The relationship of needs and quality of life in persons with schizophrenia living in the community. A Nordic multi-center study.
The relationship between needs for care and support and subjective quality of life was investigated in a cross-sectional multi-center study including 418 individuals with schizophrenia from 10 centers in Nordic countries. Needs in 22 domains were investigated by interviews with key workers and their patients using the Camberwell Assessment of Need scale, and quality of life by the Lancashire Quality of Life Profile. The results showed that key workers rated slightly more needs than patients. To have more unmet needs, as rated by both key workers and patients, were correlated to a worse overall subjective quality of life, while met needs showed no such association. A regression analysis, controlling for clinical and social characteristics of the patients, showed more unmet needs to be associated with a worse quality of life, accounting for 6% out of a total of 41% explained variance in subjective quality of life. Regression analyses of the relationship of unmet needs in specific life domains and overall quality of life showed that unmet needs in five domains as perceived by patients accounted for 17% of the explained variance in overall quality of life. More than half of this variance was related to an unmet need in the domain of social relationships. It is concluded that unmet needs are of specific importance in needs assessment and that attention must be paid to separate met needs for care and services from unmet needs, since the latter seem more important to consider in order to improve outcome of interventions with regard to quality of life. Specific attention should in this context also be paid to unmet needs concerning social relationships and problems with accommodation.


Role of the null space of the DRM in the performance of modulated polarimeters.
Imaging polarimeters infer the spatial distribution of the polarization state of the optical field as a function of time and/or wavelength. A polarimeter indirectly determines the polarization state by first modulating the intensity of the light field and then demodulating the measured data to infer the polarization parameters. This Letter considers passive Stokes parameter polarimeters and their inversion methods. The most widely used method is the data reduction matrix (DRM), which builds up a matrix equation that can be inverted to find the polarization state from a set of intensity measurements. An alternate strategy uses linear system formulations that allow band limited reconstruction through a filtering perspective. Here we compare these two strategies for overdetermined polarimeters and find that design of the null space of the inversion operator provides degrees of freedom to optimize the trade off between accuracy and signal-to-noise ratio. We further describe adaptive filtering techniques that could optimize the reconstruction for a particular experimental configuration. This Letter considers time-varying Stokes parameters, but the methods apply equally to polarimeters that are modulated in space or in wavelength.


Dependence of Cr-EDTA absorption from the rumen on luminal osmotic pressure.
A method for the measurement of [51Cr]EDTA absorption from the ventral sac of the rumen with an error of the order of +/-10% is described. When a solution present in the rumen was hypotonic or isotonic, the absorption rate of [51Cr]EDTA expressed as a clearance was about 0.2 ml/min. This gave rise to negligible errors when [51Cr]EDTA was used as an unabsorbed marker to calculate net water movements. When the osmotic pressure in the rumen exceeded that of plasma by 30-40 mos-mol/kg, the absorption rate of [51Cr]EDTA appeared to be related to the degree of hypertonicity. Absorption rates as high as 8 ml/min were observed within a range of osmotic pressures normally encountered postprandially in the rumen. Under hypertonic conditions, a correction for the absorption of this large anion was necessary if passage of water into the lumen were not to be systematically overestimated.


The significance of mucin pools following neoadjuvant chemoradiotherapy for locally advanced rectal cancer.
Neoadjuvant chemo-radiotherapy is utilized for locally advanced rectal cancer to optimize local control. A subset of patients form mucin pools following radiotherapy but the association between mucin pools and pathological and oncological outcomes following curative proctectomy for rectal cancer remains unknown. The aim of this study was to determine the significance of mucin pool formation after neoadjuvant chemoradiotherapy for rectal cancer. This is a retrospective analysis of a prospectively maintained rectal cancer database. Patients who underwent curative proctectomy for rectal cancer following long course chemoradiotherapy between January 2007 and December 2016 were eligible for inclusion. A total of 297 patients were eligible for inclusion; of these 36 (12.1%) had mucin pools on final histopathology. Tumors with mucin pools were less likely to be ypT3/T4 (25.0 vs 51.0%, P = 0.003), were more likely to have a good response (83.3 vs 53.6%, P < 0.001) and more likely to have a pathologic complete response (41.7 vs 19.2%, P = 0.006) to radiotherapy. The presence of mucin pools was associated with less distant recurrence ( P < 0.05) and improved overall survival ( P = 0.02). The presence of mucin pools following neoadjuvant chemoradiotherapy for rectal cancer represents a surrogate marker of response to treatment and downstaging and is associated with improved survival.


Physicochemical, Structural, and Biological Properties of Polysaccharides from Dandelion.
The edible and medicinal perennial herb dandelion is known to have antitumor, antioxidant, and anticomplement properties. However, the structural characterization and biological effects of its polysaccharides are not well understood. Here, we aimed to extract and investigate a novel polysaccharide from dandelion. A water-soluble polysaccharide, PD1-1, was successfully obtained from dandelion through ultrasonic-assisted extraction and purification using diethylaminoethyl (DEAE)-Sepharose fast flow and Sephadex G-75 columns. The results showed that PD1-1 is an inulin-type polysaccharide with a molecular weight of 2.6 kDa and is composed of glucose (52.39%), and mannose (45.41%). Glycosidic linkage analysis demonstrated that PD1-1 contains terminal α-d-Man/Glcp-(1→ and →1)-β-d-Man/Glcf-(2→ glycosidic linkage conformations. A physicochemical analysis indicated that PD1-1 has a triple helix structure and exhibits important properties, including good swelling, water-holding, and oil-holding capacities. Furthermore, PD1-1 showed good antioxidant activities in DPPH and hydroxyl free radical scavenging abilities, with IC50 values of 0.23 mg/mL and 0.25 mg/mL, respectively, and good hypoglycemic activities in α-amylase and α-glucosidase inhibition, with IC50 values of 0.53 mg/mL and 0.40 mg/mL, respectively, in a concentration-dependent manner. Results suggest that PD1-1 possesses efficacious antioxidant and hypoglycemic properties and has potential applications as a functional food ingredient.


Stage II palliation of hypoplastic left heart syndrome without cardiopulmonary bypass.
Bidirectional cavopulmonary anastomosis has been performed without cardiopulmonary bypass for some single-ventricle heart defects. Limited data are available for the outcomes of off-pump bidirectional cavopulmonary anastomosis in infants with hypoplastic left heart syndrome. The purpose of this study is to determine the early outcomes for stage II palliation of hypoplastic left heart syndrome without cardiopulmonary bypass. This is a retrospective review of infants having surgical palliation of hypoplastic left heart syndrome from April 2003 to March 2010 at a single institution. Seventy-five infants had a modified Norwood procedure, 65 with a right ventricle-pulmonary artery conduit, 10 with an aortopulmonary shunt, 2 with atrioventricular valve repair, and 3 with extracorporeal life support. Sixty-eight patients had hypoplastic left heart syndrome or one of its variants, and 7 had other single-ventricle lesions. There were 2 stage I deaths. Stage I survival was 97% (95% confidence interval, 88%-99%). Another 5 infants succumbed in the interstage period. Of the 68 stage I and interstage survivors, 61 had bidirectional cavopulmonary anastomoses, 20 without cardiopulmonary bypass. Median age was 6 months (range, 4-13 months), and median weight was 6.1 kg (range, 5.2-9.0 kg). There were no conversions to cardiopulmonary bypass when off-pump bidirectional cavopulmonary anastomosis was attempted. There were no hospital deaths. Median ventilation duration was 10 hours (range, 6-18 hours), and length of stay was 5 days (range, 4-9 days). Follow-up was available on all infants at a median duration of 17 months (range, 3-43 months), with no unplanned reinterventions. Bidirectional cavopulmonary anastomosis without the use of cardiopulmonary bypass can be performed safely and with low mortality for selected infants with hypoplastic left heart syndrome. Midterm to long-term outcomes remain to be determined.


Changing Educational Differentials in Female Sterilization.
Female surgical sterilization is widely used in the United States. Educational differentials in sterilization are large, but poorly understood. Improved understanding of these differences is important to ensure that all women have access to the full range of contraceptive methods. Data from the National Survey of Family Growth (1973-2015) from 8,100 women aged 40-44 were used to describe trends in sterilization and other contraceptive methods by educational attainment. Demographic standardization was employed to examine how compositional changes in marital status and age at first birth contribute to aggregate changes in sterilization prevalence. In 1982, women with a high school diploma and those with at least a bachelor's degree reported similar levels of sterilization use (38% and 32%, respectively), but by 2011-2015, prevalence had declined to 19% among college-educated women and had increased to 44% among those with a diploma. The trend among college graduates was largely attributable to delayed fertility; all other things being equal, if their age at first birth had not increased, the prevalence of sterilization would have declined by approximately 3% instead of 14% between 1982 and 2002. Increased use of sterilization among women with a high school diploma was only weakly related to changes in birth timing and marital status. Among women with a high school diploma, elements other than childbearing and marital status-such as contraceptive preferences and access-appeared to influence their contraceptive behavior. Sterilization differentials between high school and college graduates may reflect or exacerbate other socioeconomic disparities that affect women's health and well-being.


The natural treatment of hypertension.
The goal of this review is to evaluate the efficacy of commonly available dietary supplements in the treatment of hypertension, using the average blood pressure reduction achieved with the implementation of lifestyle modifications as a standard. For this reason, the authors focus on the antihypertensive potential of these agents rather than pharmacology, pharmacokinetics, adverse effects, or supplement-drug interactions. For the purpose of this review, dietary supplements are defined as exhibiting some evidence of benefit if a systolic blood pressure reduction of 9.0 mm Hg or greater and/or a diastolic blood pressure reduction of 5.0 mm Hg or greater has been observed in previously published, peer-reviewed trials. These defining limits are based on the average blood pressure reduction associated with the implementation of certain lifestyle modifications. Agents with some evidence of benefit include coenzyme Q10, fish oil, garlic, vitamin C, and L-arginine.


