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Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.

Little research has focused on the accuracy of gonad shield placement, especially by students. While studies have investigated the presence of gonad shields they do not aim to measure accuracy but only look at repeatability. This study aimed to establish students' knowledge of gonad shields and their accuracy in placing it.Following an invitation email and informed consent, students completed a 7-question questionnaire and placed a gonad shield on a Pixi full body adult phantom (male configuration). The phantom was x-rayed and images were assessed for gonad shield positioning in terms of obscuring bony anatomy, correct orientation and distance from a "gold standard" position.36% of images displayed shields covering bony anatomy while 16% of shields were incorrectly orientated. All shields incorrectly orientated also covered bony anatomy. Statistical significance was seen between incorrect shield orientation and the obscuring of bony anatomy (p = 0.01). Dispersion of positioning error measurements ranged from -6.80 mm (better placed than the "gold standard") to 62.35 mm inferiorly, with an average 28.22 mm inferiorly.The average misplacement of 28.22 mm suggests participants placed the gonad shielding lower than necessary to avoid obscuring bony anatomy. The 36% of misplaced shields, while lower than in previous studies, is still a significant number of radiographs that would require repeats.Given the associated difficulties surrounding gonad shields and their placement, this study supports previous research suggesting that the benefit of using gonad shielding is questionable.

The aim was to explore the feasibility and safety of performing common surgical steps in epiretinal membrane (ERM) peeling using the Preceyes Surgical System (PSS).In a tertiary centre, 15 pseudophakic patients with an idiopathic ERM were randomised to robot-assistance or manual surgery in a 2:1 ratio. In the robot-assisted group, the following steps were performed using PSS: (1) staining the internal limiting membrane (ILM), (2) removal of the dye, (3) creating an ILM flap, (4) completing the peeling, (5) holding a light pipe and (6) fluid-air exchange. Primary outcome measures were feasibility and safety. Secondary outcome measures were duration, best-corrected visual acuity (BCVA) and central retinal thickness (CRT). Moreover, the distance travelled by the instrument during peeling was assessed using motion tracking software.All steps performed with PSS were feasible with no clinical adverse events or complications. The surgical time was longer in the robot-assisted group (mean 56 min, SD = 12 vs. 24 min, SD = 5). During the study, the duration of robot-assisted surgeries decreased from 72 to 46 min. The distance travelled by the forceps was shorter in the robot-assisted group (mean 403 mm, SD = 186 vs. 550 mm, SD = 134). BCVA and CRT improved equally in both groups.This is the world's first randomised controlled trial on robotic surgery for ERM. Although more time-consuming, we found that several surgical steps were feasible with assistance of the PSS.

Persons living with mental health challenges are at increased risk of stigma, social isolation, and social exclusion. Due to its emphasis on member participation and community, the clubhouse model of mental health may help address these issues. In this study, we examined experiences of social belonging and of various social determinants of mental health among members attending a psychosocial clubhouse. Twelve members of a large psychosocial clubhouse were interviewed regarding their experiences of community life and belonging. Phenomenological qualitative methods were utilized to examine the meaning and structure of these experiences. Members overwhelmingly experienced the clubhouse as a central site of belonging ("an oasis"), but members also recounted devastating portraits of life in the outside world ("a desert"). This world presented fundamental restrictions on their movement and speech and held deeply sedimented norms pertaining to who is considered valuable, productive, and even human, which they were reminded of through an endless tyranny of questions ("what do you do," "where do you live," etc.). Life in the clubhouse presented an alternative world for members to experience nourishment, dignity, reaffirmed personhood, and a sense of beauty. And yet, the desert outside remained. Implications of these findings for clubhouses, mental health practice, and sociopolitical and community engagement are discussed, including the need to address profound deprivations and power imbalances within the wider world, beyond the walls of humane spaces such as these. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

PurposeTo examine perceptual adaptation when people wear spectacles that produce unequal retinal image magnification.MethodsTwo groups of 15 participants (10 male; mean age 25.6 ± 4.9 years) wore spectacles with a 3.8% horizontal magnifier over one eye. The continuous-wear group wore the spectacles for 5 hours straight. The intermittent-wear group wore them for five 1-hour intervals. To measure slant and shape distortions produced by the spectacles, participants adjusted visual stimuli until they appeared frontoparallel or equiangular, respectively. Adaptation was quantified as the difference in responses at the beginning and end of wearing the spectacles. Aftereffects were quantified as the difference before and after removing the spectacles. We hypothesized that intermittent wear may lead to visual cue reweighting, so we fit a cue combination model to the data and examined changes in weights given to perspective and binocular disparity slant cues.ResultsBoth groups experienced significant shape adaptation and aftereffects. The continuous-wear group underwent significant slant adaptation and the intermittent group did not, but there was no significant difference between groups, suggesting that the difference in adaptation was negligible. There was no evidence for cue reweighting in the intermittent wear group, but unexpectedly, the weight given to binocular disparity cues for slant increased significantly in the continuous-wear group.ConclusionsWe did not find strong evidence that adaptation to spatial distortions differed between the two groups. However, there may be differences in the cue weighting strategies employed when spectacles are worn intermittently or continuously.

STRUCTURED Summary Background Registered nurses perform numerous functions critical to the success of antimicrobial stewardship but only 63% of pre-registration nursing programmes include any teaching about stewardship. Updated nursing standards highlight nurses require antimicrobial stewardship knowledge and skills. Aim To explore the delivery of key antimicrobial stewardship competencies within updated pre-registration nursing programmes. Method A cross-sectional survey design. Data were collected between March and June 2021. Findings Lecturers from 35 UK universities responsible for teaching antimicrobial stewardship participated. The provision of antimicrobial stewardship teaching and learning was inconsistent across programmes with competencies in infection prevention and control, patient centred care, and interprofessional collaborative practice taking precedent over those pertaining to the use, management, and monitoring of antimicrobials. On-line learning and teaching surrounding hand hygiene, personal protective equipment, and immunisation theory was reported to have increased during the pandemic. Only a small number of respondents reported that students shared taught learning with other healthcare professional groups. Conclusion There is a need to ensure consistency in antimicrobial stewardship across programmes, and greater knowledge pertaining to the use, management and monitoring of antimicrobials should be included. Programmes need to adopt teaching strategies and methods that allow nurses to develop interprofessional skill in order to practice collaboratively.

