The effect of boundary and loading conditions on patient classification using finite element predicted risk of fracture.
Osteoporotic proximal femoral fractures associated to falls are a major health burden in the ageing society. Recently, bone strength estimated by finite element models emerged as a feasible alternative to areal bone mineral density as a predictor of fracture risk. However, previous studies showed that the accuracy of patients' classification under their risk of fracture using finite element strength when simulating posterolateral falls is only marginally better than that of areal bone mineral density. Patients tend to fall in various directions: since the predicted strength is sensitive to the fall direction, a prediction based on certain fall directions might not be fully representative of the physical event. Hence, side fall boundary conditions may not be completely representing the physical event. The effect of different side fall boundary and loading conditions on a retrospective cohort of 98 postmenopausal women was evaluated to test models' ability to discriminate fracture and control cases. Three different boundary conditions (Linear, Multi-point constraints and Contact model) were investigated under various anterolateral and posterolateral falls. The stratification power estimated by the area under the receiver operating characteristic curve was highest for Contact model (0.82), followed by Multi-point constraints and Linear models with 0.80. Both Contact and MPC models predicted high strains in various locations of the proximal femur including the greater trochanter, which has rarely reported previously. A full range of fall directions and less restrictive displacement constraints can improve the finite element strength ability to classify patients under their risk of fracture.


High-gain nondegenerate two-wave mixing in Cr:YAIO(3).
A gain of 22 times was obtained by nondegenerate two-wave mixing in Cr:YAlO(3). To our knowledge, this is the largest cw two-wave mixing gain obtained in a bulk solid-state nonphotorefractive material. The measured gain appears to be limited by beam breakup that is due to spatial nonuniformities in the nonlinear refractive-index change that are the result of inhomogeneities in the crystal. Predictions based on our data indicate that gain in excess of 200 times should be possible in Cr:YAlO(3) if a homogeneous crystal can be obtained.


Can wastewater feed cities? Determining the feasibility and environmental burdens of struvite recovery and reuse for urban regions.
Phosphorus (P) resources are decreasing at an alarming rate due to global fertilizer use and insufficient nutrient recovery strategies. Currently, more circular approaches are promoted, such as recovering P from wastewater in the form of struvite. This is especially attractive for urban areas, where there is a growing trend of local crop production and large volumes of wastewater are treated in centralized wastewater treatment plants (WWTPs). This research aims to assess the technical and environmental feasibility of applying a struvite recovery and reuse strategy to meet the P requirements to fertilize the agricultural fields of an urban region. To do so, we analyze the potential P recovery and the environmental impacts of integrating three recovery technologies (REM-NUT®, Ostara® and AirPrex®) in the two biggest WWTPs of the Àrea Metropolitana de Barcelona. The results show that all technologies are able to recover between 5 and 30 times the amount of P required to fertilize the agricultural area of the region annually (36.5 t). As can be expected, including P recovery technologies result in additional impacts per m3 of wastewater due to increased electricity consumption and chemicals required for the struvite precipitation. However, struvite recovery results in less eutrophication potential, especially in the REM-NUT® case, with an average reduction of 5.4 times. On the other hand, Ostara®, that recovers P from the digestate, had the lowest impacts (9 kgCO2eq/kgP), even compared to the production of mineral fertilizer. When we apply our findings to the whole region, we can see that chemical use for struvite precipitation and energy consumption during the wastewater treatment process are the elements with the greatest impact. Thus, choosing the most appropriate technology in the most suitable WWTP is the most efficient strategy to diminish the environmental impacts of the system.


Myasthenia gravis: passive transfer from man to mouse.
Daily injections into mice of an ammonium sulfate-precipitated immunoglobulin fraction of serum from patients with myasthenia gravis were carried out for up to 14 days. The mice showed reduced amplitudes of miniature endplate potentials and reduced numbers of acetylcholine receptors at the neuromuscular junctions. Some mice showed typical decremental responses on repetitive nerve stimulation, with reversal by neostigmine. This represents the first evidence of a circulating factor in the serum of patients with myasthenia gravis which on passive transfer reproduces features of the disease in experimental animals.


A nationwide analysis of laparoscopy in high-risk colorectal surgery patients.
Due to safety concerns, the use of laparoscopy in high-risk colorectal surgery patients has been limited. Small reports have demonstrated the benefit of laparoscopy in this population; however, large comparative studies are lacking. A retrospective review of the Nationwide Inpatient Sample 2009 was conducted. Patients undergoing elective colorectal resections for benign and malignant pathology were included in the high-risk group if they had at least two of the following criteria: age > 70, obesity, smoking, anemia, congestive heart failure, valvular disease, diabetes mellitus, chronic pulmonary, kidney and liver disease. Using multivariate logistic regression, the outcomes of laparoscopic surgery were compared to open and converted surgery. Of 145,600 colorectal surgery cases, 32.79% were high-risk. High-risk patients had higher mortality, hospital charges, and longer hospital stay compared to low-risk patients. The use of laparoscopy was lower in the high-risk group with higher conversion rates. In high-risk patients, compared to open surgery, laparoscopy was associated with lower mortality (OR = 0.60), shorter hospital stay, lower charges, decreased respiratory failure (OR = 0.53), urinary tract infection (OR = 0.64), anastomotic leak (OR = 0.69) and wound complications (OR = 0.46). Conversion to open surgery was not associated with higher mortality. Laparoscopy in high-risk colorectal patients is safe and may demonstrate advantages compared to open surgery.


Acute Ethanol Modulates Synaptic Inhibition in the Basolateral Amygdala via Rapid NLRP3 Inflammasome Activation and Regulates Anxiety-Like Behavior in Rats.
Chronic alcohol exposure leads to a neuroinflammatory response involving activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and proinflammatory cytokine production. Acute ethanol (EtOH) exposure activates GABAergic synapses in the central and basolateral amygdala (BLA) ex vivo, but whether this rapid modulation of synaptic inhibition is because of an acute inflammatory response and alters anxiety-like behavior in male and female animals is not known. Here, we tested the hypotheses that acute EtOH facilitates inhibitory synaptic transmission in the BLA by activating the NLRP3 inflammasome-dependent acute inflammatory response, that the alcohol-induced increase in inhibition is cell type and sex dependent, and that acute EtOH in the BLA reduces anxiety-like behavior. Acute EtOH application at a binge-like concentration (22-44 mm) stimulated synaptic GABA release from putative parvalbumin (PV) interneurons onto BLA principal neurons in ex vivo brain slices from male, but not female, rats. The EtOH facilitation of synaptic inhibition was blocked by antagonists of the Toll-like receptor 4 (TLR4), the NLRP3 inflammasome, and interleukin-1 receptors, suggesting it was mediated by a rapid local neuroinflammatory response in the BLA. In vivo, bilateral injection of EtOH directly into the BLA produced an acute concentration-dependent reduction in anxiety-like behavior in male but not female rats. These findings demonstrate that acute EtOH in the BLA regulates anxiety-like behavior in a sex-dependent manner and suggest that this effect is associated with presynaptic facilitation of parvalbumin-expressing interneuron inputs to BLA principal neurons via a local NLRP3 inflammasome-dependent neuroimmune response.SIGNIFICANCE STATEMENT Chronic alcohol exposure produces a neuroinflammatory response, which contributes to alcohol-associated pathologies. Acute alcohol administration increases inhibitory synaptic signaling in the brain, but the mechanism for the rapid alcohol facilitation of inhibitory circuits is unknown. We found that acute ethanol at binge-like concentrations in the basolateral amygdala (BLA) facilitates GABA release from parvalbumin-expressing (PV) interneuron synapses onto principal neurons in ex vivo brain slices from male rats and that intra-BLA ethanol reduces anxiety-like behavior in vivo in male rats, but not female rats. The ethanol (EtOH) facilitation of inhibition in the BLA is mediated by Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation and proinflammatory IL-1β signaling, which suggests a rapid NLRP3 inflammasome-dependent neuroimmune cascade that plays a critical role in acute alcohol intoxication.


A nonlinear effective thermal conductivity model for carbon nanotube and nanofiber suspensions.
It has been experimentally demonstrated that suspensions of carbon nanotubes (CNTs) and nanofibers (CNFs) significantly increase the thermal conductivity of nanofluids; however, a physically sound theory of the underlying phenomenon is still missing. In this study, the nonlinear nature of the effective thermal conductivity enhancement with the particle concentration of CNT and CNF nanofluids is explained physically using the excluded volume concept. Specifically, the number of contacting CNTs and CNFs could be calculated by using the excluded volume concept, where the distance for heat to travel in a cylinder between the contacting cylinders in the thermal network of percolating CNTs and CNFs increased with the excluded volume. In contrast to the effective thermal conductivity model of Sastry et al (2008 Nanotechnology 19 055704) the present revised model could reproduce the nonlinear increase of the thermal conductivity with particle concentration, as well as the dependence on the diameter and aspect ratio of the CNTs and CNFs. It was found that the alignment of CNTs and CNFs due to the long range repulsion force decreases the excluded volume, leading to both the convex and concave nonlinear as well as linear increase of the thermal conductivity with particle concentration. The difference between various carrier fluids of the suspensions could be explained as the result of the change in the excluded volume in different base fluids.