Variance component estimations and mega-environments for sweetpotato breeding in West Africa.
The current study was aimed at identifying mega-environments in Ghana and evaluating adaptability of superior sweetpotato [Ipomoea batatas (L.) Lam.] genotypes from a targeted breeding effort. Three sets of genotypes were evaluated in multi-environment trials (MET). Twelve sweetpotato varieties were evaluated across nine environments representing the main agro-ecological zones in Ghana. MET analysis was conducted using a stage-wise approach with the genotype × environment (G × E) table of means used as a starting point to model the G × E interaction for sweetpotato yield. Emphasis was given to the genetic correlation matrix used in a second-order factor analytic model that accommodates heterogeneity of genetic variances across environments. A genotype main effect and G × E interaction of storage root yield explained 82% of the variation in the first principal component, and visualized the genetic variances and discriminating power of each environment and the genetic correlation between the environments. Two mega-environments, corresponding to northern and southern trial sites, were delineated. Six breeding lines selected from the south and eight breeding lines selected from the north were tested and compared to two common check clones at five locations in Ghana. A Finlay-Wilkinson stability analysis resulted in stable performances within the target mega-environment from which the genotypes were selected, but predominantly without adaptation to the other region. Our results provide a strong rationale for running separate programs to allow for faster genetic progress in each of these two major West African mega-environments by selecting for specific and broad adaptation.


Prevalence and associated risk factors of HIV in prisons in Balochistan, Pakistan: a cross-sectional study.
Background: The prevalence of HIV is 0.1% in Pakistan, with epidemicity in high-risk groups. The infection is on verge of transmission from key populations to the general population through people who inject drugs and sexual transmission. Prisoners are vulnerable to infectious diseases like HIV. This study was conducted in four prisons in Balochistan, Pakistan to determine the prevalence of HIV and associated risk factors. Methods: This cross sectional study was conducted from March to June 2018, in the prisons of Balochistan. WHO-approved rapid diagnostic kits were used for determining the prevalence of HIV and structured interviews were conducted for the assessment of risk factors. Results: Out of 2084 screened prisoners, 33 (1.6%) were found to be positive. A subset of 104 interviews was analyzed for risk factors of HIV. Among HIV-infected prisoners 68.8% (OR 4.48; 95% CI 1.41-14.2) had extramarital sex, 43.8% (OR 2.09 95% CI 0.69-6.28) had a homosexual experience, and 50% had a history of needle sharing (OR 43; 95% CI 7.77-237). About 94% (OR 16.42; 95% CI 2.09-129.81) of prisoners had a history of drug addiction of any type while 50% (OR 13; 95% CI 2.82-60.01) of HIV-infected had a history of using injectable drugs. Around 75% of HIV-infected prisoners had spent 1-5 years in prison, and 25% had spent more than 10 years. Conclusion: The high prevalence of HIV in prisons of Balochistan demands that preventive and treatment strategies should be designed and implemented carefully, allowing early diagnosis and treatment initiation to minimize the spread of infection among the prisons and ultimately their onward transmission into the community.


Role of calcium binding proteins in the control of cerebellar granule cell neuronal excitability: experimental and modeling studies.
Calcium binding proteins, such as calretinin, are abundantly expressed in distinctive patterns in the central nervous system but their physiological function remains poorly understood. Calretinin is expressed in cerebellar granule cells which provide the major excitatory input to Purkinje cells through parallel fibers. Calretinin deficient mice exhibit dramatic alterations in motor coordination and in Purkinje cell firing recorded in vivo through unknown mechanisms. In the present paper, we review the results obtained with the patch clamp recording techniques in acute slice preparation. This data allow us to investigate the effect of a null mutation of the calretinin gene on the intrinsic electroresponsiveness of cerebellar granule cells at a mature developmental stage. Calretinin deficient granule cells exhibit faster action potentials and generate repetitive spike discharge showing an enhanced frequency increase with injected currents. These alterations disappear when 0.15 mM of the exogenous fast calcium buffer BAPTA is infused in the cytosol to restore the calcium buffering capacity. Furthermore, we propose a mathematical model demonstrating that the observed alterations of granule cell excitability can be explained by a decreased cytosolic calcium buffering capacity due to the absence of calretinin. We suggest that calcium binding proteins modulate intrinsic neuronal excitability and may therefore play a role in the information processing in the central nervous system.


Nonalcoholic fatty liver disease as an independent risk factor for carotid atherosclerosis.
Nonalcoholic fatty liver disease (NAFLD) is a frequently encountered clinical condition in clinical practice, particularly in obese and diabetic patients. Carotid atherosclerosis is regarded as surrogate marker of coronary atherosclerosis. We aimed to know whether evaluation for carotid atherosclerosis should be done in all patients of NAFLD. A total of 200 NAFLD patients and 100 age- and sex-matched controls were enrolled into the study. Ultrasound was done to document fatty liver and carotid intimal thickness, and relation between these two was observed. Grade 1 fatty liver was seen in 36% patients while Grade 2 fatty liver was found in 39% and Grade 3 fatty liver in 25%. Patients with Grade 1 fatty liver had left intima-media thickness (IMT) in the range of 0.4-0.6 mm (mean IMT - 0.69 mm) and had right IMT in the range of 0.5-0.8 mm (mean IMT - 0.71 mm). In patients with Grade 2 fatty liver, left IMT was in the range of 0.6-1.0 mm (mean IMT - 0.80 mm) and right IMT in the range of 0.7-1.0 mm (mean IMT - 0.84 mm), while in patients with Grade 3 fatty liver, left IMT was in the range of 0.8-1.2 mm (mean IMT - 0.93 mm) and right IMT in the range of 0.9-1.4 mm (mean IMT - 0.99 mm). Among controls, the mean left IMT was 0.579 mm and mean right IMT was 0.575 mm. The level of carotid intimomedial thickness was more in cases than in controls and progressively increased with the grade of fatty liver which was statistically significant.


Statins may reduce femoral osteolysis in patients with total Hip arthroplasty.
In experimental studies, statin use has been associated with reduction of osteoclastic activity and promotion of bone formation around implants. Moreover, a large clinical study recently reported a substantially reduced risk of revision for aseptic loosening among statin users with THA. Our objective was to evaluate the influence of statin use on the development of femoral osteolysis within 5 years after THA. We conducted a case-cohort study including all THAs presenting with femoral osteolysis at the 5 year visit (cases) and compared them with those without osteolysis (controls). Cases and controls were identified from a cohort of primary THAs operated between 2001 and 2005. Seven hundred thirty-five THAs were included, mean age 68 years. Five years after surgery osteolysis had developed around the femoral component of 40 THAs (5.4%). Ever-use of statins was much less frequent among cases (5 of 40, 12.5%) than among controls (199 of 695, 28.6%). The crude risk ratio of femoral osteolysis among statin users was 0.36 (95% CI 0.14; 0.92). After adjusting for age, sex, activity level, BMI, diagnosis, bearing surface, and type of stem, the adjusted risk ratio was 0.38 (95% CI 0.15; 0.99). In conclusion, statin use was associated with a reduced risk of developing femoral osteolysis 5 years after THA. Statins may be useful for reducing the risk of implant failure following THA.


Enhancement of sexual behavior in female rats by neonatal transplantation of brain tissue from males.
Transplantation of preoptic tissue from male rat neonates into the preoptic area of female littermates increased masculine and feminine sexual behavior in the recipients during adulthood. This suggests that functional connections develop between the transplanted neural tissue and the host brain. A new intraparenchymal brain transplantation technique was used to achieve these results.


Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway.
The Ras-Erk (extracellular signal-regulated kinase) pathway encodes information in its dynamics; the duration and frequency of Erk activity can specify distinct cell fates. To enable dynamic encoding, temporal information must be accurately transmitted from the plasma membrane to the nucleus. We used optogenetic profiling to show that both oncogenic B-Raf mutations and B-Raf inhibitors can cause corruption of this transmission, so that short pulses of input Ras activity are distorted into abnormally long Erk outputs. These changes can reshape downstream transcription and cell fates, resulting in improper decisions to proliferate. These findings illustrate how altered dynamic signal transmission properties, and not just constitutively increased signaling, can contribute to cell proliferation and perhaps cancer, and how optogenetic profiling can dissect mechanisms of signaling dysfunction in disease.


Real-time observation of the change in light scattering from droplets with increasing deformity.
Commercial aerodynamic particle sizing instruments generally achieve the desired particle size measurement by accelerating a sample airstream in which the particles are suspended and measuring the velocity acquired by individual particles. The accelerating flow regime can cause liquid droplets to deform and this subsequently introduces errors. In this paper, we present an apparatus that enables droplet deformation to be observed by recording the spatial light scatter intensity. The paper presents experimental data in video format showing the changes that occur in the light scattering from droplets as a function of increasing flow rate/deformation.


Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state.
Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimer's disease the amyloid-β peptide (Aβ) misfolds into neurotoxic oligomers and assembles into amyloid fibrils. The Bri2 protein associated with Familial British and Danish dementias contains a BRICHOS domain, which reduces Aβ fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible non-fibrillar aggregation. How these different activities are mediated is not known. Here we show that Bri2 BRICHOS monomers potently prevent neuronal network toxicity of Aβ, while dimers strongly suppress Aβ fibril formation. The dimers assemble into high-molecular-weight oligomers with an apparent two-fold symmetry, which are efficient inhibitors of non-fibrillar protein aggregation. These results indicate that Bri2 BRICHOS affects qualitatively different aspects of protein misfolding and toxicity via different quaternary structures, suggesting a means to generate molecular chaperone diversity.


Suicide Attempts and Homelessness: Timing of Attempts Among Recently Homeless, Past Homeless, and Never Homeless Adults.
Homelessness is associated with increased risk of suicide attempts. This study examined whether suicide attempts typically precede or occur during episodes of homelessness in a representative national sample. Data from 36,127 adults in the National Epidemiologic Survey on Alcohol and Related Conditions-III were used to identify 1,992 respondents who reported a lifetime suicide attempt. Bivariate analyses compared attempt histories between adults who reported past-year homelessness, homelessness prior to the past year, and no history of homelessness. Measures included years since most recent attempt and first attempt and proportion attempting suicide in the past year. Multivariable analyses adjusted for potentially confounding effects of age and identified independent factors associated with past-year attempts along with past-year homelessness. Among respondents who experienced homelessness in the past year, 21.0% reported a past-year suicide attempt, compared with 5.8% among those experiencing homelessness prior to the past year and 6.3% of those who were never homeless. However, the most recent attempt among those with past-year homelessness occurred 8.4 years previously, on average-3.8 years and 4.5 years more recently than among those experiencing homelessness prior to the past year and those who were never homeless, after age adjustment. Overall, first suicide attempts occurred 19.9 years previously, on average, with no significant group differences after age adjustment. Rates of past-year suicide attempts and past-year homelessness were strongly associated, suggesting that homelessness and suicidality strongly co-occur. However, among adults with recent homelessness and a suicide attempt history, suicidal behavior began decades ago and likely preceded homelessness.


