Derivation and validation of a simple, accurate and robust prediction rule for risk of mortality in patients with Clostridium difficile infection.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: Clostridium difficile infection poses a significant healthcare burden. However, the derivation of a simple, evidence based prediction rule to assist patient management has not yet been described. METHOD: Univariate, multivariate and decision tree procedures were used to deduce a prediction rule from over 186 variables; retrospectively collated from clinical data for 213 patients. The resulting prediction rule was validated on independent data from a cohort of 158 patients described by Bhangu et al. (Colorectal Disease, 12(3):241-246, 2010). RESULTS: Serum albumin levels (g/L) (P = 0.001), respiratory rate (resps /min) (P = 0.002), C-reactive protein (mg/L) (P = 0.034) and white cell count (mcL) (P = 0.049) were predictors of all-cause mortality. Threshold levels of serum albumin ≤ 24.5 g/L, C- reactive protein >228 mg/L, respiratory rate >17 resps/min and white cell count >12 × 10(3) mcL were associated with an increased risk of all-cause mortality. A simple four variable prediction rule was devised based on these threshold levels and when tested on the initial data, yield an area under the curve score of 0.754 (P < 0.001) using receiver operating characteristics. The prediction rule was then evaluated using independent data, and yield an area under the curve score of 0.653 (P = 0.001). CONCLUSIONS: Four easily measurable clinical variables can be used to assess the risk of mortality of patients with Clostridium difficile infection and remains robust with respect to independent data.This work was funded by University of Exeter, Systems Biology Initiative, a small grants fund from the RD&E NHS Trust and The National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula (PenCLAHRC). This article presents independent research funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health in England

Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface.

Targeted hybridization enrichment prior to next-generation sequencing is a widespread method for characterizing sequence variation in a research setting, and is being adopted by diagnostic laboratories. However, the number of variants identified can overwhelm clinical laboratories with strict time constraints, the final interpretation of likely pathogenicity being a particular bottleneck. To address this, we have developed an approach in which, after automatic variant calling on a standard unix pipeline, subsequent variant filtering is performed interactively, using AgileExomeFilter and AgilePindelFilter (http://dna.leeds.ac.uk/agile), tools designed for clinical scientists with standard desktop computers. To demonstrate the method's diagnostic efficacy, we tested 128 patients using (1) a targeted capture of 36 cancer-predisposing genes or (2) whole-exome capture for diagnosis of the genetically heterogeneous disorder primary ciliary dyskinesia (PCD). In the cancer cohort, complete concordance with previous diagnostic data was achieved across 793 variant genotypes. A high yield (42%) was also achieved for exome-based PCD diagnosis, underscoring the scalability of our method. Simple adjustments to the variant filtering parameters further allowed the identification of a homozygous truncating mutation in a presumptive new PCD gene, DNAH8. These tools should allow diagnostic laboratories to expand their testing portfolios flexibly, using a standard set of reagents and techniques

Challenges and Opportunities: What Can We Learn from Patients Living with Chronic Musculoskeletal Conditions, Health Professionals and Carers about the Concept of Health Literacy Using Qualitative Methods of Inquiry?

The field of health literacy continues to evolve and concern public health researchers and yet remains a largely overlooked concept elsewhere in the healthcare system. We conducted focus group discussions in England UK, about the concept of health literacy with older patients with chronic musculoskeletal conditions (mean age = 73.4 years), carers and health professionals. Our research posed methodological, intellectual and practical challenges. Gaps in conceptualisation and expectations were revealed, reiterating deficiencies in predominant models for understanding health literacy and methodological shortcomings of using focus groups in qualitative research for this topic. Building on this unique insight into what the concept of health literacy meant to participants, we present analysis of our findings on factors perceived to foster and inhibit health literacy and on the issue of responsibility in health literacy. Patients saw health literacy as a result of an inconsistent interactive process and the implications as wide ranging; healthcare professionals had more heterogeneous views. All focus group discussants agreed that health literacy most benefited from good inter-personal communication and partnership. By proposing a needs-based approach to health literacy we offer an alternative way of conceptualising health literacy to help improve the health of older people with chronic conditions

The process of nurses' role negotiation in general practice: A grounded theory study.

