of its effective concentration in human RBCs; the ability to make this estimate is a special feature of the rapid-dissolution dynamic nuclear polarization method. We found an endogenous NADH concentration in human RBCs two to four times higher than previously reported.


HIV infection and antiretroviral therapy lead to unfolded protein response activation.
The unfolded protein response (UPR) is one of the pathways triggered to ensure quality control of the proteins assembled in the endoplasmic reticulum (ER) when cell homeostasis is compromised. This mechanism is primarily composed of three transmembrane proteins serving as stress sensors: PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1). These three proteins' synergic action elicits translation and transcriptional downstream pathways, leading to less protein production and activating genes that encode important proteins in folding processes, including chaperones. Previous reports showed that viruses have evolved mechanisms to curtail or customize this UPR signaling for their own benefit. However, HIV infection's effect on the UPR has scarcely been investigated. This work investigated UPR modulation by HIV infection by assessing UPR-related protein expression under in vitro and in vivo conditions via Western blotting. Antiretroviral (ARV) drugs' influence on this stress response was also considered. In in vitro and in vivo analyses, our results confirm that HIV infection activates stress-response components and that ARV therapy contributes to changes in the UPR's activation profile. This is the first report showing UPR-related protein expression in HIV target cells derived directly from HIV-infected patients receiving different ARV therapies. Thus, two mechanisms may occur simultaneously: interference by HIV itself and the ARV drugs' pharmacological effects as UPR activators. New evidence of how HIV modulates the UPR to enhance its own replication and secure infection success is also presented.


Extracranial Venous Drainage Pattern in Multiple Sclerosis and Healthy Controls: Application of the 2011 Diagnostic Criteria for Chronic Cerebrospinal Venous Insufficiency.
The etiology of multiple sclerosis (MS) is still largely unknown and it has been proposed that an impaired venous drainage from the central nervous system, defined as chronic cerebrospinal venous insufficiency (CCSVI), may play a role in this. We investigated the prevalence of extracranial venous drainage pattern alterations in a cohort of MS patients based on the 2011 revised diagnostic criteria for CCSVI. Thirty-nine MS patients and 18 healthy subjects underwent blinded extra-cranial venous echo-color Doppler sonography to reveal the presence of CCSVI. There was no statistically significant difference between MS patients and healthy controls regarding CCSVI prevalence (p value = 0.53). The results challenge the hypothesis that CCSVI plays a primary role in the pathogenesis of MS.


An antimicrobial stewardship program improves antimicrobial treatment by culture site and the quality of antimicrobial prescribing in critically ill patients.
Increasing antimicrobial costs, reduced development of novel antimicrobials, and growing antimicrobial resistance necessitate judicious use of available agents. Antimicrobial stewardship programs (ASPs) may improve antimicrobial use in intensive care units (ICUs). Our objective was to determine whether the introduction of an ASP in an ICU altered the decision to treat cultures from sterile sites compared with nonsterile sites (which may represent colonization or contamination). We also sought to determine whether ASP education improved documentation of antimicrobial use, including an explicit statement of antimicrobial regimen, indication, duration, and de-escalation. We retrospectively analyzed consecutive patients with positive bacterial cultures admitted to a 16-bed medical-surgical ICU over 2-month periods before and after ASP introduction (April through May 2008 and 2009, respectively). We evaluated the antimicrobial treatment of positive sterile- versus nonsterile-site cultures, specified a priori. We reviewed patient charts for clinician documentation of three specific details regarding antimicrobials: an explicit statement of antimicrobial regimen/indication, duration, and de-escalation. We also analyzed cost and defined daily doses (DDDs) (a World Health Organization (WHO) standardized metric of use) before and after ASP. Patient demographic data between the pre-ASP (n = 139) and post-ASP (n = 130) periods were similar. No difference was found in the percentage of positive cultures from sterile sites between the pre-ASP period and post-ASP period (44.9% versus 40.2%; P = 0.401). A significant increase was noted in the treatment of sterile-site cultures after ASP (64% versus 83%; P = 0.01) and a reduction in the treatment of nonsterile-site cultures (71% versus 46%; P = 0.0002). These differences were statistically significant when treatment decisions were analyzed both at an individual patient level and at an individual culture level. Increased explicit antimicrobial regimen documentation was observed after ASP (26% versus 71%; P < 0.0001). Also observed were increases in formally documented stop dates (53% versus 71%; P < 0.0001), regimen de-escalation (15% versus 23%; P = 0.026), and an overall reduction in cost and mean DDDs after ASP implementation. Introduction of an ASP in the ICU was associated with improved microbiologically targeted therapy based on sterile or nonsterile cultures and improved documentation of antimicrobial use in the medical record.