Multirelational organization of large-scale social networks in an online world.
The capacity to collect fingerprints of individuals in online media has revolutionized the way researchers explore human society. Social systems can be seen as a nonlinear superposition of a multitude of complex social networks, where nodes represent individuals and links capture a variety of different social relations. Much emphasis has been put on the network topology of social interactions, however, the multidimensional nature of these interactions has largely been ignored, mostly because of lack of data. Here, for the first time, we analyze a complete, multirelational, large social network of a society consisting of the 300,000 odd players of a massive multiplayer online game. We extract networks of six different types of one-to-one interactions between the players. Three of them carry a positive connotation (friendship, communication, trade), three a negative (enmity, armed aggression, punishment). We first analyze these types of networks as separate entities and find that negative interactions differ from positive interactions by their lower reciprocity, weaker clustering, and fatter-tail degree distribution. We then explore how the interdependence of different network types determines the organization of the social system. In particular, we study correlations and overlap between different types of links and demonstrate the tendency of individuals to play different roles in different networks. As a demonstration of the power of the approach, we present the first empirical large-scale verification of the long-standing structural balance theory, by focusing on the specific multiplex network of friendship and enmity relations.


Circadian clock component PERIOD2 regulates diurnal expression of Na+/H+ exchanger regulatory factor-1 and its scaffolding function.
A number of diverse cell-surface proteins are anchored to the cytoskeleton via scaffold proteins. Na+/H+ exchanger regulatory factor-1 (NHERF1), encoded by the Slc9a3r1 gene, functions as a scaffold protein, which is implicated in the regulation of membrane expression of various cell-surface proteins. Here, we demonstrate that the circadian clock component PERIOD2 (PER2) modulates transcription of the mouse Slc9a3r1 gene, generating diurnal accumulation of NHERF1 in the mouse liver. Basal expression of Slc9a3r1 was dependent on transcriptional activation by p65/p50. PER2 bound to p65 protein and prevented p65/p50-mediated transactivation of Slc9a3r1. The time-dependent interaction between PER2 and p65 underlay diurnal oscillation in the hepatic expression of Slc9a3r1/NHERF1. The results of immunoprecipitation experiments and liquid chromatography-mass spectrometry analysis of mouse liver revealed that NHERF1 time-dependently interacted with fatty acid transport protein-5 (FATP5). Temporary accumulation of NHERF1 protein stabilized plasmalemmal localization of FATP5, thereby enhancing hepatic uptake of fatty acids at certain times of the day. Our results suggest an unacknowledged role for PER2 in regulating the diurnal expression of NHERF1 in mouse liver. This machinery also contributed to diurnal changes in the ability of hepatic cells to uptake fatty acids.


Antiplatelet therapy following transcatheter aortic valve implantation.
There is limited evidence to support decision making on antiplatelet therapy following transcatheter aortic valve implantation (TAVI). Our aim was to assess the efficacy and safety of aspirin-only (ASA) versus dual antiplatelet therapy (DAPT) following TAVI. We performed a systematic review and pooled analysis of individual patient data from 672 participants comparing single versus DAPT following TAVI. Primary endpoint was defined as the composite of net adverse clinical and cerebral events (NACE) at 1 month, including all-cause mortality, acute coronary syndrome (ACS), stroke, life-threatening and major bleeding. At 30 days a NACE rate of 13% was observed in the ASA-only and in 15% of the DAPT group (OR 0.83, 95% CI 0.48 to 1.43, p=0.50). A tendency towards less life-threatening and major bleeding was observed in patients treated with ASA (OR 0.56, 95% CI 0.28 to 1.11, p=0.09). Also, ASA was not associated with an increased all-cause mortality (OR 0.91, 95% CI 0.36 to 2.27, p=0.83), ACS (OR 0.5, 95% CI 0.05 to 5.51, p=0.57) or stroke (OR 1.21; 95% CI 0.36 to 4.03, p=0.75). No difference in 30-day NACE rate was observed between ASA-only or DAPT following TAVI. Moreover, a trend towards less life-threatening and major bleeding was observed in favour of ASA. Consequently the additive value of clopidogrel warrants further investigation.


An interactive surgical planning tool for acetabular fractures: initial results.
Acetabular fractures still are among the most challenging fractures to treat because of complex anatomy, involved surgical access to fracture sites and the relatively low incidence of these lesions. Proper evaluation and surgical planning is necessary to achieve anatomic reduction of the articular surface and stable fixation of the pelvic ring. The goal of this study was to test the feasibility of preoperative surgical planning in acetabular fractures using a new prototype planning tool based on an interactive virtual reality-style environment. 7 patients (5 male and 2 female; median age 53 y (25 to 92 y)) with an acetabular fracture were prospectively included. Exclusion criterions were simple wall fractures, cases with anticipated surgical dislocation of the femoral head for joint debridement and accurate fracture reduction. According to the Letournel classification 4 cases had two column fractures, 2 cases had anterior column fractures and 1 case had a T-shaped fracture including a posterior wall fracture.The workflow included following steps: (1) Formation of a patient-specific bone model from preoperative computed tomography scans, (2) interactive virtual fracture reduction with visuo-haptic feedback, (3) virtual fracture fixation using common osteosynthesis implants and (4) measurement of implant position relative to landmarks. The surgeon manually contoured osteosynthesis plates preoperatively according to the virtually defined deformation. Screenshots including all measurements for the OR were available.The tool was validated comparing the preoperative planning and postoperative results by 3D-superimposition. Preoperative planning was feasible in all cases. In 6 of 7 cases superimposition of preoperative planning and postoperative follow-up CT showed a good to excellent correlation. In one case part of the procedure had to be changed due to impossibility of fracture reduction from an ilioinguinal approach. In 3 cases with osteopenic bone patient-specific prebent fixation plates were helpful in guiding fracture reduction. Additionally, anatomical landmark based measurements were helpful for intraoperative navigation. The presented prototype planning tool for pelvic surgery was successfully integrated in a clinical workflow to improve patient-specific preoperative planning, giving visual and haptic information about the injury and allowing a patient-specific adaptation of osteosynthesis implants to the virtually reduced pelvis.


Nose-to-brain Delivery of Natural Compounds for the Treatment of Central Nervous System Disorders.
Several natural compounds have demonstrated potential for the treatment of central nervous system disorders such as ischemic cerebrovascular disease, glioblastoma, neuropathic pain, neurodegenerative diseases, multiple sclerosis and migraine. This is due to their well-known antioxidant, anti-inflammatory, neuroprotective, anti-tumor, anti-ischemic and analgesic properties. Nevertheless, many of these molecules have poor aqueous solubility, low bioavailability and extensive gastrointestinal and/or hepatic first-pass metabolism, leading to a quick elimination as well as low serum and tissue concentrations. Thus, the intranasal route emerged as a viable alternative to oral or parenteral administration, by enabling a direct transport into the brain through the olfactory and trigeminal nerves. With this approach, the blood-brain barrier is circumvented and peripheral exposure is reduced, thereby minimizing possible adverse effects. Herein, brain-targeting strategies for nose-to-brain delivery of natural compounds, including flavonoids, cannabinoids, essential oils and terpenes, will be reviewed and discussed. Brain and plasma pharmacokinetics of these molecules will be analyzed and related to their physicochemical characteristics and formulation properties. Natural compounds constitute relevant alternatives for the treatment of brain diseases but often require loading into nanocarrier systems to reach the central nervous system in sufficient concentrations. Future challenges lie in a deeper characterization of their therapeutic mechanisms and in the development of effective, safe and brain-targeted delivery systems for their intranasal administration.


Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation.
Y-27632, an inhibitor of the Rho-associated kinase ROCK, is a therapeutic lead for Huntington disease (HD). The downstream targets that mediate its inhibitory effects on huntingtin (Htt) aggregation and toxicity are unknown. We have identified profilin, a small actin-binding factor that also interacts with Htt, as being a direct target of the ROCK1 isoform. The overexpression of profilin reduces the aggregation of polyglutamine-expanded Htt and androgen receptor (AR) peptides. This requires profilin's G-actin binding activity and its direct interaction with Htt, which are both inhibited by the ROCK1-mediated phosphorylation of profilin at Ser-137. Y-27632 blocks the phosphorylation of profilin in HEK293 cells and primary neurons, which maintains profilin in an active state. The knockdown of profilin blocks the inhibitory effect of Y-27632 on both AR and Htt aggregation. A signaling pathway from ROCK1 to profilin thus controls polyglutamine protein aggregation and is targeted by a promising therapeutic lead for HD.


Prognostic significance of fibrinopeptide A in survivors of cerebral infarction.
We measured levels of fibrinopeptide A, beta-thromboglobulin, and fibrinogen in the plasma of 27 patients 2 months after their first stroke. Concentrations of fibrinopeptide A, a sensitive index of in vivo hypercoagulability, were significantly higher in the 18 ischemic stroke patients than in 40 age- and sex-matched controls and in the six patients who experienced recurrence within 5 years than in the 12 who remained asymptomatic. On the contrary, fibrinopeptide A levels had no prognostic significance among the nine patients with hemorrhagic stroke. Concentrations of beta-thromboglobulin, an index of platelet activation, were higher in the 27 stroke patients than in the 40 controls, but this index was not associated with stroke recurrence. Fibrinogen levels were not significantly higher in stroke patients than in controls. In a multivariate regression analysis of hemostatic and clinical variables, only fibrinopeptide A levels of greater than 4 ng/ml were significantly related to cerebral infarction. Our results support the role of hypercoagulability in the recurrence of ischemic stroke and may allow identification of subjects at high risk for it. If confirmed in more patients, our results could provide a rationale for clinical trials of anticoagulant therapy in such patients.


