Experimental Investigation of the Atmosphere-Regolith Water Cycle on Present-Day Mars.
The water content of the upper layers of the surface of Mars is not yet quantified. Laboratory simulations are the only feasible way to investigate this in a controlled way on Earth, and then compare it with remote and in situ observations of spacecrafts on Mars. Describing the processes that may induce changes in the water content of the surface is critical to determine the present-day habitability of the Martian surface, to understand the atmospheric water cycle, and to estimate the efficiency of future water extraction procedures from the regolith for In Situ Resource Utilization (ISRU). This paper illustrates the application of the SpaceQ facility to simulate the near-surface water cycle under Martian conditions. Rover Environmental Monitoring Station (REMS) observations at Gale crater show a non-equilibrium situation in the atmospheric H2O volume mixing ratio (VMR) at night-time, and there is a decrease in the atmospheric water content by up to 15 g/m2 within a few hours. This reduction suggests that the ground may act at night as a cold sink scavenging atmospheric water. Here, we use an experimental approach to investigate the thermodynamic and kinetics of water exchange between the atmosphere, a non-porous surface (LN2-chilled metal), various salts, Martian regolith simulant, and mixtures of salts and simulant within an environment which is close to saturation. We have conducted three experiments: the stability of pure liquid water around the vicinity of the triple point is studied in experiment 1, as well as observing the interchange of water between the atmosphere and the salts when the surface is saturated; in experiment 2, the salts were mixed with Mojave Martian Simulant (MMS) to observe changes in the texture of the regolith caused by the interaction with hydrates and liquid brines, and to quantify the potential of the Martian regolith to absorb and retain water; and experiment 3 investigates the evaporation of pure liquid water away from the triple point temperature when both the air and ground are at the same temperature and the relative humidity is near saturation. We show experimentally that frost can form spontaneously on a surface when saturation is reached and that, when the temperature is above 273.15 K (0 °C), this frost can transform into liquid water, which can persist for up to 3.5 to 4.5 h at Martian surface conditions. For comparison, we study the behavior of certain deliquescent salts that exist on the Martian surface, which can increase their mass between 32% and 85% by absorption of atmospheric water within a few hours. A mixture of these salts in a 10% concentration with simulant produces an aggregated granular structure with a water gain of approximately 18- to 50-wt%. Up to 53% of the atmospheric water was captured by the simulated ground, as pure liquid water, hydrate, or brine.


The compartmentation of phosphorylated thiamine derivatives in cultured neuroblastoma cells.
Thiamine transport in cultured neuroblastoma cells is mediated by a high-affinity carrier (KM = 40 nM). In contrast, the uptake of the more hydrophobic sulbutiamine (isobutyrylthiamine disulfide) is unsaturable and its initial transport rate is 20-times faster than for thiamine. In the cytoplasm, sulbutiamine is rapidly hydrolyzed and reduced to free thiamine, the overall process resulting in a rapid and concentrative thiamine accumulation. Incorporation of radioactivity from [14C]thiamine or [14C]sulbutiamine into intracellular thiamine diphosphate is slow in both cases. Despite the fact that the diphosphate is probably the direct precursor for both thiamine monophosphate and triphosphate, the specific radioactivity increased much faster for the latter two compounds than for thiamine diphosphate. This suggests the existence of two pools of thiamine diphosphate, the larger one having a very slow turnover (about 17 h); a much smaller, rapidly turning over pool would be the precursor of thiamine mono- and triphosphate. The turnover time for thiamine triphosphate could be estimated to be 1-2 h. When preloading the cells with [14C]sulbutiamine was followed by a chase with the same concentration of the unlabeled compound, the specific radioactivities of thiamine and thiamine monophosphate decreased exponentially as expected, but labeling of the diphosphate continued to increase slowly. Specific radioactivity of thiamine triphosphate increased first, but after 30 min it began to slowly decrease. These results show for the first time the existence of distinct thiamine diphosphate pools in the same homogeneous cell population. They also suggest a complex compartmentation of thiamine metabolism.


Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes through Dopamine D3 Receptor Blockade.
Background: Several efforts have been made to develop effective antipsychotic drugs. Currently, available antipsychotics are effective on positive symptoms, less on negative symptoms, but not on cognitive impairment, a clinically relevant dimension of schizophrenia. Drug repurposing offers great advantages over the long-lasting, risky and expensive, de novo drug discovery strategy. To our knowledge, the possible antipsychotic properties of buspirone, an azapirone anxiolytic drug marketed in 1986 as serotonin 5-HT1A receptor (5-HT1AR) partial agonist, have not been extensively investigated despite its intriguing pharmacodynamic profile, which includes dopamine D3 (D3R) and D4 receptor (D4R) antagonist activity. Multiple lines of evidence point to D3R as a valid therapeutic target for the treatment of several neuropsychiatric disorders including schizophrenia. In the present study, we tested the hypothesis that buspirone, behaving as dopamine D3R antagonist, may have antipsychotic-like activity. Materials and Methods: Effects of acute administration of buspirone was assessed on a wide-range of schizophrenia-relevant abnormalities induced by a single administration of the non-competitive NMDAR antagonist MK-801, in both wild-type mice (WT) and D3R-null mutant mice (D3R-/-). Results: Buspirone (3 mg⋅kg-1, i.p.) was devoid of cataleptogenic activity in itself, but resulted effective in counteracting disruption of prepulse inhibition (PPI), hyperlocomotion and deficit of temporal order recognition memory (TOR) induced by MK-801 (0.1 mg⋅kg-1, i.p.) in WT mice. Conversely, in D3R-/- mice, buspirone was ineffective in preventing MK-801-induced TOR deficit and it was only partially effective in blocking MK-801-stimulated hyperlocomotion. Conclusion: Taken together, these results indicate, for the first time, that buspirone, might be a potential therapeutic medication for the treatment of schizophrenia. In particular, buspirone, through its D3R antagonist activity, may be a useful tool for improving the treatment of cognitive deficits in schizophrenia that still represents an unmet need of this disease.


Determination of the Genome and Primary Transcriptome of Syngas Fermenting Eubacterium limosum ATCC 8486.
Autotrophic conversion of CO2 to value-added biochemicals has received considerable attention as a sustainable route to replace fossil fuels. Particularly, anaerobic acetogenic bacteria are naturally capable of reducing CO2 or CO to various metabolites. To fully utilize their biosynthetic potential, an understanding of acetogenesis-related genes and their regulatory elements is required. Here, we completed the genome sequence of the syngas fermenting Eubacterium limosum ATCC 8486 and determined its transcription start sites (TSS). We constructed a 4.4 Mb long circular genome with a GC content of 47.2% and 4,090 protein encoding genes. To understand the transcriptional and translational regulation, the primary transcriptome was augmented, identifying 1,458 TSSs containing a high pyrimidine (T/C) and purine nucleotide (A/G) content at the -1 and +1 position, respectively, along with 1,253 5'-untranslated regions, and principal promoter elements such as -10 (TATAAT) and -35 (TTGACA), and Shine-Dalgarno motifs (GGAGR). Further analysis revealed 93 non-coding RNAs, including one for potential transcriptional regulation of the hydrogenase complex via interaction with molybdenum or tungsten cofactors, which in turn controls formate dehydrogenase activity of the initial step of Wood-Ljungdahl pathway. Our results provide comprehensive genomic information for strain engineering to enhance the syngas fermenting capacity of acetogenic bacteria.


Allelic variation and prevalence of serum opacity factor among the Streptococcus suis population.
Serum opacity factor of Streptococcus suis (OFS) has recently been identified as a virulence determinant of an S. suis strain. In this study, we investigated the prevalence and variations of the ofs gene among 108 S. suis isolates from diseased and healthy pigs, and human patients. PCR screening and sequencing analysis showed that besides the ofs gene reported already (designated type 1), there were three allelic variants of ofs (designated types 2 to 4). Type-1 and type-2 ofs genes were expected to encode functional OFS, and SDS extracts of the isolates with type-1 ofs and type-2 ofs opacified horse serum. Culture supernatants of the isolates with type-2 ofs also showed strong serum opacification activity. In contrast, type-3 ofs was interrupted by a point mutation and type-4 ofs was disrupted by either insertion of an IS element or genetic rearrangement, and therefore the SDS extracts and culture supernatants of the isolates with type-3 ofs and type-4 ofs did not show serum opacification activity. Regardless of their origins, approximately 30 % of the isolates possessed functional OFSs, although type-2 ofs was found only in three isolates from healthy pigs. Multilocus sequence typing analysis showed that most of the isolates with type-1 ofs belonged to the sequence type (ST)1 complex, and most of the isolates with type-3 ofs and type-4 ofs belonged to the ST27 complex. The isolates with type-2 ofs were not assigned to a major ST complex. These results suggest that type-1 OFS contributes to the virulence of a limited number of S. suis isolates, i.e. those of the ST1 complex type, whereas other S. suis may not possess this category of virulence factor; the importance of type-2 OFS is obscure.


Living patches engineered from human umbilical cord derived fibroblasts and endothelial progenitor cells.
A major shortcoming in contemporary congenital heart surgery is the lack of viable replacement materials with the capacity of growth and regeneration. Here we focused on living autologous patches engineered from human umbilical cord derived fibroblasts and endothelial progenitor cells (EPCs) as a ready-to-use cell source for paediatric cardiovascular tissue engineering. EPCs were isolated from 20 ml fresh umbilical cord blood by density gradient centrifugation and myofibroblasts were harvested from umbilical cord tissue. Cells were differentiated and expanded in vitro using nutrient media containing growth factors. Before seeding, cell-phenotypes were assessed by immuno-histochemistry. Biodegradable patches fabricated from synthetic polymers (PGA/P4HB) were seeded with myofibroblasts followed by endothelialization with EPCs. All patches were cultured in a perfusion bioreactor. A subgroup of patches was additionally stimulated by cyclic strain. Analysis of the neo-tissues comprised histology, immuno-histochemistry, extracellular matrix (ECM) analysis and biomechanical testing. Endothelial phenotypes of EPCs before seeding were confirmed by Ac-Dil-LDL, CD 31, von-Willebrand-Factor and eNOS staining. Histology of the seeded patches demonstrated layered viable tissue formation in all samples. The cells in the newly formed tissues expressed myofibroblast markers, such as desmin and alpha-SMA. The EPCs derived neo-endothelia showed constant endothelial phenotypes (CD 31, vWF). major constituents of ECM such as collagen and proteoglycans were biochemically detected. Stress-strain properties of the patches showed features of native-analogous tissues. Living tissue engineered patches can be successfully generated from human umbilical cord derived myofibroblasts and EPCs. This new cell source may enable the tissue engineering of versatile, living, autologous replacement materials for congenital cardiac interventions.