Contextual modulation of amygdala responsivity to surprised faces.
We recently demonstrated a functional relationship between fMRI responses within the amygdala and the medial prefrontal cortex based upon whether subjects interpreted surprised facial expressions positively or negatively. In the present fMRI study, we sought to assess amygdala-medial prefrontal cortex responsivity when the interpretations of surprised faces were determined by contextual experimental stimuli, rather than subjective judgment. Subjects passively viewed individual presentations of surprised faces preceded by either a negatively or positively valenced contextual sentence (e. g., She just found $500 vs. She just lost $500). Negative and positive sentences were carefully matched in terms of length, situations described, and arousal level. Negatively cued surprised faces produced greater ventral amygdala activation compared to positively cued surprised faces. Responses to negative versus positive sentences were greater within the ventrolateral prefrontal cortex, whereas responses to positive versus negative sentences were greater within the ventromedial prefrontal cortex. The present study demonstrates that amygdala response to surprised facial expressions can be modulated by negatively versus positively valenced verbal contextual information. Connectivity analyses identified candidate cortical-subcortical systems subserving this modulation.


Feasibility of engaging caregivers in at-home surveillance of children with uncomplicated severe acute malnutrition.
Many factors can contribute to low coverage of treatment for severe acute malnutrition (SAM), and a limited number of health facilities and trained personnel can constrain the number of children that receive treatment. Alternative models of care that shift the responsibility for routine clinical and anthropometric surveillance from the health facility to the household could reduce the burden of care associated with frequent facility-based visits for both healthcare providers and caregivers. To assess the feasibility of shifting clinical surveillance to caregivers in the outpatient management of SAM, we conducted a pilot study to assess caregivers' understanding and retention of key concepts related to the surveillance of clinical danger signs and anthropometric measurement over a 28-day period. At the time of a child's admission to nutritional treatment, a study nurse provided a short training to groups of caregivers on two topics: (a) clinical danger signs in children with SAM that warrant facility-based care and (b) methods to measure and monitor their child's mid-upper arm circumference. Caregiver understanding was assessed using standardized questionnaires before training, immediately after training, and 28 days after training. Knowledge of most clinical danger signs (e.g., convulsions, edema, poor appetite, respiratory distress, and lethargy) was low (0-45%) before training but increased immediately after and was retained 28 days after training. Agreement between nurse-caregiver mid-upper arm circumference colour classifications was 77% (98/128) immediately after training and 80% after 28 days. These findings lend preliminary support to pursue further study of alternative models of care that allow for greater engagement of caregivers in the clinical and anthropometric surveillance of children with SAM.


Psychological inflexibility explains distress in parents whose children have chronic conditions.
Experiential avoidance, cognitive defusion, and mindfulness have all been associated with psychological disorders and well-being. This study investigates whether they predict psychological distress, i.e., symptoms of burnout, depression, stress and anxiety, in parents of children with chronic conditions. We hypothesized that these factors would exhibit a large degree of common variance, and that when compared to mindfulness and defusion, experiential avoidance on its own would predict a larger proportion of unique variance. 75 parents of children with chronic conditions having burnout symptoms who participated in an intervention study completed measures of burnout, stress, anxiety, depression, experiential avoidance, cognitive defusion, and mindfulness at the beginning of the intervention study (baseline). We ran several regression analyses to assess the predictive ability of these different constructs. Experiential avoidance on its own accounted for 28-48% of the variance in different psychological symptoms. Cognitive defusion and mindfulness did not make a significant contribution to explaining burnout, stress and anxiety, but cognitive defusion contributed to explaining depression. The results confirmed our hypothesis, supporting research on the importance of psychological flexibility as a central factor in understanding the occurrence of psychological distress.