Diagnostic utility of deamidated gliadin peptide antibody in celiac disease compared to anti-tissue transglutaminase and IgA- endomysium antibodies.
Deamidated gliadin peptide antibodies have recently been suggested as reliable tools for celiac disease (CD) diagnosis. We compared their utility for diagnosis CD in comparison to the routinely used anti-endomysial, and anti-tissue transglutaminase antibodies. We studied 65 patients (17 men, 48 women; age range, 17- 63 years) who underwent intestinal biopsy because of clinical suspicion of small-bowel disorders. Serum samples were obtained at the time of biopsy for measuring IgA and IgG anti-tissue transglutaminase (tTG), IgA and IgG anti-deamidated gliadin peptide (DOP) by ELISA and IgA anti-endomesial antibody (EmA) by indirect immunoflouresce. Characterization of patients was based on histological criteria (Marsh type II lesion or greater). Biopsy revealed that 14 patients had positive criteria for CD. The remaining 51 negative patients were used as controls. Assay sensitivity and specificity for diagnosing celiac disease were 85.7% and 92.2% for IgA and 92.9 and 100% for IgG antibodies to DGP respectively. Serum IgA and IgG DGP, IgA and IgG -tTG and IgA EmA were significantly higher in CD patients than in control group (P = 0.000). None of the controls was positive for IgG DGP or IgA -EmA, but 4 of 51 (7.8 %) were positive for IgA- DGP, 6 of 51 (11.8 %) were positive for IgA anti-tTG, and 2 of 51 (3.9%) were positive for IgG anti-tTG. IgG-DGP has the best sensitivity (92.9%), specificity (100%), positive predictive value (100%), and negative predictive value (96.2%). In conclusion, the DGP antibodies tests, alone or in combination with the tTG antibodies, are useful tools for screening purposes and with better patient acceptance than intestinal biopsy.


Analysis of diffracted fields with the extended theory of the boundary diffraction wave for impedance surfaces.
Uniform diffracted fields from impedance surfaces are investigated by the extended theory of boundary diffraction wave (ETBDW). The new vector potential of the ETBDW is constructed by considering the pseudoimpedance boundary condition. The method is applied to the diffraction problem from an impedance half-plane. It is shown that the total fields from an impedance half-plane reduce to the case of a perfectly electric or magnetic conducting and opaque half-plane for special values of surface impedance. The total and diffracted fields are compared numerically with the exact solution for the impedance half-plane and modified theory of physical optics (MTPO) solution for an impedance wedge. The numerical results show that the field expressions are in very good agreement with the exact and MTPO solutions.


Thin-slicing study of the oxytocin receptor (OXTR) gene and the evaluation and expression of the prosocial disposition.
Individuals who are homozygous for the G allele of the rs53576 SNP of the oxytocin receptor (OXTR) gene tend to be more prosocial than carriers of the A allele. However, little is known about how these differences manifest behaviorally and whether they are readily detectable by outside observers, both critical questions in theoretical accounts of prosociality. In the present study, we used thin-slicing methodology to test the hypotheses that (i) individual differences in rs53576 genotype predict how prosocial observers judge target individuals to be on the basis of brief observations of behavior, and (ii) that variation in targets' nonverbal displays of affiliative cues would account for these judgment differences. In line with predictions, we found that individuals homozygous for the G allele were judged to be more prosocial than carriers of the A allele. These differences were completely accounted for by variations in the expression of affiliative cues. Thus, individual differences in rs53576 are associated with behavioral manifestations of prosociality, which ultimately guide the judgments others make about the individual.


Comparison of total prostate-specific antigen and derivative levels in a screening population of black, white, and Korean-American men.
Numerous studies have assessed serum total PSA (tPSA) levels among different races. We extended the serum biomarker profiling using prostate-specific antigen (PSA) derivatives in age-matched screening populations that included white, black, and Korean-American patients. The median ages were 61 years for white and black patients and 63 years for Korean-American patients. Serum samples from 70 men in each ethnic group were analyzed using 3 different tPSA assays (Tosoh AIA 600II, Bayer Immuno-1, Roche Elecsys 2010). The percentage of free PSA (fPSA) was measured directly by Roche Elecsys 2010 immunoassay and then calculated from complexed PSA (cPSA) and tPSA results determined with the Bayer Immuno-1. The percentage of cPSA was determined using cPSA and tPSA assayed by the Immuno-1 method. Statistical analyses included nonparametric Kruskal-Wallis and analysis of variance (ANOVA) evaluations. There were no differences noted in the tPSA values based on ANOVA among the 3 races irrespective of the assay platform methodology employed. Also, the PSA derivatives, percentages of fPSA and cPSA, evaluated using the Kruskal-Wallis test, showed no significant differences for either derivative assayed on 2 different assay platforms among the 3 groups. In a contemporary screening population comparing tPSA, percentage of fPSA, and percentage of cPSA levels in 3 races, there were no significant differences identified among the groups.


Impact of XPD gene polymorphism on risk of prostate cancer on north Indian population.
Prostate cancer is the second most diagnosed cancer in men next to skin cancer in the developed world. Risk of disease varies most prominently with age, ethnicity, family history, and diet. Genetic polymorphism of some genes has been implicated in increasing the risk. The XPD (Xeroderma pigmentosum group D) gene codes for a DNA helicase involved in transcription and nucleotide excision repair. The aim of this study is to evaluate the effect of XPD 751 Lys/Gln polymorphism on risk of prostate cancer on north Indian patients. Blood sample from 150 prostate cancer patients, 150 from Prostate Hyper Plasia and equal number of samples from healthy control groups was collected from North India. The polymerase chain reaction and restrictive fragment length polymorphism techniques were implemented. Statistically non-significant increase risk of prostate cancer was observed with patients having Gln/Gln genotype (OR 1.62, 95% CI).


Quantitative ultrasound predicts hip and non-spine fracture in men: the MrOS study.
Quantitative ultrasound (QUS) is associated with fracture risk in women, but there are few data in men. We studied 5,607 older men and found that QUS predicts hip and any non-spine fracture risk nearly as well as BMD. Combined measurements of QUS and BMD are not superior to either measurement alone. Quantitative ultrasound (QUS) predicts fracture risk among older women, but there are few prospective studies among older men. We studied the ability of QUS and BMD measurements to predict hip and other non-spine fractures in a population-based study of older men. Calcaneal QUS and hip BMD were measured in 5,607 men aged > or =65 years recruited from six US centers. At baseline duplicate QUS measurements with repositioning were obtained, and subsequent hip and other non-spine fractures were documented by review of x-rays or x-ray reports. The relationships between QUS and fractures were examined with proportional hazard models adjusted for age and clinic. We used receiver operating characteristic curves and predicted fracture risk models to determine the utility of QUS alone, BMD alone or the combination of QUS+BMD. During a mean follow-up of 4.2 years with 99% complete follow-up, 239 men suffered a non-spine fracture, including 49 hip fractures. Each standard deviation reduction in broadband ultrasonic attenuation (BUA) was associated with an increased risk of hip (relative hazard=2.0, CI: 1.5, 2.8) and any non-spine fracture (relative hazard=1.6, CI: 1.4, 1.8). The area under the receiver operating characteristic curve and the predicted probability of fracture were similar for BUA alone, BMD alone and the combination of BUA+BMD, indicating that once BUA or BMD is known, the other measurement does not add useful information. Other QUS parameters gave similar results. QUS measurements predict the risk of hip and any non-spine fracture in older men, and do so nearly as well as hip BMD measurements. Combined measurements of QUS and BMD are not superior to either measurement alone.


Relationships among injury, fibrosis, and time in human kidney transplants.
Kidney transplant biopsies offer an opportunity to understand the pathogenesis of organ fibrosis. We studied the relationships between the time of biopsy after transplant (TxBx), histologic fibrosis, diseases, and transcript expression. Expression microarrays from 681 kidney transplant indication biopsies taken either early (n = 282, <1 year) or late (n = 399, >1 year) after transplant were used to analyze the molecular landscape of fibrosis in relationship to histologic fibrosis and diseases. Fibrosis was absent at transplantation but was present in some early biopsies by 4 months after transplant, apparently as a self-limited response to donation implantation injury not associated with progression to failure. The molecular phenotype of early biopsies represented the time sequence of the response to wounding: immediate expression of acute kidney injury transcripts, followed by fibrillar collagen transcripts after several weeks, then by the appearance of immunoglobulin and mast cell transcripts after several months as fibrosis appeared. Fibrosis in late biopsies correlated with injury, fibrillar collagen, immunoglobulin, and mast cell transcripts, but these were independent of time. Pathway analysis revealed epithelial response-to-wounding pathways such as Wnt/β-catenin. Fibrosis in late biopsies had different associations because many kidneys had potentially progressive diseases and subsequently failed. Molecular correlations with fibrosis in late biopsies were independent of time, probably because ongoing injury obscured the response-to-wounding time sequence. The results indicate that fibrosis in kidney transplants is driven by nephron injury and that progression to failure reflects continuing injury, not autonomous fibrogenesis. INTERCOM study (www.clinicalTrials.gov; NCT01299168). Canada Foundation for Innovation and Genome Canada.


Loss of epithelial oestrogen receptor α inhibits oestrogen-stimulated prostate proliferation and squamous metaplasia via in vivo tissue selective knockout models.
Squamous metaplasia (SQM) is a specific phenotype in response to oestrogen in the prostate and oestrogen receptor (ER) α is required to mediate this response. Previous studies utilizing tissue recombination with seminal vesicle (SV) mesenchyme and prostatic ductal tips from wild type and ERαKO mice suggested that both epithelial and stromal ERα are necessary for SQM. However, tissue recombination is conducted in the renal capsule of immune-deficient mice, in which the microenvironment is different from normal prostate microenvironment in the intact mice. Furthermore, whether the requirement of stromal ERα in the SV for developing SQM is the same as in the prostate is unknown. Therefore, there is a clear need to evaluate the respective roles of ERα in prostate epithelial versus stromal compartments in the intact mouse. Here we generated a mouse model that has selectively lost ERα in either stromal (FSP-ERαKO) or epithelial prostate cells (pes-ERαKO) to determine the requirements of ERα for oestrogen-stimulated prostate proliferation and SQM. Our results indicated that FSP-ERαKO prostates develop full and uniform SQM, which suggests that loss of the majority (~65%) of stromal ERα will not influence oestrogen-mediated SQM. In contrast, loss of epithelial ERα inhibits oestrogen-mediated prostate growth and SQM evidenced by decreasing cytokertin 10 positive squamous cell stratification and differentiation, by reduced ERα protein expression in SQM compared to wild type mice ERα, and by the presence of normal proliferative activities in the oestrogen-treated pes-ERαKO prostates. These in vivo results suggest that epithelial ERα is required for oestrogen-mediated proliferative response and could be an appropriate target for preventing aberrant oestrogen signalling in the prostate.


