Retention: An unresolved workforce issue affecting rural occupational therapy services

Failure to retain health professionals in rural areas contributes to the poor health status of these communities through an inability to deliver reliable and consistent services. Considerable attention has been focused on factors affecting recruitment of health professionals. Far less is known about factors affecting the retention of occupational therapists. This was the focus of this study. Ethnographic interviews were used to explore the experiences of 10 occupational therapists who had left rural practice. Six themes emerged from the participants' experiences, from when they first considered rural practice to reflections following their departure from it. These themes were initial appeal, facing the challenge, rural practice issues, the social sphere, reasons for leaving and the value of rural experience. These factors gave rise to a proposed Model of Retention Equilibrium, which suggests that retention can be improved by addressing the imbalance between incentives to leave and incentives to stay. The model provides a useful framework for occupational therapists contemplating rural practice, as well as for health services managers responsible for service delivery in rural areas.     

Zinc is a voltage-dependent blocker of native and heterologously expressed epithelial Na+ channels

Zn(2+) (1-1,000 microM) applied to the apical side of polarized A6 epithelia inhibits Na(+) transport, as reflected in short-circuit current and conductance measurements. The Menten equilibrium constant for Zn(2+) inhibition was 45 microM. Varying the apical Na(+) concentration, we determined the equilibrium constant of the short-circuit current saturation (34.9 mM) and showed that Zn(2+) inhibition is non-competitive. A similar effect was observed in Xenopus oocytes expressing alphabetagammarENaC (alpha-, beta-, and gamma-subunits of the rat epithelial Na(+) channel) in the concentration range of 1-10 microM Zn(2+), while at 100 microM Zn(2+) exerted a stimulatory effect. The analysis of the voltage dependence of the steady-state conductance revealed that the inhibitory effect of Zn(2+) was due mainly to a direct pore block and not to a change in surface potential. The equivalent gating charge of ENaC, emerging from these data, was 0.79 elementary charges, and was not influenced by Zn(2+). The stimulatory effect of high Zn(2+) concentrations could be reproduced by intra-oocyte injection of Zn(2+) (approximately 10 microM), which had no direct effect on the amiloride-sensitive conductance, but switched the effect of extracellular Zn(2+) from inhibition to activation.     

Contribution of the alanine-rich region of Streptococcus mutans P1 to antigenicity, surface expression, and interaction with the proline-rich repeat domain

Streptococcus mutans is considered to be the major etiologic agent of human dental caries. Attachment of S. mutans to the tooth surface is required for the development of caries and is mediated, in part, by the 185-kDa surface protein variously known as antigen I/II, PAc, and P1. Such proteins are expressed by nearly all species of oral streptococci. Characteristics of P1 include an alanine-rich repeat region and a centrally located proline-rich repeat region. The proline-rich region of P1 has been shown to be important for the translational stability and translocation of P1 through the bacterial membrane. We show here that (i) several anti-P1 monoclonal antibodies require the simultaneous presence of the alanine-rich and proline-rich regions for binding, (ii) the proline-rich region of P1 interacts with the alanine-rich region, (iii) like the proline-rich region, the alanine-rich region is required for the stability and translocation of P1, (iv) both the proline-rich and alanine-rich regions are required for secretion of P1 in Escherichia coli, and (v) in E. coli, P1 is secreted in the absence of SecB.     

Peptides derived from the whole sequence of BCR-ABL bind to several class I molecules allowing specific induction of human cytotoxic T lymphocytes