Taste-olfactory convergence, and the representation of the pleasantness of flavour, in the human brain.
The functional architecture of the central taste and olfactory systems in primates provides evidence that the convergence of taste and smell information onto single neurons is realized in the caudal orbitofrontal cortex (and immediately adjacent agranular insula). These higher-order association cortical areas thus support flavour processing. Much less is known, however, about homologous regions in the human cortex, or how taste-odour interactions, and thus flavour perception, are implemented in the human brain. We performed an event-related fMRI study to investigate where in the human brain these interactions between taste and odour stimuli (administered retronasally) may be realized. The brain regions that were activated by both taste and smell included parts of the caudal orbitofrontal cortex, amygdala, insular cortex and adjoining areas, and anterior cingulate cortex. It was shown that a small part of the anterior (putatively agranular) insula responds to unimodal taste and to unimodal olfactory stimuli, and that a part of the anterior frontal operculum is a unimodal taste area (putatively primary taste cortex) not activated by olfactory stimuli. Activations to combined olfactory and taste stimuli where there was little or no activation to either alone (providing positive evidence for interactions between the olfactory and taste inputs) were found in a lateral anterior part of the orbitofrontal cortex. Correlations with consonance ratings for the smell and taste combinations, and for their pleasantness, were found in a medial anterior part of the orbitofrontal cortex. These results provide evidence on the neural substrate for the convergence of taste and olfactory stimuli to produce flavour in humans, and where the pleasantness of flavour is represented in the human brain.


Gastric emptying in diabetic autonomic neuropathy.
Gastric emptying was studied in 12 diabetic patients, six with and six without objective evidence of autonomic neuropathy and in 20 nondiabetic controls, using a double isotope scintiscanning technique which differentiated between solid and liquid emptying. Three patients with autonomic neuropathy exhibited gastric stasis, although this was detected by conventional radiology in only one. Neither the patients with stasis nor those without exhibited abnormally rapid early gastric emptying. In patients without stasis, the normal differentiation between solid and liquid emptying was impaired, suggesting an abnormality of antral peristalsis not attributable to vagal denervation. Both intravenous and oral metoclopramide produced symptomatic improvement in two patients with gastric stasis and restored their gastric emptying to normal.


Glucagon-like peptide-1 (GLP-1) mediates cardioprotection by remote ischaemic conditioning.
Although the nature of the humoral factor which mediates cardioprotection established by remote ischaemic conditioning (RIc) remains unknown, parasympathetic (vagal) mechanisms appear to play a critical role. As the production and release of many gut hormones is modulated by the vagus nerve, here we tested the hypothesis that RIc cardioprotection is mediated by the actions of glucagon-like peptide-1 (GLP-1). A rat model of myocardial infarction (coronary artery occlusion followed by reperfusion) was used. Remote ischaemic pre- (RIPre) or perconditioning (RIPer) was induced by 15 min occlusion of femoral arteries applied prior to or during the myocardial ischaemia. The degree of RIPre and RIPer cardioprotection was determined in conditions of cervical or subdiaphragmatic vagotomy, or following blockade of GLP-1 receptors (GLP-1R) using specific antagonist Exendin(9-39). Phosphorylation of PI3K/AKT and STAT3 was assessed. RIPre and RIPer reduced infarct size by ∼50%. In conditions of bilateral cervical or subdiaphragmatic vagotomy RIPer failed to establish cardioprotection. GLP-1R blockade abolished cardioprotection induced by either RIPre or RIPer. Exendin(9-39) also prevented RIPre-induced AKT phosphorylation. Cardioprotection induced by GLP-1R agonist Exendin-4 was preserved following cervical vagotomy, but was abolished in conditions of M3 muscarinic receptor blockade. These data strongly suggest that GLP-1 functions as a humoral factor of remote ischaemic conditioning cardioprotection. This phenomenon requires intact vagal innervation of the visceral organs and recruitment of GLP-1R-mediated signalling. Cardioprotection induced by GLP-1R activation is mediated by a mechanism involving M3 muscarinic receptors.