Expression of matrix proteinases during human intrahepatic bile duct development. A possible role in biliary cell migration.
Primitive biliary cells are known to migrate from the ductal plate into the mesenchyme during human intrahepatic bile duct development, and this migration process is essential for normal development of intrahepatic bile ducts. However, its molecular mechanism is unknown. Matrix proteinases play an important role in cell migration during cancer invasion and organ development. In this study, we therefore investigated in situ expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) during human intrahepatic bile duct development, using 32 human fetal livers. We also examined in situ expression of trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B, which are matrix proteinases and activators of MMP. MMP-1 expression was noted in the ductal plate and migrating primitive biliary cells. MMP-2, MMP-3, and MMP-9 were expressed in the ductal plate. TIMP-1 and TIMP-2 were expressed in the ductal plate and migrating primitive biliary cells. Trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B were also expressed in primitive biliary cells. These data suggest that MMP, trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B play a critical role in biliary cell migration during human intrahepatic bile duct development by degrading extracellular matrix proteins. The data also suggest that MMP inhibitors (TIMP-1 and TIMP-2) and MMP activators (trypsin, chymotrypsin, and cathepsin B) play an important role in biliary cell migration. The coordinated expression of MMP, MMP inhibitors, and MMP activators may be necessary for the normal development of human intrahepatic bile ducts.


Psycho-social characteristics in patients with discopathy: Quality of Life, coping strategy and mood state.
The pathologies of the musculoskeletal apparatus are the most common cause of chronic diseases, with a huge impact on people and society. Scientific literature has discovered how experiencing chronic pain directly affects peoples' well-being, lifestyle, social relationships and can also cause psychological distress. The present study aims to investigate pain experience in patients with hernias or protrusions of the cervical and lumbosacral tract on a sample of 120 patients, recruited from patients of Poliambulatorio Oberdan, medical centre in Brescia (Italy) specialized in physical rehabilitation and CT-guided oxygen ozone therapy. In a bio-psychosocial perspective, the research aimed to investigate how the perception of pain, the mood state associated with it, the coping strategies adopted and the quality of life differ according to each patient's gender and to the more or less prolonged use of pain medication. The data were collected by means of medical and psychological anamnestic interviews and self-report tests (WHOQOL-BREF, COPE-NVI, POMS). The quantitative analysis, carried out through SPSS 25 (2017) software, showed how functional impairment of one's autonomy (walking, driving) affects mood states. In particular, the female sample expressed a more deflected mood, despite the greater use of relational and/or transcendent support (coping strategies) compared to men. The study suggests that the greater impairment of the moods of women can be attributed both to the caregiving role they play, which often results in a greater fatigue and difficulties in redefining this role following the algic condition, and more general differences in the expression of suffering, which, on a cultural level, sees men emotionally coerced. The analysis also shows how taking pain medication for a long period of time has a negative impact on the quality of life. The results suggest that the patients treated with analgesic therapy tend to adopt avoidant coping styles, which usually escalate into postponement of the time when dealing with a stressful situation and, if used in the long run, may lead to worsening health condition.


Intrinsic Size Effect in Scaffolded Porous Calcium Silicate Particles and Mechanical Behavior of Their Self-Assembled Ensembles.
Scaffolded porous submicron particles with well-defined diameter, shape, and pore size have profound impacts on drug delivery, bone-tissue replacement, catalysis, sensors, photonic crystals, and self-healing materials. However, understanding the interplay between pore size, particle size, and mechanical properties of such ultrafine particles, especially at the level of individual particles and their ensemble states, is a challenge. Herein, we focus on porous calcium-silicate submicron particles with various diameters-as a model system-and perform extensive 900+ nanoindentations to completely map out their mechanical properties at three distinct structural forms from individual submicron particles to self-assembled ensembles to pressure-induced assembled arrays. Our results demonstrate a notable "intrinsic size effect" for individual porous submicron particles around ∼200-500 nm, induced by the ratio of particle characteristic diameter to pore characteristic size distribution. Increasing this ratio results in a brittle-to-ductile transition where the toughness of the submicron particles increases by 120%. This size effect becomes negligible as the porous particles form superstructures. Nevertheless, the self-assembled arrays collectively exhibit increasing elastic modulus as a function of applied forces, while pressure-induced compacted arrays exhibit no size effect. This study will impact tuning properties of individual scaffolded porous particles and can have implications on self-assembled superstructures exploiting porosity and particle size to impart new functionalities.


Variation in fat content between liver lobes and comparison with histopathological scores in dairy cows with fatty liver.
The assessment of a liver biopsy remains the gold standard for diagnosing and staging fatty liver in dairy cows, which is often necessary for diagnostic and research purposes. Accuracy of the diagnosis relays on the quality of the biopsy, the assumed representativeness of a small tissue sample for a disease process throughout the liver and accurate human evaluation of histologic specimens. The objective of the present study was to assess the distribution of triacylglycerol (TAG) infiltration throughout the parenchyma of livers with different degrees of fatty liver in dairy cows. In addition, histopathological scores from the corresponding specimens were compared to a quantitative measurement of TAG, as well as the agreement between two observers. Thirty livers with different degrees of lipid infiltration were selected and 10 different locations throughout the liver were assessed. The TAG content was measured enzymatically, calculated in % or mg/g wet weight, and assigned to a scoring system. Corresponding tissue specimens were stained with hematoxylin-eosin (H&E) and Oil red O (ORO) for histopathological evaluation, using a scoring system. The difference in TAG content between any locations was less than 2%. Based on the scoring system the TAG concentration was even distributed in 79.3% of the livers. Based on kappa statistics the agreement between two pathologists and staining technique in scoring histological specimens was moderate to fair. Overall the distribution of TAG throughout the liver and the accuracy of human evaluation of liver biopsies may lead to acceptable diagnoses for clinical purposes. Within the liver lobules a common pattern of lipid distribution depending on severity could be observed. For the staging of lipid infiltration for research projects, some degree of variation needs to be considered.


Loss of heterozygosity and p53 gene mutations in breast cancer.
Immunopositivity for the p53 tumor suppressor gene product was evaluated in 133 breast cancers and compared to loss of heterozygosity (LOH) at various chromosomal loci. The validity of p53 immunopositivity as an indicator for p53 mutations was verified using two molecular assays of p53 mutations: single stranded conformational polymorphism (32 cases) and/or direct sequencing (14 cases). Immunopositivity was highly specific for mutations, since all of 15 strongly immunopositive tumors (> 10% of the cells are positive) and seven of nine cases with borderline immunopositivity had mutations by molecular analysis but were somewhat lower in sensitivity, p53 mutations being also detected in three of 23 (13%) immunonegative cases. LOH was measured at loci on the following chromosomes (1p,q; 2p; 3p; 7q; 11p,q; 13q; 16q; 17p; 18p,q; and 22q) by Southern blotting, polymerase chain reaction amplification of restriction fragment length polymorphisms, or repetitive cytidine and adenine stretches (CA repeats). There was no association between p53 mutations and one measure of genomic instability, namely, high incidence of overall LOH. In contrast, p53 mutations strongly associated with LOH at two specific loci, 3p24-26 (P < 0.001) and 7q31 (P < 0.05). There was no association between p53 mutations and LOH at 17p (site of the p53 gene), suggesting that breast cancers often have only one defective allele of the p53 gene.


Systematic or Test-Guided Treatment for Tuberculosis in HIV-Infected Adults.
In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death. We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization. A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment. Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events. (Funded by the Agence Nationale de Recherches sur le Sida et les Hépatites Virales; STATIS ANRS 12290 ClinicalTrials.gov number, NCT02057796.).


Strategies for Addressing the Challenges of Patient-Centered Medical Home Implementation: Lessons from Oregon.
Patient-centered medical homes (PCMHs) are at the forefront of the transformation of primary care as part of health systems reform. Despite robust literature describing implementation challenges, few studies describe strategies being used to overcome these challenges. This article addresses this gap through observations of exemplary PCMHs in Oregon, where the Oregon Health Authority supports and recognizes Patient-Centered Primary Care Homes (PCPCH). Twenty exemplary PCPCHs were selected using program scores, with considerations for diversity in clinic characteristics. Between 2015 and 2016, semistructured interviews and focus groups were completed with 85 key informants. Clinics reported similar challenges implementing the PCPCH model, including shifting patterns of care use, fidelity to the PCPCH model, and refining care processes. The following ten implementation strategies emerged: expanding access through care teams, preventing unnecessary emergency department visits through patient outreach, improved communication and referral tracking with outside providers, prioritization of selected program metrics, implementing patient-centered practices, developing continuous improvement capacity through committees and "champions," incorporating preventive services and chronic disease management, standardization of workflows, customizing electronic health records, and integration of mental health. Clinic leaders benefited from understanding the local context in which they were operating. Despite differences in size, ownership, geography, and population, all clinic leaders were observed to be proponents of strategies commonly associated with a "learning organization": systems thinking, personal mastery, mental models, shared vision, and team. Clinics can draw on their own characteristics, use state resources, and look to established PCMHs to build the evidence base for implementation in primary care.