Chronic myeloid leukemia (CML) is characterized cytogenetically by a t(9;22) translocation which generates a hybrid bcr-abl gene, encoding a p210^bcr-abl fusion protein. The induction in vitro of leukemia-specific T cells reactive with p210^bcr-abl is a strategy developed for an immunological therapeutic approach in CML. Peptides from the junction region of this chimeric protein have been considered as potential targets for a cytotoxic response against leukemic cells. However, only a few peptides encompassing the two p210^bcr-abl breakpoints have been shown to bind to the most common HLA class I molecules, which limits the number of patients who could benefit from this approach. We assume that the presence of chimeric BCR-ABL protein in leukemic cells may affect processing and delivery of peptides, possibly giving rise to new epitopes at the cell surface. We selected 162 peptides from the whole sequence of this protein, including 14 peptides of the b2a2 and b3a2 junctions, which had an anchor motif for a common HLA class I molecule. We tested their ability to bind to eight HLA class I molecules (HLA-A1, -A2, -A3, -A11, -B7, -B8, -B27, -B44). We identified 48 peptides from outside the junction region, with intermediate or strong binding capacities to these HLA class I molecules contrasting with only six junction peptides with a moderate binding capacity to HLA-A3/A11, -B8, or -B44 molecules. Moreover, cytotoxic T lymphocyte lines specific for various peptides outside the junction were generated from peripheral blood mononuclear cells of HLA-A2 or -B7 healthy donors and from one CML patient. These results contribute to evaluation of immunity to the BCR-ABL chimeric protein. Further studies are required to investigate whether such epitopes are correctly processed and presented by leukemic cells.     

Somatic translocation and differential expression of Ig mu transgene copies implicate a role for the Igh locus in memory B cell development

Memory B cells of mice with Ig mu transgenes often carry transgene copies that have moved into the Igh locus via somatic translocation. This phenomenon has been attributed to a selection pressure for somatic hypermutations, which generally are observed at much higher frequencies in translocated copies than in ectopic copies. We tested this idea by immunizing Ig-mu transgenic mice in a manner designed to select B cells that required only one V(H) mutation for a switch in antigenic specificity and recruitment into the memory pool. Despite the minimal mutation requirement, hybridomas carrying somatic translocations to the Igh locus were obtained. Importantly, this occurred despite the fact that translocated and untranslocated mu-transgenes were mutated comparably. Evidently, a strong selection advantage was conferred upon B cells by the somatic translocations. Among the hybridomas, translocated mu-transgenes were active, while ectopic mu-transgenes were uniformly silent. The translocated copy that had conferred an affinity-based selection advantage was expressed at the highest level. Moreover, translocated copies were differentially expressed among hybridoma members, which belonged to a common post-mutational lineage. This suggests that adjustments in transgene expression levels had occurred during memory cell development. These results indicate that, apart from their potential influences on somatic hypermutagenesis and class switch recombination, elements in the Igh locus promote the selection of memory B cells in another way, possibly by regulating the level of Ig expression at various stages of antigen-driven differentiation.     

Association of social determinants of health with late diagnosis and survival of patients with pancreatic cancer

BackgroundPancreatic cancer disparities have been described. However, it is unknown if they contribute to a late diagnosis and survival of patients with metastatic disease. Identifying their role is important as it will open the door for interventions. We hypothesize that social determinants of health (SDH) such as income, education, race, and insurance status impact (I) stage of diagnosis of PC (Stage IV vs. other stages), and (II) overall survival (OS) in Stage IV patients.MethodsUsing the National Cancer Database, we evaluated a primary outcome of diagnosis of Stage IV PC and a secondary outcome of OS. Primary predictors included race, income, education, and insurance. Covariates included age, sex and Charlson-Deyo comorbidity score. Univariate, multivariable logistic regression models evaluated risk of a late diagnosis. Univariate, multivariable Cox proportional hazards model examined OS. 95% confidence intervals were used.Results230,877 patients were included, median age of 68 years (SD 12.1). In univariate analysis, a better education, higher income, and insurance decreased the odds of Stage IV PC, while Black race increased it. In multivariable analysis, education [>93% high-school completion (HSC) vs. <82.4%, OR 0.96 (0.93–0.99)] and insurance [private vs. no, OR 0.72 (0.67–0.74)] significantly decreased the risk of a late diagnosis, whereas Black race increased the odds [vs. White, OR 1.09 (1.07–1.12)]. In univariate Cox analysis, having a higher income, insurance and better education improved OS, while Black race worsened it. In multivariable Cox, higher income [>$63,333 (vs. <$40,277), HR 0.87 (0.85–0.89)] and insurance [private vs. no, HR 0.77 (0.74–0.79)] improved OS.ConclusionsSDH impacted the continuum of care for patients with advanced pancreatic cancer, including stage at diagnosis and overall survival.     

