[Stabilization of protein by saccharose by spin marker method data].
HSA was covalently modified with maleimide spin-label. The model of label chemical exchange between inner (A) and outer (B) layers of water-protein matrix was applied. From van't-Hoff plots effective thermodynamic parameters of activation were calculated, the tendency of their alteration being found as sucrose concentration. It was revealed that sucrose induces the appearance of negative disjointing pressure. This leads to the forcing out of water layers from hydrophobic cavities in the interior of protein loosening structural flexibility and fluctuational mobility of the water-protein matrix.


Exploring the Quality Paradigms in Integrated Care: The Need for Emergence and Reflection.
There are four quality paradigms, of which the Empirical and Reference paradigm fit best in stable circumstances, and the Reflective and Emergence paradigms, which fit best in unstable circumstances. This study aims to explore the use of the four quality paradigms in integrated care, and to shed light on the different paradigmatic commitments and different perspectives on quality. Peer-reviewed articles from the International Journal of Integrated care published between January 2015 and December 2019 were included in this study. For each article was determined in which paradigm it belonged. Additionally, the role of the patient and domain of impact in research, policy or practice in relationship to the paradigms were investigated. In total, 255 articles were assessed based on the four quality paradigms. 55 (21.6%) of the articles were placed in the Empirical paradigm, 147 (57.6%) in the Reference paradigm and 45 (17.6%) in the Reflective paradigm. The Emergence paradigm occurred the least (n = 8, 3.1%). Of all reviewed studies, 80% were placed in the Empirical and Reference paradigm. This raises the question if the used research approaches are consistent with the complexity and contexts in the field of integrated care and support a personalised care approach. More awareness of all four paradigms and reflection on the used epistemologies is needed.


Awareness and Knowledge of Emergent Ophthalmic Disease Among Patients in an Internal Medicine Clinic.
Emergent ophthalmic disease can lead to permanent visual impairment or blindness if medical attention is delayed. Awareness and knowledge of emergent ophthalmic disease may be important for early medical presentation and maximization of visual prognosis in some cases. To assess public awareness and knowledge of 4 emergent ophthalmic diseases. This cross-sectional study was conducted from June 1 to July 30, 2015, in the waiting rooms of the outpatient internal medicine resident clinic at Mount Sinai Hospital. A written survey was administered to evaluate awareness and knowledge of retinal detachment, acute angle-closure glaucoma, giant cell arteritis, and central retinal artery occlusion. Awareness of each disease was assessed by whether participants knew what the diseases were (yes or no). Knowledge was evaluated by responses to 3 questions for each disease, including 1 question about basic pathophysiologic features, 1 question about basic symptoms, and 1 question about basic treatment options. All English-speaking patients who were physically and cognitively able to fill out the survey without assistance were considered eligible and offered the opportunity to participate during times of survey distribution; 237 completed the survey. Demographic information, including age, sex, race, income, and educational level, was collected. Data were assessed from August 1 to 7, 2015. Awareness of each ophthalmic disease was determined by the proportion of respondents who answered yes, and knowledge was determined by the proportion of aware respondents who answered the knowledge questions correctly. Two hundred thirty-seven patients (of 227 who gave complete demographic information, 76 men [33.5%], 151 women [66.5%], and mean [SD] age, 51.3 [16.8] years) completed the survey. Awareness of each of the diseases studied was low; 61 of 220 respondents (27.7%; 95% CI, 21.8%-33.6%) were aware of retinal detachment; 32 of 219 respondents (14.6%; 95% CI, 9.9%-19.3%), acute angle-closure glaucoma; 11 of 216 respondents (5.1%; 95% CI, 2.2%-8.0%), giant cell arteritis; and 10 of 218 respondents (4.6%; 95% CI, 1.8%-7.4%), central retinal artery occlusion. Respondents who were aware and knowledgeable ranged from 29 of 199 (14.6%) for the pathophysiologic features of retinal detachment, 1 of 208 (0.5%) for the symptoms and 2 of 203 (1.0%) for treatment of giant cell arteritis, and 1 of 193 (0.5%) for the pathophysiologic features of central retinal artery occlusion. Levels of awareness and knowledge of emergent ophthalmic diseases are low. These results indicate a need to educate the public about these acutely vision-threatening entities to ensure early medical presentation, to achieve the best possible visual prognosis, and to preserve quality of life.


First-time parents' expectations about the division of childcare and play.
The current study examines violated expectations regarding the division of childcare and play in first-time parents during the initial transition to parenthood. The study's goal was threefold: (a) to compare prenatal expectations with the reported postpartum division of childcare and play, (b) to compare the influence of the reported division versus violated expectations on postpartum relationship satisfaction and depression, and (c) to examine the role of persistent violations of expectations on these outcomes. Couples expecting their first child were interviewed during the third trimester of pregnancy and at 1 and 4 months postpartum. Results indicated both mothers and fathers have unrealistic expectations during pregnancy; interestingly, the direction violation was opposite but converging for mothers and fathers. As found in prior research, mothers experienced unmet expectations with fathers doing less than mothers expected. Fathers, on the other hand, experienced overmet expectations with mothers doing more than fathers expected. Violated expectations were also a stronger predictor of depression and relationship satisfaction than the reported division, although again in opposite directions for mothers and fathers. Unmet expectations were negative for mothers, while overmet expectations with regard to childcare tasks were beneficial for fathers. The one caveat was for fathers' overmet expectations with play; in this case, a mother playing with the baby more than a father expected was related to less relationship satisfaction. A similar pattern of results was found for mothers and fathers with persistent violations. This study highlights the importance of understanding violated expectations in both mothers and fathers, as well as examining play separately from childcare.


Alzheimer's Disease Neuroimaging Initiative 2 Clinical Core: Progress and plans.
This article reviews the current status of the Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), and summarizes planning for the next stage of the project. Clinical Core activities and plans were synthesized based on discussions among the Core leaders and external advisors. The longitudinal data in ADNI-2 provide natural history data on a clinical trials population and continue to inform refinement and standardization of assessments, models of trajectories, and clinical trial methods that have been extended into sporadic preclinical Alzheimer's disease (AD). Plans for the next phase of the ADNI project include maintaining longitudinal follow-up of the normal and mild cognitive impairment cohorts, augmenting specific clinical cohorts, and incorporating novel computerized cognitive assessments and patient-reported outcomes. A major hypothesis is that AD represents a gradually progressive disease that can be identified precisely in its long presymptomatic phase, during which intervention with potentially disease-modifying agents may be most useful.


Pruritic porokeratotic peno-scrotal plaques: porokeratosis or porokeratotic epidermal reaction pattern? A report of 10 cases.
Porokeratosis restricted to the genital region is rare with few cases described in the literature. Cases of porokeratosis restricted to the genital region are similar to plaque type of porokeratosis of Mibelli seen elsewhere on the body. We encountered 10 young males with pruritic plaques restricted to the peno-scrotal region, which clinically were not diagnosed as porokeratosis, but on biopsy revealed multiple cornoid lamellae, some of which were seen to arise from eccrine and follicular structures. The aim of this study is to study lesions restricted to the peno-scrotal region in males, which on biopsy showed cornoid lamellae suggestive of porokeratosis. Retrospective analysis of available data of patients who were rendered a histological diagnosis of genital porokeratosis. The database consisted of biopsies received in private consultation by the first author in the period January 2000 to March 2013. Ten young men, 8 in their third decade, presented with pruritic plaques restricted to the peno-scrotal region of variable duration. The lesions were well-demarcated on the penis, but ill-defined with a rough granular surface on the scrotum. None of patients were diagnosed clinically as porokeratosis. The lesions were poorly responsive to topical steroid/antifungal treatment, but two patients showed partial improvement with oral isotretinoin. Biopsy in nine patients revealed multiple cornoid lamellae involving epidermis (6) and adnexal structures (3). One patient had a single cornoid lamella. The clinical and histological presentation of these patients is different from typical genital porokeratosis described in the literature and we postulate that these patients have an unusual porokeratotic reaction pattern of the epidermis with multiple cornoid lamellae.


Short-term outcomes in infants with mild neonatal encephalopathy: a retrospective, observational study.
Neonatal encephalopathy due to acute perinatal asphyxia is a major cause of perinatal brain damage. Moderate to severe neonatal encephalopathy is associated with high mortality and morbidity rates. However, the neurodevelopmental outcomes in neonates with mild neonatal encephalopathy are unclear. The primary aim of this single-center observational study was to assess the short-term outcomes in term neonates with mild neonatal encephalopathy due to perinatal asphyxia. A secondary aim was to identify predictors of poor prognosis by identifying the characteristics of these infants according to their short-term outcomes. We retrospectively investigated all infants with perinatal asphyxia at Tokyo Metropolitan Children's Medical Center from January 2014 to December 2019. An abnormal short-term outcome was defined as any one of the following: seizures or abnormal electroencephalography, abnormal brain magnetic resonance imaging obtained within the first 4 weeks of life, and abnormal neurological examination findings at discharge. In total, 110 term infants with perinatal asphyxia during the study period were screened and 61 were diagnosed with mild neonatal encephalopathy. Eleven (18 %) of these infants had an abnormal short-term outcome. The median Thompson score at admission was significantly higher in infants with abnormal short-term outcomes than in those with normal short-term outcomes (5 [interquartile range, 4-5.5] vs. 2 [interquartile range, 1-3], p < 0.01). Receiver operating characteristic curve analysis showed that a cutoff value of 4 had high sensitivity and specificity (90.9 and 83.0 %, respectively) for prediction of an abnormal short-term outcome. 18 % of infants with mild encephalopathy had an abnormal short-term outcome, such as abnormal brain magnetic resonance imaging findings. The Thompson score at admission may be a useful predictor of an abnormal short-term outcome in infants with mild neonatal encephalopathy.


Ozone alters carbon allocation in loblolly pine: assessment with carbon-11 labeling.
Loblolly pine (Pinus taeda L.) seedlings were exposed to 0.120 micromol mol(-1) (ppm) ozone for 7 h per day, 5 days per week for 12 weeks. No visible damage resulted from this regime. A short-lived radioisotope of carbon ((11)C) was used to characterize changes in plant physiology caused by ozone, the first time this technique has been used for ozone exposure studies. In comparison to plants kept in charcoal-filtered air, pines exposed to ozone exhibited reductions in photosynthesis (16%), speed of phloem transport (11%), phloem photosynthate concentration (40%) and total carbon transport toward roots (45%). Photosynthate not transported to the roots appeared to accumulate in the stems. Primary branches of pines exposed to ozone were some 50-60% heavier than those of control pines. Ozone was thus shown to have a significant short-term impact on phloem transport processes that results in a shift in allocation of photosynthate favoring stems.