Cholecalciferol (vitamin D₃) improves functional recovery when delivered during the acute phase after a spinal cord trauma.
In a previous study, based on a rat model of thoracic spinal cord compression, we demonstrated that cholecalciferol (Vitamin D3), delivered at the dose of 200 IU/kg/day, significantly improved ventilatory frequency and spasticity. In order to confirm the restorative potential of vitamin D, we performed a new study, using a rat model of left cervical hemisection (C2). From Day 1 or Day 7, animals received, during three months, a weekly oral bolus of either cholecalciferol, at the dose of 500 IU/kg/day, or vehicle, namely triglycerides. Rats were assessed every month, using a ladder test for sensori-locomotor ability and neuromuscular capacity. Three months after injury, H-reflex was recorded from left extensor digitorum muscle in order to measure the reflexivity of the sub-lesional region. Ventilatory frequency was also monitored during an electrically induced muscle fatigue of the hindlimb known to enhance muscle metaboreflex and increase respiratory rate. After recording the phrenic nerve activity, ipsilateral to the lesion, during spontaneous breathing, animals were artificially ventilated while paralyzed with a neuromuscular blocking agent and then the brainstem respiratory centres were provoked to maximal output by temporarily stopping the ventilator. Spinal cords were immunostained with an anti-neurofilament antibody to evaluate axon numbers. We show here that vitamin D-treated animals display i) an enhanced locomotor activity, ii) an improved breathing when hindlimb muscle was electrically stimulated to induce fatigue, iii) an H-reflex depression similar to control animals, iv) a phrenic nerve activity response to a temporary asphyxial stress and v) a non significant decreased number of axons in the proximal stump when compared with the Sham group. This new set of data confirms that vitamin D is a potent molecule that could be tested in clinical trials assessing functional recovery in para-/tetra-plegic patients, shortly after a trauma.


Effect of exercise level on ventilatory adaptation to respirator use.
The effect of exercise on the adaptation to an air-purifying respirator type load (dead space + inspiratory resistance) was studied in a group of 13 volunteers with a rapidly incremental exercise protocol. The difference between loaded and unloaded breathing at each exercise level was determined for each subject for a series of parameters describing the ventilatory work to overcome the respirator load pattern of breathing and metabolic work. Linear regression and t tests determined the average effect of the respirator load and the extent to which this effect was affected by the level of exercise. The inspiratory time and duty cycle were increased by the load, and exercise did not significantly affect the magnitude of this adaptation. High exercise did, however, increase the magnitude of the effect of the respiratory load on ventilatory work. These findings suggest that constraints to respiratory pattern adjustment, which may decrease respirator tolerance, occur at high exercise levels.


Single-stage definitive surgical treatment for portal biliopathy.
The term portal biliopathy (PB) is used to describe the biliary abnormalities associated with portal hypertension. Between 5% and 30% of patients with PB develop biliary obstruction. We report on a patient with extrahepatic biliary obstruction caused by PB that was successfully managed with an intrahepatic segment 3 bypass. The traditional surgical approach for a patient with extrahepatic biliary obstruction caused by PB would be a portosystemic shunt followed by a hepaticojejenostomy if the jaundice persited. An intrahepatic segment 3 bypass provides definitive treatment ensuring biliary decompression and stone removal in a single procedure in appropriately selected patients.


Vestibular testing abnormalities in individuals with motion sickness.
The goal of this study was to compare the results of vestibular testing in individuals with motion sickness to a group of control subjects. Studying motion sickness is difficult, because no animal model has been developed and symptoms rarely occur outside motion environments. Tests that can be performed in normal laboratory settings, which help to identify individuals with motion sickness, may be valuable in characterizing this disorder. Twenty active duty military individuals with well-documented motion sickness were tested. The test battery included sinusoidal rotational chair testing to calculate vestibulo-ocular reflex function, step-velocity testing to calculate vestibular time constants, and posturography testing to assess vestibulo-spinal reflex status. The results of this test battery were compared with a set of age- and sex-matched controls without motion sickness. Vestibular test abnormalities were demonstrated in individuals with motion sickness. Vestibulo-spinal reflex function on posturography was normal in the control group but abnormal in 70% of the individuals with motion sickness. In addition, 5% of the control group demonstrated a minimal shortening of the absolute time constant, whereas 60% of the individuals with motion sickness had abnormal absolute time constants. A significant percentage of individuals with motion sickness demonstrate abnormalities in their time constant or vestibulo-spinal reflex function. These abnormalities can be detected using standard, land-based vestibular tests. These preliminary results have implications in understanding the etiology of motion sickness and may provide outcome measures to be used in treating motion sickness.


The predictive significance of CD20 expression in B-cell lymphomas.
In our recent study, we determined the cut-off value of CD20 expression at the level of 25, 000 molecules of equivalent soluble fluorochrome (MESF) to be the predictor of response to rituximab containing treatment in patients with B-cell lymphomas. In 17.5% of patients, who had the level of CD20 expression below the cut-off value, the response to rituximab containing treatment was significantly worse than in the rest of the patients with the level of CD20 expression above the cut-off value. The proportion of patients with low CD20 expression who might not benefit from rituximab containing treatment was not necessarily representative. Therefore the aim of this study was to quantify the CD20 expression in a larger series of patients with B-cell lymphomas which might allow us to determine more reliably the proportion of patients with the CD20 expression below the cut-off. Cytological samples of 64 diffuse large B-cell lymphomas (DLBCL), 56 follicular lymphomas (FL), 31 chronic lymphocytic leukemias (CLL), 34 mantle cell lymphomas (MCL), 18 marginal zone lymphomas (MZL) and 15 B-cell lymphomas unclassified were analyzed for CD20 expression by quantitative four-color flow cytometric measurements using FACSCalibur flow cytometer (BD Biosciences). The range of CD20 expression in different B-cell lymphomas was very broad, varying from 2 737 to 115 623 MESF in CLL and 3 549 to 679 577 MESF in DLBCL. However, when we compared the CD20 expression in the groups of patients with DLBCL, FL, MCL, MZL, CLL and B-cell lymphomas unclassified, it was found to be significantly lower (p = 0.002) only in CLL but did not significantly differ in other lymphoma types (p = NS). Fifty-three out of 218 (24.3%) patients with B-cell lymphomas had the CD20 expression below the cut-off value. The CD20 expression in CLL is significantly lower than in most histological types of mature B-cell lymphomas in which it appears to be comparable. Approximately 25% of B-cell lymphoma patients have the CD20 expression below the cut-off value showing that the low CD20 expression might be more common than presumed from our previous study.


Concept-oriented indexing of video databases: toward semantic sensitive retrieval and browsing.
Digital video now plays an important role in medical education, health care, telemedicine and other medical applications. Several content-based video retrieval (CBVR) systems have been proposed in the past, but they still suffer from the following challenging problems: semantic gap, semantic video concept modeling, semantic video classification, and concept-oriented video database indexing and access. In this paper, we propose a novel framework to make some advances toward the final goal to solve these problems. Specifically, the framework includes: 1) a semantic-sensitive video content representation framework by using principal video shots to enhance the quality of features; 2) semantic video concept interpretation by using flexible mixture model to bridge the semantic gap; 3) a novel semantic video-classifier training framework by integrating feature selection, parameter estimation, and model selection seamlessly in a single algorithm; and 4) a concept-oriented video database organization technique through a certain domain-dependent concept hierarchy to enable semantic-sensitive video retrieval and browsing.


The association between lupus serology and disease outcomes: A systematic literature review to inform the treat-to-target approach in systemic lupus erythematosus.
Serological markers such as anti-double stranded (ds)DNA antibodies and complement fractions C3/C4, are integral components of disease activity assessment in patients with systemic lupus erythematosus (SLE). However, it remains uncertain whether treatment should aim at restoration of serological abnormalities. To analyze and critically appraise the literature on the prognostic impact of active lupus serology despite clinical disease quiescence. A systematic literature review was performed in PubMed and EMBASE using the PICOT(S) (population, index, comparator, outcome(s), timing, setting) system to identify studies evaluating the association of serum anti-dsDNA, C3 and C4 levels assessed at the time of clinical remission or during the disease course, against the risk for impending flares and organ damage. Risk of bias was determined by the Quality in Prognosis Studies and ROB2 tools for observational and randomized controlled studies, respectively. Fifty-three studies were eligible, the majority having moderate (70.6%) or high (11.8%) risk of bias and not adequately controlling for possible confounders. C3 hypocomplementemia during stable/inactive disease was associated with increased risk (2.0 to 3.8-fold) for subsequent flare in three out of seven relevant studies. Three out of four studies reported a significant effect of C4 hypocomplementemia on flare risk, including one study in lupus nephritis (likelihood ratio-positive 12.0). An increased incidence of flares (2.0 to 2.8-fold) was reported in 11 out of 16 studies assessing the prognostic effect of high anti-dsDNA, and similarly, the majority of studies yielded significant relationships with renal flares. Six studies examined the effect of combined (rather than individual) serological activity, confirming the increased risk (2.0 to 2.7-fold) for relapses. No consistent association was found with organ damage. Notwithstanding the heterogeneity and risk of bias, existing evidence indicates a modest association between abnormal serology and risk for flare in patients with stable/inactive SLE. These findings provide limited support for inclusion of serology in the treat-to-target approach but rationalize to further investigate their prognostic implications especially in lupus nephritis.


