TWEAK/Fn14 Signalling Regulates the Tissue Microenvironment in Chronic Pancreatitis.

Chronic pancreatitis increases the risk of developing pancreatic cancer through the upregulation of pathways favouring proliferation, fibrosis, and sustained inflammation. We established in previous studies that the ligand tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signals through its cognate receptor fibroblast growth factor-inducible 14 (Fn14) to regulate these underlying cellular processes in the chronic liver injury niche. However, the role of the TWEAK/Fn14 signalling pathway in pancreatic disease is entirely unknown. An analysis of publicly available datasets demonstrated that the TWEAK receptor Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, with single cell RNA sequencing revealing pancreatic ductal cells as the main Fn14 producers. We then used choline-deficient, ethionine-supplemented (CDE) diet feeding of wildtype C57BL/6J and Fn14 knockout littermates to (a) confirm CDE treatment as a suitable model of chronic pancreatitis and (b) to investigate the role of the TWEAK/Fn14 signalling pathway in pancreatic ductal proliferation, as well as fibrotic and inflammatory cell dynamics. Our time course data obtained at three days, three months, and six months of CDE treatment reveal that a lack of TWEAK/Fn14 signalling significantly inhibits the establishment and progression of the tissue microenvironment in CDE-induced chronic pancreatitis, thus proposing the TWEAK/Fn14 pathway as a novel therapeutic target.

Training undergraduate students for rapid on-site evaluation of fine needle aspiration cytology samples using a simulation-based education activity.

INTRODUCTION: Demand for rapid on-site evaluation (ROSE) of fine needle aspiration (FNA) cytology is rising and the role is increasingly being performed by non-medical cytologists. Undergraduate training for cytologists has traditionally focused on laboratory-based procedural activities and their theoretical underpinning, with minimal attention given to communication and other skills required to operate in an interprofessional setting. We evaluated the effectiveness and student reaction to a simulation-based education (SBE) exercise in ROSE designed to fill this void. METHODS: We designed and evaluated an SBE exercise based on FNA ROSE across two tertiary institutions with 79 students. The exercise accurately reproduced the demands on cytologists operating as part of a multi-disciplinary team in a time- pressured environment. FINDINGS: Pre- and post-simulation questionnaires indicated an improvement in technical knowledge related to the procedure. Students' perception of their competence and confidence in their role also improved significantly post simulation. Students uniformly found the exercise engaging and a valuable addition to their curriculum. DISCUSSION: The simulation successfully provided a pseudo-clinical environment that highlighted the realities of practising technical and diagnostic tasks under time pressure and interacting with other health professionals to provide an optimal patient outcome. The exercise is a useful supplement to on-the-job training for ROSE.

Septic arthritis caused by Desulfovibrio desulfuricans: A case report and review of the literature.

Septic arthritis can occur by hematogenous seeding, direct joint inoculation, or extension of a bone infection into the joint. We report a case of septic arthritis of the hip caused by Desulfovibrio desulfuricans, an anaerobic sulfur-reducing bacteria. The patient underwent debridement followed by targeted antibiotic therapy with infection resolution.

Designing authentic simulations in ROSE and EBUS for undergraduate laboratory medicine students.

Introduction: Simulation-based education (SBE) has successfully been implemented in several healthcare professions, more so in the fields of medicine and nursing. Laboratory medicine courses prepare medical scientists for employment in pathology laboratories typically via a staged training regime. Laboratory techniques related to the diagnostic disciplines are introduced to students in a graduated fashion over time for the development of professional skills and technical competencies. For students specialising in diagnostic cytology, there are continual changes to the scope of practice of scientists in industry that require advanced training at undergraduate level to meet expectations of contemporary laboratory testing. Methods: The National Health Education and Training in Simulation (NHET-Sim) framework was applied to create and deliver bespoke simulations for laboratory medicine students. This paper outlines the steps taken, including working with actors and industry partners, to create simulations which contextualise the pressures and team interactions during diagnostic procedures. Findings: Supported by a range of expertise and personnel, five laboratory medicine simulations were developed and delivered to final year students. Details of the steps taken and range of scenarios are included for sharing and discussion. Discussion: SBE can contribute positively to student confidence in communication at interdisciplinary and interprofessional levels in ways that can be essential to successful patient management. Understanding that cytology has now evolved to become part of a multidisciplinary approach to patient-centred care will improve the overall patient outcome and experience to personalised medicine. Conclusion: This paper demonstrates how a high-fidelity SBE scenario can test students' decision-making around technical, clinical and diagnostic competencies in a complex investigation that they would likely experience in industry.