Cross-education of muscular strength following unilateral resistance training: a meta-analysis.
Cross-education (CE) of strength is a well-known phenomenon whereby exercise of one limb can induce strength gains in the contralateral untrained limb. The only available meta-analyses on CE, which date back to a decade ago, estimated a modest 7.8% increase in contralateral strength following unilateral training. However, in recent years new evidences have outlined larger contralateral gains, which deserve to be systematically evaluated. Therefore, the aim of this meta-analysis was to appraise current data on CE and determine its overall magnitude of effect. Five databases were searched from inception to December 2016. All randomized controlled trials focusing on unilateral resistance training were carefully checked by two reviewers who also assessed the eligibility of the identified trials and extracted data independently. The risk of bias was assessed using the Cochrane Risk-of-Bias tool. Thirty-one studies entered the meta-analysis. Data from 785 subjects were pooled and subgroup analyses by body region (upper/lower limb) and type of training (isometric/concentric/eccentric/isotonic-dynamic) were performed. The pooled estimate of CE was a significant 11.9% contralateral increase (95% CI 9.1-14.8; p < 0.00001; upper limb: + 9.4%, p < 0.00001; lower limb: + 16.4%, p < 0.00001). Significant CE effects were induced by isometric (8.2%; p = 0.0003), concentric (11.3%; p < 0.00001), eccentric (17.7%; p = 0.003) and isotonic-dynamic training (15.9%; p < 0.00001), although a high risk of bias was detected across the studies. Unilateral resistance training induces significant contraction type-dependent gains in the contralateral untrained limb. Methodological issues in the included studies are outlined to provide guidance for a reliable quantification of CE in future studies.


Increasing Health Care Burden of Chronic Liver Disease Compared With Other Chronic Diseases, 2004-2013.
Chronic liver disease (CLD) is a common and expensive condition, and studies of CLD-related hospitalizations have underestimated the true burden of disease. We analyzed data from a large, diverse health care system to compare time trends in CLD-related hospitalizations with those in congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD). We collected data from a large health care system in Texas on hospitalizations related to CLD (n = 27,783), CHF (n = 60,415), and COPD (n = 34,199) from January 1, 2004 through December 31, 2013. We calculated annual hospitalization rates (per 100,000) and compared hospital course, inpatient mortality, ancillary services, and readmissions. Compared with patients with CHF (median age, 71 years) or COPD (median age, 69 years), patients with CLD were significantly younger (median age, 57 years) (P < .01 vs CHF and COPD). Higher proportions of patients with CLD were uninsured (11.7% vs 5.4% for CHF and 5.4% for COPD, P < .01) and Hispanic (17% for CLD vs 9.3% for CHF and 5.0% for COPD, P < .01). A lower proportion of patients with CLD had Medicare (41.5% vs 68.6% with CHF and 70.1% with COPD, P < .01). From 2004 through 2013, the rate of CLD-related hospitalization increased by 92% (from 1295/100,000 to 2490/100,000), compared with 6.7% for CHF (from 3843/100,000 to 4103/100,000) and 48.8% for COPD (from 1775/100,000 to 2642/100,000). During this time period, CLD-related hospitalizations covered by Medicare increased from 31.8% to 41.5%, whereas hospitalizations covered by Medicare did not change for CHF (remained at 70%) or COPD (remained at 70%). Patients with CLD had longer hospital stays (7.3 days vs 6.2 days for CHF and 5.9 days for COPD, P < .01). A higher proportion of patients with CLD died or were discharged to hospice (14.2% vs 11.5% of patients with CHF and 9.3% of patients with COPD, P < .01), and a smaller proportion had access to postacute care (13.2% vs 23.2% of patients with CHF and 27.4% of patients with COPD, P < .01). A higher proportion of patients with CLD were readmitted to the hospital within 30 days (25% vs 21.9% of patients with CHF and 20.6% with COPD, P < .01). Patients with CLD, compared with selected other chronic diseases, had increasing rates of hospitalization, longer hospital stays, more readmissions, and, despite these adverse outcomes, less access to postacute care. Disease management models for CLD are greatly needed to manage the anticipated increase in hospitalizations for CLD.


Untangling the relationship between diet and visceral fat mass through blood metabolomics and gut microbiome profiling.
Higher visceral fat mass (VFM) is associated with an increased risk for developing cardio-metabolic diseases. The mechanisms by which an unhealthy diet pattern may influence visceral fat (VF) development has yet to be examined through cutting-edge multi-omic methods. Therefore, our objective was to examine the dietary influences on VFM and identify gut microbiome and metabolite profiles that link food intakes to VFM. In 2218 twins with VFM, food intake and metabolomics data available we identified food intakes most strongly associated with VFM in 50% of the sample, then constructed and tested the 'VFM diet score' in the remainder of the sample. Using linear regression (adjusted for covariates, including body mass index and total fat mass), we investigated associations between the VFM diet score, the blood metabolomics profile and the fecal microbiome (n=889), and confirmed these associations with VFM. We replicated top findings in monozygotic (MZ) twins discordant (⩾1 s.d. apart) for VFM, matched for age, sex and the baseline genetic sequence. Four metabolites were associated with the VFM diet score and VFM: hippurate, alpha-hydroxyisovalerate, bilirubin (Z,Z) and butyrylcarnitine. We replicated associations between VFM and the diet score (beta (s.e.): 0.281 (0.091); P=0.002), butyrylcarnitine (0.199 (0.087); P=0.023) and hippurate (-0.297 (0.095); P=0.002) in VFM-discordant MZ twins. We identified a single species, Eubacterium dolichum to be associated with the VFM diet score (0.042 (0.011), P=8.47 × 10-5), VFM (0.057 (0.019), P=2.73 × 10-3) and hippurate (-0.075 (0.032), P=0.021). Moreover, higher blood hippurate was associated with elevated adipose tissue expression neuroglobin, with roles in cellular oxygen homeostasis (0.016 (0.004), P=9.82x10-6). We linked a dietary VFM score and VFM to E. dolichum and four metabolites in the blood. In particular, the relationship between hippurate, a metabolite derived from microbial metabolism of dietary polyphenols, and reduced VFM, the microbiome and increased adipose tissue expression of neuroglobin provides potential mechanistic insight into the influence of diet on VFM.


Support/services and family carers of persons with stroke impairment: perceived importance and services received.
To examine what family carers of persons with stroke impairment perceive as important support and service quality characteristics in relation to their experienced strain/burden, and to explore to what extent family carers receive support/services perceived as important. Data from a cross-sectional study. A sample of 183 family carers in Sweden, 64 experiencing lower and 119 experiencing higher strain/burden, a subsample of the EUROFAMCARE project. Carers were interviewed using a structured questionnaire. There are few differences between carers experiencing high and low strain/burden in what they perceive and receive in terms of important support and service quality characteristics. Information, relief, and counselling support/services are highly valued. It is also important that services improve quality of life, and have good process qualities regarding interaction with staff and individualization. Most services regarded as important are received by less than 60% of carers. The variation is rather high on an individual level in terms of what carers regard as important, indicating that factors other than negative impact may influence their perceptions of support/service and service quality. Thus, it is important to know carers' perceptions in order to individualize support/service, and thus make it more available and efficient.


Effectiveness of streamlined admissions to methadone treatment: a simplified time-series analysis.
Increasing the availability of, and streamlining the admissions process to, methadone treatment have consistently been the focus of national plans to address the acquired immune deficiency syndrome (AIDS) epidemic. This article uses simplified time-series analysis to evaluate one of the first methadone treatment Waiting List Reduction Demonstration Grants. The demonstration grant significantly increased both the number of people requesting intake appointments from 35 to 100 per month and the percentage of kept appointments from 33% to 54%. An additional 100 slots (an entire year's waiting list) were filled in fewer than three months and actually resulted in a net increase in the length of the waiting list. Relative to the preceding two years, new clients during the grant period were significantly more likely to be 41 or older, African-American, unemployed, daily opioid users, daily cocaine users, and dependent on public assistance to finance treatment. Controlling for the source of treatment financing (a case-mix adjustment), there were no significant changes in retention rates. The program's static client capacity rose from 310 prior to the grant to a peak of 449 during the grant, with a leveling to 410 after the grant. Given that it is clearly more humane and less expensive to treat people who want treatment rather than wait for them to commit a crime and be arrested or even executed, this study strongly suggests the need to make more treatment available on demand.


Two fission yeast homologs of Drosophila Mei-S332 are required for chromosome segregation during meiosis I and II.
Meiosis produces haploid gametes from diploid progenitor cells. This reduction is achieved by two successive nuclear divisions after one round of DNA replication. Correct chromosome segregation during the first division depends on sister kinetochores being oriented toward the same spindle pole while homologous kinetochores must face opposite poles. Segregation during the second division depends on retention of sister chromatid cohesion between centromeres until the onset of anaphase II, which in Drosophila melanogaster depends on a protein called Mei-S332 that binds to centromeres. We report the identification of two homologs of Mei-S332 in fission yeast using a knockout screen. Together with their fly ortholog they define a protein family conserved from fungi to mammals. The two identified genes, sgo1 and sgo2, are required for retention of sister centromere cohesion between meiotic divisions and kinetochore orientation during meiosis I, respectively. The amount of meiotic cohesin's Rec8 subunit retained at centromeres after meiosis I is reduced in Deltasgo1, but not in Deltasgo2, cells, and Sgo1 appears to regulate cleavage of Rec8 by separase. Both Sgo1 and Sgo2 proteins localize to centromere regions. The abundance of Sgo1 protein normally declines after the first meiotic division, but extending its expression by altering its 3'UTR sequences does not greatly affect meiosis II. Its mere presence within the cell might therefore be insufficient to protect centromeric cohesion. A conserved protein family based on Mei-S332 has been identified. The two fission yeast homologs are implicated in meiosis I kinetochore orientation and retention of centromeric sister chromatid cohesion until meiosis II.