Serum Testosterone and Cognitive Function in Ageing Male: Updating the Evidence.
Testosterone (T) deficit, either in prepubertal or postpubertal form of hypogonadism, seems to play a key role in impairing cognitive function, including memory, attention, language and visuospatial abilities, especially in elderly men. Several studies have recently showed the association between low serum T levels and important cognitive dysfunctions in ageing male as well as in subjects suffering from Alzheimer's disease (AD), mild cognitive impairment (MCI) and even depression, suggesting that T could exert an active neuroprotective role. By searching PubMed and recent patents (ranging from 2010 to 2015), we identified several observational and intervention studies dealing with T and cognitive function in adult and ageing men. Findings were reviewed, thoroughly examined and, finally, summarized herein. Although a large number of studies have been carried out so far, conclusive evidence cannot be drawn, in particular, for cognitive disorders in males. Conversely, T supplementation has been suggested for depressive syndrome in young and ageing men. To date, no clinical data have been carried out on cognitive dysfunctions employing the quoted patents in men. Studies aiming to evaluate the role of serum T and its supplementation in adult and ageing men with T deficiency syndrome need to be encouraged, given that subjects affected by overt hypogonadism, either in prepubertal (i.e. Klinefelter syndrome) or postpubertal forms (chemical castration in subjects affected by prostate cancer), often complain of cognitive dysfunction, and seem to considerably benefit from T replacement therapy.


Mechanism-based discovery of novel substrates of haloalkane dehalogenases using in silico screening.
Substrate specificity is a key feature of enzymes determining their applicability in biomaterials and biotechnologies. Experimental testing of activities with novel substrates is a time-consuming and inefficient process, typically resulting in many failures. Here, we present an experimentally validated in silico method for the discovery of novel substrates of enzymes with a known reaction mechanism. The method was developed for a model system of biotechnologically relevant enzymes, haloalkane dehalogenases. On the basis of the parametrization of six different haloalkane dehalogenases with 30 halogenated substrates, mechanism-based geometric criteria for reactivity approximation were defined. These criteria were subsequently applied to the previously experimentally uncharacterized haloalkane dehalogenase DmmA. The enzyme was computationally screened against 41,366 compounds, yielding 548 structurally unique compounds as potential substrates. Eight out of 16 experimentally tested top-ranking compounds were active with DmmA, indicating a 50% success rate for the prediction of substrates. The remaining eight compounds were able to bind to the active site and inhibit enzymatic activity. These results confirmed good applicability of the method for prioritizing active compounds-true substrates and binders-for experimental testing. All validated substrates were large compounds often containing polyaromatic moieties, which have never before been considered as potential substrates for this enzyme family. Whereas four of these novel substrates were specific to DmmA, two substrates showed activity with three other tested haloalkane dehalogenases, i.e., DhaA, DbjA, and LinB. Additional validation of the developed screening strategy with the data set of over 200 known substrates of Candida antarctica lipase B confirmed its applicability for the identification of novel substrates of other biotechnologically relevant enzymes with an available tertiary structure and known reaction mechanism.


Human anterior thalamic nuclei are involved in emotion-attention interaction.
Patients treated with deep brain stimulation (DBS) provide an opportunity to study affective processes in humans with "lesion on demand" at key nodes in the limbic circuitries, such as at the anterior thalamic nuclei (ANT). ANT has been suggested to play a role in emotional control with its connection to the orbitofrontal cortex and the anterior cingulate cortex. However, direct evidence for its role in emotional function in human subjects is lacking. Reported side effects of ANT-DBS in the treatment of refractory epilepsy include depression related symptoms. In line with these mood-related clinical side effects, we have previously reported that stimulating the anterior thalamus increased emotional interference in a visual attention task as indicated by prolonged reaction times due to threat-related emotional distractors. We used event-related potentials to investigate potential attentional mechanism behind this behavioural observation. We hypothesized that ANT-DBS leads to greater attention capture by threat-related distractors. We tested this hypothesis using centro-parietal N2-P3 peak-to-peak amplitude as a measure of allocated attentional resources. Six epileptic patients treated with deep brain stimulation at ANT participated in the study. Electroencephalography was recorded while the patients performed a computer based Executive-Reaction Time test with threat-related emotional distractors. During the task, either ANT or a thalamic control location was stimulated, or the stimulation was turned off. Stimulation of ANT was associated with increased centro-parietal N2-P3 amplitude and increased reaction time in the context of threat-related emotional distractors. We conclude that high frequency electric stimulation of ANT leads to greater attentional capture by emotional stimuli. This is the first study to provide direct evidence from human subjects with on-line electric manipulation of ANT for its role in emotion-attention interaction.


Invasive mole--case report of massive uterine destruction.
Patient with malignant Gestational Trophoblastic Neoplasm (GTN) was treated by mean of MTX-FA, MAC, EMA-CO and EMA-EP. Changes in serum human chorionic gonadotropine (beta hCG) levels and changes in ultrasonographic findings were checked weekly. Finally transabdominal hysterectomy with ovaries conservation was done and polychemotherapy administrated after the operation until three consecutive serum chorionic gonadotropine values were negative. This is a case report of Invasive mole in 32 years old patient without possibility to preserve reproductive health. GTN developed two months after spontaneous abortion in 13th week gestation. No changes in uterine structure were found during the first ultrasonographic examination. Three months after abortion and one month after GTN confirmed, massive destruction of lateral uterine wall was detected during transvaginal Doppler ultrasound examination. Resistance index of 0,366 was significantly lower than normal, with hypervascularisation in affected tissue. Serum beta hCG confirmed poor effect of polychemotherapy treatment and decision for operative treatment was made. Hystological findings after the operation confirmed malignant GTN- invasive mole. Specific changes in ultrasonographic picture could have an impact in therapy making decision and could not be refereed without the most relevant parameter such is serum human chorionic gonadotropine.


Effects of magnetic stimulation over supplementary motor area on movement in Parkinson's disease.
Movement execution can be delayed by transcranial magnetic stimulation delivered over primary motor cortical areas, resulting in transient inhibition of cortico-motor output. Inhibition or disruption of higher-order motor planning and preparatory processes, such as are thought to occur in the supplementary motor area (SMA), would allow an examination of processes at other stages of the motor control system. In this study, six subjects with Parkinson's disease and six healthy control subjects performed a non-cued sequential finger movement task. At various times relative to movement, high-intensity single-pulse magnetic stimulation was delivered over the region of the SMA, with minimal current spread to primary motor areas. When magnetic stimulation was given at early stages during the movement for parkinsonian subjects, movement times were significantly increased, indicating disrupted movements. Supplementary motor area stimulation had no effect when delivered during later stages of the movement or immediately prior to movement onset, and had no apparent effect on control subjects at any time. It is therefore suggested that the SMA is important in motor planning and preparatory processes, since SMA stimulation has no effect on movements in their later stages when planning may be complete, but may disrupt movements in their early stages, when preparation for later stages may still be in progress. Further, possible instability of motor planning/preparation processes in Parkinson's disease is suggested, since these processes appeared more susceptible to disruption by magnetic stimulation in parkinsonian subjects than controls.


Predictive response biomarkers in rectal cancer neoadjuvant treatment.
Locally advanced rectal cancer (RC) treatment is a challenge, because RC has a high rate of local recurrence. To date preoperative chemoradiotherapy (pCRT) is widely accepted as standard protocol of care for middle-low RC, but complete tumour response rate ranges from 4 to 44% and 5-year local recurrence rate is 6%. Better understanding of molecular biology and carcinogenesis pathways could be used both for pre-neoplastic lesions and locally recurrence diagnosis, and for tumour response prediction to therapy. Circulating molecules, gene expression and protein signature are promising sources to biomarker discovery. Several studies have evaluated potential predictors of response and recently, cell-free Nucleic Acid levels have been associated to tumour response to neoadjuvant therapies. Alternative method is the serum or plasma proteome and peptidome analysis. It may be ideally suited for its minimal invasiveness and it can be repeated at multiple time points throughout the treatment in contrast to tissue-based methods which still remain the most reliable and specific approach. Many studies have analyzed preoperative rectal tissue prognostic factor, but data are controversial or not confirmed.


MM-1 facilitates degradation of c-Myc by recruiting proteasome and a novel ubiquitin E3 ligase.
We have reported that a novel c-Myc-binding protein, MM-1, repressed the E-box-dependent transcription activity of c-Myc by recruiting the HDAC1 complex via TIF1beta/KAP1, a transcriptional corepressor. We have also reported that a mutation of A157R in MM-1, which is often observed in patients with leukemia or lymphoma, abrogated all of the repressive activities of MM-1 toward c-Myc, indicating that MM-1 is a novel tumor suppressor. In this study, we found that MM-1 was bound to a component of proteasome and stimulated degradation of c-Myc in human cells. Knockdown of endogenous MM-1 in human HeLa cells by introduction of siRNA against MM-1 stabilized the endogenous c-Myc. To identify proteins that participate in c-Myc degradation by MM-1, in vivo and in vitro binding assays were carried out. The results showed that MM-1 directly bound to Rpt3, a subunit of 26S proteasome, and that c-Myc directly bound to Skp2, which recruited ElonginC, ElonginB and Cullin2, thereby forming a novel ubiquitin E3 ligase. Knockdown of endogenous Cullin2 stabilized the endogenous c-Myc. Thus, MM-1 is a factor that connects c-Myc to the ubiquitin E3 ligase and the proteasome.


Multi-Centre Micro-Costing of Roux-En-Y Gastric Bypass, Sleeve Gastrectomy and Adjustable Gastric Banding Procedures for the Treatment of Severe, Complex Obesity.
There is a growing interest in comparing the effectiveness and costs of alternative forms of bariatric surgery. We aimed to examine the per-patient, procedural costs of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) and adjustable gastric banding (AGB) in the United Kingdom. Multi-centre (two National Health Service; NHS and one private hospital) micro-costing, using a time-and-motion study. Prospective collection of surgery times, staff quantities, equipment, instruments and consumables for 12 patients (four RYGB, five SG, three AGB) from patients' first surgeon interaction on the day of surgery to departure from the theatre recovery area. Costs were attached to quantities and mean costs compared. Sensitivity and scenario analyses assessed the impact of varying surgery inputs and consideration of additional plausible factors respectively on total costs. Mean procedural costs were £5002 for RYGB, £4306 for SG and £2527 for AGB. Varying staff seniority or altering procedure times had small impacts on costs (± 4-6%). Reducing prices of consumables by 20% reduced costs by 10-13%. Accounting for differences in surgical technique by altering the number of staple reloads used impacted costs by ± 7-10%. Adjusted total costs from scenario analyses were similar to NHS tariffs for RYGB and SG (difference of £51 and -£119 respectively) but were much lower for AGB (difference of £1982). These detailed costs will allow for more precise reimbursement of bariatric surgery and support comprehensive assessments of cost-effectiveness. Additional work to investigate costs of post-surgical care, re-operations and life-long support received by patients following surgery is required.