A pol I transcriptional body associated with VSG mono-allelic expression in Trypanosoma brucei.
In the mammalian host, African trypanosomes generate consecutive waves of parasitaemia by changing their antigenic coat. Because this coat consists of a single type of variant surface glycoprotein (VSG), the question arises of how a trypanosome accomplishes the transcription of only one of a multi-allelic family of VSG expression site loci to display a single VSG type on the surface at any one time. No major differences have been detected between the single active expression site and the cohort of inactive expression sites. Here we identify an extranucleolar body containing RNA polymerase I (pol I) that is transcriptionally active and present only in the bloodstream form of the parasite. Visualization of the active expression site locus by tagging with green fluorescent protein shows that it is specifically located at this unique pol I transcriptional factory. The presence of this transcriptional body in postmitotic nuclei and its stability in the nucleus after DNA digestion provide evidence for a coherent structure. We propose that the recruitment of a single expression site and the concomitant exclusion of inactive loci from a discrete transcriptional body define the mechanism responsible for VSG mono-allelic expression.


Occupational adaptation: toward a holistic approach for contemporary practice, Part 2.
This paper introduces a practice model based on the occupational adaptation frame of reference (Schkade & Schultz, 1992). The occupational adaptation practice model emphasizes the creation of a therapeutic climate, the use of occupational activity, and the importance of relative mastery. Practice based on occupational adaptation differs from treatment that focuses on acquisition of functional skills because the practice model directs occupational therapy interventions toward the patient's internal processes and how such processes are facilitated to improve occupational functioning. The occupational adaptation practice model is holistic. The patient's occupational environments (as influenced by physical, social, and cultural properties) are as important as the patient's sensorimotor, cognitive, and psychosocial functioning and the patient's experience of personal limitations and potential is validated. The integration of these concepts drives the treatment process. Through a description of treatment with a variety of patients, this paper presents the model's diversity and illustrates the relationship between the concepts. The occupational adaptation practice model reflects the uniqueness of occupational therapy and integrates the profession's historical practice with contemporary interventions and methods.


Adiposity, Depression Symptoms and Inflammation in Hispanic/Latino Youth: Results From HCHS/SOL Youth.
Inflammation is implicated as one of many factors related to the development of chronic disease; thus, identifying its modifiable risk factors offers potential intervention targets to reduce risk. To investigate whether depression and anxiety symptoms may indirectly affect high-sensitivity C-reactive protein (hs-CRP) and plasminogen activator inhibitor-1 (PAI-1) through sleep duration and adiposity (i.e., percentage body fat and waist circumference). Multiple regression analyses were performed on Hispanic Community Health Study/Study of Latinos Youth (ages 8-16 years) cross-sectional baseline data, which were weighted to adjust for sampling design. Data were collected at a clinical assessment, including fasting blood samples, self-report surveys, and objectively measured anthropometrics. Adjusting for sociodemographic covariates, depression symptoms were associated with log hs-CRP (β = .011, p = .047) but not PAI-1 (p = .285). Percentage body fat and waist circumference were positively related to depression symptoms (p = .026 and p = .028, respectively) and log hs-CRP (p < .001 for both). When including adiposity in the hs-CRP model, the associations of depression symptoms with hs-CRP were attenuated and became nonsignificant. Monte Carlo confidence intervals (CIs) showed that the indirect effects from depression symptoms to CRP through percentage body fat (95% CI: .0006, .0119) and waist circumference (95% CI: .0004, .0109) were statistically significant. Results indicate that the association between psychological distress and inflammation may occur indirectly through adiposity in Hispanic/Latino children. If findings are replicated in causal designs, reducing depression symptoms and adiposity among Hispanic/Latino children may be avenues for primary prevention of inflammation in later years.


The folding of knotted proteins: insights from lattice simulations.
We carry out systematic Monte Carlo simulations of Gō lattice proteins to investigate and compare the folding processes of two model proteins whose native structures differ from each other due to the presence of a trefoil knot located near the terminus of one of the protein chains. We show that the folding time of the knotted fold is larger than that of the unknotted protein and that this difference in folding time is particularly striking in the temperature region below the optimal folding temperature. Both proteins display similar folding transition temperatures, which is indicative of similar thermal stabilities. By using the folding probability reaction coordinate as an estimator of folding progression we have found out that the formation of the knot is mainly a late folding event in our shallow knot system.


The BICAMS Battery for Assessment of Lithuanian-Speaking Multiple Sclerosis Patients: Relationship with Age, Education, Disease Disability, and Duration.
BACKGROUND Assessment of cognitive impairment (CI) in multiple sclerosis (MS) patients is very useful, but it requires time-consuming expert evaluation with specialized materials. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) was created as a brief and specific instrument for the evaluation of CI. The aims of this study were to assess the cognitive status of MS patients by using the Lithuanian version of BICAMS, to evaluate the test-retest reliability of the Lithuanian version of BICAMS, and to measure the impact of CI on disability and duration of MS. MATERIAL AND METHODS We enrolled 50 MS patients and 20 cognitively normal control subjects, matched for age, gender, and level of education. Cognitive functions were assessed by the BICAMS tests, which include the Symbol Digit Modalities Test, the Brief Visuospatial Memory Test Revised, and the California Verbal Learning Test, 2nd edition. RESULTS MS patients performed significantly worse than controls on the 3 neuropsychological tests of BICAMS (p<0.001). Younger and intellectually employed persons performed significantly better on these tests than older persons, manual workers, or unemployed persons (p<0.05). MS patients with higher disability scores tended to perform worse on the tests (p<0.05), but we found no relationship between BICAMS test scores and the duration of the disease or relapse rate (p>0.05). Test-retest reliability was excellent for all 3 subtests (r>0.8, p<0.05). CONCLUSIONS Our study shows that BICAMS is a valid and acceptable cognitive assessment tool that can be recommended for routine use in Lithuania for assessing patients with MS.


Regulation of proteoglycan synthesis rate in cartilage in vitro: influence of extracellular ionic composition.
Load-bearing cartilages regularly experience changes in fluid content as the result of changing load. It has been found that these changes in fluid content influence proteoglycan synthesis. The mechanism for this effect is not known. We have measured the influence of changes in cartilage hydration on the [35S]sulphate incorporation rate in both bovine nasal and human articular cartilage in medium whose concentration varied over the range 0.2-2-times physiological strength. In physiological medium the incorporation rate fell in proportion to fluid loss with a 10% fall in cartilage hydration resulting in a 30-50% decrease in 35S-incorporation rates. However, in medium of 0.5-times physiological strength, where the incorporation rate was only 40% of control values, the incorporation rate increased initially rather than falling as the cartilage lost fluid. These changes in hydration and hence proteoglycan content resulted in changes in the extracellular ionic composition of cartilage. When this was monitored in terms of [Na+]c, the internal sodium concentration, as a marker for changes in cartilage ionic composition, we found that incorporation rate varied with [Na+]c rather than directly with hydration.


Salmonella pathogenicity island 2-dependent macrophage death is mediated in part by the host cysteine protease caspase-1.
Salmonella typhimurium invades host macrophages and can either induce a rapid cell death or establish an intracellular niche within the phagocytic vacuole. Rapid cell death requires the Salmonella pathogenicity island (SPI)1 and the host protein caspase-1, a member of the pro-apoptotic caspase family of proteases. Salmonella that do not cause this rapid cell death and instead reside in the phagocytic vacuole can trigger macrophage death at a later time point. We show here that the human pathogen Salmonella typhi also triggers both rapid, caspase-1-dependent and delayed cell death in human monocytes. The delayed cell death has previously been shown with S. typhimurium to be dependent on SPI2-encoded genes and ompR. Using caspase-1(-/-) bone marrow-derived macrophages and isogenic S. typhimurium mutant strains, we show that a large portion of the delayed, SPI2-dependent death is mediated by caspase-1. The two known substrates of activated caspase-1 are the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and IL-18, which are cleaved to produce bioactive cytokines. We show here that IL-1beta is released during both SPI1- and SPI2-dependent macrophage killing. Using IL-1beta(-/-) bone marrow-derived macrophages and a neutralizing anti-IL-18 antibody, we show that neither IL-1beta nor IL-18 is required for rapid or delayed macrophage death. Thus, both rapid, SPI1-mediated killing and delayed, SPI2-mediated killing require caspase-1 and result in the secretion of IL-1beta, which promotes inflammation and may facilitate the spread of Salmonella beyond the gastrointestinal tract in systemic disease.


Disease progression and recurrence in women treated for vulvovaginal intraepithelial neoplasia.
The malignant potential of intraepithelial neoplasia of the vulva and vagina after treatment is not well defined. Our objective was to examine risk factors for recurrence and invasive disease. Four hundred sixty-four women with biopsy proven high-grade intraepithelial neoplasia of the vulva and vagina were identified in the electronic databases of four colposcopy clinics. Inclusion criteria were a follow-up of more than one year, no history of invasive cancer and no invasive cancer within the first year after initial treatment. We investigated the potential factors associated with recurrence and progression using a logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Of the 411 eligible patients, 123 patients (29.9%) recurred later than one year after initial treatment and 24 patients (5.8%) progressed to invasive disease. According to multivariate analyses, the risk factors associated with recurrence were multifocality (OR, 3.33; 95% CI, 2.02 to 5.51), immunosuppression (OR, 2.51; 95% CI, 1.09 to 5.81), excision as initial treatment (vs. laser evaporation; OR, 1.79; 95% CI, 1.11 to 2.91) and smoking (OR, 1.61; 95% CI, 1.02 to 2.55). Risk factors for progression to invasive disease were immunosuppression (OR, 4.00; 95% CI, 1.30 to 12.25), multifocality (OR, 3.05; 95% CI, 1.25 to 7.43) and smoking (OR, 2.97; 95% CI, 1.16 to 7.60), but not treatment modality. Laser evaporation combined with extensive biopsy is at least as efficacious as initial treatment of intraepithelial neoplasia with excision. Smoking is a risk factor for both recurrence and progression to invasive disease. Hence, smoking cessation should be advised and maintaining a long follow-up period due to late relapses is necessary.