Trochanteric Bursa Is a Source of Connective Tissue Progenitor Cells.

PURPOSE: To investigate the presence of connective tissue progenitor cells (CTPs) in the trochanteric bursa harvested over the gluteus medius muscle belly and tendon during open hip procedures. METHODS: Trochanteric bursa samples from nine patients (63.1 ± 8.6 years) undergoing total hip arthroplasty for primary osteoarthritis were obtained from 2 sites: over the gluteus medius tendon at the greater trochanter and over the muscle belly. Bursal tissue was digested with collagenase and grown in culture. The nucleated cell count, cellular concentration, cellular proliferation, fluorescence-activated cell sorting (FACS) analysis, and differentiation using immunostaining and quantitative polymerase chain reaction (PCR) were used to determine and quantify the presence of CTPs. RESULTS: Bursa-derived CTPs were identified in all harvested samples. At t = 0, there was no difference in nucleated cell count over muscle and tendon (1.69 ± 1.26 × 108 and 1.41 ± 1.12 × 108 cells/g, respectively; P = .162). Similarly, the cellular concentration at 3 weeks was not significantly different between bursa harvested over muscle and tendon (6.61 ± 5.14 × 106 and 5.58 ± 4.70 × 106 cells/g, respectively; P = .532). High cellular proliferation was identified for both bursal tissue overlying muscle and tendon (2.28 ± .95 and 1.66 ± 1.05, respectively; P = .194). FACS analysis revealed high positivity rates (>95%) of CTP-specific surface epitopes (CD105, CD90, and CD73) and low positivity rates (<1.3%) of negative markers (CD45, CD31). Osteogenic, adipogenic, and chondrogenic differentiation potential was demonstrated with immunostaining and quantitative PCR for gene expression. CONCLUSIONS: Connective tissue progenitor cells are found in the trochanteric bursa overlying the muscle and tendon of the hip abductors. CLINICAL RELEVANCE: During open hip procedures, the trochanteric bursa is often partially excised to identify muscular boundaries and tissue planes for surgical exposure. The function of the trochanteric bursa remains largely unknown. However, this tissue is a source of connective tissue progenitor cells, which may be important in the healing response of surgically repaired abductor tendons.

Evaluating the Effects of Platelet-Rich Plasma and Amniotic Viscous Fluid on Inflammatory Markers in a Human Coculture Model for Osteoarthritis.

