Search

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'IV: perspectives on practice--lenses of appreciation', authors address the following themes: 'Relational connections in the doctor-patient partnership', 'Feminism and family medicine', 'Positive family medicine', 'Mindful practice', 'The new, old ethics of family medicine', 'Public health, prevention and populations', 'Information mastery in family medicine' and 'Clinical courage.' May readers nurture their curiosity through these essays. [ABSTRACT FROM AUTHOR]

Introduction: Clinical courage can be described as a rural doctor's adaptability and willingness to undertake clinical work at the limits of their training and experience to meet the needs of their patients. This article describes the in-house development of survey items to include in a quantitative measure of clinical courage. Methods: The questionnaire development involved two key concepts: a second-order latent factor model structure and a nominal group technique, used to develop consensus among the research team members. Results: The steps taken to develop a sound clinical courage questionnaire are described in detail. The resulting initial questionnaire is presented, ready for testing with rural clinicians and refinement. Conclusion: This article outlines the psychometric process of questionnaire design and presents the resultant clinical courage questionnaire. [ABSTRACT FROM AUTHOR]

The protein kinases PAK4, PAK5 and PAK6 comprise a family of ohnologues. In multiple cancers including melanomas PAK5 most frequently carries non-synonymous mutations; PAK6 and PAK4 have fewer; and PAK4 is often amplified. To help interpret these genomic data, initially we compared the cellular regulation of the sister kinases and their roles in melanoma cells. In common with many ohnologue protein kinases, PAK4, PAK5 and PAK6 each have two 14-3-3-binding phosphosites of which phosphoSer99 is conserved. PAK4 localises to the leading edge of cells in response to phorbol ester-stimulated binding of 14-3-3 to phosphoSer99 and phosphoSer181, which are phosphorylated by two different PKCs or PKDs. These phosphorylations of PAK4 are essential for its phorbol ester-stimulated phosphorylation of downstream substrates. In contrast, 14-3-3 interacts with PAK5 in response to phorbol ester-stimulated phosphorylation of Ser99 and epidermal growth factor-stimulated phosphorylation of Ser288; whereas PAK6 docks onto 14-3-3 and is prevented from localising to cell-cell junctions when Ser133 is phosphorylated in response to cAMP-elevating agents via PKA and insulin-like growth factor 1 via PKB/Akt. Silencing of PAK4 impairs viability, migration and invasive behaviour of melanoma cells carrying BRAFV600E or NRASQ61K mutations. These defects are rescued by ectopic expression of PAK4, more so by a 14-3-3-binding deficient PAK4, and barely by PAK5 or PAK6. Together these genomic, biochemical and cellular data suggest that the oncogenic properties of PAK4 are regulated by PKC-PKD signalling in melanoma, while PAK5 and PAK6 are dispensable in this cancer. [ABSTRACT FROM AUTHOR]

The article focuses on an advice to a new Multidistrict Litigation (MDL) on discovery management. Topics include new plaintiff can complete and share with the defendants a Plaintiff Profile Form, discovery should focus on common-issue discovery such as production of relevant documents from the defendants and third parties, and establish a procedure for handling already-completed common discovery.

Abstract Background Emerging longitudinal data appear to demonstrate an alarming trend towards an increasing prevalence of osteolysis-induced mechanical failure, following total knee replacement (TKR). Even with high-quality multi-plane X-rays, accurate pre-surgical evaluation of osteolytic lesions is often difficult. This is likely to have an impact on surgical management and provides reasonable indication for the development of a model allowing more reliable lesion assessment. The aim of this study, using a simulated cadaver model, was to explore the accuracy of rapid spiral computed tomography (CT) examination in the non-invasive evaluation of peri-prosthetic osteolytic lesions, secondary to TKR, and to compare this to conventional X-ray standards. Methods A series of nine volume-occupying defects, simulating osteolytic lesions, were introduced into three human cadaveric knees, adjacent to the TKR implant components. With implants in situ, each knee was imaged using a two-stage conventional plain X-ray series and rapid-acquisition spiral CT. A beam-hardening artefact removal algorithm was employed to improve CT image quality. After random image sorting, 12 radiologists were independently shown the series of plain X-ray images and asked to note the presence, anatomic location and 'size' of osteolytic lesions observed. The same process was repeated separately for review of the CT images. The corresponding X-ray and CT responses were directly compared to elicit any difference in the ability to demonstrate the presence and size of osteolytic lesions. Results Access to CT images significantly improved the accuracy of recognition of peri-prosthetic osteolytic lesions when compared to AP and lateral projections alone (P = 0.008) and with the addition of bi-planar oblique X-rays (P = 0.03). No advantage was obtained in accuracy of identification of such lesions through the introduction of the oblique images when compared with the AP and lateral projections alone (P = 0.13) Conclusion The findings of this study suggest that peri-prosthetic osteolytic lesions can be reliably described non-invasively using a simple, rapid-acquisition CT-based imaging approach. The low sensitivity of conventional X-ray, even with provision of supplementary bi-planar 45° oblique views, suggests a limited role for use in situ for TKR implant screening where peri-prosthetic osteolytic lesions are clinically suspected. In contrast, the accuracy of CT evaluation, linked to its procedural ease and widespread availability, may provide a more accurate way of evaluating osteolysis around TKRs, at routine orthopaedic follow up. These findings have direct clinical relevance, as accurate early recognition and classification of such lesions influences the timing and aggressiveness of surgical and non-operative management strategies, and also the nature and appropriateness of planned implant revision or joint-salvaging osteotomy procedures.