Influence of diabetes mellitus, hypercholesterolemia, and their combination on EDHF-mediated responses in mice.
The endothelium synthesizes and releases several vasodilator substances, including vasodilator prostaglandins, NO, and EDHF. NO-mediated relaxations are reduced by various risk factors, such as diabetes mellitus and hypercholesterolemia. However, it remains to be elucidated whether EDHF-mediated relaxations also are reduced by those factors and their combination. In this study, we addressed this point in mice. We used small mesenteric arteries from control, diabetic (streptozotocin-induced), apolipoprotein-E-deficient (ApoE-/-), and diabetic ApoE-/- mice. In control mice, endothelium-dependent relaxations to acetylcholine were largely mediated by EDHF. This EDHF-mediated component was slightly reduced in diabetic mice, preserved in ApoE-/- mice, and markedly reduced in diabetic ApoE-/- mice with an increase in NO-mediated component and a negative contribution of indomethacin-sensitive endothelium-derived contracting factor (EDCF). Endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of calcium-activated K channels, were attenuated in ApoE-/- and diabetic ApoE-/- mice. Endothelium-dependent hyperpolarizations were significantly reduced in diabetic mice, preserved in ApoE-/- mice, and again markedly reduced in diabetic ApoE-/- mice. These results indicate that hypercholesterolemia alone minimally affects the EDHF-mediated relaxations, and diabetes mellitus significantly attenuated the responses, whereas their combination markedly attenuates the responses with a compensatory involvement of NO and a negative contribution of EDCF.


Efficacy of a telephone outcall program to reduce caregiver burden among caregivers of cancer patients [PROTECT]: a randomised controlled trial.
Informal caregivers provide extended support to people with cancer but they receive little support from the health care system to assist them in their caring role. The aim of this single-blind, multi-centre, randomised controlled trial was to test the efficacy of a telephone outcall program to reduce caregiver burden and unmet needs, and improve psychological well-being among cancer caregivers, as well as evaluating the potential impact on patient outcomes. Cancer patient/caregiver dyads (N = 216) were randomised to a telephone outcall program (n = 108) or attention control group (n = 108). The primary outcome was self-reported caregiver burden. Secondary endpoints included depressive symptoms, unmet needs, self-esteem, self-empowerment, and health literacy. Data were collected at baseline and at both 1 and 6 months post-intervention. An intention to treat analysis was performed. The intervention had no effect on the primary outcome (caregiver burden), but reduced the number of caregiver unmet needs (intervention group baseline, mean = 2.66, 95% confidence interval (CI) [1.91-3.54]; intervention group 1 month post intervention, mean = 0.85, 95%CI [0.42-1.44]; control group baseline, mean = 1.30 95%CI [0.80-1.94], control group 1 month post intervention, mean = 1.02 95%CI [0.52-1.69]; p = 0.023). For caregivers at risk for depression, the intervention had a significant effect on caregivers' confidence in having sufficient information to manage their health (p = 0.040). No effects were found for patients' depressive symptoms, unmet needs, self-empowerment, and other health literacy domains. While caregiver burden was not reduced, the outcall program was effective in reducing unmet needs in caregivers. Provision of cancer information and support via a telephone service may represent a feasible approach to reducing unmet needs among cancer caregiver populations. ACTRN12613000731796 ; prospectively registered on 02/07/2013.


Urea as a passive transport marker for arthritis biomarker studies.
To develop a method to correct for the unknown dilution of synovial fluid that occurs during lavage of a joint, we evaluated the utility of urea, a molecule that is neither synthesized nor metabolized by joint tissues, as a means of correcting for the dilutional effects of lavage procedures and effusions. Joint fluids were obtained from normal canine joints by direct aspiration (n = 41) and lavage (n = 10). Acute joint injury was induced in 4 joints by intraarticular injection of chymopapain. Serum and joint fluid levels of urea and joint fluid concentrations of glucose, lactate, cartilage oligomeric matrix protein (COMP), and keratan sulfate (KS) were measured in these 55 joints. Urea concentrations in joint fluid were directly proportional to those in serum throughout a wide range of concentrations in normal joints. From this relationship, the dilution factor introduced by joint lavage was determined. This method was applied to quantify biomarker concentrations in synovial lavage fluid and was found to successfully correct for lavage-induced dilution of glucose, lactate, COMP, and KS to levels equivalent to those in samples aspirated directly. In the context of chymopapain-induced joint effusion, urea concentrations continued to be proportional to serum concentrations, but were much lower, enabling an estimation of the change in the volume of distribution (V(d)) of a marker due to a change in joint water content in the setting of inflammation characterized by effusion. Lactate and KS levels rose markedly in response to chymopapain. After adjustment for the V(d), the glucose concentration in the chymopapain-injected joints did not change. Urea provides a robust method of quantifying and correcting for the dilution of synovial fluid due to joint lavage or inflammation. This method is potentially applicable to surrogate marker studies in human arthritis.


A novel approach to evaluate spatial resolution of MRI clinical images for optimization and standardization of breast screening protocols.
Stringent quality assurance is required in MRI breast screening to ensure that different scanners and imaging protocols reach similar diagnostic performance. The authors propose a methodology, based on power spectrum analysis (PSA), to evaluate spatial resolution in clinical images. To demonstrate this approach, the authors have retrospectively compared two MRI sequences commonly employed in breast screening. In a novel approach to PSA, spatial frequency response curves (SFRCs) were extracted from the images. The SFRC characterizes spatial resolution describing the spatial frequency content of an image over a range of frequencies. Verification of the SFRCs was performed on MRI images of Eurospin agarose gel tubes acquired with different resolution settings. SFRCs of volunteer and patient images obtained with two clinical MRI sequences were then compared. The two sequences differed primarily in k-space coverage pattern, which was either radial (RAD) or linear (LIN). The computed SFRCs were able to demonstrate the differences between RAD and LIN sequences in relatively small groups of subjects. The curves showed a similar pattern of decay in both volunteer and patient images, indicating that the spatial frequency response is mainly determined by the imaging protocol and not by intersubject anatomical differences. The LIN protocol produced images with increased sharpness; this was reflected in the corresponding SFRCs, which showed a higher content of spatial frequencies associated with image details. The SFRC can provide an objective assessment of the presence of spatial details in the image and represent a useful quality assurance tool in the evaluation of different breast screening protocols. With a reference image, a comparative analysis of the SFRCs could ensure that equivalent image quality is achieved across different scanners and sites.


Evidence that anti-CD8 abrogates anti-CD4-mediated clonal anergy but allows allograft survival in mice.
Monoclonal antibodies directed against different T cell subpopulations have been used in several rodent models of transplantation to induce long-term unresponsiveness to allografts by a variety of mechanisms. To investigate whether different mechanisms may be operative when different regimens of mAb therapy are used, we studied the effects of various combinations of anti-T-cell antibody treatment on the induction of tolerance in a mouse islet allograft model. Anti-CD4 mAb alone, anti-CD8 mAb alone, anti-CD4 mAb plus anti-CD8 mAb, and anti-Thy1.2 mAb alone were given at the time of engraftment. Only the anti-CD4 mAb and the anti-CD4 mAb plus anti-CD8 mAb regimens were successful in inducing permanent unresponsiveness to islet allografts. We have previously shown that anti-CD4 mAb alone induces permanent unresponsiveness to islet allografts by a mechanism of clonal anergy, as demonstrated by unresponsiveness of potentially alloreactive T cells to anti-T-cell receptor-specific cross-linking. Interestingly, the potentially alloreactive T cell subsets of recipient mice (V beta 5+ and V beta 11+) made unresponsive to islet allografts by anti-CD4 mAb plus anti-CD8 mAb therapy were not found to be anergic using the same assay. Differences between the repopulation kinetics of CD8+ T cells of anti-CD4 mAb plus anti-CD8 mAb treated recipient mice, which accepted islet allografts, and anti-Thy1.2 treated recipient mice, which rejected islet allografts despite similar levels of initial T cell depletion, suggest that unresponsiveness to alloantigen may have been induced in anti-CD4 mAb plus anti-CD8 mAb treated recipients by clearance of donor passenger leukocytes during prolonged CD8+ T cell depletion.


What do children observe and learn from televised sports betting advertisements? A qualitative study among Australian children.
To explore children's awareness of sports betting advertising and how this advertising may influence children's attitudes, product knowledge and desire to try sports betting. Semi-structured qualitative interviews were conducted with 48 children (8-16 years) from Melbourne, Victoria. The interview schedule explored children's recall and interpretations of sports betting advertising, strategies within advertisements that may appeal to children, children's product knowledge and understanding of betting terminology, and factors that may encourage gambling. Interviews were transcribed and thematic analysis was conducted. Children recalled in detail sports betting advertisements that they had seen, with humour the most engaging appeal strategy. They were also able to describe other specific appeal strategies and link these strategies to betting brands. Many children described how advertisements demonstrated how someone would place a bet, with some children recalling the detailed technical language associated with betting. Children had detailed recall of sports betting advertisements and an extensive knowledge of sports betting products and terminology. Implications for public health: To protect children from the potential harms associated with sports betting, governments should consider changing regulations and implementing evidence-based education campaigns to counter the positive messages children receive from the sports betting industry.


Role of multichannel magnetoencephalography in the evaluation of ablative seizure surgery candidates.
Magnetic source imaging (MSI) was performed on 30 ablative epilepsy surgery candidates. The technique involved high resolution multiplanar MRI images with lipid fiducials attached to the patient's head to define a head-based 3D coordinate space. Magnetoencephalography (MEG) was performed after digitizing the same fiducial points. A 37-channel magnetometer obtained data at two to five sites over each hemisphere. MEG epileptiform data were obtained with and without EEG triggering. A single equivalent current dipole model was used to determine orientation and location of a dipole generator whose surface isocontour map most closely fits the measured dipolar data for each event. The MEG data were then transformed to MRI images for source localization. In five of seven cases with ictal anterior temporal lobe foci, MSI data were localized to the same temporal lobe but did not provide additional spatial data. In 10 of 11 cases with convexity foci, MSI provided additional spatial localizing data. MSI did not verify depth electrode localization in one anterior temporal-orbital frontal and three orbitofrontal cases. In seven of eight cases in which depth EEG recordings were nonlocalizing, MSI provided insufficient localizing data. MSI appears to provide additional spatial localizing data in most cases with a convexity epileptic focus.