PURPOSE: To assess the anti-inflammatory effects of platelet-rich plasma (PRP) and amniotic viscous fluid using a human coculture system of cartilage and synovial tissue from osteoarthritic patients. METHODS: A coculture system was created using cartilage and synovium from 3 patients undergoing total knee arthroplasty. To induce inflammation, interleukin-1ß was added to each coculture. Biologic agents tested included 2 PRP concentrations (PRPL and PRPH) and 2 different samples of amniotic viscous fluid (Amnion and Flograft). Amnion was also tested with PRP to check for any additive effects. Quantitative polymerase chain reaction was used to measure gene expression of factors involved in osteoarthritis, including disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), tissue inhibitor of metalloproteinases 1 (TIMP-1), vascular endothelial growth factor (VEGF), aggrecan, type 1 collagen, and nitric oxide, at 0, 24, 48, and 72 hours. A synthetic nonsteroidal medication, Ketorolac, was used for baseline comparison to the biologic agents. RESULTS: When comparing from time 0, both Amnion and Flograft resulted in significant decreases of ADAMTS-5 and TIMP-1 gene expression in cartilage and synovium for up to 72 hours. Both amniotic preparations increased collagen-1 gene expression in cartilage and decreased VEGF expression in synovium. Amnion was not found to have any effect on nitric oxide concentration at any time point (P > .05), as opposed to both PRP concentrations (P < .05). All biologic agents showed differences in gene expression similar to Ketorolac in ADAMTS-5, TIMP-1, and VEGF expression. CONCLUSION: This study found that amniotic fluid had anti-inflammatory effects mostly similar to those of both PRPH and PRPL; however, no significant additive effects in reducing inflammatory gene expression were found when combining biologic agents. CLINICAL RELEVANCE: PRP and amniotic fluid may provide alternative treatment options to delay the progression of the disease without the systemic and intra-articular side effects of corticosteroids.

Psychological Distress Independently Predicts Prolonged Hospitalization After Primary Total Hip and Knee Arthroplasty.

BACKGROUND: The purpose of this study was to investigate the effect of psychological distress on hospital length of stay (LOS) in joint arthroplasty (TJA). METHODS: A retrospective review of 863 patients who underwent primary, unilateral TJA at a single tertiary academic center was performed. Two groups were compared: patients with or without psychological distress defined using the Short Form-12 mental component summary. The primary outcome was the rate of hospital LOS exceeding 2 days. Secondary outcomes were rates of in-hospital complications and 90-day emergency room visits and readmissions. Univariate and multivariate logistic regression analyses were performed. RESULTS: The prevalence of psychological distress was 23%. The mean LOS was 2.44 days. Patients with psychological distress were younger (P < .0001) and more likely to have depression (P < .0001), lower educational attainment (P < .0001), smoke tobacco (P = .003), be Hispanic/Latino (P = .001), live alone (P = .001), and have higher rates of nonprimary osteoarthritis (P < .0001). After adjusting for these differences, psychological distress was an independent predictor of LOS > 2 days (P = .049 and .006 for total hip arthroplasty [THA] and total knee arthroplasty [TKA], respectively). There were no differences in the rates of in-hospital complications (P = .913 and .782 for THA and TKA, respectively), emergency room visits (P = .467 and .355 for THA and TKA respectively), or readmissions (P = .118 and .334 for THA and TKA, respectively). CONCLUSION: Psychological distress is an independent predictor of prolonged hospitalization after primary TJA. The Short Form-12 mental component summary is a good screening tool for identifying patients with poor mental health who may not be appropriate candidates for outpatient surgery. Efforts to address psychological distress before surgery are warranted.

The Effect of Payer Type on Patient-Reported Outcomes in Total Joint Arthroplasty Is Modulated by Baseline Patient Characteristics.