Association between Medication Adherence Outcomes and Adverse Drug Reactions to Highly Active Antiretroviral Therapy in Indian Human Immunodeficiency Virus-Positive Patients.
In India, interruptions to highly active antiretroviral therapy (HAART) are due to adverse drug reactions. This study was aimed to assess the association between HAART adherence and adverse drug reactions (ADRs) in human immunodeficiency virus (HIV) patients. This prospective study was conducted at a Medicine department in a South Indian tertiary care teaching hospital. HIV-positive patients were interviewed for adherence using ACTG adherence questionnaire and intensively monitored for ADRs to HAART. The percentage of adherence was calculated based on missed doses, and graded as less than 80%, 80-95%, and >95%. The World Health Organization (WHO) probability scale was used for causality assessment. Logistic regression analysis as well as univariate analysis was used to assess the association (P value < 0.05). A total of 105 HIV-positive patients had been taking HAART out of whom 50 (47.6%) patients agreed for adherence assessment, and 23 (21.9%) refused due to social stigma. Upon evaluation of the patient characteristics in the reported adherence, 78% were in males (53.8%) and 22% were in females (46.2%) with the level of adherence greater than 95%. Six (12%) patients had a regular alcoholic intake with adherence less than 80% compared to 31 (62%) patients who never had any alcoholic intake (P < 0.05). A significant association between ADRs and adherence was found (P < 0.05). Causality found by the WHO scale was "probable." Clinicians must focus on education regarding the need for adherence, possible adverse effects, and early detection and prevention of ADRs to HAART.


The IL20 Genetic Polymorphism Is Associated with Altered Clinical Outcome in Septic Shock.
The IL10 family of genes includes crucial immune regulators. We tested the hypothesis that single nucleotide polymorphisms (SNPs) in IL10, IL19, IL20, and IL24 of the IL10 family gene cluster alter the clinical outcome of septic shock. Patients with septic shock (n = 1,193) were genotyped for 13 tag SNPs of IL10, IL19, IL20, and IL24. IL20 gene expression was measured in genotyped lymphoblastoid cells in vitro. Cardiac surgical ICU patients (n = 981) were genotyped for IL20 rs2981573 A/G. The primary outcome variable was 28-day mortality. Patients with the G allele of IL20 rs2981573 had a significantly increased hazard of death over the 28-day period compared to patients with the A allele in the septic shock cohort (adjusted hazard ratio 1.27; 95% confidence interval 1.10-1.47; p = 8.0 × 10-4). Patients with the GG genotype had more organ dysfunction (p < 0.05). The GG genotype was associated with increased IL20 gene expression in stimulated lymphoblastoid cells in vitro (p < 0.05). The cardiac surgical ICU patients with the GG genotype had an increased length of ICU stay (p = 0.032). The GG genotype of IL20 rs2981573 SNP was associated with increased IL20 gene expression and increased adverse outcomes in patients with septic shock and following cardiac surgery.


Distinctive features and differential regulation of the DRTS genes of Arabidopsis thaliana.
In plants and protists, dihydrofolate reductase (DHFR) and thymidylate synthase (TS) are part of a bifunctional enzyme (DRTS) that allows efficient recycling of the dihydrofolate resulting from TS activity. Arabidopsis thaliana possesses three DRTS genes, called AtDRTS1, AtDRTS2 and AtDRTS3, that are located downstream of three members of the sec14-like SFH gene family. In this study, a characterization of the AtDRTS genes identified alternatively spliced transcripts coding for AtDRTS isoforms which may account for monofunctional DHFR enzymes supporting pathways unrelated to DNA synthesis. Moreover, we discovered a complex differential regulation of the AtDRTS genes that confirms the expected involvement of the AtDRTS genes in cell proliferation and endoreduplication, but indicates also functions related to other cellular activities. AtDRTS1 is widely expressed in both meristematic and differentiated tissues, whereas AtDRTS2 expression is almost exclusively limited to the apical meristems and AtDRTS3 is preferentially expressed in the shoot apex, in stipules and in root cap cells. The differential regulation of the AtDRTS genes is associated to distinctive promoter architectures and the expression of AtDRTS1 in the apical meristems is strictly dependent on the presence of an intragenic region that includes the second intron of the gene. Upon activation of cell proliferation in germinating seeds, the activity of the AtDRTS1 and AtDRTS2 promoters in meristematic cells appears to be maximal at the G1/S phase of the cell cycle. In addition, the promoters of AtDRTS2 and AtDRTS3 are negatively regulated through E2F cis-acting elements and both genes, but not AtDRTS1, are downregulated in plants overexpressing the AtE2Fa factor. Our study provides new information concerning the function and the regulation of plant DRTS genes and opens the way to further investigations addressing the importance of folate synthesis with respect to specific cellular activities.


Association of the virus-like infectious agent originally reported in patients with AIDS with acute fatal disease in previously healthy non-AIDS patients.
We studied 6 patients from 6 different geographic areas who presented with acute flu-like illnesses. The patients developed persistent fevers, lymphadenopathy or diarrhea, pneumonia, and/or heart, liver, or adrenal failure. They died in 1-7 weeks. These patients had no serological evidence of HIV infection and could not be classified as AIDS patients according to CDC criteria. The clinical signs as well as laboratory and pathological studies of these patients suggested an active infectious process, although no etiological agent was found despite extensive infectious disease work-ups during their hospitalization. Post-mortem examinations showed histopathological lesions of fulminant necrosis involving the lymph nodes, spleen, lungs, liver, adrenal glands, heart, and/or brain. No viral inclusion cells, bacteria, fungi, or parasites could be identified in these tissues using special tissue stains. We report that immunohistochemistry using rabbit antiserum raised against VLIA, the virus-like infectious agent previously identified in patients with AIDS and shown to cause fatal systemic infection in primates, revealed VLIA antigens in these necrotizing lesions. In situ hybridization using an 35S labeled VLIA-specific DNA probe also detected VLIA genetic material in the areas of necrosis. Furthermore, virus-like particles closely resembling VLIA were identified ultrastructurally in these histopathological lesions. VLIA was associated with the systemic necrotizing lesions in these previously healthy non-AIDS patients with an acute fatal disease.


A Kir6.2 pore mutation causes inactivation of ATP-sensitive potassium channels by disrupting PIP2-dependent gating.
In the absence of intracellular nucleotides, ATP-sensitive potassium (KATP) channels exhibit spontaneous activity via a phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent gating process. Previous studies show that stability of this activity requires subunit-subunit interactions in the cytoplasmic domain of Kir6.2; selective mutagenesis and disease mutations at the subunit interface result in time-dependent channel inactivation. Here, we report that mutation of the central glycine in the pore-lining second transmembrane segment (TM2) to proline in Kir6.2 causes KATP channel inactivation. Unlike C-type inactivation, a consequence of selectivity filter closure, in many K(+) channels, the rate of inactivation in G156P channels was insensitive to changes in extracellular ion concentrations or ion species fluxing through the pore. Instead, the rate of G156P inactivation decreased with exogenous application of PIP2 and increased when PIP2-channel interaction was inhibited with neomycin or poly-L-lysine. These findings indicate the G156P mutation reduces the ability of PIP2 to stabilize the open state of KATP channels, similar to mutations in the cytoplasmic domain that produce inactivation. Consistent with this notion, when PIP2-dependent open state stability was substantially increased by addition of a second gain-of-function mutation, G156P inactivation was abolished. Importantly, bath application and removal of Mg(2+)-free ATP or a nonhydrolyzable analog of ATP, which binds to the cytoplasmic domain of Kir6.2 and causes channel closure, recover G156P channel from inactivation, indicating crosstalk between cytoplasmic and transmembrane domains. The G156P mutation provides mechanistic insight into the structural and functional interactions between the pore and cytoplasmic domains of Kir6.2 during gating.


Prevalence and correlates of major depression in Granada, Spain: Results from the GranadΣp study.
Major depression is one of the world's leading causes of disability. Up-to-date information about the epidemiology of this disorder is key to health care planning. The aim of our study is to report prevalence and correlates of current major depressive disorder (MDD) in the province of Granada, Southern Spain. The GranadΣp is a cross-sectional study based on a community-dwelling adult population living in the province of Granada, Southern Spain. Community-dwelling adults aged 18-80 years ( n = 810) were interviewed using the Mini-International Neuropsychiatric Interview (MINI). A variety of exposure assessments were also undertaken. Point (2 weeks) prevalence of MDD in the Granada population was 5.6%. Positive family history of mental illness, high degree of neuroticism, high number of life threatening events (LTE), poor physical health status, cognitive impairment and cannabis use were independently associated with MDD in the multivariate regression model. Being female was also associated with MDD, but the significance disappeared after adjusting for neuroticism and physical health. Prevalence of MDD in the Granada population is higher than expected. The effects of the financial crisis could be partially accountable for this excess in prevalence. Six variables were found to be independently associated with MDD. Association between female sex and depression may be partially explained by the confounding effect of neuroticism.