Experimental observation of pulse trains' destructive interference with a femtosecond optical frequency-comb-based interferometer.
A recently reported interferometric technique using a femtosecond optical frequency comb is modified to observe the destructive interference between two pairs of pulse trains with different relative delays. Experimental observation of the destructive interference shows that the present technique may offer a significantly different possibility to reduce the unnecessary reflections. This technique can be applied not only to surface profilometry and tomography but also to optical superresolution metrology.


Capillary leakage in travelers with dengue infection: implications for pathogenesis.
Dengue hemorrhagic fever is characterized by the presence of a capillary leak syndrome. Its pathogenesis is presumed to differ from that of classical dengue fever (DF) and to be associated with secondary dengue infection. Returning travelers given a diagnosis of DF were evaluated for capillary leakage with abdominal sonography. Data were compared between travelers with primary/secondary infection defined by epidemiologic and serologic parameters. A total of 12 (34.3%) of 35 patients had sonographic signs of capillary leakage. Most (85%) patients with capillary leakage had classical DF. Capillary leak was diagnosed in 32% of primary dengue cases and in 40% of secondary dengue cases (P = 0.69). The two patients given a diagnosis of dengue hemorrhagic fever had primary infections. The high prevalence of capillary leakage among travelers, most of them with primary exposure to dengue, calls into question the importance of secondary infection in causing capillary leakage in dengue infection.


Tracheal stricture and fistula: management with a barbed silicone-covered retrievable expandable nitinol stent.
The purpose of this study was to evaluate the safety and effectiveness of a barbed silicone-covered retrievable expandable nitinol stent in preventing stent migration in patients with tracheal strictures or fistulas. Under fluoroscopic guidance, barbed silicone-covered retrievable expandable nitinol stents were placed in 15 patients with tracheal strictures, two patients with fistulas, two patients with combined strictures and fistulas, and one patient with variable extrathoracic airway obstruction. The three pairs of barbs were attached to the external stent surface at the middle of the stent at equal intervals. Technical success, improvement in respiratory status, complications, and related interventions were evaluated. The technical success rate was 100%, and respiratory status improved or the fistula closed in all 20 patients. Complications included sputum retention (three patients), tumor overgrowth (three patients), pain (one patient), and granulation tissue formation (one patient). No stent migration occurred, even in the three patients without fixed strictures. Four stents subsequently were removed because of complications, and one stent was removed because the patient's condition improved. Stent removal was not difficult and was uneventful. The silicone membranes and barbs of the removed stents were intact. Use of a barbed silicone-covered retrievable expandable nitinol stent relieves dyspnea and facilitates fistula closure in patients with benign or malignant tracheal strictures or fistulas. The barbed design of the stent is important in preventing migration.


Cannabidiol and Oxygen-Ozone Combination Induce Cytotoxicity in Human Pancreatic Ductal Adenocarcinoma Cell Lines.
Pancreatic cancer (PC) is related to lifestyle risks, chronic inflammation, and germline mutations in BRCA1/2, ATM, MLH1, TP53, or CDKN2A. Surgical resection and adjuvant chemotherapy are the main therapeutic strategies but are less effective in patients with high-grade tumors. Oxygen-ozone (O2/O3) therapy is an emerging alternative tool for the treatment of several clinical disorders. O2/O3 therapy has been found to ameliorate mechanisms promoting chronic pain and inflammation, including hypoxia, inflammatory mediators, and infection. The advantages of using cannabinoids have been evaluated in vitro and in vivo models of several human cancers. Regarding PDAC, activation of cannabinoid receptors was found to induce pancreatic cancer cell apoptosis without affecting the normal pancreas cells. In a murine model of PDAC, a combination of cannabidiol (CBD) and gemcitabine increased survival length by nearly three times. Herein, we evaluate the anticancer effect of CBD and O2/O3, alone or in combination, on two human PDAC cell lines, PANC-1 and MiaPaCa-2, examining expression profiles of 92 pancreatic adenocarcinoma associated genes, cytotoxicity, migration properties, and cell death. Finally, we assess the combination effects with gemcitabine and paclitaxel. Summarizing, for the first time the antitumoral effect of combined therapy with CBD and oxygen-ozone therapy in PDAC is evidenced.