BACKGROUND: Patient-reported outcomes (PROs) are gaining an important role in the assessment of quality of care. There are currently limited data on the effect of payer type on PROs in total joint arthroplasty (TJA). This study compared both disease-specific and general health PROs among patients stratified according to their payer type. METHODS: Our institutional joint registry was queried for patients who underwent primary, elective, and unilateral hip and knee arthroplasty. Patients were divided according to their insurance type at the time of surgery into 3 groups: Medicaid, Medicare, or commercial. The outcomes assessed were the net changes in PROs as well as absolute scores at 6 months and 1 year. Six of the most commonly used PROs were assessed: Short Form-12 physical and mental components, Western Ontario and McMaster Universities Osteoarthritis Index, Single Assessment Numerical Evaluation, University of Californian Los Angeles activity level rating, and Oxford Hip Score. Analysis of variance and covariance were used. RESULTS: We evaluated 756 procedures (273 Medicaid, 270 Medicare, and 213 commercial insurance). Medicaid patients had significantly lower mean baseline scores across all PROs compared to either Medicare or commercial insurance patients. Medicaid patients were also more likely to be smokers, live alone, have lower educational level, African-American, and have nonprimary osteoarthritis as the indication for TJA. At 1-year follow-up, the net mean outcome gains were comparable among the 3 payer types (P > .05), but Medicaid patients continued to score lower while Medicare and commercial insurance patients continued to score higher (P < .01). When adjusting for all baseline differences among Medicaid patients, the negative effects of payer type resolved except for Oxford Hip Score which remained lower in the Medicaid group (P = .006). CONCLUSION: When using PROs to assess the value of care, the preoperative to postoperative changes are a better indicator of surgical success than comparing absolute values, especially in Medicaid patients. While TJA imparts similar net improvements to patients of all payer types, Medicaid coverage is a predictor of lower absolute outcome scores at any given time as result of increased baseline health burden (eg, depression, tobacco smoking, and poor overall well-being). Arthroplasty surgeons should be aware of these factors when counseling patients and seek optimization when necessary. The findings should be taken into account by stakeholders when constructing value-based payment models. Further research is needed to better understand the barriers leading to higher prevalence of increased health disparities among Medicaid beneficiaries and how to effectively address them.

Patient Dissatisfaction After Primary Total Joint Arthroplasty: The Patient Perspective.

BACKGROUND: Despite improvements in surgical technique and implant longevity, some patients continue to report dissatisfaction after total joint arthroplasty (TJA). As patient satisfaction is increasingly used as a quality metric, the objective of this study was to gain better understanding of satisfaction with total joint arthroplasty from the patient perspective. METHODS: Five hundred fifty-one primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) with a minimum of 1-year follow-up and were responsive to a satisfaction survey were analyzed. The incidence, predictive factors, and subjective reasoning for patient dissatisfaction were assessed. Univariate and multivariate logistic regression analyses were performed. RESULTS: Patient satisfaction was 89% for THA and 88% for TKA. Hispanic race was the most significant predictor of dissatisfaction (P = .037). The most common reasons for dissatisfaction after THA were persistent pain (N = 14/34, 41%), functional limitation (N = 12/34, 35%), surgical complication and reoperation (N = 4/34, 12%), staff or quality of care issues (N = 2/34, 6%), and slow recovery (N = 2/34, 6%). The most common reasons for dissatisfaction after TKA were persistent pain (N = 19/46, 41%), functional limitation (N = 12/46, 26%), surgical complication and reoperation (N = 8/46, 17%), staff or quality of care issues (N = 5/46, 11%), and unmet expectations (N = 2/46, 4%). CONCLUSION: While persistent pain and functional limitation are the 2 leading reasons for dissatisfaction in both TKA and THA, a subset of patients view satisfaction as an evaluation of the process by which care is delivered. Patient satisfaction is not solely a reflection of surgical outcome and should be interpreted with caution. Potential for incomplete pain relief or full functional recovery should be discussed during preoperative counseling. Empathic care is also important and should be encouraged to enhance the overall patient experience.

Tobacco Smoking Independently Predicts Lower Patient-Reported Outcomes: New Insights on a Forgotten Epidemic.