Purpose North Carolina macular dystrophy (NCMD) is an autosomal dominant, congenital disorder affecting the central retina. Here, we report clinical and genetic findings in three families segregating NCMD and use epigenomic datasets from human tissues to gain insights into the effect of NCMD-implicated variants. Methods Clinical assessment and genetic testing were performed. Publicly available transcriptomic and epigenomic datasets were analyzed and the activity-by-contact method for scoring enhancer elements and linking them to target genes was used. Results A previously described, heterozygous, noncoding variant upstream of the PRDM13 gene was detected in all six affected study participants (chr6:100,040,987G>C [GRCh37/hg19]). Interfamilial and intrafamilial variability were observed; the visual acuity ranged from 0.0 to 1.6 LogMAR and fundoscopic findings ranged from visually insignificant, confluent, drusen-like macular deposits to coloboma-like macular lesions. Variable degrees of peripheral retinal spots (which were easily detected on widefield retinal imaging) were observed in all study subjects. Notably, a 6-year-old patient developed choroidal neovascularization and required treatment with intravitreal bevacizumab injections. Computational analysis of the five single nucleotide variants that have been implicated in NCMD revealed that these noncoding changes lie within two putative enhancer elements; these elements are predicted to interact with PRDM13 in the developing human retina. PRDM13 was found to be expressed in the fetal retina, with greatest expression in the amacrine precursor cell population. Conclusions We provide further evidence supporting the role of PRDM13 dysregulation in the pathogenesis of NCMD and highlight the usefulness of widefield retinal imaging in individuals suspected to have this condition.

Curriculum that informs students about social work practice with Native Peoples must be culturally relevant and responsive. However, the voices of Native Peoples are often excluded from identification of needs and relevant practice models for services. A unique partnership between the Native People from several tribes and a rural southwestern social work program led to an innovative project of curriculum development for social work practice with Native Peoples. The curriculum content evolved directly from the experiences of Native tribal members in the region. A retreat format initiated the process with subsequent quarterly meetings that provided a venue for course development with specific attention to the development of Native faculty as authors and teachers. The impact of this process is discussed through the voices of Council members, students, and Native instructors. This paper offers guidance to social work programs who are interested in expanding their understanding of Native curriculum development.

Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by an expanded CTG repeat in the 3′ UTR of the dystrophia myotonica protein kinase (DMPK) gene. Short, DNA-based antisense oligonucleotides termed gapmers are a promising strategy to degrade toxic CUG expanded repeat (CUGexp) RNA. Nucleoside analogs are incorporated to increase gapmer affinity and stability; however, some analogs also exhibit toxicity. In this study, we demonstrate that the 2′,4′-BNANC[NMe] (BNANC) modification is a promising nucleoside analog with high potency similar to 2′,4′-LNA (LNA). BNANC gapmers targeting a nonrepetitive region of the DMPK 3′ UTR show allele-specific knockdown of CUGexp RNA and revert characteristic DM1 molecular defects including mis-splicing and accumulation of RNA foci. Notably, the BNANC gapmers tested in this study did not induce caspase activation, in contrast to a sequence matched LNA gapmer. This study indicates that BNANC gapmers warrant further study as a promising RNA targeting therapeutic.

The acquisition of cell motility is an early step in melanoma metastasis. Here we use intravital imaging of signalling reporter cell-lines combined with genome-wide transcriptional analysis to define signalling pathways and genes associated with melanoma metastasis. Intravital imaging revealed heterogeneous cell behaviour in vivo: less than 10% of cells were motile and both singly moving cells and streams of cells were observed. Motile melanoma cells had increased Notch- and SRF-dependent transcription. Subsequent genome-wide analysis identified an overlapping set of genes associated with high Notch and SRF activity. We identified EZH2, a histone methyltransferase in the Polycomb Repressor Complex 2, as a regulator of these genes. Heterogeneity of EZH2 levels is observed in melanoma models and co-ordinated up-regulation of genes positively regulated by EZH2 is associated with melanoma metastasis. EZH2 was also identified as regulating the amelanotic phenotype of motile cells in vivo by suppressing expression of the P-glycoprotein Oca2. Analysis of patient samples confirmed an inverse relationship between EZH2 levels and pigment. EZH2 targeting with siRNA and chemical inhibition reduced invasion in mouse and human melanoma cell lines. The EZH2 regulated SRF target genes KIF2C and KIF22 are required for melanoma cell invasion and important for lung colonisation. We propose that heterogeneity in EZH2 levels leads to heterogeneous expression of a cohort of genes associated with motile behaviour including KIF2C and KIF22. EZH2 dependent increased expression of these genes promotes melanoma cell motility and early steps in metastasis.