Population Dynamics of Early Visual Cortex during Working Memory.
Although the content of working memory (WM) can be decoded from the spatial patterns of brain activity in early visual cortex, how populations encode WM representations remains unclear. Here, we address this limitation by using a model-based approach that reconstructs the feature encoded by population activity measured with fMRI. Using this approach, we could successfully reconstruct the locations of memory-guided saccade goals based on the pattern of activity in visual cortex during a memory delay. We could reconstruct the saccade goal even when we dissociated the visual stimulus from the saccade goal using a memory-guided antisaccade procedure. By comparing the spatiotemporal population dynamics, we find that the representations in visual cortex are stable but can also evolve from a representation of a remembered visual stimulus to a prospective goal. Moreover, because the representation of the antisaccade goal cannot be the result of bottom-up visual stimulation, it must be evoked by top-down signals presumably originating from frontal and/or parietal cortex. Indeed, we find that trial-by-trial fluctuations in delay period activity in frontal and parietal cortex correlate with the precision with which our model reconstructed the maintained saccade goal based on the pattern of activity in visual cortex. Therefore, the population dynamics in visual cortex encode WM representations, and these representations can be sculpted by top-down signals from frontal and parietal cortex.


Goal-oriented and habitual decisions: Neural signatures of model-based and model-free learning.
Human decision-making is mainly driven by two fundamental learning processes: a slow, deliberative, goal-directed model-based process that maps out the potential outcomes of all options and a rapid habitual model-free process that enables reflexive repetition of previously successful choices. Although many model-informed neuroimaging studies have examined the neural correlates of model-based and model-free learning, the concordant activity among these two processes remains unclear. We used quantitative meta-analyses of functional magnetic resonance imaging experiments to identify the concordant activity pertaining to model-based and model-free learning over a range of reward-related paradigms. We found that: 1) both processes yielded concordant ventral striatum activity, 2) model-based learning activated the medial prefrontal cortex and orbital frontal cortex, and 3) model-free learning specifically activated the left globus pallidus and right caudate head. Our findings suggest that model-free and model-based decision making engage overlapping yet distinct neural regions. These stereotaxic maps improve our understanding of how deliberative goal-directed and reflexive habitual learning are implemented in the brain.


Lamellar bone: structure-function relations.
The term "bone" refers to a family of materials that have complex hierarchically organized structures. These structures are primarily adapted to the variety of mechanical functions that bone fulfills. Here we review the structure-mechanical relations of one bone structural type, lamellar bone. This is the most abundant type in many mammals, including humans. A lamellar unit is composed of five sublayers. Each sublayer is an array of aligned mineralized collagen fibrils. The orientations of these arrays differ in each sublayer with respect to both collagen fibril axes and crystal layers, such that a complex rotated plywood-like structure is formed. Specific functions for lamellar bone, as opposed to the other bone types, could not be identified. It is therefore proposed that the lamellar structure is multifunctional-the "concrete" of the bone family of materials. Experimentally measured mechanical properties of lamellar bone demonstrate a clear-cut anisotropy with respect to the axis direction of long bones. A comparison of the elastic and ultimate properties of parallel arrays of lamellar units formed in primary bone with cylindrically shaped osteonal structures in secondary formed bone shows that most of the intrinsic mechanical properties are built into the lamellar structure. The major advantages of osteonal bone are its fracture properties. Mathematical modeling of the elastic properties based on the lamellar structure and using a rule-of-mixtures approach can closely simulate the measured mechanical properties, providing greater insight into the structure-mechanical relations of lamellar bone.


Comorbidities, Sociodemographic Factors, and Hospitalizations in Outpatients With Heart Failure and Preserved Ejection Fraction.
Patients with heart failure and preserved ejection fraction (HFpEF) tend to be older and have a high co-morbidity burden. The impact of co-morbid conditions and sociodemographic risk factors on outcomes in these patients has not been quantified. We evaluated 445 consecutive outpatients with HFpEF, defined as established diagnosis of heart failure (HF) with left ventricular ejection fraction at presentation >40% and no previous left ventricular ejection fraction ≤40%. Patients with specific cardiomyopathies, congenital heart disease, primary right-sided disease, valvular disease, or previous advanced HF therapies were excluded. After 2 years, there were 44 deaths and 609 all-cause hospitalizations; of these, 260 (42.7%) were cardiovascular hospitalizations, including HF, and 173 (28.4%) were specifically for HF. The highest attributable risk for hospitalizations was associated with marital status (single, divorced, and widowed had higher hospitalization rates compared with married patients), hypoalbuminemia, diabetes, atrial fibrillation, and renal dysfunction. The proportion of hospitalizations potentially attributable to these factors was 66.6% (95% confidence interval [CI] 56.4 to 74.4) for all-cause hospitalizations, 76.9% (95% CI 65.2 to 84.6) for cardiovascular hospitalizations, and 83.0% (95% CI 70.3 to 90.3) for HF hospitalizations. For composite end points, the proportion was 46.9% (95% CI 34.0% to 57.3%) for death or all-cause hospitalization, 45.7% (95% CI 29.3% to 58.2%) for death or cardiovascular hospitalization, and 43.7% (95% CI 24.2% to 58.2%) for death or HF-related hospitalization. In conclusion, among outpatients with HFpEF, most hospitalizations could be attributed to co-morbidities and sociodemographic factors. Effects of HF therapies on hospitalizations and related end points may be difficult to demonstrate in these patients. Multidisciplinary approaches are more likely to impact hospitalizations in HFpEF.


Reconstruction of a directed acyclic graph with intervention.
Identification of causal relations among variables is central to many scientific investigations, as in regulatory network analysis of gene interactions and brain network analysis of effective connectivity of causal relations between regions of interest. Statistically, causal relations are often modeled by a directed acyclic graph (DAG), and hence that reconstruction of a DAG's structure leads to the discovery of causal relations. Yet, reconstruction of a DAG's structure from observational data is impossible because a DAG Gaussian model is usually not identifiable with unequal error variances. In this article, we reconstruct a DAG's structure with the help of interventional data. Particularly, we construct a constrained likelihood to regularize intervention in addition to adjacency matrices to identify a DAG's structure, subject to an error variance constraint to further reinforce the model identifiability. Theoretically, we show that the proposed constrained likelihood leads to identifiable models, thus correct reconstruction of a DAG's structure through parameter estimation even with unequal error variances. Computationally, we design efficient algorithms for the proposed method. In simulations, we show that the proposed method enables to produce a higher accuracy of reconstruction with the help of interventional observations.


Changes in proportion of canine urinary calculi composed of calcium oxalate or struvite in specimens analyzed from 1981 through 2001.
The objective of this report was to characterize 20-year changes in proportion of calcium oxalate (CaOx) calculi and struvite calculi in dogs, and associations with breed, age, and sex. In this retrospective study, results of analysis of urinary calculi from dogs were reviewed for specimens received between July 1, 1981, and December 31, 2001. Breed, sex, age, year of submission of the specimen, and mineral type(s) were analyzed statistically. CaOx or Struvite or both were contained in 18,966 of 20,884 (91%) specimens. For both sexes, a 20-year statistically significant increase was observed in the proportion of calculus specimens that contained CaOx. The increase in this proportion was greater in females (1% to 31%) than in males (18% to 82%). From 1998 to 2001, when proportions may have plateaued, the odds of specimens containing CaOx were markedly higher in 18 breeds, markedly lower in 5 breeds, and not significantly different in 13 breeds compared with crossbreds. For both sexes, a 20-year statistically significant decrease was observed in the proportion of calculus specimens that contained struvite. This decrease in proportion was greater for males (79-16%) than for females (97-68%). From 1998 to 2001, when proportions plateaued, the odds of calculi containing struvite were markedly lower in 20 breeds, markedly higher in 1 breed, and not significantly different in 15 breeds when compared with crossbreds. Breed, age, and sex were associated statistically with CaOx or struvite urolithiasis. In conclusion, there appears to have been a long-term increase in the proportion of specimens of canine urinary calculi that contain CaOx as well as a long-term decrease in the proportion of specimens of calculi that contain struvite for both male and female dogs. The rate of change appeared to begin leveling off in the period 1998 to 2001. The recent proportion of dogs with either CaOx- or struvite-associated urolithiasis may depend on breed, age, and sex, and on interactions among these 3 factors.


Architectural Change of the Shell-Forming Block from Linear to V-Shaped Accelerates Micellar Disassembly, but Slows the Complete Enzymatic Degradation of the Amphiphiles.
Tuning the enzymatic degradation and disassembly rates of polymeric amphiphiles and their assemblies is crucial for designing enzyme-responsive nanocarriers for controlled drug delivery applications. The common methods to control the enzymatic degradation of amphiphilic polymers are to tune the molecular weights and ratios of the hydrophilic and hydrophobic blocks. In addition to these approaches, the architecture of the hydrophilic block can also serve as a tool to tune enzymatic degradation and disassembly. To gain a deeper understanding of the effect of the molecular architecture of the hydrophilic block, we prepared two types of well-defined PEG-dendron amphiphiles bearing linear or V-shaped PEG chains as the hydrophilic blocks. The high molecular precision of these amphiphiles, which emerges from the utilization of dendrons as the hydrophobic blocks, allowed us to study the self-assembly and enzymatic degradation and disassembly of the two types of amphiphiles with high resolution. Interestingly, the micelles of the V-shaped amphiphiles were significantly smaller and disassembled faster than those of the amphiphiles based on linear PEG. However, the complete enzymatic cleavage of the hydrophobic end groups was significantly slower for the V-shaped amphiphiles. Our results show that the V-shaped architecture can stabilize the unimer state and, hence, plays a double role in the enzymatic degradation and the induced disassembly and how it can be utilized to control the release of encapsulated or bound molecular cargo.