BACKGROUND: Although smoking is a well-accepted risk factor for surgical complications, the effect of smoking on patient-reported outcomes (PROs) has not been previously investigated. Prompted by an increasingly value-conscious healthcare environment, the purpose of this study is to investigate the association between smoking and PROs in total joint arthroplasty (TJA). METHODS: A retrospective review of 713 primary total hip and knee replacements was performed. Two cohorts were compared: (1) current smokers and (2) previous/never smokers at the time of TJA. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Short Form-12 Physical Composite Summary (SF-12 PCS) and Short Form-12 Mental Composite Summary were assessed preoperatively and again at 6 and 12 months postoperatively. The primary outcomes were the net changes and absolute outcome scores at final follow-up. Postoperative patient satisfaction was also assessed as a secondary outcome. Linear mixed-effects regression analysis was performed. RESULTS: There were significant demographic and preoperative health disparities as measured by PROs among smokers. After adjusting for baseline differences, smokers achieved significantly lower improvements in WOMAC (P = .002) and SF-12 PCS (P = .03) compared to nonsmokers. For each unit increase in packs per day smoked, the WOMAC scores increased (worsened) by 7.7 points (P = .003) and SF-12 PCS decreased by 4.8 points (P = .001). At final follow up, nonsmokers had significantly better absolute scores for all outcomes (except for mental health) and were more likely to be satisfied with surgery (89% vs 82%, P = .052). CONCLUSION: Tobacco smoking is an independent predictor for lower PROs after TJA and this relationship is dose-dependent. The negative impact of smoking does not appear to be related to impaired psychological health. As we transition to value-based care delivery models, this study provides further evidence that smoking cessation should be strongly recommended as a modifiable risk factor before embarking on elective TJA. Studies are still needed to define the optimal window for smoking cessation.

The Most Significant Risk Factors for Urinary Retention in Fast-track Total Joint Arthroplasty are Iatrogenic.

BACKGROUND: Postoperative urinary retention (POUR) remains a common complication after total joint arthroplasty (TJA). The objective of this study was to determine the incidence and risk factors for POUR in fast-track TJA emphasizing rapid mobilization, multimodal analgesia, and shorter hospital stay. METHODS: Our institutional joint registry was queried for patients who underwent primary TJA between January 2016 and November 2017. The primary outcome was the development of POUR. A panel of demographic, intraoperative, and postoperative variables was investigated. Multivariable regression analyses were performed to control for possible confounding factors. RESULTS: One hundred eighty-seven patients who underwent total hip arthroplasty (THA) and 191 patients who underwent total knee arthroplasty (TKA) were included in the study. Forty percent of TKA and 36% of THA patients developed POUR requiring bladder catheterization. Among THA patients, POUR was significantly associated with age >60 years, intraoperative fluid volume >1350 mL, and intraoperative placement of an indwelling bladder catheter (P = .016, P = .035, and P < .001, respectively). Among TKA patients, POUR was only significantly associated with intraoperative indwelling bladder catheter placement (P < .001). CONCLUSION: The most significant risk factors for POUR in modern-day fast-track TJA are iatrogenic. Routine intraoperative placement of an indwelling bladder catheter and fluid administration exceeding 1350 mL, especially in patients older than 60 years, are discouraged.

An unusual case of pigmented villonodular synovitis after total knee arthroplasty presenting with recurrent hemarthrosis.

Pigmented villonodular synovitis (PVNS) is a benign proliferative joint disease, which is a rare finding after total knee arthroplasty (TKA). There is currently no link between PVNS and TKA, and it has been described infrequently in the literature. Its presentation has varied along with the time that it presents postoperatively. We describe a case of a patient who presents with recurrent hemarthrosis 4 years after TKA. The patient had no previous history of PVNS and had an arthroscopy 1 year after the index operation with no evidence of synovitis. We present details of the first case with a review of imaging and pathology and a brief review of the literature on PVNS occurring after TKA.

The Effect of Depression on Patient-Reported Outcomes After Total Joint Arthroplasty Is Modulated by Baseline Mental Health: A Registry Study.