Introduction: Viral hemorrhagic fever (VHF) outbreaks, with high mortality rates, have often been amplified in African health institutions due to person-to-person transmission via infected body fluids. By collating and analyzing epidemiological data from documented outbreaks, we observed that diagnostic delay contributes to epidemic size for Ebola and Marburg hemorrhagic fever outbreaks. Methodology: We used a susceptible-exposed-infectious-removed (SEIR) model and data from the 1995 outbreak in Kikwit, Democratic Republic of Congo, to simulate Ebola hemorrhagic fever epidemics. Our model allows us to describe the dynamics for hospital staff separately from that for the general population, and to implement health worker-specific interventions. Results: The model illustrates that implementing World Health Organization/US Centers for Disease Control and Prevention guidelines of isolating patients who do not respond to antimalarial and antibacterial chemotherapy reduces total outbreak size, from a median of 236, by 90% or more. Routinely employing diagnostic testing in post-mortems of patients that died of refractory fevers reduces the median outbreak size by a further 60%. Even greater reductions in outbreak size were seen when all febrile patients were tested for endemic infections or when febrile health-care workers were tested. The effect of testing strategies was not impaired by the 1-3 day delay that would occur if testing were performed by a reference laboratory. Conclusion: In addition to improving the quality of care for common causes of febrile infections, increased and strategic use of laboratory diagnostics for fever could reduce the chance of hospital amplification of VHFs in resource-limited African health systems.

A goal of human genetics studies is to determine the mechanisms by which genetic variation produces phenotypic differences that affect human health. Efforts in this respect have previously focused on genetic variants that affect mRNA levels by altering epigenetic and transcriptional regulation. Recent studies show that genetic variants that affect RNA processing are at least equally as common as, and are largely independent from, those variants that affect transcription. We highlight the impact of genetic variation on pre-mRNA splicing and polyadenylation, and on the stability, translation and structure of mRNAs as mechanisms that produce phenotypic traits. These results emphasize the importance of including RNA processing signals in analyses to identify functional variants.

Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted. DOI: http://dx.doi.org/10.7554/eLife.16118.001

The dynamic process underlying muscle contraction is the parallel sliding of thin actin filaments along an immobile thick myosin fiber powered by oar-like movements of protruding myosin cross bridges (myosin heads). The free energy for functioning of the myosin nanomotor comes from the hydrolysis of ATP bound to the myosin heads. The unit step of translational movement is based on a mechanical-chemical cycle involving ATP binding to myosin, hydrolysis of the bound ATP with ultimate release of the hydrolysis products, stress-generating conformational changes in the myosin cross bridge, and relief of built-up stress in the myosin power stroke. The cycle is regulated by a transition between weak and strong actin-myosin binding affinities. The dissociation of the weakly bound complex by addition of salt indicates the electrostatic basis for the weak affinity, while structural studies demonstrate that electrostatic interactions among negatively charged amino acid residues of actin and positively charged residues of myosin are involved in the strong binding interface. We therefore conjecture that intermediate states of increasing actin-myosin engagement during the weak-to-strong binding transition also involve electrostatic interactions. Methods of polymer solution physics have shown that the thin actin filament can be regarded in some of its aspects as a net negatively charged polyelectrolyte. Here we employ polyelectrolyte theory to suggest how actin-myosin electrostatic interactions might be of significance in the intermediate stages of binding, ensuring an engaged power stroke of the myosin motor that transmits force to the actin filament, and preventing the motor from getting stuck in a metastable pre-power stroke state. We provide electrostatic force estimates that are in the pN range known to operate in the cycle.

Here we use intravital imaging to demonstrate a reversible transition to a motile state as breast cancer cells spread. Imaging primary tumours revealed heterogeneity in cell morphology and motility. Two distinct modes of motility were observed: collective and single-celled. By monitoring the localization of Smad2 and the activity of a TGFbeta-dependent reporter gene during breast cancer cell dissemination, we demonstrate that TGFbeta signalling is transiently and locally activated in motile single cells. TGFbeta1 switches cells from cohesive to single cell motility through a transcriptional program involving Smad4, EGFR, Nedd9, M-RIP, FARP and RhoC. Blockade of TGFbeta signalling prevented cells moving singly in vivo but did not inhibit cells moving collectively. Cells restricted to collective invasion were capable of lymphatic invasion but not blood-borne metastasis. Constitutive TGFbeta signalling promoted single cell motility and intravasation but reduced subsequent growth in the lungs. Thus, transient TGFbeta signalling is essential for blood-borne metastasis.

A previously unrecognized function of normal human hemoglobins occurring during protein assembly is described, i.e. self-regulation of subunit pairings and their durations arising from the variable strengths of their subunit interactions. Although many mutant human hemoglobins are known to have altered subunit interface strengths, those of the normal embryonic, fetal, and adult human hemoglobins have not been considered to differ significantly. However, in a comprehensive study of both types of subunit interfaces of seven of the eight normal oxy human hemoglobins, we found that the strengths, i.e., the free energies of the tetramer-dimer interfaces, contrary to previous reports, differ by 3 orders of magnitude and display an undulating profile similar to the transitions ("switches") of various globin subunit types over time. The dimer interface strengths are also variable and correlate linearly with their developmental profile. Embryonic hemoglobins are the weakest; fetal hemoglobin is of intermediate strength, and adult hemoglobins are the strongest. The pattern also correlates generally with their different O(2) affinities and responses to allosteric regulatory molecules. Acetylation of fetal hemoglobin weakens its unusually strong subunit interactions and occurs progressively as its level of expression diminishes and adult hemoglobin A formation begins; a causal relationship is suggested. The relative contributions of globin gene order and competition among subunits due to differences in their interface strengths were found to be complementary and establish a connection among genetics, thermodynamics, and development.

Hepatic fibrosis is the final common pathway for many different liver insults. Originally considered to be irreversible, hepatic fibrosis is now known to be a dynamic process with a significant potential for resolution. The diagnosis and quantitation of fibrosis have traditionally relied on liver biopsy. However, there are a number of drawbacks including the invasive nature of the procedure, sampling error, and interobserver variability. This article reviews the current role of liver biopsy in the assessment of hepatic fibrosis and discusses the role of the newer noninvasive methods including serum markers and radiologic tests.