AIM: To explain the process by which nurses' roles are negotiated in general practice. BACKGROUND: Primary care nurses do important work within a social model of health to meet the needs of the populations they serve. Latterly, in the face of increased demand and workforce shortages, they are also taking on more medical responsibilities through task-shifting. Despite the increased complexity of their professional role, little is known about the processes by which it is negotiated. DESIGN: Constructivist grounded theory. METHODS: Semi-structured interviews were conducted with 22 participants from 17 New Zealand general practices between December 2020 and January 2022. Due to COVID-19, 11 interviews were via Zoom™. Concurrent data generation and analysis, using the constant comparative method and common grounded theory methods, identified the participants' main concern and led to the construction of a substantive explanatory theory around a core category. RESULTS: The substantive explanatory theory of creating place proposes that the negotiation of nurse roles within New Zealand general practice is a three-stage process involving occupying space, positioning to do differently and leveraging opportunity. Nurses and others act and interact in these stages, in accordance with their conceptualizations of need-responsive nursing practice, towards the outcome defining place. Defining place conceptualizes an accommodation between the values beliefs and expectations of individuals and pre-existing organizational norms, in which individual and group-normative concepts of need-responsive nursing practice are themselves developed. CONCLUSION: The theory of creating place provides new insights into the process of nurses' role negotiation in general practice. Findings support strategies to enable nurses, employers and health system managers to better negotiate professional roles to meet the needs of the populations they serve, while making optimum use of nursing skills and competencies. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Findings can inform nurses to better negotiate the complexities of the primary care environment, balancing systemic exigencies with the health needs of populations. IMPACT: What Problem Did the Study Address? In the face of health inequity, general practice nurses in New Zealand, as elsewhere, are key to meeting complex primary health needs. There is an evidence gap regarding the processes by which nurses' roles are negotiated within provider organizations. A deeper understanding of such processes may enable better use of nursing skills to address unmet health need. What Were the Main Findings? Nurses' roles in New Zealand general practice are determined through goal-driven negotiation in accordance with individual concepts of need-responsive nursing practice. Individuals progress from occupying workspaces defined by the care-philosophies of others to defining workplaces that incorporate their own professional beliefs, values and expectations. Negotiation is conditional upon access to role models, scheduled dialogue with mentors and decision-makers, and support for safe practice. Strong clinical and organizational governance and individuals' own positive personal self-efficacy are enablers of effective negotiation. Where and on Whom Will the Research Have Impact? The theory of Creating Space can inform organizational and individual efforts to advance the roles of general practice nurses to meet the health needs of their communities. General practice organizations can provide safe, supported environments for effective negotiation; primary care leaders can promote strong governance and develop individuals' sense of self-efficacy by involving them in key decisions. Nurses themselves can use the theory as a framework to support critical reflection on how to engage in active negotiation of their professional roles. REPORTING METHOD: The authors adhered to relevant EQUATOR guidelines using the COREQ reporting method. PATIENT OR PUBLIC CONTRIBUTION: Researchers and participants currently working in general practice were involved in the development of this study. By the process of theoretical sampling and constant comparison, participants' comments helped to shape the study design. WHAT DOES THIS PAPER CONTRIBUTE TO THE WIDER GLOBAL CLINICAL COMMUNITY?: An understanding of the processes by which health professionals negotiate their roles is important to support them to meet the challenges of increased complexity across all health sectors globally.fals

Post-depositional fracturing and subsidence of pumice flow deposits: Lascar Volcano, Chile

Unconsolidated pyroclastic flow deposits of the 1993 eruption of Lascar Volcano, Chile, have, with time, become increasingly dissected by a network of deeply penetrating fractures. The fracture network comprises orthogonal sets of decimeter-wide linear voids that form a pseudo-polygonal grid visible on the deposit surface. In this work, we combine shallow surface geophysical imaging tools with remote sensing observations and direct field measurements of the deposit to investigate these fractures and their underlying causal mechanisms. Based on ground penetrating radar images, the fractures are observed to have propagated to depths of up to 10 m. In addition, orbiting radar interferometry shows that deposit subsidence of up to 1 cm/year occurred between 1993 and 1996 with continued subsidence occurring at a slower rate thereafter. In situ measurements show that 1 m below the surface, the 1993 deposits remain 5°C to 15°C hotter, 18 years after emplacement, than adjacent deposits. Based on the observed subsidence as well as estimated cooling rates, the fractures are inferred to be the combined result of deaeration, thermal contraction, and sedimentary compaction in the months to years following deposition. Significant environmental factors, including regional earthquakes in 1995 and 2007, accelerated settling at punctuated moments in time. The spatially variable fracture pattern relates to surface slope and lithofacies variations as well as substrate lithology. Similar fractures have been reported in other ignimbrites but are generally exposed only in cross section and are often attributed to formation by external forces. Here we suggest that such interpretations should be invoked with caution, and deformation including post-emplacement subsidence and fracturing of loosely packed ash-rich deposits in the months to years postemplacement is a process inherent in the settling of pyroclastic material

Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children

Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling

Despite substantial efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain largely unclear. Here we examined cellular uptake of siRNA delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy as well as defined perturbations of cellular pathways paired with systems biology approaches to uncover protein-protein and protein-small molecule interactions. We show that multiple cell signaling effectors are required for initial cellular entry of LNPs through macropinocytosis, including proton pumps, mTOR, and cathepsins. SiRNA delivery is substantially reduced as ≅70% of the internalized siRNA undergoes exocytosis through egress of LNPs from late endosomes/lysosomes. Niemann Pick type C1 (NPC1) is shown to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes/lysosomes and increased gene silencing of the target gene. Our data suggests that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways

A proteomic approach to investigating gene cluster expression and secondary metabolite functionality in Aspergillus fumigatus.