BACKGROUND: Depression and poor mental health are known to be negative predictors of patient-reported outcomes after total joint arthroplasty. Although previous studies have examined these risk factors in isolation to each other, they are, in reality, closely related, and yet each represents a different aspect of one's psychological well-being. The objective of this study was to investigate the association between depression and patient-reported outcomes, taking into account patients' baseline mental health. METHODS: Our prospective, institutional joint registry was queried for patients who had undergone primary elective total joint arthroplasty and had a minimum follow-up of 1 year. Baseline mental health was measured by the Short Form-12 Mental Component Summary (SF-12 MCS). Four cohorts were analyzed on the basis of the presence or absence of depression and patients' SF-12 MCS scores at the time of the surgical procedure, which were categorized as either poor or good on the basis of previously defined cutoffs. The primary outcomes were the net changes in SF-12 MCS, SF-12 Physical Component Summary (PCS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at 4 and 12 months postoperatively. Univariate and mixed-effects model analyses were performed to control for potential confounding factors. RESULTS: Patients with depression but good baseline mental health achieved gains in patient-reported outcomes that were comparable with those of normal controls (p > 0.05). Patients with poor baseline mental health achieved significant gains in all patient-reported outcomes, but the changes were largest for those without depression (p < 0.05). Only patients with depression and poor baseline mental health did not cross the threshold for good mental health at the time of the latest follow-up despite achieving similar gains in physical function compared with their counterparts who did not have depression. CONCLUSIONS: The effect of depression on patient-reported outcomes is more complex but less pessimistic than previously thought. Patients with depression undergoing total joint arthroplasty may have significant improvements in their patient-reported outcomes, but the net gains are modulated by their mental health at the time of the surgical procedure. Preoperative screening of patients with depression using the SF-12 MCS may help to identify those who are at risk for attaining suboptimal patient-reported outcomes and may benefit from counseling or psychiatric referral for optimization before undergoing a surgical procedure. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

A review of the importance of immune responses in luminal B breast cancer.

Historically, the immune environment was not considered an important target for breast cancer treatment. However, the association of lymphocytic infiltrates in triple negative and HER-2 over-amplified breast cancer subtypes with better outcomes, has provoked interest in evaluating the role of the immune system in the luminal B subtype that accounts for 39% of breast cancers and has a poor patient prognosis. It is unknown which immunosuppressive cell types or molecules (e.g., checkpoint molecules) are relevant, or where measurement is most informative. We hypothesize that a profound immunosuppressive tumor and/or lymph node milieu is prognostic and impacts on responses to therapies.

Mammary Gland Pathology Subsequent to Acute Infection with Strong versus Weak Biofilm Forming Staphylococcus aureus Bovine Mastitis Isolates: A Pilot Study Using Non-Invasive Mouse Mastitis Model.

BACKGROUND: Biofilm formation by Staphylococcus aureus is an important virulence attribute because of its potential to induce persistent antibiotic resistance, retard phagocytosis and either attenuate or promote inflammation, depending upon the disease syndrome, in vivo. This study was undertaken to evaluate the potential significance of strength of biofilm formation by clinical bovine mastitis-associated S. aureus in mammary tissue damage by using a mouse mastitis model. METHODS: Two S. aureus strains of the same capsular phenotype with different biofilm forming strengths were used to non-invasively infect mammary glands of lactating mice. Biofilm forming potential of these strains were determined by tissue culture plate method, ica typing and virulence gene profile per detection by PCR. Delivery of the infectious dose of S. aureus was directly through the teat lactiferous duct without invasive scraping of the teat surface. Both bacteriological and histological methods were used for analysis of mammary gland pathology of mice post-infection. RESULTS: Histopathological analysis of the infected mammary glands revealed that mice inoculated with the strong biofilm forming S. aureus strain produced marked acute mastitic lesions, showing profuse infiltration predominantly with neutrophils, with evidence of necrosis in the affected mammary glands. In contrast, the damage was significantly less severe in mammary glands of mice infected with the weak biofilm-forming S. aureus strain. Although both IL-1ß and TNF-α inflammatory biomarkers were produced in infected mice, level of TNF-α produced was significantly higher (p<0.05) in mice inoculated with strong biofilm forming S. aureus than the weak biofilm forming strain. CONCLUSION: This finding suggests an important role of TNF-α in mammary gland pathology post-infection with strong biofilm-forming S. aureus in the acute mouse mastitis model, and offers an opportunity for the development of novel strategies for reduction of mammary tissue damage, with or without use of antimicrobials and/or anti-inflammatory compounds for the treatment of bovine mastitis.