Time to Face Language: Embodied Mechanisms Underpin the Inception of Face-Related Meanings in the Human Brain.
In construing meaning, the brain recruits multimodal (conceptual) systems and embodied (modality-specific) mechanisms. Yet, no consensus exists on how crucial the latter are for the inception of semantic distinctions. To address this issue, we combined electroencephalographic (EEG) and intracranial EEG (iEEG) to examine when nouns denoting facial body parts (FBPs) and nonFBPs are discriminated in face-processing and multimodal networks. First, FBP words increased N170 amplitude (a hallmark of early facial processing). Second, they triggered fast (~100 ms) activity boosts within the face-processing network, alongside later (~275 ms) effects in multimodal circuits. Third, iEEG recordings from face-processing hubs allowed decoding ~80% of items before 200 ms, while classification based on multimodal-network activity only surpassed ~70% after 250 ms. Finally, EEG and iEEG connectivity between both networks proved greater in early (0-200 ms) than later (200-400 ms) windows. Collectively, our findings indicate that, at least for some lexico-semantic categories, meaning is construed through fast reenactments of modality-specific experience.


Predictors of In-Hospital Mortality after Recovered Out-of-Hospital Cardiac Arrest in Patients with Proven Significant Coronary Artery Disease: A Retrospective Study.
Recovered Out-of-Hospital Cardiac Arrest (rOHCA) population is heterogenous. Few studies focused on outcomes in the rOHCA subgroup with proven significant coronary artery disease (SigCAD). We aimed to characterize this subgroup and study the determinants of in-hospital mortality. Retrospective study of consecutive rOHCA patients submitted to coronary angiography. Only patients with SigCAD were included. 60 patients were studied, 85% were male, mean age was 62.6 ± 12.1 years. In-hospital mortality rate was 43.3%. Patients with diabetes and history of stroke were less likely to survive. Significant univariate predictors of in-hospital mortality were further analysed separately, according to whether they were present at hospital admission or developed during hospital evolution. At hospital admission, initial non-shockable rhythm, low-flow time>12min, pH<7.25mmol/L and lactates >4.75mmol/L were the most relevant predictors and therefore included in a score tested by Kaplan-Meyer. Patients who had 0/4 criteria had 100% chance of survival till hospital discharge, 1/4 had 77%, 2/4 had 50%, 3/4 had 25%. Patients with all 4 criteria had 0% survival. During in-hospital evolution, a pH<7.35 at 24h, lactates>2mmol/L at 24h, anoxic brain injury and persistent hemodynamic instability proved significant. Patients who had 0/4 of these in-hospital criteria had 100% chance of survival till hospital discharge, 1/4 had 94%, 2/4 had 47%, 3/4 had 25%. Patients with all 4 criteria had 0% survival. Contrarily, CAD severity and ventricular dysfunction didn't significantly correlate to the outcome. Classic prehospital variables retain their value in predicting mortality in the specific group of OHCA with SigCAD. In-hospital evolution variables proved to add value in mortality prediction. Combining these simple variables in risk scores might help refining prognostic prediction in these patients's subset.


Behavioral and neural correlates of increased self-control in the absence of increased willpower.
People often exert willpower to choose a more valuable delayed reward over a less valuable immediate reward, but using willpower is taxing and frequently fails. In this research, we demonstrate the ability to enhance self-control (i.e., forgoing smaller immediate rewards in favor of larger delayed rewards) without exerting additional willpower. Using behavioral and neuroimaging data, we show that a reframing of rewards (i) reduced the subjective value of smaller immediate rewards relative to larger delayed rewards, (ii) increased the likelihood of choosing the larger delayed rewards when choosing between two real monetary rewards, (iii) reduced the brain reward responses to immediate rewards in the dorsal and ventral striatum, and (iv) reduced brain activity in the dorsolateral prefrontal cortex (a correlate of willpower) when participants chose the same larger later rewards across the two choice frames. We conclude that reframing can promote self-control while avoiding the need for additional willpower expenditure.


Contraction modulates the capacity for protein synthesis during growth of neonatal heart cells in culture.
Neonatal ventricular myocytes that were incubated in a well-defined serum-free medium containing 50 mM KCl did not contract and maintained stable cell size, as assessed by the protein/DNA ratio. The present study utilized KCl-arrested cells to examine the effect of constant rates of synchronous contraction in normal [K+]o (4 mM) as a physiological stimulus for myocyte growth. Cell growth increased following the onset of contraction when measured over 3 days. The rate of protein synthesis was accelerated in parallel by contraction, but the rate of protein degradation remained similar to rates in noncontracting cells. The capacity for protein synthesis was estimated by total RNA content and was increased in contracting as compared with KCl-arrested cells. This increase was accompanied by faster rates of RNA synthesis as determined from the incorporation of [3H]uridine into RNA and the specific activity of the cellular UTP pool. The rate of RNA degradation was accelerated during contraction but the difference between the rates of RNA synthesis and degradation resulted in net RNA accumulation of 49% after 3 days. These data demonstrated that 1) contractile activity stimulated myocyte growth through an increased capacity for protein synthesis and 2) the increased capacity for protein synthesis involved acceleration of the rate of RNA synthesis. Since enhancement of protein synthetic capacity is a common feature of myocyte hypertrophy in vivo and in vitro, this model can be used to examine the regulation of ribosome synthesis during hypertrophic growth.


A comparison of compression ultrasound with color Doppler ultrasound for the diagnosis of symptomless postoperative deep vein thrombosis.
Despite advances in primary prophylaxis, venous thromboembolism still occurs in a considerable number of high-risk surgical patients. Screening with conventional ultrasound imaging to detect asymptomatic deep vein thrombosis (DVT) has been suggested as a strategy to improve management of such patients, but it is insufficiently sensitive. We evaluated the ability of color Doppler ultrasound to improve the sensitivity of compression ultrasound in the detection of asymptomatic DVT in high-risk orthopedic patients. We prospectively evaluated bilateral compression and color Doppler ultrasound measurements of the entire leg in 204 consecutive patients who underwent elective hip or knee replacement surgery, using contrast venography as the reference test. The sensitivity, specificity, and positive predictive value of the ultrasonography tests were determined. The sensitivity, specificity, and positive predictive value (with 95% confidence intervals [CIs]) of compression ultrasound for the detection of proximal DVT were 60% (39%-81%), 96% (92%-99%), and 71% (48%-89%) respectively. The sensitivity, specificity, and positive predictive value (with 95% CIs) of compression ultrasound for the detection of calf vein thrombosis were 33% (18%-52%), 91% (83%-96%), and 58% (34%-80%), respectively. Color Doppler ultrasonography did not identify any additional proximal or calf vein thrombi to those detected by compression ultrasound alone. The sensitivity for all thrombi was 47% (95% CI, 34%-61%) with a positive predictive value of 65% (95% CI, 48%-79%). Color Doppler ultrasonography has a moderate to low accuracy for the detection of DVT in patients who have had hip and knee replacement surgery. Color Doppler ultrasonography does not increase the detection rate for asymptomatic DVT over compression ultrasound and thus cannot be recommended as a screening test in this setting.


Effects of axial boundary conductivity on a free Stewartson-Shercliff layer.
The effects of axial boundary conductivity on the formation and stability of a magnetized free Stewartson-Shercliff layer (SSL) in a short Taylor-Couette device are reported. As the axial field increases with insulating endcaps, hydrodynamic Kelvin-Helmholtz-type instabilities set in at the SSLs of the conducting fluid, resulting in a much reduced flow shear. With conducting endcaps, SSLs respond to an axial field weaker by the square root of the conductivity ratio of endcaps to fluid. Flow shear continuously builds up as the axial field increases despite the local violation of the Rayleigh criterion, leading to a large number of hydrodynamically unstable modes. Numerical simulations of both the mean flow and the instabilities are in agreement with the experimental results.


Outcome survey of early intensive behavioral intervention for young children with autism in a community setting.
This article presents findings from an outcome survey of the effects of early intensive behavioral intervention (EIBI) for young children with autism in a community setting. Results from both individual case reviews and parent questionnaires are presented, with the data failing to support any instances of'recovery' while still yielding a high degree of parental satisfaction with the treatment. Moreover, a follow-up inquiry into the type of services each child was receiving in his or her post-EIBI setting documents continued dependence on extensive educational and related developmental services, suggesting that the promise of future treatment sparing did not materialize. Limitations of the survey in evaluating community-based EIBI services are discussed along with the need for further research designed to document the effectiveness of services provided to young children with ASD in the community.


Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma.
Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NFκB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for patients with GBM. Our results suggest that the PROS1-AXL pathway regulates intrinsic mesenchymal signaling and the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors.Significance: These findings suggest that development of combination treatments of AXL and immune checkpoint inhibitors may provide benefit to patients with GBM. Cancer Res; 78(11); 3002-13. ©2018 AACR.