Platelet Function Testing: A Role for Personalised Therapy in Coronary Disease.
Whilst there exist general guidelines regarding administration of antiplatelet therapy to prevent thrombotic events in patients with cardiovascular disease, the optimal therapy for a particular individuals in particular settings remains unclear. For patients with acute coronary syndrome (ACS) or those undergoing percutaneous coronary intervention (PCI), the use of potent antiplatelet agent combinations is recommended. However, some patients continue to have thrombotic events or experience bleeding events, which have been linked to the widely known variability in individual response to antiplatelet therapy, particularly to clopidogrel. Platelet function tests (PFTs) have been used in an attempt to predict ongoing thrombotic risk and to monitor the response to antiplatelet drugs. Although the cause of both thrombotic and bleeding events is multifactorial in origin, the observation that enhanced platelet reactivity is associated with recurrent thrombosis and reduced platelet reactivity with bleeding has raised hopes of identifying those at risk through the use of PFTs. Consequently, there was initial enthusiasm for the use of PFTs to guide individualized antiplatelet therapy. Few studies have been conducted, but the alteration of treatment based on the results of PFTs has not been shown to influence outcomes. Inherent limitations of the studies utilizing PFTs may indeed have contributed to the failure of this approach. Further, there are important limitations to the relevance of currently available PFTs to the in vivo situation. Refinement of existing techniques to allow the use of native blood, high shear, use of a global stimulus instead of individual agonists, assessment of thrombin generation by activated platelets, and assessment of fibrinolytic potential, should be considered to make these tests more physiological. Perhaps the results of PFTs need to be considered in combination with other prognostic factors in a more complex prediction model. The present manuscript provides an overview on the role of and value of available PFTs in contemporary clinical practice, with particular focus on possible individualized antiplatelet regimens in high risk patients.


The presence of Nipah virus in respiratory secretions and urine of patients during an outbreak of Nipah virus encephalitis in Malaysia.
To study the excretion of Nipah virus in the upper respiratory secretions and urine of infected patients in relation to other clinical features. Isolation of Nipah virus from the respiratory secretions and urine was made in Vero cells and identified by indirect immunofluorescence assay using anti-Hendra specific hyperimmune mouse ascitic fluid and FITC-conjugated goat anti-mouse IgG. During the peak outbreak of Nipah virus encephalitis in Malaysia, Nipah virus was isolated from the upper respiratory secretions and urine in eight of 20 patients who were virologically and/or serologically confirmed to be infected with the virus. From these eight patients, Nipah virus was isolated from six throat swab specimens, three urine specimens and only one nasal swab specimen. The positive virus isolation rate was related to the collection of these specimens during the early phase of the illness (P = 0.068). The presence of serum anti-Nipah specific IgM appeared to reduce the chance of isolating the virus (P = 0.049). There was no significant difference in the isolation rate with respect to the age, gender, ethnic group and clinical features associated with grave prognosis and mortality outcome of the patients. This study shows that it is possible to be infected from secretions of infected patients, but epidemiological survey on close contacts so far did not suggest that human-to-human transmission is common.


Accelerating Improvement and Narrowing Gaps: Trends in Patients' Experiences with Hospital Care Reflected in HCAHPS Public Reporting.
Measure HCAHPS improvement in hospitals participating in the second and fifth years of HCAHPS public reporting; determine whether change is greater for some hospital types. Surveys from 4,822,960 adult inpatients discharged July 2007-June 2008 or July 2010-June 2011 from 3,541 U.S. hospitals. Linear mixed-effect regression models with fixed effects for time, patient mix, and hospital characteristics (bedsize, ownership, Census division, teaching status, Critical Access status); random effects for hospitals and hospital-time interactions; fixed-effect interactions of hospital characteristics and patient characteristics (gender, health, education) with time predicted HCAHPS measures correcting for regression-to-the-mean biases. National probability sample of adult inpatients in any of four approved survey modes. HCAHPS scores increased by 2.8 percentage points from 2008 to 2011 in the most positive response category. Among the middle 95 percent of hospitals, changes ranged from a 5.1 percent decrease to a 10.2 percent gain overall. The greatest improvement was in for-profit and larger (200 or more beds) hospitals. Five years after HCAHPS public reporting began, meaningful improvement of patients' hospital care experiences continues, especially among initially low-scoring hospitals, reducing some gaps among hospitals.


Structural relationship of lambda-type light chains with AL amyloidosis.
Three human amyloidogenic Bence Jones proteins, NIG76 VlambdaII, NIG204 VlambdaI, and NIG250 VlambdaV, were characterized. In a comparative study, three amino acids, Ser-25a, Thr-68, and Val-95, were found to be common to amyloidogenic proteins of the VlambdaII subgroup. NIG204 had an insertion of Pro residue following position 30 (30a). Proteins having an insertion at this position are invariantly amyloidogenic. NIG250 had a characteristic VlambdaV VL domain, with Mcg+ and KERN+ CL domain isotypes. Following the protein DEL, this is the second example of this subgroup. No common residue is found in the other subgroup proteins but unique substitutions do occur. It would seem that any substitution that causes an alteration in the protein conformation may lead to its being more prone to association with the amyloid processes.


[Intraoperative neurophysiological monitoring: methods in neurosurgery].
IONM uses different neurophysiological techniques during surgery time, thus avoiding possible lesions to the neurological structures, making surgery safer and better. We describe two types of IONM: mapping techniques and monitoring techniques, as well as their advantages, disadvantages and complications. We look into the more useful techniques in this field, as well as providing orientation about its use according to the surgical areas and the neurological structures under risk. In conclusion, we affirm that IONM is one of the most important advances in modern neurosurgery.


Poly-beta-hydroxybutyric acid in staphylococci.
Poly-beta-hydroxybutyric acid (PHB) was extracted from various species of staphylococci isolated from different sources. IR and UV spectrophotometry and NMR analysis revealed that the compound consisted only of the beta-hydroxybutyrate. The PHB level in the richest strain among investigated staphylococci is about 64-fold less than in bacilli. The intrinsic viscosity number of this polymer is more than twice greater in the case of the staphylococcal product than that of bacilli.


Clinical and biochemical study of 28 patients with mucopolysaccharidosis type VI.
This paper presents data collected by a Brazilian center in a multinational multicenter observational study of patients with mucopolysaccharidosis type VI (MPS VI), aiming at determining the epidemiological, clinical, and biochemical profile of these patients. Twenty-eight south-American patients with MPS VI were evaluated through medical interview, physical exam, echocardiogram, electrocardiogram, ophthalmologic evaluation, quantification of glycosaminoglycans (GAGs) in urine, and measurement of the activity of N-acetylgalactosamine-4-sulfatase (ARSB) in leukocytes. 92.9% of patients were Brazilian. Mean age at diagnosis and at evaluation was 48.4 months and 97.1 months, respectively. 88% of patients had onset of symptomatology before the age of 36 months. Consanguinity was reported by 27% of the families. Mean weight and height at birth were 3.481 kg and 51.3 cm, respectively. The most frequently reported clinical manifestations were short stature, corneal clouding, coarse facial features, joint contractures, and claw hands. All patients presented with echocardiogram changes as well as corneal clouding. Mean ARSB activity in leukocytes was 5.4 nmoles/h/mg protein (reference values: 72-174), and urinary excretion of GAGs was on average 7.9 times higher than normal. The number of clinical manifestations did not show a significant correlation with the levels of urinary GAGs nor with the ARSB activity. Also, no significant correlation was found between the levels of urinary GAGs and the ARSB activity. It was concluded that MPS VI has high morbidity and that, when compared with data published in the literature, patients in our study were diagnosed later and presented with a higher frequency of cardiological findings.


Left ventricular long-axis changes in early diastole and systole: impact of systolic function on diastole.
Impaired long-axis motion is a sensitive marker of systolic myocardial dysfunction, but no data are available that relate long-axis changes in systole with those in diastole, particularly in subjects with diastolic dysfunction and a 'normal' left ventricular (LV) ejection fraction. A total of 311 subjects (including 105 normal healthy volunteers) aged 20-89 years with variable degrees of systolic function (LV ejection fraction range 0.15-0.84) and diastolic function were studied using tissue Doppler echocardiography and M-mode echocardiography to determine mean mitral annular amplitude and peak velocity in systole and early and late diastole. The LV systolic mitral annular amplitude (S(LAX), where LAX is long-axis amplitude) and peak velocity (S(m)) correlated well with the respective early diastolic components (E(LAX) and E(m)) and late diastolic (atrial) components (A(LAX) and A(m)). A non-linear equation fitted better than a linear relationship (non-linear model: S(LAX) against E(LAX), r(2)=0.67; S(m) against E(m), r(2)=0.60; S(LAX) against A(LAX) and S(m) against A(m), r(2)=0.42). After adjusting for age, sex and heart rate, linear relationships of early diastolic (E(LAX), r(2)=0.70; E(m), r(2)=0.60) and late diastolic (A(LAX), r(2)=0.61; A(m), r(2)=0.64) long-axis amplitudes and velocities with the respective values for S(LAX) and S(m) were found, even in those subjects with apparently 'isolated' diastolic dysfunction. Long-axis changes in systole or diastole did not correlate with Doppler mitral velocities. We conclude that ventricular long-axis changes in early diastole are closely related to systolic function, even in subjects with diastolic dysfunction. 'Pure' or isolated diastolic dysfunction is uncommon.


Global Epidemiology of Diphtheria, 2000-20171.
In 2017, a total of 8,819 cases of diphtheria were reported worldwide, the most since 2004. However, recent diphtheria epidemiology has not been well described. We analyzed incidence data and data from the literature to describe diphtheria epidemiology. World Health Organization surveillance data were 81% complete; completeness varied by region, indicating underreporting. As national diphtheria-tetanus-pertussis (DTP) 3 coverage increased, the proportion of case-patients <15 years of age decreased, indicating increased protection of young children. In countries with higher case counts, 66% of case-patients were unvaccinated and 63% were <15 years of age. In countries with sporadic cases, 32% of case-patients were unvaccinated and 66% were >15 years of age, consistent with waning vaccine immunity. Global DTP3 coverage is suboptimal. Attaining high DTP3 coverage and implementing recommended booster doses are necessary to decrease diphtheria incidence. Collection and use of data on subnational and booster dose coverage, enhanced laboratory capacity, and case-based surveillance would improve data quality.