Comparison of 2D and 3D ultrasound methods to measure serial bladder volumes during filling: Steps toward development of non-invasive ultrasound urodynamics.
Non-invasive methods to objectively characterize overactive bladder (OAB) and other forms of voiding dysfunction using real-time ultrasound are currently under development but require accurate and precise serial measurements of bladder volumes during filling. This study's objective was to determine the most accurate and precise ultrasound-based method of quantifying serial bladder volumes during urodynamics (UD). Twelve female participants with OAB completed an extended UD procedure with the addition of serial bladder ultrasound images captured once per minute. Bladder volume was measured using three ultrasound methods: (1) Vspheroid: two-dimensional (2D) method calculated assuming spheroid geometry; (2) Vbih: 2D correction method obtained by multiplying Vspheroid by a previously derived correction factor of 1.375; and (3) V3D: three-dimensional (3D) method obtained by manually tracing the bladder outline in six planes automatically reconstructed into a solid rendered volume. These volumes were compared to a control (Vcontrol) obtained by adding UD infused volume and the volume of estimated urine production. Based on linear regression analysis, both Vbih and V3D were fairly accurate estimators of Vcontrol, but V3D was more precise. Vspheroid significantly underestimated Vcontrol. Although the Vbih and V3D methods were more accurate than the more-commonly used Vspheroid method for measuring bladder volumes during UD, the V3D method was the most precise and could best account for non-uniform bladder geometries. Therefore, the V3D method may represent the best tool required for the continued development of non-invasive methods to diagnose OAB and other forms of voiding dysfunction.


Pediatric hospital and intensive care unit capacity in regional disasters: expanding capacity by altering standards of care.
Federal planners have suggested that one strategy to accommodate disaster surges of 500 inpatients per million population would involve altering standards of care. No data are available indicating the extent of alterations necessary to meet disaster surge targets. Our goal was to, in a Monte Carlo simulation study, determine the probability that specified numbers of children could be accommodated for PICU and non-ICU hospital care in a disaster by a set of strategies involving altered standards of care. Simulated daily vacancies at each hospital in New York City were generated as the difference between peak capacity and daily occupancy (generated randomly from a normal distribution on the basis of empirical data for each hospital). Simulations were repeated 1000 times. Capacity for new patients was explored for normal standards of care, for expansion of capacity by a discretionary 20% increase in vacancies by altering admission and discharge criteria, and for more strictly reduced standards of care to double or quadruple admissions for each vacancy. Resources were considered to reliably serve specified numbers of patients if that number could be accommodated with a probability of 90%. Providing normal standards of care, hospitals in New York City would reliably accommodate 250 children per million age-specific population. Hypothetical strict reductions in standards of care would reliably permit hospital care of 500 children per million, even if the disaster reduced hospital resources by 40%. On the basis of historical experience that as many as 30% of disaster casualties may be critically ill or injured, existing pediatric intensive care beds will typically be insufficient, even with modified standards of care. Extending resources by hypothetical alterations of standards of care would usually satisfy targets for hospital surge capacity, but ICU capacity would remain inadequate for large disasters.


Characterization of a low molecular weight glycolipid antigen from Cryptosporidium parvum.
Cryptosporidium parvum, an Apicomplexan parasite of the mammalian gut epithelium, causes a diarrheal illness in a wide range of hosts and is transmitted by contamination of food or water with oocyst-laden feces from an infected animal. We have identified a glycosylinositol phospholipid from the sporozoite stage of the parasite that is frequently recognized by serum antibodies from human cryptosporidiosis patients. The humoral immune response is dominated by IgG1 subclass antibodies but can also include IgA and IgM antibodies. The glycosylinositol phospholipids were purified by butanol extraction of a Triton X-114-soluble fraction followed by octyl-Sepharose column chromatography and preparative high performance TLC and were shown to include at least 5 species. By using mass spectrometry and radiolabeled neutral glycan analysis, we found that the structure of the dominant glycosylinositol phospholipid antigen contained a C18:0 lyso-acylglycerol, a C16:0-acylated inositol, and an unsubstituted mannose3-glucosamine glycan core. Other diacyl species were also identified, most notably a series of glycosylinositol phospholipids having an acyl-linked C20:0 to C28:0 lipid on the inositol ring. Less abundant species having three acyl-linked fatty acids and species with an additional 1-3 hexoses linked to the mannose core were also observed. We are currently working to determine the role that these glycolipids may play in the development of disease and in the clearance of infection.


Microbial source tracking of private well water samples across at-risk regions in southern Ontario and analysis of traditional fecal indicator bacteria assays including culture and qPCR.
Many people living in rural areas rely on privately owned wells as their primary source of drinking water. These water sources are at risk for fecal contamination of human, wildlife, and livestock origin. While traditional bacteriological testing involves culture-based methods, microbial source tracking (MST) assays present an opportunity to additionally determine the source of fecal contamination. This study investigated the main host sources of contamination in private well water samples with high levels of Escherichia coli (E. coli), using MST with human and multi-species specific markers. Fecal contamination of human origin was detected in approximately 50% of samples, indicating that current contamination prevention strategies require reconsideration. The relationship between cattle density and fecal contamination of bovine origin was investigated using a Bovine Bacteroidales specific MST assay. Regional variations of microbial sources were examined, and may inform local primary prevention strategies. Additionally, in order to assess MST and E. coli quantitative real time polymerase chain reaction (qPCR) assays as indicators of fecal contamination, these were compared to E. coli culture methods. Variation in results was observed across all assay methods investigated, suggesting the most appropriate routine bacteriological testing methodology cannot be determined without comparison to a method that directly detects the presence of fecal contamination.


Global effects on gene expression in fission yeast by silencing and RNA interference machineries.
Histone modifications influence gene expression in complex ways. The RNA interference (RNAi) machinery can repress transcription by recruiting histone-modifying enzymes to chromatin, although it is not clear whether this is a general mechanism for gene silencing or whether it requires repeated sequences such as long terminal repeats (LTRs). We analyzed the global effects of the Clr3 and Clr6 histone deacetylases, the Clr4 methyltransferase, the zinc finger protein Clr1, and the RNAi proteins Dicer, RdRP, and Argonaute on the transcriptome of Schizosaccharomyces pombe (fission yeast). The clr mutants derepressed similar subsets of genes, many of which also became transcriptionally activated in cells that were exposed to environmental stresses such as nitrogen starvation. Many genes that were repressed by the Clr proteins clustered in extended regions close to the telomeres. Surprisingly few genes were repressed by both the silencing and RNAi machineries, with transcripts from centromeric repeats and Tf2 retrotransposons being notable exceptions. We found no correlation between repression by RNAi and proximity to LTRs, and the wtf family of repeated sequences seems to be repressed by histone deacetylation independent of RNAi. Our data indicate that the RNAi and Clr proteins show only a limited functional overlap and that the Clr proteins play more global roles in gene silencing.


Acute disseminated encephalomyelitis in an adult patient. Magnetic resonance and diffusion-weighted imaging findings.
Acute disseminated encephalomyelitis ADEM is an uncommon inflammatory disease of the central nervous system and can be defined strictly as scattered focal or multifocal disseminated inflammation of brain or spinal cord, or both. An ADEM usually reveals patchy demyelinated lesions with a high signal on T2-weighted sequences. Here, we report a case of a 39-year-old man with ADEM. Echo-planar trace diffusion magnetic resonance imaging revealed high signal intensity changes at the lesion sites on b=1000 s/mm2 images, initially suggesting restricted diffusion. On corresponding apparent diffusion coefficient ADC maps, however, the lesions have a high signal intensity and high ADC values, compared with the normal white matter. This was consistent with the presence of elevated diffusion, and hence, vasogenic edema.


Spatial Variation in Nutrient and Water Color Effects on Lake Chlorophyll at Macroscales.
The nutrient-water color paradigm is a framework to characterize lake trophic status by relating lake primary productivity to both nutrients and water color, the colored component of dissolved organic carbon. Total phosphorus (TP), a limiting nutrient, and water color, a strong light attenuator, influence lake chlorophyll a concentrations (CHL). But, these relationships have been shown in previous studies to be highly variable, which may be related to differences in lake and catchment geomorphology, the forms of nutrients and carbon entering the system, and lake community composition. Because many of these factors vary across space it is likely that lake nutrient and water color relationships with CHL exhibit spatial autocorrelation, such that lakes near one another have similar relationships compared to lakes further away. Including this spatial dependency in models may improve CHL predictions and clarify how well the nutrient-water color paradigm applies to lakes distributed across diverse landscape settings. However, few studies have explicitly examined spatial heterogeneity in the effects of TP and water color together on lake CHL. In this study, we examined spatial variation in TP and water color relationships with CHL in over 800 north temperate lakes using spatially-varying coefficient models (SVC), a robust statistical method that applies a Bayesian framework to explore space-varying and scale-dependent relationships. We found that TP and water color relationships were spatially autocorrelated and that allowing for these relationships to vary by individual lakes over space improved the model fit and predictive performance as compared to models that did not vary over space. The magnitudes of TP effects on CHL differed across lakes such that a 1 μg/L increase in TP resulted in increased CHL ranging from 2-24 μg/L across lake locations. Water color was not related to CHL for the majority of lakes, but there were some locations where water color had a positive effect such that a unit increase in water color resulted in a 2 μg/L increase in CHL and other locations where it had a negative effect such that a unit increase in water color resulted in a 2 μg/L decrease in CHL. In addition, the spatial scales that captured variation in TP and water color effects were different for our study lakes. Variation in TP-CHL relationships was observed at intermediate distances (~20 km) compared to variation in water color-CHL relationships that was observed at regional distances (~200 km). These results demonstrate that there are lake-to-lake differences in the effects of TP and water color on lake CHL and that this variation is spatially structured. Quantifying spatial structure in these relationships furthers our understanding of the variability in these relationships at macroscales and would improve model prediction of chlorophyll a to better meet lake management goals.