Recent advances in understanding and managing chronic constipation.
Constipation, a condition characterized by heterogeneous symptoms, is common in Western society. It is associated with reduced physical health, mental health, and social functioning. Because constipation is rarely due to a life-threatening disease (for example, colon cancer), current guidelines recommend empiric therapy. Limited surveys suggest that fewer than half of treated individuals are satisfied with treatment, perhaps because the efficacy of drugs is limited, they are associated with undesirable side effects, or they may not target the underlying pathophysiology. For example, although a substantial proportion of constipated patients have a defecatory disorder that is more appropriately treated with pelvic floor biofeedback therapy than with laxatives, virtually no pharmacological trials formally assessed for anorectal dysfunction. Recent advances in investigational tools have improved our understanding of the physiology and pathophysiology of colonic and defecatory functions. In particular, colonic and anorectal high-resolution manometry are now available. High-resolution anorectal manometry, which is increasingly used in clinical practice, at least in the United States, provides a refined assessment of anorectal pressures and may uncover structural abnormalities. Advances in our understanding of colonic molecular physiology have led to the development of new therapeutic agents (such as secretagogues, pro-kinetics, inhibitors of bile acid transporters and ion exchangers). However, because clinical trials compare these newer agents with placebo, their efficacy relative to traditional laxatives is unknown. This article reviews these physiologic, diagnostic, and therapeutic advances and focuses particularly on newer therapeutic agents.


Neutralizing tumor necrosis factor activity leads to remission in patients with refractory noninfectious posterior uveitis.
To evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibition with the p55 TNF receptor fusion protein (TNFr-Ig) for severe sight-threatening noninfectious posterior segment intraocular inflammation. Seventeen patients with refractory noninfectious posterior segment intraocular inflammation received TNFr-Ig by intravenous infusion in this nonrandomized, open-label, pilot study. The primary outcome measure was logMAR visual acuity. Secondary outcome measures were binocular indirect ophthalmoscopy score, cystoid macular edema, adverse effects, and vision-related (visual core module 1) and health-related (36-Item Short-Form Health Survey) quality of life. Within 1 month of TNFr-Ig therapy, 9 patients (53%) achieved at least a 2-line improvement in visual acuity, 8 (57%) of 14 patients with vitreous haze before treatment achieved an improvement in binocular indirect ophthalmoscopy score to 0, and macular edema resolved in 5 (56%) of 9 affected patients. Twelve (71%) of the patients achieved complete cessation of intraocular inflammation following TNFr-Ig therapy. A reduction in concomitant immunosuppression was possible for 11 patients (65%) following TNFr-Ig therapy. However, all but 1 patient required continuing adjuvant therapy during the response to TNFr-Ig, which had a median duration of 3 months. Adverse effects included mild infusion reactions in 3 patients and transient lymphocytopenia in 2 patients. Therapy with TNFr-Ig was safe and effective for treating patients with sight-threatening noninfectious posterior segment intraocular inflammation resistant to conventional immunotherapy, but adjuvant immunosuppression and repeat infusions would be required to maintain long-term remission.


Prioritizing Patient Safety Efforts in Office Practice Settings.
Outpatient care settings face unique risks of adverse events and medico-legal liability, often worsened by inconsistent processes and fragmented care. Health systems are increasingly providing integrated care that includes outpatient care, but models of how to systematically target medico-legal risk in office practices are largely absent. Innovative and scalable efforts are needed to guide large health systems in their approach to outpatient safety. A malpractice consortium consisting of five large health care delivery systems identified that its ambulatory care cases (including office practices, outpatient hospital settings, and emergency departments) account for 30% to 35% of annual medical malpractice costs, and missed or delayed diagnoses account for approximately 50% of office practice liability risk. To further understand risks and opportunities in office-based practices, a team of patient safety and loss prevention professionals conducted site visits to seven outpatient-affiliated sites of the five health systems from January to March 2016 and interviewed several key informant members of physician, nursing, and administrative leadership. We identified eight common patient safety risk domains based on analysis of eight sets of group interviews. Risk domains were then prioritized by members of the consortium leadership using scoring criteria that we developed based on existing risk assessment and prioritization approaches. The method helped identify communication and follow-up of diagnostic test results in the outpatient setting as the single most important risk area to target improvement efforts. A targeted approach to identify a single high-risk area led to development of dedicated teams to conduct local patient safety improvement projects at the affiliated health systems and for sharing lessons learned. Similar efforts elsewhere could lead to safety improvements in office practices at other large health systems.


Mapping the EORTC QLQ-C30 and QLQ-H&N35 to the EQ-5D for head and neck cancer: Can disease-specific utilities be obtained?
Innovations in head and neck cancer (HNC) treatment are often subject to economic evaluation prior to their reimbursement and subsequent access for patients. Mapping functions facilitate economic evaluation of new treatments when the required utility data is absent, but quality of life data is available. The objective of this study is to develop a mapping function translating the EORTC QLQ-C30 to EQ-5D-derived utilities for HNC through regression modeling, and to explore the added value of disease-specific EORTC QLQ-H&N35 scales to the model. Data was obtained on patients with primary HNC treated with curative intent derived from two hospitals. Model development was conducted in two phases: 1. Predictor selection based on theory- and data-driven methods, resulting in three sets of potential predictors from the quality of life questionnaires; 2. Selection of the best out of four methods: ordinary-least squares, mixed-effects linear, Cox and beta regression, using the first set of predictors from EORTC QLQ-C30 scales with most correspondence to EQ-5D dimensions. Using a stepwise approach, we assessed added values of predictors in the other two sets. Model fit was assessed using Akaike and Bayesian Information Criterion (AIC and BIC) and model performance was evaluated by MAE, RMSE and limits of agreement (LOA). The beta regression model showed best model fit, with global health status, physical-, role- and emotional functioning and pain scales as predictors. Adding HNC-specific scales did not improve the model. Model performance was reasonable; R2 = 0.39, MAE = 0.0949, RMSE = 0.1209, 95% LOA of -0.243 to 0.231 (bias -0.01), with an error correlation of 0.32. The estimated shrinkage factor was 0.90. Selected scales from the EORTC QLQ-C30 can be used to estimate utilities for HNC using beta regression. Including EORTC QLQ-H&N35 scales does not improve the mapping function. The mapping model may serve as a tool to enable cost-effectiveness analyses of innovative HNC treatments, for example for reimbursement issues. Further research should assess the robustness and generalizability of the function by validating the model in an external cohort of HNC patients.


Right hemisphere recruitment during language processing in frontotemporal lobar degeneration and Alzheimer's disease.
Right hemisphere recruitment of areas homotopical to affected left-sided language areas has classically been described in aphasia following stroke or brain tumors. It may also be a clinically significant mechanism in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). In a pooled analysis of previous functional magnetic resonance imaging studies of a modified version of the Pyramids and Palm Trees test, we probed the language network in 19 patients with primary progressive aphasia (nine semantic (SV) and ten agrammatic variant; neuropathologically confirmed FTLD in three cases to date), 15 patients with AD (14 clinically probable and one neuropathologically definite AD to date), and 37 healthy controls. The upper and lower bank of the left posterior superior temporal sulcus (STS) was affected in AD and the left anterior temporal pole (ATP) in primary progressive aphasia (PPA; mainly driven by SV). In the right hemisphere, the posterior STS showed an activity increase in both patient groups compared with controls. In AD, this activity increase correlated positively with naming accuracy. Both in AD and in PPA, the connection strength between right STS and right ATP was decreased compared with controls and this correlated with naming and comprehension scores, respectively. Only in PPA did the right anterior temporal pole show an activity increase, which correlated negatively with comprehension. Right-hemispheric recruitment and disconnections within the right temporal lobe may affect the degree of aphasia in cortical neurodegenerative disease.


Coupling interval variability differentiates ventricular ectopic complexes arising in the aortic sinus of valsalva and great cardiac vein from other sources: mechanistic and arrhythmic risk implications.
The objective of this study was to determine whether premature ventricular contractions (PVCs) arising from the aortic sinuses of Valsalva (SOV) and great cardiac vein (GCV) have coupling interval (CI) characteristics that differentiate them from other ectopic foci. PVCs occur at relatively fixed CI from the preceding normal QRS complex in most patients. However, we observed patients with PVCs originating in unusual areas (SOV and GCV) in whom the PVC CI was highly variable. We hypothesized that PVCs from these areas occur seemingly randomly because of the lack of electrotonic effects of the surrounding myocardium. Seventy-three consecutive patients referred for PVC ablation were assessed. Twelve consecutive PVC CIs were recorded. The ΔCI (maximum - minimum CI) was measured. We studied 73 patients (age 50 ± 16 years, 47% male). The PVC origin was right ventricular (RV) in 29 (40%), left ventricular (LV) in 17 (23%), SOV in 21 (29%), and GCV in 6 (8%). There was a significant difference between the mean ΔCI of RV/LV PVCs compared with SOV/GCV PVCs (33 ± 15 ms vs. 116 ± 52 ms, p < 0.0001). A ΔCI of >60 ms demonstrated a sensitivity of 89%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 94%. Cardiac events were more common in the SOV/GCV group versus the RV/LV group (7 of 27 [26%] vs. 2 of 46 [4%], p < 0.02). ΔCI is more pronounced in PVCs originating from the SOV or GCV. A ΔCI of 60 ms helps discriminate the origin of PVCs before diagnostic electrophysiological study and may be associated with increased frequency of cardiac events.