Abstract Background Pim-1, 2 and 3 are a group of enzymes related to the calcium calmodulin family of protein kinases. Over-expression of Pim-1 and Pim-2 in mice promotes the development of lymphomas, and up-regulation of Pim expression has been observed in several human cancers. Results Here we show that the pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. In vitro mapping showed that Pim-2 predominantly phosphorylated Ser112, while Pim-1 phosphorylated Ser112, but also Ser136 and Ser155 at a reduced rate compared to Ser112. Pim-3 was found to be the least specific for Ser112, and the most effective at phosphorylating Ser136 and Ser155. Pim-3 was also able to phosphorylate other sites in Bad in vitro, including Ser170, another potential in vivo site. Mutation of Ser136 to alanine prevented the phosphorylation of Ser112 and Ser155 by Pim kinases in HEK-293 cells, suggesting that this site must be phosphorylated first in order to make the other sites accessible. Pim phosphorylation of Bad was also found to promote the 14-3-3 binding of Bad and block its association with Bcl-XL. Conclusion All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death.

Pentosan polysulphate sodium (PPS) is a promising therapeutic agent for blocking knee pain in individuals with knee osteoarthritis (KOA). The mode of action of PPS in this context is unknown. We hypothesised that the osteocyte, being the principal cell type in the sub-chondral bone, was capable of expressing the pain mediator Nerve Growth Factor (NGF), and that this may be altered in the presence of PPS. We tested the expression of NGF and the response to PPS in the presence or absence of the proinflammatory cytokine tumour necrosis factor-alpha (TNFα), in human osteocytes. For this we differentiated human primary osteoblasts grown from subchondral bone obtained at primary knee arthroplasty for KOA to an osteocyte-like stage over 28d. We also tested NGF expression in fresh osteocytes obtained by sequential digestion from KOA bone and by immunofluorescence in KOA bone sections. We demonstrate for the first time the production and secretion of NGF/proNGF by this cell type derived from patients with KOA, implicating osteocytes in the pain response in this pathological condition and possibly others. PPS inhibited TNFα-induced levels of proNGF secretion and TNFα induced NGF mRNA expression. Together, this provides evidence that PPS may act to suppress the release of NGF in the subchondral bone to ameliorate pain associated with knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Background and objectives The literature reveals a lack of consensus on recommendations for follow-up of skin cancer in general practice for all types of skin cancer. The objective of this paper was to evaluate post-treatment surveillance practices for both melanotic and non-melanotic skin cancers (NMSC) by general practitioners (GPs) in regional Victoria, and to identify challenges in follow-up for skin cancers in rural areas. Method A mixed-method study involving a survey and semi-structured interviews with GPs and registrars in Gippsland was carried out in 2015. Results The survey of 65 participants showed that 69% (45/65) followed up NMSC opportunistically, while 66% (43/65) reported using a structured follow-up practice for melanoma. Six practitioners from the interviews identified the patient's level of education, time constraints, practitioner accessibility and specialists' availability as some common challenges in follow-up. Discussion We recommend that rural GPs review follow-up strategies for all skin cancers, through the establishment of guidelines and a recall system. [ABSTRACT FROM AUTHOR]

Background: Total knee replacement (TKR) has been shown to perform differently in patients with rheumatoid arthritis (RA) when compared to osteoarthritis (OA). In this study, we compare the survivorship between these two groups and examine patient and prosthesis factors that impact the revision rate. Methods: All RA and OA patients undergoing TKR in Australia from 1 September 1999 to 31 December 2016 were included. Revision rates were assessed using Kaplan–Meier estimates of survivorship. The cumulative percent revision analysed age, gender, prosthesis constraint and revision for infection. Results: There were 541 744 TKR procedures performed including 7542 patients with RA. RA declined as the primary diagnosis from 2.4% of all TKR in 2003 to 0.9% in 2016. Male sex was an independent revision risk in RA patients (hazard ratio (HR) = 1.66, P < 0.001) and OA patients (3.5 years+: HR = 1.09 (1.04–1.15), P < 0.001). Male RA patients had a higher revision rate for infection than females (HR = 3.14, P < 0.001). Females with RA had a lower cumulative percent revision compared to OA females, but males showed no difference between diagnoses. Revision in RA patients was not influenced by age. Compared to OA, RA patients had a decreased revision rate for those aged <65 years, but not for patients aged ≥65 years. Conclusion: The rate of revision after TKR in RA patients is lower than those with OA, but patients with RA are at increased risk of infection, particularly the male group. Prosthesis constraint had no influence on revision rate. Mortality in those undergoing TKR with RA was higher than in those with OA. This study shows that the use of primary total knee replacement (TKR) for rheumatoid arthritis (RA) is declining. The rate of revision after TKR in RA patients is lower than those with osteoarthritis, but patients with RA are at increased risk of infection, particularly the male group. For patients diagnosed with RA undergoing TKR, the rate of revision varies with gender but not with age. [ABSTRACT FROM AUTHOR]