Changes in Ect2 localization couple actomyosin-dependent cell shape changes to mitotic progression.
As they enter mitosis, animal cells undergo profound actin-dependent changes in shape to become round. Here we identify the Cdk1 substrate, Ect2, as a central regulator of mitotic rounding, thus uncovering a link between the cell-cycle machinery that drives mitotic entry and its accompanying actin remodeling. Ect2 is a RhoGEF that plays a well-established role in formation of the actomyosin contractile ring at mitotic exit, through the local activation of RhoA. We find that Ect2 first becomes active in prophase, when it is exported from the nucleus into the cytoplasm, activating RhoA to induce the formation of a mechanically stiff and rounded metaphase cortex. Then, at anaphase, binding to RacGAP1 at the spindle midzone repositions Ect2 to induce local actomyosin ring formation. Ect2 localization therefore defines the stage-specific changes in actin cortex organization critical for accurate cell division.


Younger Onset Dementia.
This literature review focused on the experience, care, and service requirements of people with younger onset dementia. Systematic searches of 10 relevant bibliographic databases and a rigorous examination of the literature from nonacademic sources were undertaken. Searches identified 304 articles assessed for relevance and level of evidence, of which 74% were academic literature. The review identified the need for (1) more timely and accurate diagnosis and increased support immediately following diagnosis; (2) more individually tailored services addressing life cycle issues; (3) examination of the service needs of those living alone; (4) more systematic evaluation of services and programs; (5) further examination of service utilization, costs of illness, and cost effectiveness; and (6) current Australian clinical surveys to estimate prevalence, incidence, and survival rates. Although previous research has identified important service issues, there is a need for further studies with stronger research designs and consideration of the control of potentially confounding factors.


New pleasures and old dangers: reinventing male sex work.
Understandings of male sex workers (MSWs) shift with technological, conceptual, and social changes. Research has historically constructed MSWs as psychologically unstable, desperate, or destitute victims and their clients as socially deviant perverts. These perceptions, however, are no longer supported by contemporary research and changing societal perceptions of the sex industry, challenging how we understand and describe "escorts." The changing understandings of sexuality and the increasing power of the Internet are both important forces behind recent changes in the structure and organization of MSWs. The growth in the visibility and reach of escorts has created opportunities to form an occupational account of MSWs that better accounts for the dynamic and diverse nature of the MSW experience in the early 21st century. Recent changes in the structure and organization of male sex work have provided visibility to the increasingly diverse geographical distribution of MSW, the commodification of race and racialized desire, new populations of heterosexual men and women as clients, and the successful dissemination of safer sexual messages to MSWs through online channels. This article provides a broad overview of the literature on MSWs, concentrating its focus on studies that have emerged over the past 20 years and identifying areas for future research.


Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarctions.
Previous work from our laboratory demonstrated that interleukin (IL)-6 plays a potentially critical role in postreperfusion myocardial injury and is the major cytokine responsible for induction of intracellular adhesion molecule (ICAM)-1 on cardiac myocytes during reperfusion. Myocyte ICAM-1 induction is necessary for neutrophil-associated myocyte injury. We have previously demonstrated the induction of IL-6 in the ischemic myocardium, and the current study addresses the cells of origin of IL-6. In the present study, we combined Northern blot analysis and in situ hybridization to demonstrate IL-6 gene expression in cardiac myocytes. Isolated ventricular myocytes were stimulated with tumor necrosis factor-alpha, IL-1beta, lipopolysaccharide, preischemic lymph, and postischemic lymph. Unstimulated myocytes showed no significant IL-6 mRNA expression. Myocytes stimulated with preischemic lymph showed minimal or no IL-6 mRNA expression, whereas myocytes stimulated with tumor necrosis factor-alpha, IL-1beta, lipopolysaccharide, or postischemic lymph showed a strong IL-6 mRNA induction. Northern blot with ICAM-1 probe revealed ICAM-1 expression under every condition that demonstrated IL-6 induction. We then investigated the expression of IL-6 mRNA in our canine model of ischemia and reperfusion. Cardiac myocytes in the viable border zone of a myocardial infarction exhibited reperfusion-dependent expression of IL-6 mRNA within 1 hour after reperfusion. Mononuclear cells infiltrate the border zone and express IL-6 mRNA. Isolated cardiac myocytes produce IL-6 mRNA in response to several cytokines as well as postischemic cardiac lymph. In addition to its production by inflammatory cells, we demonstrate that IL-6 mRNA is induced in myocytes in the viable border zone of a myocardial infarct. The potential roles of IL-6 in cardiac myocytes in an infarct border are discussed.


Performance Analysis of Evolutionary Algorithms for Steiner Tree Problems.
The Steiner tree problem (STP) aims to determine some Steiner nodes such that the minimum spanning tree over these Steiner nodes and a given set of special nodes has the minimum weight, which is NP-hard. STP includes several important cases. The Steiner tree problem in graphs (GSTP) is one of them. Many heuristics have been proposed for STP, and some of them have proved to be performance guarantee approximation algorithms for this problem. Since evolutionary algorithms (EAs) are general and popular randomized heuristics, it is significant to investigate the performance of EAs for STP. Several empirical investigations have shown that EAs are efficient for STP. However, up to now, there is no theoretical work on the performance of EAs for STP. In this article, we reveal that the (1+1) EA achieves 3/2-approximation ratio for STP in a special class of quasi-bipartite graphs in expected runtime [Formula: see text], where [Formula: see text], [Formula: see text], and [Formula: see text] are, respectively, the number of Steiner nodes, the number of special nodes, and the largest weight among all edges in the input graph. We also show that the (1+1) EA is better than two other heuristics on two GSTP instances, and the (1+1) EA may be inefficient on a constructed GSTP instance.


Surgical determinants of clinical success of osseointegrated oral implants: a review of the literature.
This article reviews the current knowledge about the influence of surgical factors on implant failure in routine cases and in those where implants have been used in conjunction with bone augmentation procedures. Clinical reports published in major scientific journals served as the basis for this review. With few exceptions, most clinical reports were on screw-shaped titanium implants. High failure rates are associated with poor bone quality and the use of short implants in the athrophic maxilla, irradiation, and bone-grafting procedures of the athrophic maxilla. Evidence for high long-term failure rates of press-fit cylinders was found. Moreover, limited clinical experience, lack of preoperative antibiotics, and smoking may lead to higher failure rates. There is a need for further research to increase the success rates in the severely resorbed maxilla. Because of a lack of proper documentation with respect to the great majority of currently used oral implant designs, the influence of different factors and their long-term results remain unknown.


Flexibility in the patterning and control of axial locomotor networks in lamprey.
In lower vertebrates, locomotor burst generators for axial muscles generally produce unitary bursts that alternate between the two sides of the body. In lamprey, a lower vertebrate, locomotor activity in the axial ventral roots of the isolated spinal cord can exhibit flexibility in the timings of bursts to dorsally-located myotomal muscle fibers versus ventrally-located myotomal muscle fibers. These episodes of decreased synchrony can occur spontaneously, especially in the rostral spinal cord where the propagating body waves of swimming originate. Application of serotonin, an endogenous spinal neurotransmitter known to presynaptically inhibit excitatory synapses in lamprey, can promote decreased synchrony of dorsal-ventral bursting. These observations suggest the possible existence of dorsal and ventral locomotor networks with modifiable coupling strength between them. Intracellular recordings of motoneurons during locomotor activity provide some support for this model. Pairs of motoneurons innervating myotomal muscle fibers of similar ipsilateral dorsoventral location tend to have higher correlations of fast synaptic activity during fictive locomotion than do pairs of motoneurons innervating myotomes of different ipsilateral dorsoventral locations, suggesting their control by different populations of premotor interneurons. Further, these different motoneuron pools receive different patterns of excitatory and inhibitory inputs from individual reticulospinal neurons, conveyed in part by different sets of premotor interneurons. Perhaps, then, the locomotor network of the lamprey is not simply a unitary burst generator on each side of the spinal cord that activates all ipsilateral body muscles simultaneously. Instead, the burst generator on each side may comprise at least two coupled burst generators, one controlling motoneurons innervating dorsal body muscles and one controlling motoneurons innervating ventral body muscles. The coupling strength between these two ipsilateral burst generators may be modifiable and weakening when greater swimming maneuverability is required. Variable coupling of intrasegmental burst generators in the lamprey may be a precursor to the variable coupling of burst generators observed in the control of locomotion in the joints of limbed vertebrates.


Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability.
To examine n-3 polyunsaturated fatty acid (PUFA) incorporation into atherosclerotic plaques and the association with plaque inflammation and stability. Patients awaiting carotid endarterectomy (n=121) were randomised to consume control capsules or n-3 PUFA ethyl ester capsules until surgery (median 21 days). The fatty acid compositions of plasma and carotid plaque phospholipids, plaque features, and expression of inflammatory genes were determined. The proportion of eicosapentaenoic acid (EPA) was higher (P<0.0001) in carotid plaque phospholipids in patients in the n-3 PUFA group. Plaques from patients in the n-3 PUFA group had fewer foam cells (P=0.0390). There were no other differences between plaques in the two groups with regard to histological characteristics or morphology. Plaque stability was not different between the two groups. However, the EPA content of plaque phospholipids was inversely associated with plaque instability (P=0.0209), plaque inflammation (P=0.0108), the number of T cells in the plaque (P=0.0097) and a summary score considering a range of plaque features (P=0.0425). Plaques from patients who received n-3 PUFAs had significantly lower levels of mRNA for matrix metalloproteinases (MMP)-7 (P=0.0055), -9 (P=0.0048) and -12 (P=0.0044) and for interleukin-6 (P=0.0395) and intercellular adhesion molecule 1 (P=0.0142). Atherosclerotic plaques readily incorporate EPA. A higher plaque EPA content is associated with a reduced number of foam cells and T cells, less inflammation and increased stability.