Spinal Fusion for Pediatric Spondylolisthesis: National Trends, Complications, and Short-Term Outcomes.
Current surgical management guidelines for pediatric spondylolisthesis (PS) are reliant on data from single-center cohorts. To analyze national trends and predictors of short-term outcomes in spinal fusion surgery for PS by performing a retrospective cross-sectional analysis of the Kids' Inpatient Database (KID). The KID (sampled every 3 yr) was queried from 2003 to 2012 to identify all cases (age 5-17) of spinal fusion for PS (n = 2646). We analyzed trends in patient characteristics, surgical management, and short-term outcomes. Both univariate and multivariable analyses were utilized. The 2646 spinal fusions for PS included posterior-only fusions (86.8%, PSF), anterior lumbar interbody fusions (4.8%, ALIF), and combined anterior and posterior fusions (8.4%, APLF) procedures. The utilization of APLF decreased over time (9.9%-6.4%, P = .023), whereas the number of total spinal fusions and the proportion of PSF and ALIF procedures have not changed significantly. Uptrends in Medicaid insured individuals (1.2%-18.9%), recombinant human bone morphogenetic protein-2 insertion (8.8%-16.6%), decompression (34.7%-42.8%), and mean inflation-adjusted hospital costs ($21 855-$32 085) were identified (all P < .001). In multivariable analysis, Medicaid status (odds ratio [OR] = 1.93, P = .004), teaching hospitals (OR = 1.94, P = .01), decompression (OR = 1.78, P = .004), and the APLF procedure (OR = 2.47, P = .001) increased the likelihood of complication occurrence (all P < .001). The addition of decompression during fusion and the APLF procedure were associated with more in-hospital complications, though this may have been indicative of greater surgical complexity. The utilization of the APLF procedure has decreased significantly, while costs associated with the treatment of PS have increased over time.


Repopulation of oligodendrocyte progenitor cell depleted tissue in a model of chronic demyelination.
Some, but not all chronically demyelinated MS lesions are depleted of oligodendrocyte progenitor cells (OPCs) suggesting that OPCs are destroyed during the process of demyelination and some factor impedes OPC repopulation of the depleted tissue. The chronically demyelinated axons in MS lie in an astrocytic environment and it has been proposed that this might impede entry of OPCs into such regions. By depleting a short length of spinal cord of its OPCs using 40 Gy of X-irradiation in both normal rats and rats with progressive myelin loss accompanied by an astrocytosis (taiep rats), we investigated whether such changes affect the ability of OPCs to repopulate OPC-depleted tissue. In both taiep and normal rats, the rate of repopulation decreases with age, but no difference was detected in the rate at which OPCs repopulated normally myelinated and chronically demyelinated and astrocytosed tissue. This indicates that, if the astrocytic environment of the taiep CNS is comparable to that found in MS lesions, then the presence of chronically demyelinated axons and astrocytosis in chronic MS lesions does not represent a barrier to repopulation of the tissue by OPCs. However, similar to the situation in the normal adult rodent CNS, the rate of repopulation by endogenous OPCs in aged taiep rats is very slow, approximately 0.2 mm per week.


Characterization of clogging deposits in an irrigation pipeline and effect of post-aeration on clogging potential of tertiary-treated wastewater.
In Agadir, a water-scarce Moroccan region, municipal and industrial wastewater is tertiary-treated to be reused in golf courses. Wastewater reuse has been constrained by severe clogging of emitters, which caused technical and financial problems. This study aimed to perform an in-depth characterization of the treated wastewater (TWW) in relation to its susceptibility to cause clogging, and to assess the capacity of an aeration post-treatment to reduce the clogging potential. The post-treatment consisted of injecting different airflows (0-33 L/(h Lreactor) into the TWW. The structural, morphological and elemental composition of the clogging matter collected in the irrigation pipeline was characterized using scanning electron microscopy, scanning transmission electron microscopy, X-ray diffraction and X-ray energy dispersive spectroscopy. The 15-day aeration post-treatment at 16.5 L/(h Lreactor) presented the best cost-benefit ratio. Organic matter was totally degraded. Calcium was reduced by 9%, bicarbonates by 54%. The analysis of the deposits induced by the aeration post-treatment revealed a relevant decrease of the major constituents of the clogging deposits found in the irrigation pipeline. The results show the effectiveness of post-aeration in biodegrading residual organic matter and precipitating several salts, thus reducing the clogging potential.


Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.
In this series of projects of sequencing human cDNA clones which correspond to relatively long and nearly full-length transcripts, we newly determined the sequences of 80 clones, and predicted the coding sequences of the corresponding genes, named KIAA0201 to KIAA0280. Among the sequenced clones, 68 were obtained from human immature myeloid cell line KG-1 and 12 from human brain. The average size of the clones was 5.3 kb, and that of distinct ORFs in clones was 2.8 kb, corresponding to a protein of approximately 100 kDa. Computer search against the public databases indicated that the sequences of 22 genes were unrelated to any reported genes, while the remaining 58 genes carried sequences which show some similarities to known genes. Protein motifs that matched those in the PROSITE motif database were found in 25 genes and significant transmembrane domains were identified in 30 genes. Among the known genes to which significant similarity was shown, the genes that play key roles in regulation of developmental stages, apoptosis and cell-to-cell interaction were included. Taking into account of both the search data on sequence similarity and protein motifs, at least seven genes were considered to be related to transcriptional regulation and six genes to signal transduction. When the expression profiles of the cDNA clones were examined with different human tissues, about half of the clones from brain (5 of 11) showed significant tissue-specificity, while approximately 80% of the genes from KG-1 were expressed ubiquitously.


Expansion and activation of minor histocompatibility antigen HY-specific T cells associated with graft-versus-leukemia response.
The immune system of females is capable of recognizing and reacting against the male-specific minor histocompatibility antigen (mHA), HY. Thus, cytotoxic T-lymphocytes (CTLs) recognizing this antigen may be useful in eradicating leukemic cells of a male patient if they can be generated in vivo or in vitro from a human leukocyte antigen (HLA)-identical female donor. The HLA-A*0201-restricted HY antigen, FIDSYICQV, is a male-specific mHA. Using HLA-A2/HY peptide tetrameric complexes, we reveal a close association between the emergence of HY peptide-specific CD8(+) T cells in peripheral blood and molecular remission of relapsed BCR/ABL(+) chronic myelogenous leukemia in lymphoid blast crisis in a patient who underwent female-to-male transplantation. Assessment of intracellular cytokine levels identified T cells that produce interferon-gamma in response to the HY peptide during the presence of HY tetramer-positive T cells. These results indicate that transplant with allogeneic HY-specific CTLs has therapeutic potential for relapsed leukemia, and that expansion of such T cells may be involved in the development of a graft-versus-leukemia response against lymphoblastic leukemia cells.


Value of Ultrasonic Image Features in Diagnosis of Perinatal Outcomes of Severe Preeclampsia on account of Deep Learning Algorithm.
This study is aimed at discussing the value of ultrasonic image features in diagnosis of perinatal outcomes of severe preeclampsia on account of deep learning algorithm. 140 pregnant women singleton with severe preeclampsia were selected as the observation group. At the same time, 140 normal singleton pregnant women were selected as the control group. The hemodynamic indexes were detected by color Doppler ultrasound. The CNN algorithm was used to classify ultrasound images of two groups of pregnant women. The differential scanning calorimetry (DSC), mean pixel accuracy (MPA), and mean intersection of union (MIOU) values of CNN algorithm were 0.9410, 0.9228, and 0.8968, respectively. Accuracy, precision, recall, and F1-score were 93.44%, 95.13%, 95.09%, and 94.87%, respectively. The differences were statistically significant (P < 0.05). Compared with the normal control group, the umbilical artery (UA), uterine artery-systolic/diastolic (UTA-S/D), uterine artery (UTA), and digital video (DV) of pregnant women in the observation group were remarkably increased; the minimum alveolar effective concentration (MCA) of the observation group was obviously lower than the MCA of the control group, and the differences between groups were statistically valid (P < 0.05). Logistic regression analysis showed that UA-S/D, UA-resistance index (UA-RI), UTA-S/D, UTA-pulsatility index (UTA-PI), DV-peak velocity index for veins (DV-PVIV), and MCA-S/D were independent risk factors for the outcome of perinatal children with severe preeclampsia. In the perinatal management of severe epilepsy, the combination of the above blood flow indexes to select the appropriate delivery time had positive significance to improve the pregnancy outcome and reduce the perinatal mortality.


DNA methylation and transcriptional trajectories during human development and reprogramming of isogenic pluripotent stem cells.
Determining cell identity and maturation status of differentiated pluripotent stem cells (PSCs) requires knowledge of the transcriptional and epigenetic trajectory of organs during development. Here, we generate a transcriptional and DNA methylation atlas covering 21 organs during human fetal development. Analysis of multiple isogenic organ sets shows that organ-specific DNA methylation patterns are highly dynamic between week 9 (W9) and W22 of gestation. We investigate the impact of reprogramming on organ-specific DNA methylation by generating human induced pluripotent stem cell (hiPSC) lines from six isogenic organs. All isogenic hiPSCs acquire DNA methylation patterns comparable to existing hPSCs. However, hiPSCs derived from fetal brain retain brain-specific DNA methylation marks that seem sufficient to confer higher propensity to differentiate to neural derivatives. This systematic analysis of human fetal organs during development and associated isogenic hiPSC lines provides insights in the role of DNA methylation in lineage commitment and epigenetic reprogramming in humans.While DNA methylation and gene expression data are widely available for animal models, comprehensive data from human development is rarer. Here, the authors generated transcriptional and DNA methylation data from 21 organs during human development and 6 isogenic induced pluripotent stem cell lines.


Quantifying language development from birth to 3 years using the Early Language Milestone Scale.
A point-scoring technique for the Early Language Milestone Scale is described. Normative data based on the original 1982 cross-sectional sample and validation data based on a separate longitudinal sample are presented. Mean Early Language Milestone Scale point scores, standard deviations, and percentile equivalents for raw point scores are presented for all ages from birth to 36 months. Correlations between point scores on the Early Language Milestone Scale and scores on other standardized developmental tests such as the Stanford-Binet Intelligence Scale, the Peabody Picture Vocabulary Test, and the Illinois Test of Psycholinguistic Abilities are presented. The clinical and research advantages of this point-scoring technique are presented and compared with the original pass/fail scoring method.