Higher-order wide-angle split-step spectral method for non-paraxial beam propagation.
We develop a higher-order method for non-paraxial beam propagation based on the wide-angle split-step spectral (WASSS) method previously reported [Clark and Thomas, Opt. Quantum. Electron., 41, 849 (2010)]. The higher-order WASSS (HOWASSS) method approximates the Helmholtz equation by keeping terms up to third-order in the propagation step size, in the Magnus expansion. A symmetric exponential operator splitting technique is used to simplify the resulting exponential operators. The HOWASSS method is applied to the problem of waveguide propagation, where an analytical solution is known, to demonstrate the performance and accuracy of the method. The performance enhancement gained by implementing the HOWASSS method on a graphics processing unit (GPU) is demonstrated. When highly accurate results are required the HOWASSS method is shown to be substantially faster than the WASSS method.


Removal of heavy metals from aluminum anodic oxidation wastewaters by membrane filtration.
Aluminum manufacturing has been reported as one of the largest industries and wastewater produced from the aluminum industry may cause significant environmental problems due to variable pH, high heavy metal concentration, conductivity, and organic load. The management of this wastewater with a high pollution load is of great importance for practitioners in the aluminum sector. There are hardly any studies available on membrane treatment of wastewater originated from anodic oxidation. The aim of this study is to evaluate the best treatment and reuse alternative for aluminum industry wastewater using membrane filtration. Additionally, the performance of chemical precipitation, which is the existing treatment used in the aluminum facility, was also compared with membrane filtration. Wastewater originated from anodic oxidation coating process of an aluminum profile manufacturing facility in Kayseri (Turkey) was used in the experiments. The characterization of raw wastewater was in very low pH (e.g., 3) with high aluminum concentration and conductivity values. Membrane experiments were carried out with ultrafiltration (PTUF), nanofiltration (NF270), and reverse osmosis (SW30) membranes with MWCO 5000, 200-400, and 100 Da, respectively. For the chemical precipitation experiments, FeCl3 and FeSO4 chemicals presented lower removal performances for aluminum and chromium, which were below 35% at ambient wastewater pH ~ 3. The membrane filtration experimental results show that, both NF and RO membranes tested could effectively remove aluminum, total chromium and nickel (>90%) from the aluminum production wastewater. The RO (SW30) membrane showed a slightly higher performance at 20 bar operating pressure in terms of conductivity removal values (90%) than the NF 270 membrane (87%). Although similar removal performances were observed for heavy metals and conductivity by NF270 and SW30, significantly higher fluxes were obtained in NF270 membrane filtration at any pressure that there were more than three times the flux values in SW30 membrane filtration. Due to the lower heavy metal (<65%) and conductivity (<30%) removal performances of UF membrane, it could be evaluated as pretreatment followed by NF filtration to protect and extend NF membrane life. The water treated by both NF and RO could be recycled back into the process to be reused with economic and environmental benefits.


Range-resolved vibrometry using a frequency comb in the OSCAT configuration.
Two methods for performing range-resolved vibrometry measurements using frequency combs are presented. A modified correction algorithm taking into account the differences from the typical dual comb spectroscopic technique is developed. Results are presented showing the recovery of a human voice sample and other sounds from different vibrating surfaces, including a diffuse wall and a glass slab. When multiple surfaces are present, range selection makes it possible to select the surface from which the vibration is demodulated.