Background and Aim: Cyclooxygenase-2 (COX-2), a target of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), is upregulated in chronic hepatitis B and may have a role in hepatocellular carcinoma. Little is known about the expression of COX-2 in chronic hepatitis C (HCV) infection. The aim the present study was to evaluate the extent of COX-2 expression in liver biopsies in patients with HCV infection and to determine the effect of treatment with interferon α (IFN). Methods: Percutaneous liver biopsy specimens were retrieved. Following formalin fixation and paraffin embedding, the biopsies were histologically evaluated for inflammation and fibrosis. The extent of COX-2 expression was measured by the avidin biotin immunohistochemical technique using a monoclonal COX-2 antibody. The extent of COX-2 expression was graded according to the number of hepatocytes expressing COX-2. Data were analyzed using Student's t-test. Results: Liver biopsies from 10 patients before and after treatment with IFN were obtained and compared with nine normal liver biopsies. All of the liver biopsies showed some COX-2 expression. COX-2 expression was confined to hepatocytes and bile duct epithelium and was not detected in vascular endothelium or inflammatory cells. The extent of COX-2 expression was greater in hepatitis C infected liver biopsies than in normal biopsies. Following treatment with IFN, there was a greater than threefold reduction in COX-2 expression (P

Background Although drug-induced peripheral eosinophilia complicates antimicrobial therapy, little is known about its frequency and implications. Objective We aimed to determine the frequency and predictors of antibiotic-induced eosinophilia and subsequent hypersensitivity reactions (HSRs). Methods We evaluated a prospective cohort of former inpatients receiving intravenous antibiotic therapy as outpatients with at least 1 differential blood count. We used multivariate Cox proportional hazards models with time-varying antibiotic treatment indicators to assess the effect of demographic data and antibiotic exposures on eosinophilia and subsequent HSRs, including documented rash, renal injury, and liver injury. Possible drug rash with eosinophilia and systemic symptoms (DRESS) syndrome cases were identified and manually validated. Results Of 824 patients (60% male; median age, 60 years; median therapy duration, 41 days), 210 (25%) had eosinophilia, with median peak absolute eosinophil counts of 726/mL (interquartile range, 594-990/mL). Use of vancomycin, penicillin, rifampin, and linezolid was associated with a higher hazard of having eosinophilia. There was a subsequent HSR in 64 (30%) of 210 patients with eosinophilia, including rash (n = 32), renal injury (n = 31), and liver injury (n = 13). Patients with eosinophilia were significantly more likely to have rash (hazard ratio [HR], 4.16; 95% CI, 2.54-6.83; P P = .0009) but not liver injury (HR, 1.75; 95% CI, 0.92-3.33; P = .09). Possible DRESS syndrome occurred in 7 (0.8%) of 824 patients; 4 (57%) were receiving vancomycin. Conclusions Drug-induced eosinophilia is common with parenteral antibiotics. Although most patients with eosinophilia do not have an HSR, eosinophilia increases the hazard rate of having rash and renal injury. DRESS syndrome was more common than previously described.

The toxic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the small bowel have been reported extensively. A growing number of reports of toxic effects of NSAIDs on the colon have appeared recently. The clinical presentation, endoscopic appearances and histological findings of so-called NSAID colopathy are quite varied, as illustrated by a series of four patients described in this report. Presenting symptoms and signs in this series include iron-deficiency anaemia and crampy abdominal pain, but alteration of bowel habit, weight loss, and even nausea and vomiting have also been described. One patient in this series has large-bowel diaphragms, considered by some to be pathognomonic of NSAID effects. Each of the four patients had right-sided colonic lesions only, possibly supporting a direct toxic effect of NSAIDs. Management usually involves simply stopping the offending NSAID. A review of the literature on this under-recognized entity is presented.

The present study assessed (1) the impact of the measurement site (lower versus upper extremity) on the corresponding compliance variables and (2) the overall reliability of diastolic pulse contour (Windkessel-derived) analysis in normal and hypertensive subjects. Arterial tonograms were recorded in the supine position from the radial and posterior tibial arteries in 20 normotensive (116±12/68±8 mm Hg) and 27 essential hypertensive subjects (160±16/94±14 mm Hg). Ensemble-averaged data for each subject were fitted to a first-order lumped-parameter model (basic Windkessel) to compute whole-body arterial compliance (C A ) and to a third-order lumped-parameter model (modified Windkessel) to compute proximal compliance (C 1 ) and distal compliance (C 2 ). Despite high-fidelity waveforms in each subject, the first-order Windkessel model did not yield interpretable (positive) values for C A in 50% of normotensives and 41% of hypertensives, whereas the third-order model failed to yield interpretable C 1 or C 2 results in 15% of normotensives and 41% of hypertensives. No between-site correlations were found for the first-order time constant, 2 of the 3 third-order model curve-fitting constants, or C A , C 1 , or C 2 ( P >0.50). Mean values for all 3 compliance variables were higher for the leg than the arm ( P

Because of rising interest in new methods to detect arterial diseases, we compared data from 3 different compliance-related techniques to measure arterial stiffness: systolic pulse contour analysis, diastolic pulse contour analysis (modified Windkessel model), and muscular (brachial) artery compliance by cuff plethysmography. Variables measured in the sitting position were compared with each other, with clinic blood pressures (BPs), and with the cardiac time-tension integral (CTTI) in 63 established hypertensive and 28 age-matched normotensive subjects. Hypertensives demonstrated marginal reductions in C 1 (thought to represent reduced large vessel compliance) and increased central systolic BP augmentation. In contrast, muscular artery compliance tended to be greater in the hypertensives despite normal brachial arterial diameters. C 2 , suggested to be an indicator of small artery properties, was similar in both groups. CTTI was strongly related to systolic pressure ( r =0.81), integrated mean arterial pressure ( r =0.83), and systolic pressure-heart rate product ( r =0.85) and was less strongly related to diastolic ( r =0.71) or pulse pressure ( r =0.57). Weak correlations were observed between CTTI and measured compliance-related variables, which also showed absent or weak correlations among themselves. We conclude that the weak relationships among BP and compliance-related variables could be due to intrinsic differences in the properties of large and small arteries, theoretical methodological weaknesses, measurement artifacts, or intrinsic hemodynamic differences of the sitting position. At present, compliance-related variables provide little additional advantage over cuff BP in the office estimation of cardiac work.