Ethics at the end of life in transplant recipients.
The field of transplantation is intended to try to save or improve people's lives. In some situations though, the length of a person's life is not as vital as the quality of that life. As a member of a transplant team, one must recognize the differences between quality and quantity and apply the ethical principles of autonomy, justice, nonmaleficence, and beneficence. When a lung transplant recipient became ill with posttransplant lymphoproliferative disease 10 months after her surgery, these ethical principles came to the foreground. This dynamic, vibrant woman, recently engaged, faced her own mortality with grace. There is a time for everything. When death is a long time coming, many people are referred to hospice care and the death is viewed as a blessing. This situation rarely occurs in the transplant field. Many people, whether professionals or laypersons, have a difficult time letting go. Our team and this very special woman all knew when it was time. Creating a warm and open environment in the intensive care unit helped her through the rhythms of transition in dying.


Targeting Peroxisome Proliferator-Activated Receptor γ to Increase Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells.
Peroxisome proliferator-activated receptor γ (PPARγ) is an important transcription factor that modulates lipid metabolism and inflammation. However, it remains unclear whether PPARγ is involved in modulation of estrogen (E2)-induced inflammation, thus affecting apoptosis of E2-deprived breast cancer cells, MCF-7:5C and MCF-7:2A. Here, we demonstrated that E2 treatment suppressed the function of PPARγ in both cell lines, although the suppressive effect in MCF-7:2A cells was delayed owing to high PPARγ expression. Activation of PPARγ by a specific agonist, pioglitazone, selectively blocked the induction of TNFα expression by E2, but did not affect other adipose inflammatory genes, such as fatty acid desaturase 1 and IL6. This suppression of TNFα expression by pioglitazone was mainly mediated by transrepression of nuclear factor-κB (NF-κB) DNA-binding activity. A novel finding was that NF-κB functions as an oxidative stress inducer in MCF-7:5C cells but an antioxidant in MCF-7:2A cells. Therefore, the NF-κB inhibitor JSH-23 displayed effects equivalent to those of pioglitazone, with complete inhibition of apoptosis in MCF-7:5C cells, but it increased E2-induced apoptosis in MCF-7:2A cells. Depletion of PPARγ by siRNA or the PPARγ antagonist T0070907 accelerated E2-induced apoptosis, with activation of NF-κB-dependent TNFα and oxidative stress. For the first time, we demonstrated that PPARγ is a growth signal and has potential to modulate NF-κB activity and oxidative stress in E2-deprived breast cancer cell lines. All of these findings suggest that anti-PPARγ therapy is a novel strategy to improve the therapeutic effects of E2-induced apoptosis in E2-deprived breast cancer.


Ubiquitin-mediated regulation of autophagy.
Autophagy is a major degradation pathway that utilizes lysosome hydrolases to degrade cellular constituents and is often induced under cellular stress conditions to restore cell homeostasis. Another prime degradation pathway in the cells is ubiquitin-proteasome system (UPS), in which proteins tagged by certain types of polyubiquitin chains are selectively recognized and removed by proteasome. Although the two degradation pathways are operated independently with different sets of players, recent studies have revealed reciprocal cross talks between UPS and autophagy at multiple layers. In this review, we summarize the roles of protein ubiquitination and deubiquitination in controlling the initiation, execution, and termination of bulk autophagy as well as the role of ubiquitination in signaling certain types of selective autophagy. We also highlight how dysregulation of ubiquitin-mediated autophagy pathways is associated with a number of human diseases and the potential of targeting these pathways for disease intervention.


High research productivity in vertically undifferentiated higher education systems: Who are the top performers?
The growing scholarly interest in research top performers comes from the growing policy interest in research top performance itself. A question emerges: what makes someone a top performer? In this paper, the upper 10% of Polish academics in terms of research productivity are studied, and predictors of entering this class are sought. In the science system (and Poland follows global patterns), a small number of scholars produce most of the works and attract huge numbers of citations. Performance determines rewards, and small differences in talent translate into a disproportionate level of success, leading to inequalities in resources, research outcomes, and rewards. Top performers are studied here through a bivariate analysis of their working time distribution and their academic role orientation, as well as through a model approach. Odds ratio estimates with logistic regression of being highly productive Polish academics are presented. Consistently across major clusters of academic disciplines, the tiny minority of 10% of academics produces about half (44.7%) of all Polish publications (48.0% of publications in English and 57.2% of internationally co-authored publications). The mean research productivity of top performers across major clusters is on average 7.3 times higher than that of the other academics, and in terms of internationally co-authored publications, 12.07 times higher. High inequality was observed: the average research productivity distribution is highly skewed with a long tail on the right not only for all Polish academics but also for top performers. The class of top performers is as internally stratified as that of their lower-performing colleagues. Separate regression models for all academics, science, technology, engineering and mathematics academics, and social sciences and humanities academics are built based on a large national sample (2525 usable observations), and implications are discussed.


Washing of cut persimmon with thyme or lemon essential oils.
The aim of this study was to develop a minimally processed persimmon product by applying different concentrations of thyme essential oil or lemon essential oil on the product in order to increase its shelf life. Essential oils were applied on cut persimmon in a preliminary stage of immersion, and the samples were then stored at 4 ℃ for seven days. Moisture content, soluble solids content, antioxidant capacity, total phenols, pH, optical and mechanical properties and microbiology counts were periodically analysed. Noteworthy was that the application of thyme essential oil in the washing stage improved the preservation of the fruits' colour. All samples would be considered safe according to microbiology requirements and based on the period of study, regardless of the type of essential oil applied.


Suppression of lithium dendrite growth using cross-linked polyethylene/poly(ethylene oxide) electrolytes: a new approach for practical lithium-metal polymer batteries.
Solid polymer electrolyte (SPE) membranes are a critical component of high specific energy rechargeable Li-metal polymer (LMP) batteries. SPEs exhibit low volatility and thus increase the safety of Li-based batteries compared to current state-of-the-art Li-ion batteries that use flammable small-molecule electrolytes. However, most SPEs exhibit low ionic conductivity at room temperature, and often allow the growth of lithium dendrites that short-circuit the batteries. Both of these deficiencies are significant barriers to the commercialization of LMP batteries. Herein we report a cross-linked polyethylene/poly(ethylene oxide) SPE with both high ionic conductivity (>1.0 × 10(-4) S/cm at 25 °C) and excellent resistance to dendrite growth. It has been proposed that SPEs with shear moduli of the same order of magnitude as lithium could be used to suppress dendrite growth, leading to increased lifetime and safety for LMP batteries. In contrast to the theoretical predictions, the low-modulus (G' ≈ 1.0 × 10(5) Pa at 90 °C) cross-linked SPEs reported herein exhibit remarkable dendrite growth resistance. These results suggest that a high-modulus SPE is not a requirement for the control of dendrite proliferation.


The Drosophila TNF ortholog eiger is required in the fat body for a robust immune response.
Eiger is the sole TNF family member found in Drosophila melanogaster. This signaling molecule is induced during infection and is required for an appropriate immune response to many microbes; however, little is known about where eiger is produced. Here, we show that eiger is made in the fly's fat body during a Salmonella typhimurium infection. Using tissue-specific knockdown, we found that eiger expression in the fat body is required for all of the phenotypes we observed in eiger null mutant flies. This includes reduced melanization, altered antimicrobial peptide expression and reduced feeding rates. The effect of eiger on feeding rates alone may account for the entire phenotype seen in eiger mutants infected with S. typhimurium.


[Formation of cells secreting antigen-dependent nonspecific immunoglobulins during immunization of mice with 2 T-independent antigens].
Immunization of BALB/c and C3H/A mice with T-independent antigens (Vi-antigen of Salmonella typhi and polyvinyl pyrrolidone PVP350) induces the appearance of both antibody-forming cells (AFC) and a sharp increase in the number of cells forming nonspecific immunoglobulins (nIFC). This effect is not related to mitogenic properties of the antigens. The number of nIFC formed after simultaneous injection of both T-independent antigens does not differ from that of nIFC formed during immunization with each of these antigens alone. Thus, there was no summation of nIFC number after injection of two T-dependent or one T-dependent and one T-independent antigens. The mechanisms of nIFC formation under the influence of T-dependent and T-independent antigens are discussed.


Dispersion of gas flaring emissions in the Niger delta: Impact of prevailing meteorological conditions and flare characteristics.
An understanding of the dispersion and level of emissions source of atmospheric pollutants; whether point, area or volume sources, is required to inform policies on air pollution and day-to-day predictions of pollution level. Very few studies have carried out simulations of the dispersion pattern and ground-level concentration of pollutants emitted from real-world gas flares. The limited availability of official data on gas flares from the oil and gas industries makes accurate dispersion calculations difficult. Using ADMS 5 and AERMOD, this study assessed the sensitivity of dispersion and ground-level concentration of pollutants from gas flares in the Niger Delta to prevailing meteorological condition; fuel composition; and flare size. Although, during the non-WAM (West African Monsoon) months (November and March), the simulated ground-level concentrations of pollutants from a single flare are lower, the dispersion of pollutants is towards both the inland and coastal communities. In the WAM months, the ground-level concentrations are higher and are dispersed predominantly over the inland communities. Less buoyant plumes from smaller flares (lower volume flow rates) and/or flaring of fuel with lower heat content results in higher ground-level concentrations in areas closer to the flare. Considering the huge number of flares scattered around the region, a mitigation of the acute local pollution level would be to combine short stacks flaring at lower volume flow rates to enhance the volume flow rate of a single exhaust, and hence, the buoyancy of the plume exiting the stack.


Effect of Hygrothermal Ageing on the Mechanical and Fire Properties of a Flame Retardant Flax Fiber/Epoxy Composite.
In engineering applications, natural fiber composites must comply with fire requirements including the use of flame retardant. Furthermore, biocomposites are known to be water sensitive. Whether flame retardants affect the water sensitivity and whether water absorption affects the fire behavior and the mechanical performance of biocomposites are the two main topics addressed in this work. In this study, a flax fiber/epoxy composite flame retardant with 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) or aluminum diethyl phosphinate (AlPi) was aged in humid atmosphere or by immersion in water. Water absorption kinetics revealed that DOPO induces an increase in equilibrium water content by approximately a factor of 2 due to its intrinsic hygroscopicity and/or its plasticizing effect on the epoxy matrix. In contrast, AlPi does not significantly change the water sensitivity of the biocomposite. Mechanical testing highlighted that, whatever the FR, the evolution of mechanical properties with ageing is governed by the moisture content. The drop of elastic modulus was attributed to a decrease in fiber rigidity due to plasticization, while the increase in tensile strength was assigned to an increase in fiber/matrix friction due to fiber swelling. As regards flame retardancy, only the highest water contents modified the fire behavior. For the AlPi containing biocomposite, the water release resulted in an increase by 50% of the time to ignition, while for the DOPO flame retardant biocomposite the water release was mainly postponed after ignition.