Risk of persistent and recurrent cervical neoplasia following incidentally detected adenocarcinoma in situ.

BACKGROUND: Adenocarcinoma in situ of the uterine cervix is a precursor to cervical adenocarcinoma and may coexist with both adenocarcinoma and high-grade squamous dysplasia (cervical intraepithelial neoplasia 2 and 3). Up to 60% of adenocarcinoma in situ lesions are detected incidentally following excisional biopsies performed for the treatment of cervical intraepithelial neoplasia 2/3. To date there are no data regarding risk factors for persisting or progressive cervical neoplasia in these patients. OBJECTIVE: We sought to investigate patient outcomes following incidentally detected cervical adenocarcinoma in situ after loop electrosurgical excision procedure or cold knife cone biopsy performed for the treatment of high-grade cervical intraepithelial neoplasia. STUDY DESIGN: We conducted a retrospective, population-based cohort study of Western Australian patients with an incidental diagnosis of adenocarcinoma in situ from 2001 through 2012. Primary outcomes were persistent or recurrent cervical intraepithelial neoplasia 2/3 and or adenocarcinoma in situ, and invasive adenocarcinoma during follow-up (<12 months) and surveillance (≥12 months) periods. RESULTS: The cohort comprised 298 patients, with 228 (76.5%) treated initially by loop electrosurgical excision procedure and 70 (23.5%) treated by cold knife cone biopsy. The mean age was 31.2 (range 18-68) years and the median length of follow-up was 2.4 (range 0.3-12.2) years. Overall, 11 (3.7%) patients had cervical intraepithelial neoplasia 2/3, 23 (7.7%) had adenocarcinoma in situ, and 3 (1.0%) had adenocarcinoma diagnosed during the follow-up and surveillance periods. Age >30 years, pure adenocarcinoma in situ lesions, and larger lesions (>8 mm) were associated with a greater risk of disease persistence or recurrence. CONCLUSION: Following the incidental detection of adenocarcinoma in situ, age >30 years, pure adenocarcinoma in situ lesions, and lesions >8 mm were significantly associated with disease persistence/recurrence. In younger women, incidentally detected adenocarcinoma in situ that coexists with cervical intraepithelial neoplasia 2/3 and is <8 mm extent with clear margins may not require reexcision.

Intramammary Immunization of Pregnant Mice with Staphylococcal Protein A Reduces the Post-Challenge Mammary Gland Bacterial Load but Not Pathology.

Protein A, encoded by the spa gene, is one of the major immune evading MSCRAMM of S. aureus, demonstrated to be prevalent in a significant percentage of clinical bovine mastitis isolates in Australia. Given its' reported significance in biofilm formation and the superior performance of S. aureus biofilm versus planktonic vaccine in the mouse mastitis model, it was of interest to determine the immunogenicity and protective potential of Protein A as a potential vaccine candidate against bovine mastitis using the mouse mastitis model. Pregnant Balb/c mice were immunised with Protein A emulsified in an alum-based adjuvant by subcutaneous (s/c) or intramammary (i/mam) routes. While humoral immune response of mice post-immunization were determined using indirect ELISA, cell-mediated immune response was assessed by estimation of interferon-gamma (IFN-γ) produced by protein A-stimulated splenocyte supernatants. Protective potential of Protein A against experimental mastitis was determined by challenge of immunized versus sham-vaccinated mice by i/mam route, based upon manifestation of clinical symptoms, total bacterial load and histopathological damage to mammary glands. Significantly (p<0.05) higher levels of IgG1 isotype were produced in mice immunized by the s/c route. In contrast, significantly higher levels of the antibody isotype IgG2a were produced in mice immunized by the i/mam route (p<0.05). There was significant reduction (p<0.05) in bacterial loads of the mammary glands of mice immunized by Protein A regardless of the route of immunization, with medium level of clinical symptoms observed up to day 3 post-challenge. However, Protein A vaccine failed to protect immunized mice post-challenge with biofilm producing encapsulated S. aureus via i/mam route, regardless of the route of immunization, as measured by the level of mammary tissue damage. It was concluded that, Protein A in its' native state was apparently not a suitable candidate for inclusion in a cell-free vaccine formulation against mastitis.