A combined proteomics and metabolomics approach was utilised to advance the identification and characterisation of secondary metabolites in Aspergillus fumigatus. Here, implementation of a shotgun proteomic strategy led to the identification of non-redundant mycelial proteins (n = 414) from A. fumigatus including proteins typically under-represented in 2-D proteome maps: proteins with multiple transmembrane regions, hydrophobic proteins and proteins with extremes of molecular mass and pI. Indirect identification of secondary metabolite cluster expression was also achieved, with proteins (n = 18) from LaeA-regulated clusters detected, including GliT encoded within the gliotoxin biosynthetic cluster. Biochemical analysis then revealed that gliotoxin significantly attenuates H2O2-induced oxidative stress in A. fumigatus (p>0.0001), confirming observations from proteomics data. A complementary 2-D/LC-MS/MS approach further elucidated significantly increased abundance (p<0.05) of proliferating cell nuclear antigen (PCNA), NADH-quinone oxidoreductase and the gliotoxin oxidoreductase GliT, along with significantly attenuated abundance (p<0.05) of a heat shock protein, an oxidative stress protein and an autolysis-associated chitinase, when gliotoxin and H2O2 were present, compared to H2O2 alone. Moreover, gliotoxin exposure significantly reduced the abundance of selected proteins (p<0.05) involved in de novo purine biosynthesis. Significantly elevated abundance (p<0.05) of a key enzyme, xanthine-guanine phosphoribosyl transferase Xpt1, utilised in purine salvage, was observed in the presence of H2O2 and gliotoxin. This work provides new insights into the A. fumigatus proteome and experimental strategies, plus mechanistic data pertaining to gliotoxin functionality in the organism

A review of tennis racket performance parameters

The application of advanced engineering to tennis racket design has influenced the nature of the sport. As a result, the International Tennis Federation has established rules to limit performance, with the aim of protecting the nature of the game. This paper illustrates how changes to the racket affect the player-racket system. The review integrates engineering and biomechanical issues related to tennis racket performance, covering the biomechanical characteristics of tennis strokes, tennis racket performance, the effect of racket parameters on ball rebound and biomechanical interactions. Racket properties influence the rebound of the ball. Ball rebound speed increases with frame stiffness and as string tension decreases. Reducing inter-string contacting forces increases rebound topspin. Historical trends and predictive modelling indicate swingweights of around 0.030–0.035 kg/m2 are best for high ball speed and accuracy. To fully understand the effect of their design changes, engineers should use impact conditions in their experiments, or models, which reflect those of actual tennis strokes. Sports engineers, therefore, benefit from working closely with biomechanists to ensure realistic impact conditions

The relationship between job satisfaction, burnout, and turnover intention among physicians from urban state-owned medical institutions in Hubei, China: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Throughout China, a growing number of physicians are leaving or intending to depart from their organizations owing to job dissatisfaction. Little information is available about the role of occupational burnout in this association. We set out to analyze the relationship between job satisfaction, burnout, and turnover intention, and further to determine whether occupational burnout can serve as a mediator among Chinese physicians from urban state-owned medical institutions.</p> <p>Methods</p> <p>A cross-sectional survey was carried out in March 2010 in Hubei Province, central China. The questionnaires assessed sociodemographic characteristics, job satisfaction, burnout, and turnover intention. The job satisfaction and occupational burnout instruments were obtained by modifying the Chinese Physicians' Job Satisfaction Questionnaire (CPJSQ) and the Chinese Maslach Burnout Inventory (CMBI), respectively. Such statistical methods as one-way ANOVA, Pearson correlation, GLM-univariate and structural equation modeling were used.</p> <p>Results</p> <p>Of the 1600 physicians surveyed, 1451 provided valid responses. The respondents had medium scores (3.18 +/-0.73) on turnover intention, in which there was significant difference among the groups from three urban areas with different development levels. Turnover intention, which significantly and negatively related to all job-satisfaction subscales, positively related to each subscale of burnout syndrome. Work environment satisfaction (<it>b </it>= -0.074, <it>p < 0.01</it>), job rewards satisfaction (<it>b </it>= -0.073, <it>p < 0.01</it>), organizational management satisfaction (<it>b </it>= -0.146, <it>p < 0.01</it>), and emotional exhaustion (<it>b </it>= 0.135, <it>p < 0.01</it>) were identified as significant direct predictors of the turnover intention of physicians, with 41.2% of the variance explained unitedly, under the control of sociodemographic variables, among which gender, age, and years of service were always significant. However, job-itself satisfaction no longer became significant, with the estimated parameter on job rewards satisfaction smaller after burnout syndrome variables were included. As congregated latent concepts, job satisfaction had both significant direct effects (gamma₂₁= -0.32, <it>p < 0.01</it>) and indirect effects (gamma₁₁× beta₂₁= -0.13, <it>p < 0.01</it>) through occupational burnout (62% explained) as a mediator on turnover intention (47% explained).</p> <p>Conclusions</p> <p>Our study reveals that several, but not all dimensions of both job satisfaction and burnout syndrome are relevant factors affecting physicians' turnover intention, and there may be partial mediation effects of occupational burnout, mainly through emotional exhaustion, within the impact of job satisfaction on turnover intention. This suggests that enhancements in job satisfaction can be expected to reduce physicians' intentions to quit by the intermediary role of burnout as well as the direct path. It is hoped that these findings will offer some clues for health-sector managers to keep their physician resource motivated and stable.</p