[Postoperative complications after orthotopic heart transplantation].
We analysed postoperative complications in 106 patients after orthotopic heart transplantation based on the results of prospective observations during 2 year follow-up. Survival was estimated at 83% (88 patients). Deaths were caused by pyoseptic complications, pulmonary thromboembolism, acute pancreatitis, cardiac arrhythmia or transplant rejection due to non-compliance with the immunotherapeutic regime. The most frequent causes of deaths were pneumonia (28.3%), transplant rejection (11.3%), steroid-induced diabetes (14.6%). It is concluded that heart transplantation should be followed by thorough observation of the patients based at a specialized multi-field clinic to ensure continuous treatment and reduce lethality. Risk factors of unfavourable prognosis of heart transplantation are identified.


Aflatoxin B1 activation in human lung.
Inhalation exposure to the carcinogen aflatoxin B1 (AFB1) in certain occupations is considerable. Because circumstantial epidemiological evidence suggests that AFB1 inhalation may cause primary lung cancer, we investigated AFB1 activation by human lung microsomes. Microsomes were incubated with [3H]AFB1 (124 microM), and activation to the AFB1-8,9-epoxide was measured as the AFB1-glutathione (AFB1-GSH) conjugate by HPLC. The formation of AFB1-GSH was in the range of 0.05-0.073 fmol/mg protein/min. The role of cytochrome P450 (CYP) 3A in this activation was investigated by oxidation of nifedipine (a prototype substrate for CYP 3A), by immunoinhibition, and by immunoblot analysis. Nifedipine oxidation varied from 0.2 to 19.2 pmol/mg protein/min in microsomes from different subjects, but did not correlate with AFB1 activation. Anti-human polyclonal CYP 3A4 IgG inhibited AFB1 activation. CYP 3A isoforms were immunoestimated to be in the range of 0.01-1.90 pmol/mg protein. Neither CYP 1A2 nor associated activity was detected in the lung microsomes. These data indicate that human lung microsomes activate AFB1 to form the exo-AFB1-8,9-epoxide and that CYP(s) of the 3A subfamily may be responsible for this activity. The relatively low amount of AFB1 activation in human lung compared to that in human liver can be explained by the scarcity of CYP-containing cells in the lung. In situ AFB1 activation and resultant carcinogenic risk are distinctly possible in occupational settings where inhalation of AFB1-contaminated dusts occurs.


Fires prime terrestrial organic carbon for riverine export to the global oceans.
Black carbon (BC) is a recalcitrant form of organic carbon (OC) produced by landscape fires. BC is an important component of the global carbon cycle because, compared to unburned biogenic OC, it is selectively conserved in terrestrial and oceanic pools. Here we show that the dissolved BC (DBC) content of dissolved OC (DOC) is twice greater in major (sub)tropical and high-latitude rivers than in major temperate rivers, with further significant differences between biomes. We estimate that rivers export 18 ± 4 Tg DBC year-1 globally and that, including particulate BC fluxes, total riverine export amounts to 43 ± 15 Tg BC year-1 (12 ± 5% of the OC flux). While rivers export ~1% of the OC sequestered by terrestrial vegetation, our estimates suggest that 34 ± 26% of the BC produced by landscape fires has an oceanic fate. Biogeochemical models require modification to account for the unique dynamics of BC and to predict the response of recalcitrant OC export to changing environmental conditions.


Measurement by ICP-MS of lead in plasma and whole blood of lead workers and controls.
To test a simple procedure for preparing samples for measurement of lead in blood plasma (P-Pb) and whole blood (B-Pb) by inductively coupled plasma mass spectrometry (ICP-MS), to measure P-Pb and B-Pb in lead workers and controls, and to evaluate any differences in the relation between B-Pb and P-Pb between people. P-Pb and B-Pb were measured by ICP-MS in 43 male lead smelter workers and seven controls without occupational exposure to lead. For analysis, plasma and whole blood were diluted 1 in 4 and 1 in 9, respectively, with a diluted ammonia solution containing Triton-X 100 and EDTA. The samples were handled under routine laboratory conditions, without clean room facilities. P-Pb was measured with good precision (CV = 5%) even at concentrations present in the controls. Freeze storage of the samples had no effect on the results. The detection limit was 0.015 microgram/l. The P-Pb was 0.15 (range 0.1-0.3) microgram/l in controls and 1.2 (0.3-3.6) micrograms/l in lead workers, although the corresponding B-Pbs were 40 (24-59) micrograms/l and 281 (60-530) micrograms/l (1 microgram Pb/I = 4.8 nmol/l). B-Pb was closely associated with P-Pb (r = 0.90). The association was evidently non-linear; the ratio B-Pb/P-Pb decreased with increasing P-Pb. By means of ICP-MS and a simple dilution procedure, P-Pb may be measured accurately and with good precision down to concentrations present in controls. Contamination of blood at sampling and analysis is no major problem. With increasing P-Pb, the percentage of lead in plasma increases. In studies of lead toxicity, P-Pb should be considered as a complement to current indicators of lead exposure and risk.


Induction, purification, and characterization of two extracellular alpha-L-arabinofuranosidases from Fusarium oxysporum.
In the presence of L-arabinose as sole carbon source, Fusarium oxysporum produces two alpha-L-arabinofuranosidases (ABFs) named ABF1 and ABF2, with molecular masses of 200 and 180 kDa, respectively. The two F. oxysporum proteins have been purified to homogeneity. The purified enzymes are composed of three equal subunits and are neutral proteins with pIs of 6.0 and 7.3 for ABF1 and ABF2, respectively. With p-nitrophenyl alpha-L-arabinofuranoside (pNPA) as the substrate, ABF1 and ABF2 exhibited Km values of 0.39 and 0.28 mmol.L(-1), respectively, and Vmax values of 1.6 and 4.6 micromol.min(-1).(mg of protein)(-1), respectively, and displayed optimal activity at pH 6.0 and 50-60 degrees C. ABFs released arabinose only from sugar beet arabinan and not from wheat soluble and insoluble arabinoxylans. The enzymes were not active on substrates containing ferulic acid ester linked to C-5 and C-2 linkages of pNPA showing that phenolic substituents of pNPA sterically hindered the action of ABFs.


Pharmacotherapy in allergy medicine: from 'ipse dixit' to the evidence-based medicine.
The aim of the article is to examine the contributions made in recent years by evidence-based medicine to the understanding, positioning, and use of drugs for the treatment of the main allergic conditions. Several antiasthmatic drugs have been reappraised for their efficacy characteristics and drug interactions in Cochrane reviews. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines have been reformulated in evidence-based medicine (EBM) terms in 2017; over these years, new point of care instruments contributed to the approximation of the guidelines to real life by drawing from the patients themselves information that allows to finely modeling the pharmacological suggestions. Last, at the time of the emergence of new drugs for the treatment of peanut allergy, new systematic reviews have helped to focus on the most suitable reference outcomes with the aim to respond promptly and adherently to patients' needs. EBM has contributed to changes in the GINA guidelines in the last two years. It has been instrumental in translating the ARIA guidelines in real life. It has also contributed to profiling the potential and limitations of oral peanut immunotherapy. In allergy medicine, EBM is a formidable aid for the advancement of knowledge.


Permanent Deiodinase Type 2 Deficiency Strongly Perturbs Zebrafish Development, Growth, and Fertility.
Iodothyronine deiodinases are selenocysteine-containing enzymes that activate or inactivate thyroid hormones (THs). Deiodinase type 2 (Dio2) catalyzes the conversion of the prohormone T4 into the transcriptionally active T3 and is the predominant activating deiodinase in zebrafish. Using zinc finger nucleases, we generated two different dio2(-/-) mutant zebrafish lines to investigate the physiological function of this TH activator. The first line contains a deletion of 9 bp, resulting in an in-frame elimination of three conserved amino acids. The other line is characterized by an insertion of 4 bp, leading to the introduction of a premature stop-codon. Both lines completely lack Dio2 activity, resulting in a strong reduction of T3 abundancy in all tissues tested. Early development is clearly perturbed in these animals, as shown by a diverse set of morphometric parameters, defects in swim bladder inflation, and disturbed locomotor activity tested between 1 and 7 days after fertilization. Permanent Dio2 deficiency also provokes long-term effects because growth and especially fertility are severely hampered. Possible compensatory mechanisms were investigated in adult dio2(-/-) mutants, revealing a down-regulation of the inactivating deiodinase Dio3 and TH receptor transcript levels. As the first nonmammalian model with permanent Dio2 deficiency, these mutant zebrafish lines provide evidence that Dio2 is essential to assure normal development and to obtain a normal adult phenotype.


Injury patterns in selected high school sports: a review of the 1995-1997 seasons.
To characterize the risk of injury associated with 10 popular high school sports by comparing the relative frequency of injury and selected injury rates among sports, as well as the participation conditions within each sport. A cohort observational study of high school athletes using a surveillance protocol whereby certified athletic trainers recorded data during the 1995-1997 academic years. Players listed on the school's varsity team rosters for football, wrestling, baseball, field hockey, softball, girls' volleyball, boys' or girls' basketball, and boys' or girls' soccer. Injuries and opportunities for injury (exposures) were recorded daily. The definition of reportable injury used in the study required that certified athletic trainers evaluate the injured players and subsequently restrict them from participation. Football had the highest injury rate per 1000 athlete- exposures at 8.1, and volleyball had the lowest rate at 1.7. Only boys' (59.3%) and girls' (57.0%) soccer showed a larger proportion of reported injuries for games than practices, while volleyball was the only sport to demonstrate a higher injury rate per 1000 athlete-exposures for practices than for games. More than 73% of the injuries restricted players for fewer than 8 days. The proportion of knee injuries was highest for girls' soccer (19.4%) and lowest for baseball (10.5%). Among the studied sports, sprains and strains accounted for more than 50% of the injuries, except in field hockey (45.7%). Of the injuries requiring surgery, 60.3% were to the knee. An inherent risk of injury is associated with participation in high school sports based on the nature of the game and the activities of the players. Therefore, injury prevention programs should be in place for both practices and games. Preventing reinjury through daily injury management is a critical component of an injury prevention program. Although sports injuries cannot be entirely eliminated, consistent and professional evaluation of yearly injury patterns can provide focus for the development and evaluation of injury prevention strategies.