Influence of hospital guidelines on management of children hospitalized with pneumonia.
Clinical practice guidelines (CPGs) assist clinicians in making appropriate diagnostic and treatment decisions based on available evidence. The objective of this study was to describe the availability and content of institutional community-acquired pneumonia (CAP) CPGs, and to evaluate the association between institutional CPGs and care utilization, antibiotic administration, and outcomes among children hospitalized with CAP. This multicenter retrospective cohort study included children aged 1 to 18 years hospitalized with CAP from July 1, 2009, to June 30, 2011. CPGs from each institution were reviewed to abstract information regarding diagnostic testing and antimicrobial selection. We compared overall and specific utilization patterns, antimicrobial use, and hospital length of stay (LOS) for children with CAP between hospitals with and without CPGs. Thirteen (31.7%) of 41 hospitals had an institutional CPG for nonsevere CAP. There was marked heterogeneity among CPGs. Among the 19,710 children hospitalized with CAP, cost of care, hospital LOS, and 14-day readmission rate were not associated with the presence of a CPG. CPGs did not influence ordering patterns for most diagnostic tests, including blood culture and chest radiographs. Penicillin or aminopenicillins were prescribed to 46.3% of children at institutions where a CPG recommended the use of these antibiotics as first-line agents compared with 23.9% of children at institutions without a CPG (odds ratio = 2.7; 95% confidence interval = 1.4-5.5). The availability of a CAP CPG had minimal impact on resource utilization and was not associated with cost or hospital LOS. Institutional CPGs, however, did influence patterns of antimicrobial use.


Factors influencing the risk of local recurrence after resection of a single brain metastasis.
Local recurrence (LR) of a resected brain metastasis occurs in up to 46% of patients. Postoperative whole-brain radiation therapy (WBRT) reduces that incidence. To isolate factors associated with the risk of LR after resection, the authors only studied patients who did not receive adjuvant radiotherapy. The authors reviewed data from 570 cases involving patients who had undergone resection of a previously untreated single brain metastasis at The University of Texas M. D. Anderson Cancer Center between 1993 and 2006 without receiving postoperative WBRT. All tumors were measured preoperatively on MR images. The resection method (en bloc resection [EBR] or piecemeal resection [PMR]) was noted at the time of surgery. Predictors of LR were assessed using the Cox proportional hazards model. The median patient age was 58 years, 55% were male, and 88% had a Karnofsky Performance Scale Score > or = 80. The most common primary cancers were those of the lung (28%), skin (melanoma, 21%), kidney (19%), and breast (11%). Piecemeal resection was performed in 201 patients (35%) and EBR in 369 (65%). Local recurrence developed in 84 patients (15%). The histological type of the primary cancer did not significantly predict LR; however, 7 of 22 patients with sarcoma developed LR (p = 0.16). The authors identified 2 variables that increased the risk of LR. Undergoing PMR carried a significantly higher LR risk than EBR (crude hazard ratio [HR] 1.7, 95% CI 1.1-2.6, p = 0.03). Tumors exceeding the median volume (9.7 cm(3)) had a significantly higher LR risk than those that were < 9.7 cm(3) (crude HR 1.7; 95% CI 1.1-2.6; p = 0.02). In the multivariate analysis, small tumors removed by EBR had a significantly lower LR risk. The LR risk of a single brain metastasis is influenced by biological factors (such as tumor volume) and treatments (such as the resection method). Early administration of postoperative WBRT may be particularly warranted when such negative tumor-related prognostic factors are noted or when treatment-related ones such as PMR are unavoidable.


Anti-tuberculosis therapy-induced hepatotoxicity among Ethiopian HIV-positive and negative patients.
To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH) in HIV positive and HIV negative tuberculosis (TB) patients in Ethiopia. In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3% of the patients and 8 out of the 197 (4.1%) developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg. Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002), concomitant drug intake (p = 0.008), and decrease in CD4 count (p = 0.001). Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk.


The efficacy of omega-3 fatty acids on cognitive function in aging and dementia: a systematic review.
We systematically reviewed the published literature on the effects of omega-3 fatty acids on measures of cognitive function in normal aging, incidence and treatment of dementia. Computerized databases were searched for published literature to identify potentially relevant studies with the intent to conduct a meta-analysis. We screened 5,865 titles, reviewed 497 studies of which 49 underwent a detailed review, and found 5 studies that pertained to our objectives. We included controlled clinical trials and observational studies, including prospective cohort, case-control, and case series designs; we excluded case reports. We had no language restrictions. We abstracted data on the effects of omega-3 fatty acids and on study design, relevant outcomes, study population, source, type, amount, and duration of omega-3 fatty acid consumption, and parameters of methodological quality. A single cohort study has assessed the effects of omega-3 fatty acids on cognitive function with normal aging and found no association for fish or total omega-3 consumption. In four studies that assessed the effects of omega-3 fatty acids on incidence and treatment of dementia, a trend in favor of omega-3 fatty acids (fish and total omega-3 consumption) toward reducing risk of dementia and improving cognitive function was reported. The available data are insufficient to draw strong conclusions about the effects of omega-3 fatty acids on cognitive function in normal aging or on the incidence or treatment of dementia. However, limited evidence suggests a possible association between omega-3 fatty acids and reduced risk of dementia.


Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas.
We have previously described a group of non-small cell lung carcinomas without morphological evidence of neo-angiogenesis. In these tumours neoplastic cells fill up the alveoli and the only vessels present appear to belong to the trapped alveolar septa. In the present study we have characterised the phenotype of the vessels present in these non-angiogenic tumours, in normal lung and in angiogenic non-small cell lung carcinomas. The vessels, identified by the expression of CD31, were scored as mature when expressing the epitope LH39 in the basal membrane and as newly formed when expressing alphaVbeta3 on the endothelial cells and/or lacking LH39 expression. In the nine putative non-angiogenic cases examined, the vascular phenotype of all the vessels was the same as that of alveolar vessels in normal lung: LH39 positive and alphaVbeta3 variable or negative. Instead in 104 angiogenic tumours examined, only a minority of vessels (mean 13.1%; range 0--60%) expressed LH39, while alphaVbeta3 (in 45 cases) was strongly expressed on many vessels (mean 55.5%; range 5--90%). We conclude that in putative non-angiogenic tumours the vascular phenotype is that of normal vessels and there is no neo-angiogenesis. This type of cancer may be resistant to some anti-angiogenic therapy and different strategies need to be developed.


A functional and structural Mongolian Scots pine (Pinus sylvestris var. mongolica) model integrating architecture, biomass and effects of precipitation.
Mongolian Scots pine (Pinus sylvestris var. mongolica) is one of the principal tree species in the network of Three-North Shelterbelt for windbreak and sand stabilisation in China. The functions of shelterbelts are highly correlated with the architecture and eco-physiological processes of individual tree. Thus, model-assisted analysis of canopy architecture and function dynamic in Mongolian Scots pine is of value for better understanding its role and behaviour within shelterbelt ecosystems in these arid and semiarid regions. We present here a single-tree functional and structural model, derived from the GreenLab model, which is adapted for young Mongolian Scots pines by incorporation of plant biomass production, allocation, allometric rules and soil water dynamics. The model is calibrated and validated based on experimental measurements taken on Mongolian Scots pines in 2007 and 2006 under local meteorological conditions. Measurements include plant biomass, topology and geometry, as well as soil attributes and standard meteorological data. After calibration, the model allows reconstruction of three-dimensional (3D) canopy architecture and biomass dynamics for trees from one- to six-year-old at the same site using meteorological data for the six years from 2001 to 2006. Sensitivity analysis indicates that rainfall variation has more influence on biomass increment than on architecture, and the internode and needle compartments and the aboveground biomass respond linearly to increases in precipitation. Sensitivity analysis also shows that the balance between internode and needle growth varies only slightly within the range of precipitations considered here. The model is expected to be used to investigate the growth of Mongolian Scots pines in other regions with different soils and climates.


Are your engineers talking to one another when they should?
Communication may not be on managers' minds at companies that design complex, highly engineered products, but it should be. When mistakes take place, it's often because product-component teams fail to talk. The consequences can be huge: Ford and Bridgestone Firestone lost billions by not coordinating the design of the Explorer with the design of its tires. The major delays and cost overruns involved in the development of Airbus's A380 "superjumbo"--which most likely led to the CEO's exit--were a result of unforeseen design incompatibilities. To help managers mitigate such problems, the authors present a new application of the design structure matrix, a project management tool that maps the flow of information and its impact on product development. Drawing on research into how Pratt & Whitney handled the development of the PW4098 jet engine, they have developed an approach that uncovers (a) areas where communication should be occurring but is not (unattended interfaces, usually bad) and (b) areas where communication is occurring but has not been planned for (unidentified interfaces, usually good). After finding the unattended and unidentified interfaces, the next step is to figure out the causes of the critical ones. If a significant number of unattended interfaces cross organizational boundaries, executives may need to redraw organizational lines. Executives can then manage the remaining critical interfaces by extending the responsibilities of existing integration teams (those responsible for cross-system aspects, such as a jet engine's fuel economy) to include supervising the interaction, by dedicating teams to specific interfaces, or by formally charging teams already involved with the interfaces to oversee them. Finally, it's important to ensure that the teams are working with compatible design equipment; inconsistencies between CAD tools have cost Airbus dearly.


A demonstration of the efficacy of two of the components of cognitive therapy for social phobia.
Cognitive-behavioral treatments have demonstrated efficacy in the treatment of social phobia. However, such treatments comprise a complex set of procedures, and there has been little investigation of the effects of individual procedures. The current study investigates the effects of two single session procedures that form part of cognitive therapy for social phobia [Clark, D., Ehlers, A., McManus, F., Hackmann, A., Fennell, M., Campbell, H., et al. (2003). Cognitive therapy vs fluoxetine in the treatment of social phobia: A randomised placebo controlled trial. Journal of Consulting and Clinical Psychology, 71, 1058-1067; Clark, D., Ehlers, A., McManus, F., Fennell, M., Grey, N., Waddington, L., et al. (2006). Cognitive therapy versus exposure and applied relaxation in social phobia: A randomised controlled trial. Journal of Consulting and Clinical Psychology, 74, 568-578], namely the "self-focused attention and safety behaviors experiment" and the "video feedback experiment." Results suggest that both procedures are effective in achieving their aims, which are: (i) demonstrating to patients the role of self-focused attention, safety behaviors, and excessively negative self-impressions in maintaining social phobia and (ii) reducing the symptoms of social phobia.