Plasma sarcosine does not distinguish early and advanced stages of prostate cancer.
Diagnosis of prostate cancer by prostate specific antigen (PSA) is error-prone and cannot distinguish benign prostatic hyperplasia (BPH) from malignant disease, nor identify aggressive and indolent types. We determined serum sarcosine (N-methylglycine) in 328 cancer patients by gas chromatography (GC)/mass spectroscopy (MS) and searched for correlations with early (stage T1/T2) and advanced (stage T3/T4) disease. Serum sarcosine of male control patients ranged from 1.7 µmol/l to 4.8 µmol/l. In prostate cancer patients, sarcosine ranged from 2.8 µmol/l to 20.1 µmol/l. Expressed as the sarcosine/alanine ratio, serum control values were 9.4 ± 5.5 x 10(-3) (mean ± SD) compared with 21.6 ± 9.0; 28.5 ± 16.6; 22.7 ± 7.7 and 22.2 ± 11.0 for patients diagnosed with T1, T2, T3 and T4 prostate tumours, respectively. The small differences between T1, T2, T3 and T4 patients were not statistically significant (p=0.51). However, the conventional PSA marker significantly correlated with T stage in these patients (r=0.63; p<0.009). The median sarcosine/alanine ratios among patients with early and advanced prostatic cancer ranged from 21.6 ± 9.0 to 28.5 ± 16.6 and were fairly constant, showing no statistically significant differences between T-stages. The results are consistent with published data in urine and serum which find differences between controls and patients with metastatic prostate cancer to be small and sarcosine to be uninformative regarding prostate cancer progression. By multi-comparison of PSA with T-stages in the same group of patients, we found significant correlations confirming the well-known merits and limitations of this marker.


Plasma levels of galectin-3-binding protein reflect type I interferon activity and are increased in patients with systemic lupus erythematosus.
Simple measures of type I interferon (IFN) activity constitute highly attractive biomarkers in systemic lupus erythematosus (SLE). We explore galectin-3-binding protein (G3BP) as a novel measure of type I IFN activity and serum/plasma biomarker in large independent cohorts of patients with SLE and controls. Serum and plasma G3BP concentrations were quantified using ELISA. Type I IFN activity was assessed by Mx1 reporter gene expression assays and correlated to serum G3BP concentrations (SLE-IFN-α, n=26 and healthy controls (HCs), n=10). Plasma G3BP concentrations in the SLE-Denmark (DK) (n=70) and SLE-Sweden (SE) (n=68) cohorts were compared with the HC-DK (n=47) and HC-SE (n=50) cohorts and patients with systemic sclerosis (n=111). In 15 patients with SLE, serum G3BP in consecutive samples was correlated to disease activity. Correlation analysis between G3BP, clinical parameters including disease activity in the four SLE cohorts was performed. G3BP concentrations correlated significantly with the IFN-α reporter gene assay (r=0.56, p=0.0005) and with IFN-α gene expression scores (r=0.54, p=0.0002). Plasma concentrations were significantly increased in the SLE-DK and SLE-SE cohorts compared with HCs and patients with systemic sclerosis (p<0.0001 and p=0.0009). G3BP concentrations correlated with disease activity measures in the SLE-DK- and SLE-IFN-α cohorts (p=0.0004 and p=0.05) but not in the SLE-SE cohort (p=0.98). Markedly temporal variation was observed in G3BP levels in the consecutive SLE-samples and was significantly associated with changes in disease activity (r=0.44, p=0.014). G3BP plasma levels reflect type I IFN activity and are increased in SLE. Associations with disease activity or clinical manifestations are uncertain. This study highlights G3BP as a convenient measure of type I IFN-dependent gene activation.