Snake venom C-type lectins interacting with platelet receptors. Structure–function relationships and effects on haemostasis

Snake venoms contain components that affect the prey either by neurotoxic or haemorrhagic effects. The latter category affect haemostasis either by inhibiting or activating platelets or coagulation factors. They fall into several types based upon structure and mode of action. A major class is the snake C-type lectins or C-type lectin-like family which shows a typical folding like that in classic C-type lectins such as the selectins and mannose-binding proteins. Those in snake venoms are mostly based on a heterodimeric structure with two subunits and β, which are often oligomerized to form larger molecules. Simple heterodimeric members of this family have been shown to inhibit platelet functions by binding to GPIb but others activate platelets via the same receptor. Some that act via GPIb do so by inducing von Willebrand factor to bind to it. Another series of snake C-type lectins activate platelets by binding to GPVI while yet another series uses the integrin ₂β₁ to affect platelet function. The structure of more and more of these C-type lectins have now been, and are being, determined, often together with their ligands, casting light on binding sites and mechanisms. In addition, it is relatively easy to model the structure of the C-type lectins if the primary structure is known. These studies have shown that these proteins are quite a complex group, often with more than one platelet receptor as ligand and although superficially some appear to act as inhibitors, in fact most function by inducing thrombocytopenia by various routes. The relationship between structure and function in this group of venom proteins will be discussed.     

Pharmacometabonomic association of cyclophosphamide 4‐hydroxylation in hematopoietic cell transplant recipients

The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug‐metabolizing enzymes that metabolize CY to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY’s cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY), and 24 h after the first dose of PT‐CY (24‐h post‐CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre‐CY time point, no EMCs were associated at FDR less than 0.1. At pre‐HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre‐graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24‐h post‐CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

We report the first pharmacometabonomic study of the association of plasma EMCs with cyclophosphamide pharmacokinetics, specifically the ratio of 4HCY/CY AUC.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addresses the question regarding if EMCs in the plasma before PT‐CY administration are associated with the ratio of 4HCY/CY AUC.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study adds to our knowledge that longitudinal collection of plasma EMC samples is feasible in HCT patients receiving PT‐CY. In addition, the plasma EMC changes over the ~21‐day time period that starts pre‐HCT to 24‐hr after the first PT‐CY dose.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study demonstrates the possibility of pharmacometabolomic research to evaluate the pharmacokinetics of a drug – in this case, cyclophosphamide – with a complex pharmacokinetic disposition.     

An interactive Internet site for the management of patients with congestive heart failure

BACKGROUND: The Internet is a useful tool for improving communication between patients and their health care providers. However, no study has examined an efficient use of the Internet to improve quality of care for these patients. The purpose of this pilot study is to determine the feasibility of using an Internet-based communication tool with heart failure patients and to assess the effect of this system on the patients' quality of life. METHODS AND RESULTS: A prospective study was conducted among patients (n=16) attending a university-based heart failure clinic. An Internet communication Web site (www.heartfunction.com) was developed for the pilot study. The system was designed to be an information resource for patients and a daily communication method between patients and health care providers. Quality of life scores based on the Minnesota Living with Heart Failure Questionnaire (MLHFQ) were obtained at baseline and at three months. The mean MLHFQ score was 59.75+/-1.5 at baseline and 49.87+/-1.3 at three months (P=0.093). Significant differences were found at three months in the scale items that measured relationships with friends and family (3.062 versus 2.06; P=0.03), working around the house and yard (3.68 versus 2.81; P=0.008) and side effects of medication (2.81 versus 1.93; P=0.048). All patients reported high levels of satisfaction with the Web site. CONCLUSIONS: Internet-based communication is a feasible tool for the management of heart failure patients, providing an effective medium through which health care professionals can interact with their patients. This approach may also improve patient quality of care and quality of life.