Blocking tactile input to one finger using anaesthetic enhances touch perception and learning in other fingers.
Brain plasticity is a key mechanism for learning and recovery. A striking example of plasticity in the adult brain occurs following input loss, for example, following amputation, whereby the deprived zone is "invaded" by new representations. Although it has long been assumed that such reorganization leads to functional benefits for the invading representation, the behavioral evidence is controversial. Here, we investigate whether a temporary period of somatosensory input loss to one finger, induced by anesthetic block, is sufficient to cause improvements in touch perception ("direct" effects of deafferentation). Further, we determine whether this deprivation can improve touch perception by enhancing sensory learning processes, for example, by training ("interactive" effects). Importantly, we explore whether direct and interactive effects of deprivation are dissociable by directly comparing their effects on touch perception. Using psychophysical thresholds, we found brief deprivation alone caused improvements in tactile perception of a finger adjacent to the blocked finger but not to non-neighboring fingers. Two additional groups underwent minimal tactile training to one finger either during anesthetic block of the neighboring finger or a sham block with saline. Deprivation significantly enhanced the effects of tactile perceptual training, causing greater learning transfer compared with sham block. That is, following deafferentation and training, learning gains were seen in fingers normally outside the boundaries of topographic transfer of tactile perceptual learning. Our results demonstrate that sensory deprivation can improve perceptual abilities, both directly and interactively, when combined with sensory learning. This dissociation provides novel opportunities for future clinical interventions to improve sensation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Mechanism of unresponsiveness to the alpha 1-6 epitope of dextran B512 in a C57BL substrain.
C57BL/10ScCr mice are low responders to the alpha 1-6 epitope of dextran B512, although other C57BL mice are high responders. Both thymus-independent and thymus-dependent forms of dextran failed to induce an immune response in C57BL/10ScCr mice, but dextran functioned as a good carrier for antihapten responses in this strain. Dextran is a potent polyclonal B cell activator for cells from C57BL/10ScCr mice, although such cells are not activated by LPS. The C57BL/10ScCr mice possess the Igh-V gene coding for antibodies against dextran and the antidextran antibodies induced in (A X C57BL/10ScCr)F1 hybrids share an idiotype with antidextran antibodies produced in C57BL/10 mice. Bone marrow cells from C57BL/10ScCr mice do not respond to dextran when transferred into lethally irradiated C57BL/10 mice and C57BL/10 cells transferred into C57BL/10ScCr mice give a strong antidextran response. Thus, B cells having both the Igh-V gene coding for antibodies against dextran and activation receptors for dextran cannot be activated into antibody synthesis against any form of this immunogen. This determinant specific immunodeficiency suggests the existence of as yet unknown regulatory influences on Igh-V gene expression or B cell activation.


Vascular responses to arachidonic acid in the perfused canine lung.
We compared the effects of arachidonic acid (AA), the bisenoic prostaglandin precursor, with those of prostaglandin F2a (PGF2a) and norepinephrine (NE) on pulmonary vascular resistance in the isolated (in situ), perfused canine lung lobe. The isolated lobe was perfused with autologous blood or an artificial perfusate under conditions of constant flow. Lobar artery and venous pressures were constantly monitored after bolus injections of AA, PGF2a, and NE into the inflow cannula. AA (100 mug/kg produced a significant increase in the pressure gradient (93.3 +/- 8.4%, SE) in the lobe. Similarly, PGF2a (1 mug/kg) significantly increased the pressure gradient (41.2 +/- 6.5%), as did NE (1 mug/kg, 41.6 +/- 3.2%). Aspirin (25 mg/kg) completely blocked the pulmonary vascular effect of AA, but did not affect the response to PGF2a, Linoleic acid, a control fatty acid, did not produce pulmonary vasoconstriction. The pressor effect of AA was not blocked by pretreatment with phentolamine, propranolol, cyproheptadine, or atropine. The use of an artificial perfusate free of cellular elements did not prevent the vasoconstrictor action of AA. The times to onset of action of the three agents were similar, and short. These results suggest that AA is converted into vasoactive intermediates or a prostaglandin, and the vasoactive intermediates or the prostaglandin act directly on precapillary pulmonary vascular smooth muscle rather than through platelet, plasma, adrenergic, or cholinergic mechanisms.


Selective mass treatment with ivermectin to control intestinal helminthiases and parasitic skin diseases in a severely affected population.
To assess the short-term and long-term impact of selective mass treatment with ivermectin on the prevalence of intestinal helminthiases and parasitic skin diseases in an economically depressed community in north-east Brazil. An intervention was carried out in a traditional fishing village in north-east Brazil where the population of 605 is heavily affected by ectoparasites and enteroparasites. The prevalence of intestinal helminths was determined by serial stool examination and the prevalence of parasitic skin diseases by clinical inspection. A total of 525 people out of a target population of 576 were treated at baseline. The majority of these were treated with ivermectin (200 microg/kg with a second dose given after 10 days). If ivermectin was contraindicated, participants were treated with albendazole or mebendazole for intestinal helminths or with topical deltamethrin for ectoparasites. Follow-up examinations were performed at 1 month and 9 months after treatment. Prevalence rates of intestinal helminthiases before treatment and at 1 month and 9 months after mass treatment were: hookworm disease 28.5%, 16.4% and 7.7%; ascariasis 17.1%, 0.4% and 7.2%; trichuriasis 16.5%, 3.4% and 9.4%; strongyloidiasis 11.0%, 0.6% and 0.7%; and hymenolepiasis 0.6%; 0.4% and 0.5%, respectively. Prevalence rates of parasitic skin diseases before treatment and 1 month and 9 months after mass treatment were: active pediculosis 16.1%, 1.0% and 10.3%; scabies 3.8%, 1.0% and 1.5%; cutaneous larva migrans 0.7%, 0% and 0%; tungiasis 51.3%, 52.1% and 31.2%, respectively. Adverse events occurred in 9.4% of treatments. They were all of mild to moderate severity and were transient. Mass treatment with ivermectin was an effective and safe means of reducing the prevalence of most of the parasitic diseases prevalent in a poor community in north-east Brazil. The effects of treatment lasted for a prolonged period of time.


Genetic and Biological Diversity of Trichoderma stromaticum, a Mycoparasite of the Cacao Witches'-Broom Pathogen.
ABSTRACT The witches'-broom disease, caused by the basidiomycete Crinipellis perniciosa, is the most limiting factor for cacao cultivation in Brazil. Trichoderma stromaticum is a mycoparasite of the witches'-broom pathogen of cacao that is currently being applied in the field to manage the disease in Bahia State, Brazil. In this work, molecular and traditional methods were used to study the genetic and biological diversity of this mycoparasite. Ninety-one isolates, mostly collected from farms not sprayed with the fungus, were analyzed by amplified fragment length polymorphisms (AFLP), which showed that two genetic groups (I and II) of T. stromaticum occur in Bahia State. This classification of T. stromaticum into two distinct AFLP groups was also in agreement with several other characteristics, including growth on agar media at different temperatures and sporulation on infected stem segments (broom pieces) and rice grains. Group II favors higher temperatures compared with group I. The genetic and biological differences of the isolates, however, were not evident in field experiments, where sporulation was evaluated on the surface of brooms under natural conditions. Our results show that there is considerable genetic and biological diversity within T. stromaticum in Bahia and other cacao-growing regions of South America that are affected by the witches'-broom disease. This diversity could be explored in the development of efficient biological control agents against the disease. Factors that may affect the application and performance of this biocontrol agent in the field, such as sporulation on rice substrate and on the brooms and growth at various temperatures, are discussed.


Mechanism of neutralization of influenza virus by secretory IgA is different from that of monomeric IgA or IgG.
We have found that bile is a useful source of secretory IgA (scIgA) which can specifically neutralize influenza virus infectivity. Using purified scIgA, we compared the mechanism of neutralization with that mediated by IgA monomers (prepared from scIgA by differential reduction) and IgG. At 4 degrees C, scIgA prevented the attachment of neutralized virus, while neither monomeric IgA nor IgG had any affect on this process or on the subsequent stages of infection by which virion RNA accumulates in nuclei. At 25 and 37 degrees C, scIgA permitted the attachment of approximately half the neutralized virus, but the virus was not internalized. Clearly, the neutralization depends on the character of the antibody used. scIgA may act by steric hindrance (with attachment or penetration, depending on temperature), whereas IgA and IgG neutralize infectivity at a stage subsequent to accumulation of the virus genome in the nucleus.


Antisense inhibition of the iron-sulphur subunit of succinate dehydrogenase enhances photosynthesis and growth in tomato via an organic acid-mediated effect on stomatal aperture.
Transgenic tomato (Solanum lycopersicum) plants expressing a fragment of the Sl SDH2-2 gene encoding the iron sulfur subunit of the succinate dehydrogenase protein complex in the antisense orientation under the control of the 35S promoter exhibit an enhanced rate of photosynthesis. The rate of the tricarboxylic acid (TCA) cycle was reduced in these transformants, and there were changes in the levels of metabolites associated with the TCA cycle. Furthermore, in comparison to wild-type plants, carbon dioxide assimilation was enhanced by up to 25% in the transgenic plants under ambient conditions, and mature plants were characterized by an increased biomass. Analysis of additional photosynthetic parameters revealed that the rate of transpiration and stomatal conductance were markedly elevated in the transgenic plants. The transformants displayed a strongly enhanced assimilation rate under both ambient and suboptimal environmental conditions, as well as an elevated maximal stomatal aperture. By contrast, when the Sl SDH2-2 gene was repressed by antisense RNA in a guard cell-specific manner, changes in neither stomatal aperture nor photosynthesis were observed. The data obtained are discussed in the context of the role of TCA cycle intermediates both generally with respect to photosynthetic metabolism and specifically with respect to their role in the regulation of stomatal aperture.