Alternative splicing of the human IgA Fc receptor CD89 in neutrophils and eosinophils.
Receptors for the Fc portion of IgA (Fc alpha R) trigger important immunological elimination processes against IgA-coated targets. Investigation of human Fc alpha R (CD89) transcripts in neutrophils, eosinophils and a monocyte-like cell line, THP-1, with the use of reverse transcriptase PCR, Northern blotting and RNase protection analysis, has provided evidence in these cell types for at least two distinct transcripts generated by alternative splicing. The cDNAs derived from the two major transcripts of both neutrophils and eosinophils have been cloned and sequenced. For both cell types, the larger clone represents the previously described full-length receptor, whereas the second, shorter, splice variant lacks the entire second, membrane-proximal, Ig-like domain. Stable CHO-K1 transfectants have been obtained for both full-length and truncated variant neutrophil receptors. Whereas the full-length receptor is recognized by a panel of five anti-Fc alpha R monoclonal antibodies (mAbs), the shorter variant is bound weakly by only two of the antibodies, suggesting that the epitopes recognized by the majority of the mAbs lie at least in part in the second Ig-like domain of Fc alpha R. Both full-length and splice variant forms of the receptor bind secretory IgA, but the weak binding to serum IgA seen with the full-length receptor is not evident with the shorter variant. Alternative splicing might therefore serve as a means of diversifying Fc alpha R structure and function.


Organizational Factors Affecting the Likelihood of Cancer Screening Among VA Patients.
Preventive service delivery, including cancer screenings, continues to pose a challenge to quality improvement efforts. Although many studies have focused on person-level characteristics associated with screening, less is known about organizational influences on cancer screening. This study aims to understand the association between organizational factors and adherence to cancer screenings. This study employed a cross-sectional design using organizational-level, patient-level, and area-level data. Dependent variables included breast, cervical, and colorectal cancer screening. Organizational factors describing resource sufficiency were constructed using factor analyses from a survey of 250 Veterans Affairs primary care directors. We conducted random-effects logistic regression analyses, modeling cancer screening as a function of organizational factors, controlling for patient-level and area-level factors. Overall, 87% of the patients received mammograms, 92% received cervical and 78% had colorectal screening. Quality improvement orientation increased the odds of cervical [odds ratio (OR): 1.27; 95% confidence interval (CI), 1.03-1.57] and colorectal cancer screening (OR: 1.10; 95% CI, 1.00-1.20). Authority in determining primary care components increased the odds of mammography screening (OR: 1.23; 95% CI, 1.03-1.51). Sufficiency in clinical staffing increased the odds of mammography and cervical cancer screenings. Several patient-level factors, serving as control variables, were associated with achievement of screenings. Resource sufficiency led to increased odds of screening possibly because they promote excellence in patient care by conveying organizational goals and facilitate goal achievement with resources. Complementary to patient-level factors, our findings identified organizational processes associated with better performance, which offer concrete strategies in which facilities can evaluate their capabilities to implement best practices to foster and sustain a culture of quality care.


[The role of angiogenetic factors in the pathogenesis and the progression of cardiac valve disease].
Recently, the aging of population and the changing dietary habit to western-style have led to increase in atherosclerotic diseases, such as myocardial infarction and cerebral infarction, in our country. Aortic valve diseases, whose mechanism is similar to atherosclerosis, are also increasing. The medication proved to be effective does not exist, and surgical management is major in treatment of these diseases. Although development of safer medication is expected, little is known about their molecular mechanism of the pathogenesis and the progression. The balance of angiogenetic and angioinhibitory factors is important for normal developing and homeostasis in many organs. The tissue of cardiac valves is mostly avascular like cartilages and tendons, although the heart is the organ having abundance of vessels. We focused on angiogenetitic and angioinhibitory factors expressing in the cartilages and tendons, and found Chondromodulin- I, Tenomodulin and Periostin have crucial roles in degeneration of the cardiac valve by controlling angiogenesis and production of Matrix metalloproteinase protein (MMP) . Now, we review the mechanism of cardiac valve disease focusing on the role of angiogenetic factors.


Protein-Based Classifier to Predict Conversion from Clinically Isolated Syndrome to Multiple Sclerosis.
Multiple sclerosis is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. In most patients, the disease initiates with an episode of neurological disturbance referred to as clinically isolated syndrome, but not all patients with this syndrome develop multiple sclerosis over time, and currently, there is no clinical test that can conclusively establish whether a patient with a clinically isolated syndrome will eventually develop clinically defined multiple sclerosis. Here, we took advantage of the capabilities of targeted mass spectrometry to establish a diagnostic molecular classifier with high sensitivity and specificity able to differentiate between clinically isolated syndrome patients with a high and a low risk of developing multiple sclerosis. Based on the combination of abundances of proteins chitinase 3-like 1 and ala-β-his-dipeptidase in cerebrospinal fluid, we built a statistical model able to assign to each patient a precise probability of conversion to clinically defined multiple sclerosis. Our results are of special relevance for patients affected by multiple sclerosis as early treatment can prevent brain damage and slow down the disease progression.


Rate and timing of spontaneous resolution in a vitreomacular traction group: should the role of watchful waiting be re-evaluated as an alternative to ocriplasmin therapy?
The incidence of spontaneous resolution of vitreomacular traction (VMT) is low in studies of Ocriplasmin that have had a limited follow-up. Previous studies did not look for morphological parameters in the natural history using spectral-domain ocular coherence tomography (SD-OCT) imaging. The purpose of this study was to investigate how often and when spontaneous VMT resolution occurs in candidates for Ocriplasmin therapy. The study is a retrospective chart review of patients who would have high chances of a benefit by an Ocriplasmin injection, without epiretinal membrane or vitreomacular adhesion of 1500 µm or more on SD-OCT. Main outcome measures were the frequency of complete VMT resolution and the best corrected visual acuity seen in the natural history. Out of the 46 patients that were included after screening 889 SD-OCT images, 20 were found to exhibit spontaneous resolution during the follow-up period (median: 594 days, 95% CI 567 to 719 days), the majority after 6-12 months of observation (95% CI 266 to 617 days). The group with spontaneous VMT resolution and a mean improvement of one line in best corrected visual acuity included a few patients losing vision by macular hole formation. In the absence of resolution, patients lost on average one early treatment diabetic retinopathy study letter per year. Younger age was found to increase the chance of spontaneous resolution. A shorter follow-up might underestimate the incidence of spontaneous VMT resolution as the functional outcome of watchful waiting. The likelihood of resolution does not seem to decrease after 12 months.


The effect of insulin suppression on postprandial nutrient metabolism: studies with infusion of somatostatin and insulin.
Utilization of fat, carbohydrate and protein before and after feeding was studied in six healthy subjects using simultaneous respiratory gas exchange measurement and [1-13C] leucine infusion. The role of insulin was investigated by repeating a control study with the addition of an infusion of somatostatin, a hormone which can suppress insulin release. Where near-complete insulin suppression was effected, subjects were studied on a third occasion with the further addition of exogenous insulin infusion. The normal switch on feeding from fat to carbohydrate as principal energy source was reproduced at insulin levels of only 17%-33% of control values, which were inadequate to prevent hyperglycaemia. At fed levels below 10%, a fat-predominant pattern persisted unless insulin was infused. Protein degradation was reduced and synthesis unaffected by feeding, regardless of insulin concentration. Leucine oxidation was dependent on its plasma concentration in the presence of circulating insulin. Thus insulin appears to be necessary for the normal switch to carbohydrate oxidation on feeding but not for postprandial changes in protein metabolism.


The intestinal microbiome is a co-determinant of the postprandial plasma glucose response.
Elevated postprandial plasma glucose is a risk factor for development of type 2 diabetes and cardiovascular disease. We hypothesized that the inter-individual postprandial plasma glucose response varies partly depending on the intestinal microbiome composition and function. We analyzed data from Danish adults (n = 106), who were self-reported healthy and attended the baseline visit of two previously reported randomized controlled cross-over trials within the Gut, Grain and Greens project. Plasma glucose concentrations at five time points were measured before and during three hours after a standardized breakfast. Based on these data, we devised machine learning algorithms integrating bio-clinical, as well as shotgun-sequencing-derived taxa and functional potentials of the intestinal microbiome to predict individual postprandial glucose excursions. In this post hoc study, we found microbial and clinical features, which predicted up to 48% of the inter-individual variance of postprandial plasma glucose responses (Pearson correlation coefficient of measured vs. predicted values, R = 0.69, 95% CI: 0.45 to 0.84, p<0.001). The features were age, fasting serum triglycerides, systolic blood pressure, BMI, fasting total serum cholesterol, abundance of Bifidobacterium genus, richness of metagenomics species and abundance of a metagenomic species annotated to Clostridiales at order level. A model based only on microbial features predicted up to 14% of the variance in postprandial plasma glucose excursions (R = 0.37, 95% CI: 0.02 to 0.64, p = 0.04). Adding fasting glycaemic measures to the model including microbial and bio-clinical features increased the predictive power to R = 0.78 (95% CI: 0.59 to 0.89, p<0.001), explaining more than 60% of the inter-individual variance of postprandial plasma glucose concentrations. The outcome of the study points to a potential role of the taxa and functional potentials of the intestinal microbiome. If validated in larger studies our findings may be included in future algorithms attempting to develop personalized nutrition, especially for prediction of individual blood glucose excursions in dys-glycaemic individuals.


Regional vascular effects of MPC-1304, a novel dihydropyridine derivative, in conscious normotensive and spontaneously hypertensive rats.
The purpose of this study was to compare the regional vascular effect of a novel dihydropyridine derivative, MPC-1304 [(+/-)- methyl-2-oxopropyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3, 5-pyridinedicarboxylate], with that of nifedipine and manidipine in conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The radioactive microsphere technique was used to measure systemic and regional hemodynamic parameters before and 1 hr after p.o. administration of drugs. In SHR, MPC-1304 at a dose of 1 mg/kg reduced the mean blood pressure and systemic vascular resistance and increased cardiac output, as did nifedipine (10 mg/kg) and manidipine (3 mg/kg). MPC-1304, as well as nifedipine, significantly increased the blood flow in pulmonary, gastric, small intestinal and skeletal muscular beds and reduced their vascular resistance. Manidipine increased regional blood flow only in small intestinal and skeletal muscular beds. Only MPC-1304 increased the renal blood flow. In WKY, MPC-1304 and nifedipine reduced the mean blood pressure and systemic vascular resistance to lesser degrees than in SHR. Both drugs significantly increased coronary and skeletal muscular blood flow. MPC-1304 significantly reduced the renal blood flow without altering renal vascular resistance, in striking contrast to its renal effect in SHR. These findings suggest that MPC-1304 possesses a genetic hypertension-dependent renal vasodilating action, unlike nifedipine and manidipine. One possible mechanism for this difference in the effect on renal circulation between SHR and WKY may involve the potent antagonizing effects of MPC-1304 on alpha-2 adrenoceptor-mediated vasoconstriction.