BackgroundAn important issue in the transplantation of livers procured from cardiac death donors (CDDs) concerns why some centres report equivalent outcomes and others report inferior outcomes in transplantations using CDD organs compared with standard criteria donor (SCD) organs. Resolving this discrepancy may increase the number of usable organs.ObjectivesThis study aimed to test whether differences in cold ischaemic time (CIT) are critical during CDD organ transplantation and whether such differences might explain the disparate outcomes.MethodsResults of CDD liver transplants in our own centre were compared retrospectively with results in a matched cohort of SCD liver recipients. Endpoints of primary non-function (PNF) and ischaemic cholangiopathy (IC) were used because these outcomes are clearly associated with CDD organ use.ResultsIn 22 CDD organ transplants, CIT was a strong predictor of PNF or IC (P= 0.021). Minimising CIT in CDD organ transplants produced outcomes similar to those in a matched SCD organ transplant cohort at our centre and in SCD organ transplant results nationally (1- and 3-year graft and patient survival rates: 90.9% and 73.3% vs. 77.6% and 69.2% in CDD and SCD grafts, respectively. A review of the published literature demonstrated that centres with higher CITs tend to have higher rates of PNF or IC (correlation coefficient: 0.41).ConclusionsThese findings suggest that a targeted effort to minimise CIT might improve outcomes and allow the safer use of CDD organs.

Aim To identify the nature of services for children and young people with progressive neuromuscular disorders (NMD) provided by Children’s Hospices in the UK. Methods A questionnaire requesting aggregate data on the number of patients with a neuromuscular condition was sent to all children’s hospices in the UK, in addition, specific data was collected on services for young people with DMD presenting to a single local hospice. Results 87% of eligible hospices responded (27/31). 756 young people with an NM condition were being cared for by the hospices. These patients accounted for a mean of 17% of the total hospice population (range 5–35%). The age at which young people were required to leave the children’s hospices varied from 18 up to 35 years. 73% of ‘visits’ were described as ‘planned stays’. Although ‘end of life care’ is provided, few young people with NMD died in a hospice. Conclusions Children and young people with NMD form a large proportion of the Children’s Hospice’s caseload. Many valued services provided by children’s hospices are not available through NHS funding. The lack of similar adult based services is a concern as increasing numbers of young people are surviving into adulthood.

We report the construction of a genome-wide fish metabolic network model, MetaFishNet, and its application to analyzing high throughput gene expression data. This model is a stepping stone to broader applications of fish systems biology, for example by guiding study design through comparison with human metabolism and the integration of multiple data types. MetaFishNet resources, including a pathway enrichment analysis tool, are accessible at http://metafishnet.appspot.com.

This study aimed to measure rates of hand sanitiser use in a hospital entrance foyer four months after a baseline study during New Zealand s influenza pandemic. Of the 743 people observed over one (summer) day in December 2009, 8.2% used the hand sanitiser, which was significantly lower (p0.0001) than the 18.0% reported in the August (winter) study. Health authorities may need to intensify promotion of hand hygiene to reduce the impact of future influenza pandemic waves.

SUMMARYGiardiasis is a common waterborne gastrointestinal illness. In 2007, a community giardiasis outbreak occurred in New Hampshire, USA. We conducted a cohort study to identify risk factors for giardiasis, and stool and environmental samples were analysed. Consuming tap water was significantly associated with illness (risk ratio 4·7, 95% confidence interval 1·5–14·4). Drinking-water samples were coliform-contaminated and a suspectGiardiacyst was identified in a home water filter. One well was coliform-contaminated, and testing indicated that it was potentially under the influence of surface water. The well was located 12·5 m from aGiardia-contaminated brook, although the genotype differed from clinical specimens. Local water regulations require well placement at least 15 m from surface water. This outbreak, which caused illness in 31 persons, represents the largest community drinking-water-associated giardiasis outbreak in the USA in 10 years. Adherence to well placement regulations might have prevented this outbreak.