Tearing down the wall: peptidoglycan metabolism and the WalK/WalR (YycG/YycF) essential two-component system.
In order to survive, bacteria have developed avariety of highly sophisticated and sensitive signal transduction pathways with which they adapt their genetic expression to meet the challenges of their ever-changing surroundings. These mechanisms enable bacterial cells to communicate with their environment, their hosts and each other, allowing them adopt specific responses, or develop specialised structures such as biofilms or spores to ensure survival, colonization of their ecological niches and dissemination. As highlighted in this book, the so-called two-component systems (TCSs) are one of the most widespread and efficient strategies used for this purpose, where signal acquisition involves autophosphorylation of a sensor histidine kinase and transduction takes place when the kinase phosphorylates its cognate response regulator protein, leading in turn to specific alteration ofgene expression. In their simplest form, TCSs elegantly combine sensing, transducing and transcription activation modules within two proteins, effectively coupling external signals to genetic adaptation. The high degree of conservation among TCS phosphotransfer domains, their ubiquitous nature and the fact that several are essential for cell viability has made them an attractive target for novel classes of antimicrobial compounds. The WalK/WalR (aka YycG/YycF) two-component system, originally identified in Bacillus subtilis, is very highly conserved and specific to low G + C Gram-positive bacteria, including several pathogens such as Staphylococcus aureus. While this system is essential for cell viability, both the nature of its regulon and its physiological role had remained mostly uncharacterized. A number of recent studies have now unveiled a conserved function for this system in different bacteria, defining this signal transduction pathway as a master regulatory system for cell wall metabolism, which we have accordingly renamed WalK/WalR. This review will focus on the cellular function of the WalK/WalR TCS in different bacterial species and the attractive target it constitutes for novel classes of antimicrobial compounds.


Leukocyte Ig-like receptor complex (LRC) in mice and men.
Here, we compare the architecture of membrane receptors with extracellular Ig-like domains located within the leukocyte Ig-like receptor complex (LRC) of humans and mice. The receptors can be classified broadly into four groups, based on the homology of their Ig-like domains and gene architecture. Receptors in the first group are characterized by the presence of the Ig constant type 2-1 (IgC2-1) and variant Ig (vlg) domains, and include the leukocyte Ig-like receptors (LILRs) and murine paired Ig-activating receptors (PIRs). The second group of receptors possess an IgC2-2 domain and comprise the killer-cell Ig-like receptors (KIRs) and platelet collagen receptor glycoprotein VI (GPVI). The third group consists of receptors with IgC2-1, and IgC2-3 or IgC2-4 domains, and includes the receptor for IgA Fc (FCAR), NKp46 and murine Ly94. The fourth group, with a single extracellular IgC2-1 domain, consists of the leukocyte-associated Ig-like receptors (LAIRs). The genomic organization of and evolutionary associations between these receptors and their domains are examined.


Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage.
Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.


Temperature acclimation: improved sustained swimming performance in carp at low temperatures.
At low temperatures, the reduction in mechanical power output of the aerobic muscle forces cold-blooded animals, such as carp, to recruit their rapidly fatiguing anaerobic fibers at relatively slow swimming speeds. Previous experimental data have suggested that changes in the biochemistry and morphology of the aerobic muscle during cold acclimation might increase its output of mechanical power. The present experiments show that, because of these changes, carp can swim faster at low temperature using only their aerobic muscle, which results in an increase in their sustainable swimming speed. By modifying their musculature, cold-blooded animals can achieve some independence from the effects of seasonal changes in environmental temperature.


Agro-ecological options for fall armyworm (Spodoptera frugiperda JE Smith) management: Providing low-cost, smallholder friendly solutions to an invasive pest.
Fall armyworm (FAW), a voracious agricultural pest native to North and South America, was first detected on the African continent in 2016 and has subsequently spread throughout the continent and across Asia. It has been predicted that FAW could cause up to $US13 billion per annum in crop losses throughout sub-Saharan Africa, thereby threatening the livelihoods of millions of poor farmers. In their haste to respond to FAW governments may promote indiscriminate use of chemical pesticides which, aside from human health and environmental risks, could undermine smallholder pest management strategies that depend to a large degree on natural enemies. Agro-ecological approaches offer culturally appropriate low-cost pest control strategies that can be readily integrated into existing efforts to improve smallholder incomes and resilience through sustainable intensification. Such approaches should therefore be promoted as a core component of integrated pest management (IPM) programmes for FAW in combination with crop breeding for pest resistance, classical biological control and selective use of safe pesticides. Nonetheless, the suitability of agro-ecological measures for reducing FAW densities and impact need to be carefully assessed across varied environmental and socio-economic conditions before they can be proposed for wide-scale implementation. To support this process, we review evidence for the efficacy of potential agro-ecological measures for controlling FAW and other pests, consider the associated risks, and draw attention to critical knowledge gaps. The evidence indicates that several measures can be adopted immediately. These include (i) sustainable soil fertility management, especially measures that maintain or restore soil organic carbon; (ii) intercropping with appropriately selected companion plants; and (iii) diversifying the farm environment through management of (semi)natural habitats at multiple spatial scales. Nevertheless, we recommend embedding trials into upscaling programmes so that the costs and benefits of these interventions may be determined across the diverse biophysical and socio-economic contexts that are found in the invaded range.


Comparison of Mycobacterium tuberculosis genomes reveals frequent deletions in a 20 kb variable region in clinical isolates.
The Mycobacterium tuberculosis complex is associated with a remarkably low level of structural gene polymorphism. As part of a search for alternative forms of genetic variation that may act as a source of biological diversity in M. tuberculosis, we have identified a region of the genome that is highly variable amongst a panel of unrelated clinical isolates. Fifteen of 24 isolates examined contained one or more copies of the M. tuberculosis-specific IS6110 insertion element within this 20 kb variable region. In nine of the isolates, including the laboratory-passaged strain H37Rv, genomic deletions were identified, resulting in loss of between two and 13 genes. In each case, deletions were associated with the presence of a copy of the IS6110 element. Absence of flanking tri- or tetra-nucleotide repeats identified homologous recombination between adjacent IS6110 elements as the most likely mechanism of the deletion events. IS6110 insertion into hot-spots within the genome of M. tuberculosis provides a mechanism for generation of genetic diversity involving a high frequency of insertions and deletions.


A Physiologically-Based Pharmacokinetic Modeling Approach Using Biomonitoring Data in Order to Assess the Contribution of Drinking Water for the Achievement of an Optimal Fluoride Dose for Dental Health in Children.
Due to an optimal fluoride concentration in drinking water advised for caries prevention purposes, the population is now exposed to multiple sources of fluoride. The availability of population biomonitoring data currently allow us to evaluate the magnitude of this exposure. The objective of this work was, therefore, to use such data in order to estimate whether community water fluoridation still represents a significant contribution toward achieving a suggested daily optimal fluoride (external) intake of 0.05 mg/kg/day. Therefore, a physiologically-based pharmacokinetic model for fluoride published in the literature was used and adapted in Excel for a typical 4-year-old and 8-year-old child. Biomonitoring data from the Canadian Health Measures Survey among people living in provinces with very different drinking water fluoridation coverage (Quebec, 2.5%; Ontario, 70% of the population) were analyzed using this adapted model. Absorbed doses for the 4-year-old and 8-year-old children were, respectively, 0.03 mg/kg/day and 0.02 mg/kg/day in Quebec and of 0.06 mg/kg/day and 0.05 mg/kg/day in Ontario. These results show that community water fluoridation contributes to increased fluoride intake among children, which leads to reaching, and in some cases even exceeding, the suggested optimal absorbed dose of 0.04 mg/kg/day, which corresponds to the suggested optimal fluoride intake mentioned above. In conclusion, this study constitutes an incentive to further explore the multiple sources of fluoride intake and suggests that a new balance between them including drinking water should be examined in accordance with the age-related physiological differences that influence fluoride metabolism.


A re-evaluation of the effects of dual growing rods on apical vertebral rotation in patients with early-onset scoliosis and a minimum of two lengthening procedures: a CT-based study.
OBJECTIVE This study aimed to evaluate the correction results of traditional dual growing rods (DGRs) on axial rotation using CT scans and to further explore the relationships between axial and torso deformities in patients with early-onset scoliosis (EOS). METHODS Patients with EOS who were treated with traditional DGRs between January 2006 and December 2014 were retrospectively reviewed. Plain radiographs were used to assess the degree of coronal and sagittal deformity. The apical vertebral rotation (AVR) and rib hump (RH) were measured on CT scans at the apical vertebra. Pearson or Spearman rank correlation analyses were used to analyze the associations between spinal and torso deformities. RESULTS A total of 27 patients (10 boys and 17 girls, average age 6.5 ± 1.7 years) were enrolled in this study. The average number of lengthenings per patient was 5.0 ± 1.9, with a mean follow-up duration of 52.9 ± 18.2 months. The apical vertebral translation, apical vertebral body-rib ratio (AVB-R), AVR, and RH parameters were significantly decreased after the initial surgery (p < 0.05) but showed notable progression at the latest follow-up evaluation (p < 0.05). The preoperative AVR and its correction after index surgery were significantly correlated with the preoperative values as well as with the corrections of the major Cobb angle, AVB-R, and RH. During the follow-up period, significant correlations were found between the deterioration of AVR and the AVB-R and also between the deterioration of AVR and the RH from the initial surgery to the latest follow-up. CONCLUSIONS Significant AVR correction can be achieved by DGR techniques after the initial surgery. However, this technique weakly prevents the deterioration of AVR during the follow-up period.