Human hypoxic pulmonary vasoconstriction is unaltered by 8 h of preceding isocapnic hyperoxia.
Exposure to sustained hypoxia of 8 h duration increases the sensitivity of the pulmonary vasculature to acute hypoxia, but it is not known whether exposure to sustained hyperoxia affects human pulmonary vascular control. We hypothesized that exposure to 8 h of hyperoxia would diminish the hypoxic pulmonary vasoconstriction (HPV) that occurs in response to a brief exposure to hypoxia. Eleven healthy volunteers were studied in a crossover protocol with randomization of order. Each volunteer was exposed to acute isocapnic hypoxia (end-tidal PO2 = 50 mmHg for 10 min) before and after 8 h of hyperoxia (end-tidal PO2 = 420 mmHg) or euoxia (end-tidal PO2 = 100 mmHg). After at least 3 days, each volunteer returned and was exposed to the other condition. Systolic pulmonary artery pressure (an index of HPV) and cardiac output were measured, using Doppler echocardiography. Eight hours of hyperoxia had no effect on HPV or the response of cardiac output to acute hypoxia.


Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS.
Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS), where aggregation of Cu/Zn superoxide dismutase (SOD1) is implicated in causing neurodegeneration. Recent studies have suggested that destabilization and aggregation of the most immature form of SOD1, the disulfide-reduced, unmetallated (apo) protein is particularly important in causing ALS. We report herein in depth analyses of the effects of chemically and structurally diverse ALS-associated mutations on the stability and aggregation of reduced apo SOD1. In contrast with previous studies, we find that various reduced apo SOD1 mutants undergo highly reversible thermal denaturation with little aggregation, enabling quantitative thermodynamic stability analyses. In the absence of ALS-associated mutations, reduced apo SOD1 is marginally stable but predominantly folded. Mutations generally result in slight decreases to substantial increases in the fraction of unfolded protein. Calorimetry, ultracentrifugation, and light scattering show that all mutations enhance aggregation propensity, with the effects varying widely, from subtle increases in most cases, to pronounced formation of 40-100 nm soluble aggregates by A4V, a mutation that is associated with particularly short disease duration. Interestingly, although there is a correlation between observed aggregation and stability, there is minimal to no correlation between observed aggregation, predicted aggregation propensity, and disease characteristics. These findings suggest that reduced apo SOD1 does not play a dominant role in modulating disease. Rather, additional and/or multiple forms of SOD1 and additional biophysical and biological factors are needed to account for the toxicity of mutant SOD1 in ALS.