Sex and drug risk behavior pre- and post-emigration among Latino migrant men in post-Hurricane Katrina New Orleans.
High rates of sex and drug risk behaviors have been documented among Latino migrant men in the US. Whether these behaviors were established in the migrants' home countries or were adopted in the US has not been described and has implications for prevention strategies. Quarterly surveys were conducted to gather information on selected sex and drug risk practices of Latino migrant men who arrived in New Orleans after Hurricane Katrina seeking work. Both kappa scores and McNemar's tests were performed to determine if practice of these behaviors in home country was similar to practice post-emigration to the US. Female sex worker (FSW) patronage, same sex encounters (MSM), and crack cocaine use was more likely to occur post- rather than pre-emigration. Of those who ever engaged in these selected behaviors, most adopted the behavior in the US (i.e., 75.8% of FSW patrons, 72.7% of MSM participants, and 85.7% of crack cocaine users), with the exception of binge drinking (26.8%). Men who were living with a family member were less likely to adopt FSW patronage OR = 0.27, CI = 0.10-0.76, whereas men who earned >$465 per week were more likely to adopt crack cocaine use OR = 6.29 CI = 1.29, 30.57. Interventions that facilitate the maintenance of family cohesion and provide strategies for financial management may be useful for reducing sex and drug risk among newly arrived migrants.


Prevalence and Risk Factor Profiles for Chronic Axonal Polyneuropathy in the General Population.
Chronic axonal polyneuropathy is a common disease with increasing prevalence with age. It majorly impacts quality of life and leads to difficulties with various activities. Persons with polyneuropathy often not seek medical care and thus the societal burden of disease is likely underreported. Given the aging populations contemporary data on the prevalence as well as risk factor profiles of polyneuropathy in the general population are required. Therefore, we estimated the current and expected prevalence, and investigated the (co-)occurrence of risk factors in participants with chronic axonal polyneuropathy. Between June 2013 and January 2020, participants of the population-based Rotterdam Study underwent extensive in-person examination to diagnose polyneuropathy. Age-standardized prevalence's were calculated for populations aged ≥40 years of the Netherlands, Europe, United States and the world population. Putative risk factors were identified using laboratory findings, interviews, questionnaire data and a review of medical records. In total, 4114 participants were included (mean age 64.3 years, 55.2% females) of whom 167 had chronic axonal polyneuropathy. More than half (54.5%) had yet not received the diagnosis through regular care. Age-standardized prevalence's were 3.3% (95% CI 2.8-4.0) for the European, 3.0% (95% CI 2.5-3.5) for the US and 2.3% (95% CI 1.9-2.8) for the world population. Based on the expected age distributions, the prevalence of chronic axonal polyneuropathy will increase with ±25% in the next 20 years. Known risk factors were present in 62.9% (N=105) of the cases with polyneuropathy and most often included diabetes (34.1%) and vitamin deficiencies (15.1%). Importantly, combinations of various risk factors were found in 20.4% (N=34) of cases with polyneuropathy. Prevalence of chronic axonal polyneuropathy increases with age and is expected to further rise over time. Combinations of multiple known risk factors are often present, indicating the need for a full diagnostic workup, even when a single risk factor for polyneuropathy is known. These findings suggest that cumulative effects of multiple risk factors are important in the development and course of disease.


Fields as limit functions of stochastic discrimination and their adaptability.
For a particular type of elementary function, stochastic discrimination is shown to have an analytic limit function. Classifications can be performed directly by this limit function instead of by a sampling procedure. The limit function has an interpretation in terms of fields that originate from the training examples of a classification problem. Fields depend on the global configuration of the training points. The classification of a point in input space is known when the contributions of all fields are summed. Two modifications of the limit function are proposed. First, for nonlinear problems like high-dimensional parity problems, fields can be quantized. This leads to classification functions with perfect generalization for high-dimensional parity problems. Second, fields can be provided with adaptable amplitudes. The classification corresponding to a limit function is taken as an initialization; subsequently, amplitudes are adapted until an error function for the test set reaches minimal value. It is illustrated that this increases the performance of stochastic discrimination. Due to the nature of the fields, generalization improves even if the amplitude of every training example is adaptable.


The relationships between hemoglobin and insulin resistance, glucose effectiveness, and first- and second-phase insulin secretion in adult Chinese.
We denote the four major factors related to the development of type 2 diabetes (T2D) as "diabetes factor" (DF); increased insulin resistance (IR); decreased glucose effectiveness (GE); and the first-and-second-phase of insulin secretion (FPIS, SPIS). The level of hemoglobin (Hb) was found to be related to IR and FPIS, but no-known studies focused on its role in relation to SPIS and GE. In this study, we aim to evaluate the relationships between Hb and all four DFs in the same individual. We randomly enrolled 24,407 men and 24,889 women between 30 and 59 years old. IR, FPIS, SPIS and GE were measured according to equations published in our previous studies. To compare the slopes between Hb and the four DFs with different units, we converted their units to percent of change per unit of increased Hb. Age, HDL-cholesterol and GE were higher in women; BMI, blood pressure, LDL-cholesterol, TG, Hb, FPIS, SPIS and IR were higher in men. After they were converted into percentage, the closeness of their relationships to Hb, from the highest to the lowest, were GE, IR, FPIS and SPIS for women and IR, GE, FPIS and SPIS for men. GE was the only one negatively related to Hb. Our data showed that IR, FPIS and SPIS were both positively and, GE negatively, related to the Hb in adult Chinese. For women, GE had the closest association with Hb; for men, it was IR. Both phases of insulin secretion had relatively weaker relationships than IR and GE.


A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD.
The long-term use of inhaled anticholinergic agents has recently been suggested to be associated with an excess risk of adverse cardiovascular (CV) outcomes in patients with COPD. We identified 15 published studies that reported on the association between long-term inhaled anticholinergic use and adverse CV outcomes. Only 3 of the studies were adequately designed randomized controlled trials (RCTs). The first RCT that suggested that anticholinergic agents increased the risk of adverse CV outcomes was the Lung Health Study (LHS). Smokers randomized to inhaled ipratropium had a significantly increased risk of CV death than smokers receiving placebo. The LHS results have been questioned as the statistical tests used in the study were not adjusted for multiple tests and endpoints, a convincing dose-effect relationship between ipratropium use and the adverse CV outcomes was not established, and most of the CV deaths in the ipratropium group occurred in patients who were non-compliant to ipratropium. The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) was a RCT that compared the combination of salmeterol plus fluticasone against tiotropium in patients with COPD. All-cause mortality was significantly lower in the salmeterol plus fluticasone group (3%) compared to the tiotropium group (6%). Fatal CV events occurred in 1% of the salmeterol plus fluticasone group compared to 3% in the tiotropium group. The INSPIRE trial was not designed to be a mortality trial, lacked adequate adjudication of fatal outcomes, and lacked a full intention-to-treat analysis of the data. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a RCT comparing tiotropium and placebo in patients with COPD. Follow-up in UPLIFT was planned for 1440 days (4 years) plus 30 days (1470 days) of post-treatment follow-up. At 1440 days with 95% of patient outcome accounted for, tiotropium was associated with a significant 13% reduction in all-cause mortality compared to placebo. However, at 1470 days with only 75% of patient outcome accounted for, tiotropium was associated with a non-significant 11% reduction in all-cause mortality compared to placebo. The relative risks for serious CV events, heart failure, and myocardial infarction were all significantly lower with tiotropium than placebo. It is not certain why such a wide disparity in findings exists among the published studies evaluating the CV risks of inhaled anticholinergic agents. Prospective, adequately powered RCTs are needed to provide more evidence for the CV safety of tiotropium.


Myelopathies in patients with cancer.
Myelopathy is a devastating neurologic complication of cancer. The resulting pain, paralysis, and incontinence can turn a patient with cancer from a functioning individual to one who is confined to a chair or bed. Early diagnosis and appropriate therapy can prevent or ameliorate these symptoms and improve both duration of survival and quality of life. Accurate neurologic assessment of patients is crucial for early diagnosis and correct therapy. Myelopathy in patients with cancer is not rare. Epidural spinal cord compression (SCC) affects an estimated 5% of patients with cancer; other disorders such as intramedullary spinal cord metastases, adverse effects of therapy, and paraneoplastic spinal cord syndromes, although less common, are equally devastating. Because of space limitations, this review addresses the pathophysiology, clinical findings, diagnosis, and treatment of only some of the myelopathies that affect patients with cancer (Table 1). Because of new data, epidural SCC and paraneoplastic syndromes are emphasized.


An integrative view of obesity.
Obesity is the result of the accumulation of excess body fat and not simply excess weight that can be muscle or fat. Adipocytes function in the adaptation to starvation, in exercise energetics, and in the immune defense against pathogens. Sustained positive energy balance results in excessive accumulation of adipocytes, which, in the abdomen, leads to chronic inflammation. Although informative studies have been performed with cultured adipocytes, an integrative approach to the regulation of abdominal adipose tissue involves feedback from autocrine and paracrine effectors secreted by adipocytes, the immune system, and blood flow through adipose tissue. Numerous adipokines, chemokines, and cytokines feed back to other bodily systems to regulate both energy balance and immune function. Studies of the interactions of the gastrointestinal tract and the central nervous system, as well as psychophysiological considerations of reward circuitry in the central nervous system, have shown a general adaptation to starvation that is opposed to those strategies being proposed for the prevention and treatment of obesity, ie, food restriction and increased physical activity. The obesogenic environment of highly palatable foods with hidden fats and sugars can promote metabolic syndrome and obesity, whereas fruit and vegetables with antiinflammatory phytochemicals can counteract metabolic syndrome. Therefore, a plant-based diet and the seamless integration of increased physical activity and social support to alter modern diets and lifestyles hold out the greatest hope for the solution of the obesity epidemic. Both public health and medical nutrition approaches can benefit from this integrative view of obesity.