The expression of HLA antigens by a tumor may determine its progression and metastatic potential by influencing the immune response to that tumor. The upregulation of HLA antigen expression on some cell types by interferons (IFNs) may contribute to their antitumor activity. Malignant mesothelioma (MM) is a tumor that has a poor prognosis and is unaffected by conventional therapy, although immunotherapy has not been adequately assessed. In this study, we have examined the constitutive and IFN-inducible expression of class I and class II HLA antigens on MM cell lines using indirect immunofluorescence and Northern blotting. All MM cell lines constitutively expressed class I, but not class II, surface antigen, and all three class I loci (HLA-A, HLA-B, and HLA-C) were expressed. The MM cell lines were heterogeneous in their response to the IFNs. Treatment with IFN-alpha marginally increased class I surface expression, but not class II. Class I mRNA was, however, clearly increased in all cell lines after IFN-alpha treatment, suggesting that class I surface antigen was already maximally expressed. IFN-gamma increased class I mRNA expression in all but one cell line and induced DR expression on three of the cell lines. DQ-beta, but not DQ-alpha, mRNA was inducible in the same three cell lines, but DQ surface antigen was never demonstrable.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant mesothelioma (MM) is an aggressive tumour of the serosal cavities which is associated with exposure to asbestos. Studies of this tumour have been limited by a paucity of well-characterized human MM cell lines. In this study, 5 human MM cell lines were established from pleural effusions of patients with this malignancy. All 5 patients were males with known crocidolite asbestos exposure, who had received no treatment for their disease and in whom the diagnosis was confirmed by cytology, histology and electron microscopy (EM). These lines have been in culture from 11 to 25 months, and all of them for more than 18 passages. The appearance of the cells in culture was extremely varied; in 3 of the lines they were spindle-shaped with few vacuoles (JU77, LO68 and ONE58); in 1 line they had a thick, stellate shape with vacuoles (NO36) and in 1 they were very pleomorphic in both shape and size with irregular membranes and numerous vacuoles [DeH128 (M)]. Upon reaching confluence, cells in 3 of the 5 lines assumed the cobblestone-like pattern characteristic of epithelial-type cells, whereas in the other 2 (LO68 and ONE58) they remained spindle-shaped. All 5 lines demonstrated a loss of contact inhibition (i.e., piling) at confluence. Minimum doubling times varied significantly from 18 hr (JU77) to more than 30 hr [DeH128 (M)]. Cytological examination showed characteristic mesothelial/mesothelioma morphology, and epithelial membrane antigen (EMA) and cytokeratin were demonstrated in cells from all 5 lines. These cells lacked CEA and epithelial mucin. The presence of cell junctions, glycogen and numerous long, thin, branching microvilli was readily demonstrable by EM. All lines had abnormal karyotypes, with the modal chromosome number varying from 40 to 80. Variable chromosome numbers, numerous structural rearrangements and unrecognizable marker chromosomes were readily observed; however, the only consistent change seen was del 6q21 in 4 of the 5 lines. The establishment of these 5 cultured human MM cell lines now provides an opportunity for comparative study of several aspects of the biology of MM in vitro as well as screening new treatment modalities.

Recombinant human tumor necrosis factor (rHuTNF) was evaluated both for direct anti-tumor action against human malignant mesothelioma and for its capacity to augment the generation and lytic phases of lymphocyte-mediated cytotoxicity against this tumor. rHuTNF was directly toxic by MTT assay to one of two mesothelioma cell lines evaluated, but had no effect on susceptibility to subsequent lymphocyte-mediated lysis of either line. TNF alone was incapable of generating anti-mesothelioma lymphokine-activated killer cell (LAK) activity. Furthermore, it did not augment the degree or LAK activity produced by submaximal interleukin-2 (IL-2) concentrations nor did it augment lysis of mesothelioma cells by natural killer (NK) or LAK effector cells during the 4-hr 51chromium release cytolytic reaction. The studies also suggest that mesothelioma targets are less responsive to TNF plus submaximal IL-2 concentrations than the standard LAK sensitive target Daudi, raising the possibility that intermediate LAK sensitive tumors such as mesothelioma may require separate and specific evaluation in immunomodulation studies. This in vitro study indicates that use of low-dose rHuTNF and IL-2 is unlikely to be an effective substitute for high-dose IL-2 in generation and maintenance of LAK activity in adoptive immunotherapy for mesothelioma.

Malignant mesothelioma arises in serosal tissues, is locally invasive, and is usually resistant to chemotherapeutic agents used clinically. To determine whether resistance to cytotoxic drugs was an inherent characteristic of mesothelioma cells, we performed in vitro chemosensitivity testing on five fully characterised human malignant mesothelioma cell lines and, for comparison, on three lines representative of clinically drug-resistant solid-tissue carcinomas using the MTT (tetrazolium bromide) assay system. Mesothelioma cell lines were intrinsically resistant to eight common antineoplastic drugs, with concentrations that produced a 50% reduction in optical density (IC50 values) for all drugs being equivalent, if not higher, for mesothelioma cell lines as compared with lung and colon carcinoma cell lines. We then investigated the direct anti-mesothelioma activity of recombinant human cytokines with their antineoplastic properties. All five mesothelioma cell lines were resistant to tumour necrosis factor, but they displayed varying degrees of sensitivity to interferons (IFNs). IFN gamma directly inhibited the growth of two of five mesothelioma lines. IFN alpha displayed little activity against four of five mesothelioma lines. The mesothelioma cells that were sensitive to IFN alpha were resistant to IFN gamma, indicating that sensitivity to IFNs is not a genetic characteristic of malignant mesothelioma cells. Significant interactions between cytokines in combination were not observed.

Major depression is associated with both hypothalamic-pituitary-adrenal (HPA) axis overactivity and immune system activation. Depression is a common occurrence following interferon (IFN)-a treatment. While IFN-alpha is known to stimulate the HPA axis, little is known about the effects of exogenous IFN-a in humans on the proinflammatory cytokine interleukin (IL)-6, a marker of immune system activation. This study examined the acute effects of IFN-alpha on cortisol and IL-6 release, and the time course of any changes in these variables. Serum cortisol and plasma IL-6 were assessed in healthy volunteers over an 8-h period following 3 million units subcutaneous IFN-alpha or placebo using a double-blind, placebo-controlled crossover design. IFN-alpha resulted in a significant increase in both cortisol and IL-6. Regular sampling over 8 h did not delineate any sequential effect of the rise in these variables over time. We conclude that IFN-alpha acutely stimulates both the HPA axis and proinflammatory cytokine release. The hypothesis that the effect of IFN-alpha on the HPA axis is indirect and mediated by IL-6 was not supported by this study. Our findings are nonetheless of relevance to the aetiology of depression following IFN-alpha.

The decision to provide root canal treatment is based on the desire of the patient to keep his or her tooth and likelihood of success. As there are good options for the replacement of teeth the success of root canal treatment should be weighed against these alternatives. This paper aims to review the literature and give an insight into the factors affecting endodontic success and when it may be best to create a space with extraction.