Regional effects of streptozotocin-induced diabetes on shortening and calcium transport in epicardial and endocardial myocytes from rat left ventricle.
In the heart, the left ventricle pumps blood at higher pressure than the right ventricle. Within the left ventricle, the electromechanical properties of ventricular cardiac myocytes vary transmurally and this may be related to the gradients of stress and strain experienced in vivo across the ventricular wall. Diabetes is also associated with alterations in hemodynamic function. The aim of this study was to investigate shortening and Ca2+ transport in epicardial (EPI) and endocardial (ENDO) left ventricular myocytes in the streptozotocin (STZ)-induced diabetic rat. Shortening, intracellular Ca2+ and L-type Ca2+ current (ICa,L) were measured by video detection, fura-2 microfluorimetry, and whole-cell patch clamp techniques, respectively. Time to peak (TPK) shortening was prolonged to similar extents in ENDO and EPI myocytes from STZ-treated rats compared to ENDO and EPI myocytes from controls. Time to half (THALF) relaxation of shortening was prolonged in ENDO myocytes from STZ-treated rats compared to ENDO controls. TPK Ca2+ transient was prolonged in ENDO myocytes from STZ-treated rats compared to ENDO controls. THALF decay of the Ca2+ transient was prolonged in ENDO myocytes from STZ-treated rats compared to ENDO controls. Sarcoplasmic reticulum (SR) fractional release of Ca2+ was reduced in EPI myocytes from STZ-treated rats compared to EPI controls. ICa,L activation, inactivation, and recovery from inactivation were not significantly altered in EPI and ENDO myocytes from STZ-treated rats or controls. Regional differences in Ca2+ transport may partly underlie differences in ventricular myocyte shortening across the wall of the healthy and the STZ-treated rat left ventricle.


Dietary strategy to manipulate ad libitum macronutrient intake, and glycaemic index, across eight European countries in the Diogenes Study.
The aim of this study was to describe the development and implementation of a multifaceted, low-fat, weight-loss strategy for a Pan-European randomized controlled dietary intervention study, Diogenes. There were 891 families with at least one overweight/obese parent who underwent screening. Eligible, overweight/obese adults followed an 8-week weight-loss phase with a fixed low-energy diet (800 kcal). On attaining weight loss of > or = 8%, families were randomized to a 6- or 12-month low-fat (25-30%E) diet either based on national dietary guidelines or one of four interventions: low protein (LP)/low glycaemic index (LGI), LP/high GI (HGI), high protein (HP)/LGI and HP/HGI. The impact of each diet in preventing weight (re)gain was tested. A points-based system was used to manipulate dietary protein and carbohydrate. Manipulating carbohydrate composition involved substituting foods with a relatively high or low GI. A questionnaire was designed and completed by study investigators, providing feedback on the dietary intervention methods used to inform future interventions. The points system allowed macronutrient manipulations without compromising dietary flexibility or enforcing energy restrictions. Reported centre/participant differences in the ease of implementing the intervention may reflect dietary diversity and personal preferences for specific weight-management strategies. The points system provides a useful starting point for designing improved experimental paradigms for the manipulation of dietary intake in future trials.


Safe application of a restrictive transfusion protocol in moderate-risk patients undergoing cardiac operations.
Perioperative red blood cell transfusion is associated with adverse outcomes after cardiac operations. Although restrictive transfusion protocols have been developed, their safety and efficacy are not well demonstrated, and considerable variation in transfusion practice persists. We report our experience with a restrictive transfusion protocol. We analyzed the outcomes in 409 patients undergoing cardiac operations enrolled in a trial conducted at 30 centers worldwide. Blood products were administered on the basis of a transfusion algorithm applied across all centers, with a restrictive transfusion trigger of hemoglobin less than or equal to 6 g/dL. Transfusion was acceptable but not mandatory for hemoglobin 6 to 8 g/dL. For hemoglobin 8 to 10 g/dL, transfusion was acceptable only with evidence for end-organ ischemia. The patient population was moderately complex, with 20.5% having combined procedures and 29.6% having nonelective operations. The mean EuroSCORE for the population was 4.3, which predicted a substantial incidence of morbidity and mortality. Actual outcomes were excellent, with observed mortality of 0.49% and rates of cerebrovascular accident, myocardial infarction, and acute renal failure 1.2%, 6.1%, and 0.98%, respectively. The frequency of red blood cell transfusion was 33.7%, which varied significantly by center. Most transfusions (71.9%) were administered for hemoglobin 6 to 8 g/dL; 21.4% were administered for hemoglobin 8 to 10 g/dL with evidence for end-organ ischemia; 65.0% of patients avoided allogeneic transfusion altogether. A restrictive transfusion protocol can be safely applied in the care of moderate-risk patients undergoing cardiac operations. This strategy has significant potential to reduce transfusion and resource utilization in these patients, standardize transfusion practices across institutions, and increase the safety of cardiac operations.


Specific interaction of Egr1 and c/EBPbeta leads to the transcriptional activation of the human low density lipoprotein receptor gene.
The sterol-independent regulatory element (SIRE) of the LDL receptor (LDLR) promoter mediates oncostatin M (OM)-induced transcription of the LDLR gene through a cholesterol-independent pathway. Our prior studies have detected specific associations of the zinc finger transcription factor Egr1 with the SIRE sequence in OM-stimulated HepG2 cells. Because the SIRE motif is composed of a c/EBP binding site and a cAMP response element, both of which are quite divergent from the classical GC-rich Egr1 recognition sequences, we hypothesized that Egr1 may regulate LDLR transcription through interacting with members of the c/EBP and CREB families. Here, we show that treating HepG2 cells with OM specifically leads to prominent increases of the levels of c/EBPbeta and Egr1 bound to the LDLR promoter in vivo. In vitro, the binding of Egr1 to the SIRE sequence is weak, but is strikingly enhanced in the presence of HepG2 nuclear extract. Mammalian two-hybrid assays demonstrate that the N-terminal transactivation domain of Egr1 specifically interacts with c/EBPbeta but not with c/EBPalpha or CREB. The OM treatment further enhances this interaction, resulting in a large increase in the Egr1 transactivating activity. The direct protein to protein contact between Egr1 and c/EBPbeta is also demonstrated by co-immunoprecipitation experiments. Furthermore, we show that a mutation of the phosphorylation motif of c/EBPbeta diminished the OM-stimulated interaction of Egr1 and c/EBPbeta. Taken together, we provide strong evidence that Egr1 regulates LDLR transcription via a novel mechanism of protein-protein interaction with c/EBPbeta.


Trouble at rest: how correlation patterns and group differences become distorted after global signal regression.
Resting-state functional magnetic resonance imaging (RS-FMRI) holds the promise of revealing brain functional connectivity without requiring specific tasks targeting particular brain systems. RS-FMRI is being used to find differences between populations even when a specific candidate target for traditional inferences is lacking. However, the problem with RS-FMRI is a lacking definition of what constitutes noise and signal. RS-FMRI is easy to acquire but is not easy to analyze or draw inferences from. In this commentary we discuss a problem that is still treated lightly despite its significant impact on RS-FMRI inferences; global signal regression (GSReg), the practice of projecting out signal averaged over the entire brain, can change resting-state correlations in ways that dramatically alter correlation patterns and hence conclusions about brain functional connectedness. Although Murphy et al. in 2009 demonstrated that GSReg negatively biases correlations, the approach remains in wide use. We revisit this issue to argue the problem that GSReg is more than negative bias or the interpretability of negative correlations. Its usage can fundamentally alter interregional correlations within a group, or their differences between groups. We used an illustrative model to clearly convey our objections and derived equations formalizing our conclusions. We hope this creates a clear context in which counterarguments can be made. We conclude that GSReg should not be used when studying RS-FMRI because GSReg biases correlations differently in different regions depending on the underlying true interregional correlation structure. GSReg can alter local and long-range correlations, potentially spreading underlying group differences to regions that may never have had any. Conclusions also apply to substitutions of GSReg for denoising with decompositions of signals aggregated over the network's regions to the extent they cannot separate signals of interest from noise. We touch on the need for careful accounting of nuisance parameters when making group comparisons of correlation maps.


Micrometer-sized dihydrogenphosphate-intercalated layered double hydroxides: synthesis, selective infrared absorption properties, and applications as agricultural films.
High-performance heat-retention agents for multifunctional green agricultural films are today largely suitable to increase the production yield as well as to save energy. Here, an adapted ammonia releasing hydrothermal method was used to produce a series of micrometer-sized carbonate-layered double hydroxide (CO3-LDH) precursors of sizes ranging from 1.32 μm to 8.64 μm by simply adjusting the feeding Mg2+ concentration from 0.80 mol L-1 to 0.20 mol L-1. From these pristine LDH materials, μm-sized dihydrogenphosphate-intercalated LDHs (H2PO4-LDHs) were prepared by an anion-exchange method. The structure, the platelet size, and the associated selective IR absorption properties of the H2PO4-LDH and the derivative H2PO4-LDH/EVA composite as well as the related visible transmittance and the photostability of the H2PO4-LDH/EVA film were investigated. The results show that the selective IR absorption in the wavelength range of 7-14 μm enabling the heat retention of the H2PO4-LDHs and H2PO4-LDH/EVA composites depends on the corresponding number-averaged particle size of H2PO4-LDH in the range of 2.01 μm to 8.80 μm. Compared with EVA, the H2PO4-LDH/EVA composites demonstrate a significant improvement of selective IR absorption, while maintaining acceptable visible transmittance, and similar photostability. An optimized particle size of H2PO4-LDH of ca. 5.85 μm leads to 60% selective IR absorption and 64% selective IR absorption when dispersed in EVA, while the polymer free of filler exhibits less than 50% absorption in the 7-14 μm IR domain.