The effect of 300 mW, 830 nm laser on chronic neck pain: a double-blind, randomized, placebo-controlled study.
A randomized, double-blind, placebo-controlled study of low-level laser therapy (LLLT) in 90 subjects with chronic neck pain was conducted with the aim of determining the efficacy of 300 mW, 830 nm laser in the management of chronic neck pain. Subjects were randomized to receive a course of 14 treatments over 7 weeks with either active or sham laser to tender areas in the neck. The primary outcome measure was change in a 10 cm Visual Analogue Scale (VAS) for pain. Secondary outcome measures included Short-Form 36 Quality-of-Life questionnaire (SF-36), Northwick Park Neck Pain Questionnaire (NPNQ), Neck Pain and Disability Scale (NPAD), the McGill Pain Questionnaire (MPQ) and Self-Assessed Improvement (SAI) in pain measured by VAS. Measurements were taken at baseline, at the end of 7 weeks' treatment and 12 weeks from baseline. The mean VAS pain scores improved by 2.7 in the treated group and worsened by 0.3 in the control group (difference 3.0, 95% CI 3.8-2.1). Significant improvements were seen in the active group compared to placebo for SF-36-Physical Score (SF36 PCS), NPNQ, NPAD, MPQVAS and SAI. The results of the SF-36 - Mental Score (SF36 MCS) and other MPQ component scores (afferent and sensory) did not differ significantly between the two groups. Low-level laser therapy (LLLT), at the parameters used in this study, was efficacious in providing pain relief for patients with chronic neck pain over a period of 3 months.


Increase in global emissions of HFC-23 despite near-total expected reductions.
Under the Kigali Amendment to the Montreal Protocol, new controls are being implemented to reduce emissions of HFC-23 (CHF[Formula: see text]), a by-product during the manufacture of HCFC-22 (CHClF[Formula: see text]). Starting in 2015, China and India, who dominate global HCFC-22 production (75% in 2017), set out ambitious programs to reduce HFC-23 emissions. Here, we estimate that these measures should have seen global emissions drop by 87% between 2014 and 2017. Instead, atmospheric observations show that emissions have increased and in 2018 were higher than at any point in history (15.9 [Formula: see text]). Given the magnitude of the discrepancy between expected and observation-inferred emissions, it is likely that the reported reductions have not fully materialized or there may be substantial unreported production of HCFC-22, resulting in unaccounted-for HFC-23 by-product emissions. The difference between reported and observation-inferred estimates suggests that an additional ~309 Tg [Formula: see text]-equivalent emissions were added to the atmosphere between 2015 and 2017.


Multidisciplinary development of the Geriatric Core Dataset for clinical research in older patients with cancer: A French initiative with international survey.
To define a core set of geriatric data to be methodically collected in clinical cancer trials of older adults, enabling comparison across trials. Following a consensus approach, a panel of 14 geriatricians from oncology clinics identified seven domains of importance in geriatric assessment. Based on the international recommendations, geriatricians selected the mostly commonly used tools/items for geriatric assessment by domain (January-October 2015). The Geriatric Core Dataset (G-CODE) was progressively developed according to RAND appropriateness ratings and feedback during three successive Delphi rounds (July-September 2016). The face validity of the G-CODE was assessed with two large panels of health professionals (55 national and 42 international experts) involved both in clinical practice and cancer trials (March-September 2017). After the last Delphi round, the tools/items proposed for the G-CODE were the following: (1) social assessment: living alone or support requested to stay at home; (2) functional autonomy: Activities of Daily Living (ADL) questionnaire and short instrumental ADL questionnaire; (3) mobility: Timed Up and Go test; (4) nutrition: weight loss during the past 6 months and body mass index; (5) cognition: Mini-Cog test; (6) mood: mini-Geriatric Depression Scale and (7) comorbidity: updated Charlson Comorbidity Index. More than 70% of national experts (42 from 20 cities) and international experts (31 from 13 countries) participated. National and international surveys showed good acceptability of the G-CODE. Specific points discussed included age-year cut-off, threshold of each tool/item and information about social support, but no additional item was proposed. We achieved formal consensus on a set of geriatric data to be collected in cancer trials of older patients. The dissemination and prospective use of the G-CODE is needed to assess its utility.


Measuring Functional Status in Hospitalized Older Adults Through Electronic Health Record Documentation.
Hospitalization-associated disability affects up to 60% of older adults; however, standardized measures of function are not routinely used and documented. We sought to determine whether nursing documentation in electronic medical records can be used to determine mobility status and associated clinical outcomes. A retrospective study of 2383 medical patients aged 75 years and older was conducted at a large academic tertiary hospital in New York. Mobility (low, intermediate, and high) was the primary variable of interest. Short-term clinical outcomes, including length of stay (LOS), discharge disposition, and readmissions, were the primary outcome variables. Average age and Charlson Comorbidity Index were 84.7 (range 74-107) and 6.46, respectively; 84.5% of patients were documented to have been ambulatory before admission. More than half (52.8%) of the subjects with in-hospital mortality were in the low mobility group (27.2 vs 0.27 vs 0, P < 0.0001). Low mobility was associated with increased LOS (7.42 vs 5.69 vs 4.14, P < 0.0001), discharge to a skilled nursing facility (39.36 vs 14.67 vs 1.91, P < 0.0001), and 30-day readmission (24.40 vs 16.67 vs 10.93, P < 0.0001). After controlling for demographics, ambulatory status before admission, and Charlson Comorbidity Index, low mobility was statistically significantly associated with increased LOS, discharge to a skilled nursing facility, and 30-day readmissions. The use of documented nursing observation may provide a practical way to systematically identify patients at risk for poor outcomes associated with low mobility to ultimately improve outcomes of hospitalized older adults.


Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator.
A significant reduction in parasite clearance rates following artesunate treatment of falciparum malaria, and increased failure rates following artemisinin combination treatments (ACT), signaled emergent artemisinin resistance in Western Cambodia. Accurate measurement of parasite clearance is therefore essential to assess the spread of artemisinin resistance in Plasmodium falciparum. The slope of the log-parasitaemia versus time relationship is considered to be the most robust measure of anti-malarial effect. However, an initial lag phase of numerical instability often precedes a steady exponential decline in the parasite count after the start of anti-malarial treatment. This lag complicates the clearance estimation, introduces observer subjectivity, and may influence the accuracy and consistency of reported results. To address this problem, a new approach to modelling clearance of malaria parasites from parasitaemia-time profiles has been explored and validated. The methodology detects when a lag phase is present, selects the most appropriate model (linear, quadratic or cubic) to fit log-transformed parasite data, and calculates estimates of parasite clearance adjusted for this lag phase. Departing from previous approaches, parasite counts below the level of detection are accounted for and not excluded from the calculation. Data from large clinical studies with frequent parasite counts were examined. The effect of a lag phase on parasite clearance rate estimates is discussed, using individual patient data examples. As part of the World Wide Antimalarial Resistance Network's (WWARN) efforts to make innovative approaches available to the malaria community, an automated informatics tool: the parasite clearance estimator has been developed. The parasite clearance estimator provides a consistent, reliable and accurate method to estimate the lag phase and malaria parasite clearance rate. It could be used to detect early signs of emerging resistance to artemisinin derivatives and other compounds which affect ring-stage clearance.


Relative sensitivity to change of the erythrocyte sedimentation rate and serum C-reactive protein concentration in rheumatoid arthritis.
To compare the sensitivity to change of the erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) concentration used as measures of rheumatoid arthritis (RA) activity. A literature search was conducted to identify all clinical trials and observational studies of disease-modifying medications and corticosteroids in RA that reported results for both ESR and CRP before treatment and 4 weeks to 24 weeks after treatment in the same patients. For each test, effect sizes were computed as the change in the test with treatment divided by the pretreatment standard deviation. A pooled analysis was performed on the paired differences in effect sizes for ESR and CRP within each study. One hundred twenty-three studies with 184 active treatment arms were identified that included measurements of both ESR and CRP. Sixty-three studies with 90 active treatment arms provided sufficient data to permit calculation of effect sizes, and were included in the analysis. In the 36 treatment arms that reported results at 12 weeks, the ESR was more sensitive to change than the CRP, with a paired difference in effect sizes of 0.09 units (95% confidence interval 0.03, 0.15; p = 0.005). In the 76 treatment arms that reported results at 24 weeks, the ESR was also more sensitive to change than the CRP, with a paired difference in effect sizes of 0.11 units (95% CI 0.05, 0.17; p = 0.0004). In these studies of disease-modifying medications in RA, the ESR was more sensitive to change than the CRP at 12 weeks and 24 weeks of treatment. Few studies examined changes in these measures at times earlier than 12 weeks.


Favorable neurological outcome after ischemic cerebrovascular events in patients treated with percutaneous left atrial appendage occlusion compared with warfarin.
This study sought to investigate neurological disability after ischemic cerebrovascular events in patients treated with left atrial appendage (LAA) occlusion compared with those on warfarin. Prior studies demonstrated that cerebrovascular events after LAA occlusion in patients with nonvalvular atrial fibrillation (NVAF) is largely nondisabling. From the 1,189 patients in the Korean LAA Occlusion and European Amplatzer Cardiac Plug Multi-Center Registry, 24 patients who experienced ischemic cerebrovascular events after LAA occlusion were enrolled. The neurological outcomes were compared with those in 68 patients who experienced an ischemic cerebrovascular event while on warfarin (Yonsei Stroke Registry). A modified Rankin scale (mRS) score of 3-6 categorized the cerebrovascular event as disabling. The mRS at discharge and at 3 and 12 months postcerebrovascular event in the two groups was compared. The percentages of disabling cerebrovascular events were 37.5% and 58.8% at discharge (P = 0.07), 20.8% and 42.6% at 3 months (P = 0.08), and 12.5% and 39.7% at 12 months (P = 0.02) in the LAA occlusion and warfarin groups, respectively. The mRS was significantly lower in the LAA occlusion group at discharge and at 3 months (P < 0.01) and 12 months (P < 0.01) postcerebrovascular event despite no significant difference in mRS before cerebrovascular events (P = 0.98). Patients in the LAA occlusion group demonstrated a significant reduction in mRS between discharge and 12 months (P < 0.01), unlike patients in the warfarin group (P = 0.10). Ischemic cerebrovascular events in patients who previously underwent percutaneous LAA occlusion for NVAF were more favorable than in patients on warfarin.