The study examined the effects of repeated strenuous live-fire drills on cardiovascular and psychological responses of male recruit firefighters (n = 7). Participants performed three trials of a standardized set of tasks while inside a training structure containing several live fires. Measurements of heart rate, aortic blood flow, perceived exertion, respiratory and thermal distress, reaction time, and error rate were obtained before testing, after each trial and during recovery. Heart rate increased significantly during each of the trials, reaching age-predicted maximal values. Stroke volume was significantly lower after trial 3 versus trial 1 and prevalues. Perceived exertion, respiratory distress, and thermal distress all increased, indicating greater stress following firefighting activities. Reaction time and error rate did not change significantly, but there was a tendency for more errors following trials 2 and 3 versus trial 1. The training drills resulted in considerable physiological and psychological strain, which has the potential to impair cognitive function. Firefighters are encouraged to take all possible steps to mitigate the extent of the cardiovascular strain.

The lumbar vertebrae of rowers are subjected to high levels of shear and compression at mid-drive, but intra-abdominal pressure (IAP) may partially neutralize these forces. IAP fluctuates with breathing. This study compared the IAP between inspiring during the drive and expiring during the drive.ten volunteers performed one 5x2-minute repetition test while inspiring during the drive and one 5x2-minute repetition test while expiring during the drive on a rowing ergometer. The five work rates were: 100, 125, 150, 175 and 200 watts at 22, 24, 26, 28 and 30 strokes per minute, respectively.the movement of the body while rowing was analyzed using a position sensor, and IAP was measured using a pressure transducer catheter.A 2x5 repeated measures analysis of variance showed that there was a significant interaction for the dependent variable mid-drive IAP (p0.05), with the mid-drive IAP increasing at a greater rate while expiring during the drive relative to inspiring during the drive. Across work rate, the mid-drive IAP and minimal IAP were significantly higher while expiring during the drive than inspiring during the drive (p0.05). Across breathing pattern, the minimal IAP, maximal IAP, average change in IAP and mid-drive IAP increased significantly with work rate (p0.05).The data show that expiring during the drive leads to a greater mid-drive IAP than inspiring during the drive.

Federal courts have split on the question of the applicability of the Americans with Disabilities Act to insurance coverage decisions that insurance companies make on the basis of disability; they have similarly split on other issues pertaining to the scope of that Act's application. In deciding whether to read the Act as prohibiting discrimination in insurance decisions that are often crucial in the lives of people with disabilities, courts have faced two problems. First, where it prohibits discrimination in the equal enjoyment of the goods and services of places of public accommodation, the Act's area of concern may be limited to the ability of people with disabilities to gain physical access to facilities; or that area may extend to all forms of disability-based discrimination in the provision of goods and services. This Comment argues that the language and legislative history of the Act are consistent only with the latter view. Second, the provision limiting the Act's applicability to insurance may create an exemption for all insurance decisions; or it may protect only the ability of an insurance company to make an insurance decision to the disadvantage of an insured with a disability where actuarial data support the decision. This comment argues that the ambiguous language of the limiting provision should be resolved in favor of the latter view. Legislative history and the broader background of the history of insurance discrimination law support this resolution. Consequently, the Act should be interpreted as prohibiting disability-based discrimination by insurance companies in selling insurance policies and as defining discrimination as making disability-based insurance decisions without the support of actuarial data. By accepting this interpretation, courts can help stop the pattern of judicial narrowing of the Act's application through inappropriately restrictive statutory construction.

Salmonella ajiobo is a relatively unusual subtype of the bacterium with only an annual average of seven cases being noted from 1990 to 2005. Here we record a case of tubo-ovarian abscess requiring ...

Many NHS staff feel that they are unable to put their values into action because of the constraints on the service. They want a working environment where trust is possible and mistakes can be made without retribution. The reality is often bullying and attempts at innovation being met with reproach.

Microvillous lymphomas (MVLs) are rare, poorly defined, large transformed cell lymphomas characterized by a cohesive sinus growth pattern and ultrastructural cytoplasmic processes. Most MVLs express B-cell antigens and have been compared ultrastructurally to transformed follicular center cells and follicular dendritic cells. For additional definition of the immunophenotype of these unusual B-cell lymphomas, we evaluated eight cases of MVL for B-cell-associated antigens (CD21, CD35, CDw75, DBA.44, bcl-2) using paraffin immunoperoxidase. CD56, the neural cell adhesion molecule, was tested because of the unusual, cohesive, sinus pattern of tumor cell growth seen in MVL. Molecular analysis for immunoglobulin heavy chain and bcl-2 gene rearrangements was performed to confirm B-cell clonality and to evaluate cases for possible follicular origin. All of the cases were marked as B cells (CD20 positive), and the clonal nature confirmed by immunoperoxidase in five cases (63%) of eight and polymerase chain reaction for immunoglobulin heavy chain in seven cases (88%) of eight. CDw75 staining was present in six cases and CD74 in seven. DBA.44 and CD21 and CD35 were negative in all of the cases, and four cases (50%) of eight expressed CD56. bcl-2 protein expression was seen in seven of eight cases; bcl-2 gene rearrangement was present in one case (33%) of three studied. In conclusion, MVLs are B-cell lymphomas demonstrating clonal immunoglobulin heavy chain gene rearrangement. The neoplastic cells express CDw75 and bcl-2 protein. The presence of bcl-2 rearrangements in a limited number of cases implies that at least some MVLs have a follicular origin. Fifty percent of MVLs express CD56, suggesting a role for adhesion molecules in the distribution of this lymphoma.