[Anisotropic electric conductivity of bacterial suspensions induced by external electric field].
The anisotropy of electrical conductivity of suspensions of such bacteria, as E. coli, Serratia marcescens, Pseudomonas fluorescens induced by a sinusoidal external electric field and relaxation of the anisotropy after switching off the field were investigated. On the basis of the experimental relationships the anisotropy of electrical polarizability and coefficient of rotational diffusion of the cells were evaluated. The anisotropy of electrical polarizability and coefficient of the rotational diffusion obtained are in a good agreement with the available data of other methods.


Synthetic pathways to tetrahydrocannabinol (THC): an overview.
The therapeutic effects of molecules produced by the plant species Cannabis sativa have since their discovery captured the interest of scientists and society, and have spurred the development of a multidisciplinary scientific field with contributions from biologists, medical specialists and chemists. Decades after the first isolation of some of the most bioactive tetrahydrocannabinols, current research is mostly dedicated to exploiting the chemical versatility of this relevant compound class with regard to its therapeutic potential. This review will primarily focus on synthetic pathways utilised for the synthesis of tetrahydrocannabinols and derivatives thereof, including chiral pool-based and asymmetric chemo- and biocatalytic approaches.


Simplification of Rabies Postexposure Prophylaxis: A New 2-Visit Intradermal Vaccine Regimen.
A 2-visit multiple-site intradermal (ID) vaccine protocol would be the most economical, immunogenic, and practicable regimen for postexposure rabies prophylaxis (PEP) in clinics seeing few patients a month. This regimen with an additional day 28 dose is now recommended by the WHO. The difficulties surrounding ID rabies vaccination have hindered progress in provision of prophylaxis, especially in rural Asia and Africa. Although the latest WHO recommendations include 1-week ID postexposure vaccine regimens, these are unlikely to prove economical where rabies vaccination is presently unavailable. The new protocol uses a whole vial of vaccine divided between 4-sites ID on the first day and half a vial at 2-sites ID on day 7. Gavi has recently approved support for rabies PEP. This 2-visit 4-site ID regimen, with or without a day 28 dose, should be considered for implementation in this remarkable new initiative.


[The iatrogenic fornix rupture after endoscopic extraction of an ureteral stone via ureterorenoscopy].
Iatrogenic fornix rupture caused during retrograde manipulation of the ureter is a rather rare or rarely diagnosed phenomenon. A 22 year-old female patient presented with fornix rupture following endoscopic ureteral stone extraction under ureterorenoscopy, the rupture having become symptomatic 2 days later. Diagnostics were done by means of sonography and radiography and confirmed by CT-scan performed to rule out abscess formation which may have occurred in this case of delayed symptoms. Conservative antibiotic therapy was sufficient in this case. Ca. 10 % of all perirenal abscesses are attributed to urinary extravasation due to fornix ruptures, requiring surgical intervention. Regular sonographic control is therefore strongly recommended when fornix rupture is suspected to ensure appropriate counter measures.


[REASONS FOR NON-VACCINATION AGAINST INFLUENZA IN HEALTH WORKERS].
Health workers are a risk group for acquisition and transmission of influenza. Therefore each year the vaccine is indicated for them. However vaccination coverage against seaso nable influenza virus in our country is often low. To determine why the professionals of health centers have low rates of vaccination against influenza. knowing the reasons for to have intention to be vaccinated and analyze knowledge about influenza and vaccination. A descriptive study carried out in Hospital Center of Vigo between 2014-2015. Data were collected by a self-administered questionnaire aimed at health professionals. Variables recorded were age, sex, profession, workplace, work experience, previous influenza vaccines, intention to be vaccinated, reasons for non-vaccination and knowledge about the disease and influenza vaccine. Statistical analysis was performed with the PSPP program and the associations between variables were evaluated using Chi-square test. 375 questionnaires were obtained. Only 18 % of workers were vaccinated last season. The reasons for not having intention to be vaccinated were: believe that it is not necessary (28 %), it is not effective (27 %) and risk of side effects (26 %). The main reason to have intention to be vaccinated was self-protection in 71 %. Working in a health center means risk of getting the flu for 66 % of survey respondents, though 68 % of them think unimportant the vaccination in health professionals. Statistical significance between sexand vaccination lastseason was found (p = 0.023). It is necessary to increase knowledge about influenza and vaccination by developing specific training to improve vaccination coverage among health care workers.


Insights into the inhibitory mechanisms of the regulatory protein IIA(Glc) on melibiose permease activity.
The phosphotransfer protein IIA(Glc) of the bacterial phosphoenolpyruvate:carbohydrate phosphotransferase system plays a key role in the regulation of carbohydrate metabolism. Melibiose permease (MelB) is one among several permeases subject to IIA(Glc) regulation. The regulatory mechanisms are poorly understood; in addition, thermodynamic features of IIA(Glc) binding to other proteins are also unknown. Applying isothermal titration calorimetry and amine-specific cross-linking, we show that IIA(Glc) directly binds to MelB of Salmonella typhimurium (MelB(St)) and Escherichia coli MelB (MelB(Ec)) at a stoichiometry of unity in the absence or presence of melibiose. The dissociation constant values are 3-10 μM for MelB(St) and 25 μM for MelB(Ec). All of the binding is solely driven by favorable enthalpy forces. IIA(Glc) binding to MelB(St) in the absence or presence of melibiose yields a large negative heat capacity change; in addition, the conformational entropy is constrained upon the binding. We further found that the IIA(Glc)-bound MelB(St) exhibits a decreased binding affinity for melibiose or nitrophenyl-α-galactoside. It is believed that sugar binding to the permease is involved in an induced fit mechanism, and the transport process requires conformational cycling between different states. Thus, the thermodynamic data are consistent with the interpretation that IIA(Glc) inhibits the induced fit process and restricts the conformational dynamics of MelB(St).


JBI's Systematic Reviews: Study selection and critical appraisal.
This article is the fourth in a series on the systematic review from the Joanna Briggs Institute, an international collaborative supporting evidence-based practice in nursing, medicine, and allied health fields. The purpose of the series is to describe how to conduct a systematic review-one step at a time. This article focuses on the study selection and critical appraisal steps in the process. These steps ensure that the review produces valid results capable of providing a useful basis for informing policy, clinical practice, and future research.


The clinical effectiveness of fluorescence and reflectance spectroscopy for the in vivo diagnosis of cervical neoplasia: an analysis by phase of trial design.
In this review, we focus on the pilot, Phase I, II, and III clinical trials of fluorescence spectroscopy, reflectance spectroscopy, and their combination for the in vivo diagnosis of cervical neoplasia using both point probe and multi-spectral imaging approaches. Research groups that have progressed from pilot through Phase II/III clinical trials were analyzed. A formal search was conducted to identify articles which report the performance of fluorescence and reflectance spectroscopy trials which diagnose cervical neoplasia in vivo. This report focuses on the funding source, prevalence of disease in the trials, type of population (screening versus diagnostic), gold standard criterion for diagnosis (histopathology versus colposcopy alone and histopathology), histopathologic classification (World Health Organization (WHO) 8 categories, Bethesda 5 categories, or both (13 categories)), number of clinical trial sites, number of medical investigators, number of histopathology reviews by histopathologists for a consensus diagnosis, use of acetic acid, explicit sample size calculation in the published report, actual sample size in the trial, ages of patients included in the trial, and the phase of the trial design, as they affect performance and plotted as sensitivity and 1-specificity. Twenty-six studies were included and their heterogeneity precluded formal meta-analytic combination. While most factors inherent in the review were not significant sources of variability; there were three variables that affected performance, i.e., sample size, age of patients, and phase of trial design. As with pharmaceutical trials, as the sample size increased, as the heterogeneity of the population increased, as the age of the patients included patients over 50 years old, and as the phase of clinical trial design progressed from pilot through Phase III randomized trial, the performance of all devices decreased.


Abrogation of tumorigenicity by MHC class II antigen expression requires the cytoplasmic domain of the class II molecule.
Transfection of syngeneic MHC class II genes into the lethal mouse SaI tumor abrogates the malignancy of the tumor in the autologous host, and protects the host against subsequent challenges with the wild type class II- tumor. We have hypothesized that the transfectants induce protective immunity by functioning as APC for tumor peptides, and stimulating tumor-specific Th cells. Recent in vitro studies suggest that Ag presentation by class II-restricted APC requires the cytoplasmic domain of the class II molecule, and may involve intracellular signaling via the cytoplasmic domain. To determine if the class II cytoplasmic domain is required for enhanced tumor-specific immunity, SaI mouse sarcoma cells were transfected with syngeneic Aak and Abk genes with truncated cytoplasmic domains. These transfectants are as malignant as wild type class II- SaI cells in autologous A/J mice. Stimulation of tumor-specific immunity by class II+ tumor cells is therefore dependent on the class II cytoplasmic region, and may involve intracellular signaling events.


Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways.
The development of colorectal cancer (CRC) is strongly correlated with the aberrant activation of multiple intracellular signaling transduction cascades including STAT3, ERK, JNK and p38 pathways which usually function redundantly. In addition, crosstalk between these pathways forms a complicated signaling network that is regulated by compensatory mechanisms. Therefore, most of the currently used and single-target-based antitumor agents might not always be therapeutically effective. Moreover, long-term use of these agents often generates drug resistance. These problems highlight the urgent need for the development of novel anticancer chemotherapies. Ursolic acid (UA) is a major active compound present in many medicinal herbs that have long been used for the clinical treatment of CRC. Although previous studies have demonstrated an antitumor effect for UA, the precise mechanisms of its tumoricidal activity are not well understood. In the present study, using CRC mouse xenograft model and the HT-29 human colon carcinoma cell line, we evaluated the efficacy of UA against tumor growth in vivo and in vitro and investigated the underlying molecular mechanisms. We found that UA inhibits cancer growth without apparent toxicity. Furthermore, UA significantly suppresses the activation of several CRC-related signaling pathways and alters the expression of critical target genes. These molecular effects lead to the induction of apoptosis and inhibition of cellular proliferation. These data demonstrate that UA possesses a broad range of anticancer activities due to its ability to affect multiple intracellular targets, suggesting that UA could be a novel multipotent therapeutic agent for cancer treatment.