Patient and Radiographic Factors Help to Predict Metal-on-Metal Hip Resurfacings with Evidence of a Pseudotumor.
The role of radiographs in the follow-up of patients with metal-on-metal hip resurfacing (MoMHR) implants is unclear. We investigated whether a combination of patient and radiographic factors predicted MoMHRs with evidence of a pseudotumor. We performed a retrospective single-center case-control study of 384 MoMHRs. The pseudotumor group of 130 hips all had evidence of a symptomatic pseudotumor on cross-sectional imaging, with the diagnosis confirmed at revision. The nonpseudotumor group of 254 hips (a subgroup of these hips were previously reported on) all had normal findings on cross-sectional imaging. Radiographs taken immediately prior to revision were assessed in the pseudotumor group and were compared with radiographs taken at the time of normal cross-sectional imaging in the nonpseudotumor group. Two blinded independent observers analyzed the radiographs for signs of failure, with excellent interobserver agreement. Logistic regression modeling identified the patient and radiographic predictors of revision for pseudotumor. Hips with a pseudotumor more commonly had abnormal findings on radiographs compared to hips without a pseudotumor (80.0% compared with 63.4%; p = 0.001). Patient and radiographic factors predictive of revision for pseudotumor in the multivariable model were female sex (odds ratio [OR], 3.14; 95% confidence interval [CI], 1.85 to 5.35; p < 0.001), high inclination (OR, 1.04 per degree; 95% CI, 1.01 to 1.07 per degree; p = 0.006), acetabular osteolysis (OR, 5.06; 95% CI, 2.14 to 12.0; p < 0.001), femoral osteolysis (OR, 17.8; 95% CI, 5.09 to 62.2; p < 0.001), and acetabular loosening (OR, 3.35; 95% CI, 1.34 to 8.35; p = 0.009). Factors predictive of not having a pseudotumor were anteversion of ≥5° (5° to <10°: OR, 0.31; 95% CI, 0.12 to 0.77; p = 0.012; and ≥10°: OR, 0.32; 95% CI, 0.15 to 0.70; p = 0.004) and heterotopic ossification (OR, 0.19; 95% CI, 0.05 to 0.72; p = 0.015). The final multivariable model was well calibrated (p = 0.589), with good discriminatory ability (area under the curve = 0.801; sensitivity = 74.4%; specificity = 71.7%). A combination of patient and radiographic factors provided useful information for distinguishing between MoMHRs with and without evidence of a pseudotumor. Surgeons may wish to consider these specific patient and radiographic factors before proceeding with cross-sectional imaging. Radiographs are important when assessing patients with MoMHR implants and should be included in all follow-up protocols. Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Accuracy of Endoscopic Ultrasonography for Determining the Depth of Invasion in Early Gastric Cancer.
Accurate staging for depth of invasion (T stage) of early gastric cancer is critical for determining the treatment modality. Endoscopic ultrasonography is a reliable method for assessing the T stage. However, its diagnostic accuracy varies. The aim of this study is to investigate clinicopathologic factors affecting the diagnostic accuracy of endoscopic ultrasonography in early gastric cancer. Patients with early gastric cancer who had undergone endoscopic resection or gastrectomy were included. The diagnostic accuracy of endoscopic ultrasonography was evaluated by comparing the T stage by endoscopic ultrasonography with histopathology of the resected specimen. Subgroup analysis was performed according to the endoscopic resection criteria. A total of 223 early gastric cancer lesions were included. The overall accuracy of endoscopic ultrasonography for T staging was 66.4%. The diagnostic accuracy for lesions ≤2 cm was significantly higher than for those of 2-3 cm (odds ratio 3.59) or those >3 cm (odds ratio 5.47). The diagnostic accuracy was significantly decreased in lesions with ulceration (odds ratio 2.62) or non-flat morphology (odds ratio 2.94). The accuracy of endoscopic ultrasonography for lesions corresponding to the absolute endoscopic resection criteria was significantly higher than for those corresponding to the expanded criteria (97.3% vs 71.9%, P = .002). Of the tumors that were overestimated by endoscopic ultrasonography treated with gastrectomy, 93.3% corresponded to the expanded criteria. Endoscopic ultrasonography had poor accuracy in early gastric cancer lesions larger than 2 cm, those with ulceration, and those with non-flat morphology, that is, lesions corresponding to the expanded criteria were more frequently overstaged by endoscopic ultrasonography. Such early gastric cancers should be carefully considered when staging by endoscopic ultrasonography before gastrectomy.


Consumers' Views on the Importance of Specific Front-of-Pack Nutrition Information: A Latent Profile Analysis.
Nutrition labelling can influence consumers' assessments of food healthiness and their food choices. However, there is a lack of consensus about the optimal type and amount of nutrition information to provide on food packages. This study analysed consumers' preferences for front-of-pack information relating to energy and various nutrients (sugar, saturated fat, sodium, fibre, carbohydrate, and protein). The aim was to identify discrete preference segments within the Australian market where the current Health Star Rating front-of-pack labelling system can be displayed with different levels of nutrition information. Adults (n = 1558) completed a survey assessing socio-demographics, self-reported nutrition knowledge, diet healthiness, special dietary requirements, and perceived importance of the provision of energy and nutrient information on the front of food packs. Latent profile analysis identified five consumer segments within the sample that ranged from groups exhibiting high levels of interest in various forms of nutrition information to one with very low interest and one with divergent scores according to whether nutrients were perceived as positive or negative for health. The results indicate that different forms of front-of-pack labelling featuring varying degrees of information about energy and specific nutrients are likely to be of interest and use to different market segments.