All three subtypes of beta-adrenoceptors are coupled to stimulation of adenylyl cyclase activity via the stimulatory guanine-nucleotide-binding protein. Nevertheless, the beta3 adrenoceptor (beta3-AR) differs significantly from the other subtypes in terms of pharmacology. Most strikingly, it recognizes as agonists several compounds acting as potent beta1-AR and beta2-AR antagonists. Furthermore, the human beta3-AR is quite different from the animal beta3-AR. Molecular modelling studies followed by site-directed mutagenesis was used here to identify some of the amino acid residues which may be implicated in ligand binding and signal transduction of the beta3-AR. Three contiguous residues, valine-leucine-alanine, which are present in the first transmembrane domain at positions 48-50 of the human receptor but are absent in all known rodent sequences, were thought to be important for species specificity. When these three residues were deleted from the human receptor, no 'rodent-like' pharmacological profile was obtained in terms of either binding or adenylyl cyclase activation. Glycine at position 53, also in the first transmembrane domain in the human beta3-AR, has been suggested to participate in beta2-/beta3-AR subtype selectivity. Replacement of this glycine residue by phenylalanine, which is the residue present at the homologous position in the human beta2-AR, left the beta3-AR pharmacological profile unaltered in terms of specificity and selectivity. Aspartate residue 117, in the third transmembrane domain, has been found to be essential for ligand binding and consequently adenylyl cyclase activation in several bioamine receptors. When this residue was replaced by a leucine residue in the beta3-AR, ligand binding and signal transduction were suppressed. Finally, replacement of asparagine at position 312 in the sixth transmembrane domain by an alanine residue, led to alterations in the signal-transduction pathway.

Phenotypic expression of the Trp64Arg mutation in the beta 3-adrenoceptor gene (beta 3-AR) has been found to be somewhat variable among different populations, suggesting that it may be influenced by genetic background and environmental factors. As sex may also influence gene allellic expression, we evaluated a potential gender effect of the Trp64Arg mutation in 292 morbidly obese subjects [body mass index (BMI)or = m/kg2]. Although the 15 mutated obese females were younger than the non-mutated ones, the difference between their current weight and their weight at 20 years was significantly higher (62.4 +/- 20.0 kg versus 47.0 +/- 24.0 kg; p = 0.017). Moreover, in the mutated heterozygous female group, the mean Zscore (individual BMI minus reference French population mean BMI/SD of reference population BMI) was significantly higher (8.0 +/- 2.5 versus 6.0 +/- 2.0 SD of BMI, p = 0.0018), as was the maximal Zscore calculated from the maximal BMI that obese females reached during life (9.0 +/- 3.0 versus 7.0 +/- 2.5, p = 0.005). The regression curves of the Zscore against age showed that the curve of mutated females was shifted to the top, indicating that their BMI was higher regardless of age. These effects were not observed in the male group (the Zscore was 6.7 +/- 3.0 vs. 7.2, p = 0.7 respectively in mutated and non-mutated men). These data reinforce the hypothesis that the expression of the beta 3-AR susceptibility gene depends on additional factors including gender and possibly hormonal status.

Social workers today face some of the most complex ethical dilemmas in the history of the profession. This article presents a framework of moral citizenship to guide ethical social work practice. The framework includes the action philosophies of philosopher Hannah Arendt and Lutheran theologian Paul Tillich integrated with concepts of professional responsibility and the unique contributions of social work pioneer Charlotte Towle. Social conscience and social consciousness, including awareness, thinking, feeling, and action, are major components of the framework.

SUMMARY Informed consent is a critical variable in the self-determination of consumers receiving health and mental health services. Consent has become a more stringent requirement in recent years. However, providers emphasize legal requirements rather than the true participation of consumers-the “spirit” of informed consent. This article discusses the elements of informed consent, the issues that reflect the “spirit” of consent, and recommendations for actions that foster self-determination in practice.

Data mining is an emerging technique used more widely by the business world than the world of nursing and health care. However, this strategy can be helpful for improving the quality of decision making by clinicians and health care administrators. This paper addresses the concepts and techniques of data mining that could be useful for practicing nurses as well as nurse administrators. Data mining can be an important tool for the development of nursing knowledge and knowledge structures. An example of the use of the technique in an inpatient setting is provided and insights from the process are discussed.

A pharmacoeconomic study of 15 antibiotics available in Barbados was performed. The antibiotics studied were amoxycillin/clavulanate, ampicillin, ampicillin/sulbactam, cefazolin, cefotaxime, ceftazidime, ceftriaxone, clindamycin, cloxacillin, cotrimoxazole, gentamicin, imipenem, metronidazole, piperacillin, piperacillin/tazobactam, and vancomycin. The costs of use of these compounds were calculated for a five-day course using a formula comprising eight categories: antibiotic purchase cost, maintenance of intravenous access, drug delivery cost, drug monitoring cost, dose readjustment, general monitoring cost, 'sharps' disposal cost and adverse effects. The costs of adverse effects were not included in this study due to lack of accurate data. The total cost of antibiotic use (in U.S. dollars) ranged from $42.52 to $463.73 per five-day course. Generic compounds were less expensive ($45.52 - $98.23) than brand-name compounds ($106.18 - $106.18 - $463.73). Antibiotic purchase costs accounted for proportions of total costs ranging from 7 to 93%. Non-drug costs represented a much greater proportion of total costs of generic compounds. For most compounds the non-drug costs were related to the frequency of dosing, but for gentamicin the non-drug costs were relatively higher because of the need for monitoring of serum gentamicin levels. Efficacy and freedom from side-effects will remain the most important determinants in the choice of antibiotic therapy. However, pharmacoeconomic analyses can provide prescribers with the information required to make cost-effective choices for treatment of their patients.

Depression is one of the most prevalent disorders seen in primary care. About 50% of depression is treated in general medical settings. Although depression is highly treatable, incomplete response to a single antidepressant is common. We describe two clinical cases in which antidepressant augmentation was a therapeutic option and lithium carbonate was an appropriate choice. A brief review of the practical aspects of the clinical pharmacology of lithium is included. Lithium is a well-tolerated, safe, and effective medication for antidepressant augmentation.