Succinate dehydrogenase-dependent nutritional requirement for succinate in mutants of Escherichia coli K12.
Lipoic acid (lip) and 2-oxoglutarate dehydrogenase (sucA) mutants of Escherichia coli K12 exhibit a requirement for exogenous succinate during aerobic growth on glucose minimal medium. Reversion studies have shown that this requirement can be suppressed by gal-linked mutations which inactivate succinate dehydrogenase. Biochemical and genetic studies confirmed that the succinate dehydrogenase gene (sdh) is affected and that suppression is mediated by the same intergenic and indirect mechanism that generates succinate independence in partial revertants of lipoamide dehydrogenase mutants (Creaghan & Guest, 1977). A series of isogenic strains containing all combinations of mutations affecting 2-oxoglutarate dehydrogenase (sucA), succinate dehydrogenase (sdh), isocitrate lyase (aceA) and fumarate reductase (frd) in a background lacking succinate semialdehyde dehydrogenase, was constructed to assess the importance of these enzymes as sources of endogenous succinate (succinyl-CoA) during aerobic and anaerobic growth on glucose. Only strains combining a deficiency in 2-oxoglutarate dehydrogenase with the presence of an active succinate dehydrogenase required succinate for aerobic growth. In all mutants, including the triple mutant (frd sucA aceA), the succinate requirement was suppressed by inactivating succinate dehydrogenase. The aerobic growth rates of succinate-independent strains were most affected by lack of isocitrate lyase but only two mutants (sdh sucA aceA and frd sdh sucA aceA) grew faster with added succinate: the growth yields were lowered by deficiencies in isocitrate lyase and also succinate dehydrogenase. It is concluded that very little succinate is needed for biosynthesis during aerobic growth on glucose and the requirement for relatively high concentrations of succinate (2 mM) by mutants lacking 2-oxoglutarate dehydrogenase or related functions stems from the presence of active succinate dehydrogenase. Anaerobically, either isocitrate lyase or fumarate reductase is essential for succinate-independent growth on glucose.


Use of cumulative meta-analysis in the design, monitoring, and final analysis of a clinical trial: a case study.
From 1983 to 1987, the Department of Veterans Affairs (DVA) Cooperative Studies Program (CSP) conducted a multicenter clinical trial (CSP #207) to determine whether four different antiplatelet regimens compared to placebo could prevent the occlusion of grafts following coronary artery bypass surgery. The study showed that all of the active regimens tended to be better than placebo and that the three regimens containing aspirin were statistically significantly better. A cumulative meta-analysis of 12 trials performed shortly before the end of CSP #207 raised the issue as to whether the meta-analysis, if done earlier, would have changed the conduct of the trial. At the start of the planning period, one trail of size n = 37 had been published with a nonsignificant odds ratio (OR) of 0.74 (95% CI: 0.18, 3.12). At the time that CSP # 207 was approved by the DVA Cooperative Studies Evaluation Committee, two trials had been published (cumulative n = 150, OR = 0.44, 95% CI 0.19, 0.99). At the time patient intake started, five trials showed cumulative n = 769, OR = 0.42, 95% CI = 0.26, 0.68. Although the first 6-month CSP #207 progress report showed no treatment effect, by the time of the 12-month review by the Data Monitoring Board (DMB) a trend was developing in favor of active treatment. If the results of the meta-analysis had been available to the DMB at that time, conceivably the Board would have recommended stopping the placebo arm because of a convincing treatment effect based on the totality of the evidence. Cumulative meta-analysis could be useful as an adjunct in the planning, conduct, and final analysis of a clinical trial. It could also be used as one piece of evidence in the monitoring of the ongoing phase of a trial.


Quantification of intrathoracic fat adds prognostic value in women undergoing myocardial perfusion imaging.
Amongst patients with coronary artery disease (CAD), women experience relatively worse outcomes as compared to men. Evidence to date has failed to explore unique female imaging targets as major determinants of cardiovascular risk. We sought to assess the prognostic value of epicardial (EFV) and intrathoracic fat volume (IFV) quantification in women and men with suspected and known CAD. Intrathoracic fat volume and EFV were calculated from non-contrast CT and analyzed in a propensity-matched cohort of 190 patients (95 women, mean age 62.5 ± 11.3 years) undergoing myocardial perfusion imaging (MPI) and coronary computed tomography angiography (CCTA) for evaluation of CAD. IFV and EFV were significantly lower in women as compared to men (198.2 ± 78.4 vs 293.2 ± 114.7 cm3 and 105.6 ± 48.9 vs 135.8 ± 60.9 cm3, p < 0.001) and showed a strong association with coronary artery calcium score (CACS) and obstructive CAD in women (p < 0.05), but not in men. Fat volumes were not related to abnormal MPI in either population (p = NS). During a median follow-up of 2.8 years, high IFV was associated with reduced event free survival (log rank = 0.019 vs low IFV) in women, but not in men. Accordingly, a multivariate Cox regression model adjusted for cardiovascular risk factors, CACS, CCTA, and MPI findings selected IFV as a significant predictor of major adverse cardiovascular events (MACE) in women (HR 1.32, 95%CI 1.18-1.55, p = 0.001). Quantification of IFV provides incremental prognostic value for MACE in women, beyond that provided by traditional risk factors and imaging findings.


Activation of Slo2.1 channels by niflumic acid.
Slo2.1 channels conduct an outwardly rectifying K(+) current when activated by high [Na(+)](i). Here, we show that gating of these channels can also be activated by fenamates such as niflumic acid (NFA), even in the absence of intracellular Na(+). In Xenopus oocytes injected with <10 ng cRNA, heterologously expressed human Slo2.1 current was negligible, but rapidly activated by extracellular application of NFA (EC(50) = 2.1 mM) or flufenamic acid (EC(50) = 1.4 mM). Slo2.1 channels activated by 1 mM NFA exhibited weak voltage dependence. In high [K(+)](e), the conductance-voltage (G-V) relationship had a V(1/2) of +95 mV and an effective valence, z, of 0.48 e. Higher concentrations of NFA shifted V(1/2) to more negative potentials (EC(50) = 2.1 mM) and increased the minimum value of G/G(max) (EC(50) = 2.4 mM); at 6 mM NFA, Slo2.1 channel activation was voltage independent. In contrast, V(1/2) of the G-V relationship was shifted to more positive potentials when [K(+)](e) was elevated from 1 to 300 mM (EC(50) = 21.2 mM). The slope conductance measured at the reversal potential exhibited the same [K(+)](e) dependency (EC(50) = 23.5 mM). Conductance was also [Na(+)](e) dependent. Outward currents were reduced when Na(+) was replaced with choline or mannitol, but unaffected by substitution with Rb(+) or Li(+). Neutralization of charged residues in the S1-S4 domains did not appreciably alter the voltage dependence of Slo2.1 activation. Thus, the weak voltage dependence of Slo2.1 channel activation is independent of charged residues in the S1-S4 segments. In contrast, mutation of R190 located in the adjacent S4-S5 linker to a neutral (Ala or Gln) or acidic (Glu) residue induced constitutive channel activity that was reduced by high [K(+)](e). Collectively, these findings indicate that Slo2.1 channel gating is modulated by [K(+)](e) and [Na(+)](e), and that NFA uncouples channel activation from its modulation by transmembrane voltage and intracellular Na(+).


Assessing Bone Mineral Density Using Radiographs of the Hand: A Multicenter Validation.
Osteoporosis and fragility fractures incur substantial costs to quality of life and global health care systems. The current gold standard for quantifying bone density is dual-energy X-ray absorptiometry. Our hypothesis is that bone density can be accurately predicted with a simpler method using plain radiographs of the hand. This retrospective cohort study was undertaken in two centers in the United Kingdom, where the second metacarpal cortical percentage (2MCP) scores were calculated from radiographs. This study included patients who had sustained a distal radius fracture between 2020 and 2022 and had received both a posteroanterior radiograph of the hand and a dual-energy X-ray absorptiometry scan within 12 months of their radiograph and fracture. The Pearson correlation coefficient was calculated to determine the correlation between 2MCP scores and t-scores of the femoral neck on dual-energy X-ray absorptiometry scans. Of the 188 patients, the 2MCP score significantly correlated with bone density t-scores of the femoral neck. A 2MCP score <50% demonstrated 100% sensitivity and 100% specificity for differentiating osteoporotic from normal subjects, whereas a 2MCP score <60% demonstrated 94.4% sensitivity and 83.0% specificity in differentiating osteopenic from normal subjects. These data confirm that the likelihood of osteoporosis being present can be determined via the 2MCP score. Diagnostic I.


Real-World Practice Patterns in the Era of Rectal Indomethacin for Prophylaxis Against Post-ERCP Pancreatitis in a High-Risk Cohort.
The benefit of indomethacin suppositories for prophylaxis against post-ERCP pancreatitis (PEP) in high-risk patients was established in a landmark trial published in 2012. The aims of this study were to measure the adoption of indomethacin prophylaxis in widespread clinical practice, evaluate concurrent trends in pancreatic duct (PD) stent utilization, and estimate the impact of these changes on PEP in a high-risk population. Data were extracted from a commercial database (Explorys, IBM Watson Health, Somers, NY) that aggregates electronic health records from 26 US healthcare systems from 2009 to 2018. Using Systematized Nomenclature of Medicine Clinical Terms, we identified a cohort of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) and were at high risk for PEP based on narrow criteria. PEP was defined as an emergency department or hospital admission 1-5 days after ERCP with an associated diagnosis of pancreatitis. Twenty six thousand eight hundred twenty ERCPs were performed on this high-risk cohort from 2009 to 2018. The overall PEP rate during the study period was 8.6%. There was no decrease in PEP rates from 2012 to 2018. Beginning in 2012, indomethacin usage increased linearly (P < 0.001), but remained below 50% in 2018. As indomethacin increased, utilization of PD stents declined abruptly from 2013 to 2014 (40.7%-8.5%) and trended to a nadir of 3.0%. Despite its low cost, widespread availability, and level I evidence of benefit in reducing the risk of PEP in high-risk patients, the adoption of rectal indomethacin during ERCP has been slow and the medication continues to be under-utilized. In parallel, the PD stent usage has declined dramatically. The lack of change in PEP rates during the study period could be attributable to the persistent low usage of rectal indomethacin or the decline in PD stent use. Further educational efforts and quality assurance measures are warranted to ensure that rectal indomethacin and PD stent placement are more appropriately used in clinical practice.