Spontaneous regression of CIN2 in women aged 18-24 years: a retrospective study of a state-wide population in Western Australia.

INTRODUCTION: CIN2 has a high rate of spontaneous regression in young women and may be managed conservatively in appropriately selected patients. This study aimed to investigate health outcomes in women aged 18-24 years with biopsy-confirmed CIN2. MATERIAL AND METHODS: A retrospective cohort study of Western Australian women aged 18-24 years diagnosed with CIN2 on cervical biopsy from 1 January 2001 to 31 December 2010. Women who had not received treatment at ≥4 months following CIN2 diagnosis were classified as managed 'conservatively'. Subsequent cervical cytology and/or biopsy test results were used to report lesion regression (absence of dysplasia or an epithelial lesion of lower grade than CIN2) and disease persistence (CIN2, CIN3 or ACIS). RESULTS: Follow-up data were available for 2417 women of whom 924 (38.2%) were 'conservatively' managed. In all, 152 (16.4%) conservatively managed women had a lesion more severe than CIN2 detected within 24 months of initial diagnosis, of which 144 were CIN3 and eight were ACIS. There was no statistically significant association between rates of regression and patient age, Socio-economic Indexes for Areas or Accessibility/Remoteness Index of Australia indices. The 2-year regression rate for CIN2 was estimated to be 59.5% (95%CI 0.5-0.6) in this cohort of women. CONCLUSION: In conservatively managed young women with CIN2 there was a high rate of spontaneous disease regression. Thus, excisional or ablative treatments may be avoided in selected patients who receive appropriate counseling and who are able to comply with more intensive and prolonged follow-up requirements.

Comparative studies of the immunogenicity and protective potential of biofilm vs planktonic Staphylococcus aureus vaccine against bovine mastitis using non-invasive mouse mastitis as a model system.

This study was undertaken to compare the immunogenicity and protective potential of biofilm vs planktonic Staphylococcus aureus vaccine for the prevention of mastitis using the mouse as a model system. Mice immunized with formalin-killed whole cell vaccine of S. aureus residing in a biofilm when delivered via an intramammary route produced a cell mediated immune response. Mice immunized with this biofilm vaccine showed significant reductions in colonization by S. aureus in mammary glands, severity of clinical symptoms and tissue damage in mammary glands in comparison with the mice immunized with formalin-killed whole cells of planktonic S. aureus. The planktonic vaccine administered by a subcutaneous route produced a significantly higher humoral immune response (IgG1 and IgG) than the biofilm vaccine. However, considering the host response, tissue damage, the clinical severity and colonization of S. aureus in mammary glands, the biofilm vaccine performed better in immunogenicity and protective potential when administered by the intramammary route.

Risk of high-grade cervical dysplasia and gynaecological malignancies following the cytologic diagnosis of atypical endocervical cells of undetermined significance: a retrospective study of a state-wide screening population in Western Australia.

BACKGROUND: In 2006, Australia adopted a revised cervical cytology terminology system, known as the Australian Modified Bethesda System (AMBS). One substantial change in the AMBS was the introduction of the diagnostic category of atypical endocervical cells (AEC) of undetermined significance. AIM: The aim of this study was to investigate the incidence of histologically confirmed high-grade cervical dysplasia (cervical intra-epithelial neoplasia (CIN) grades 2 and 3 and adenocarcinoma in situ (ACIS)), cervical carcinoma and endometrial carcinoma in women presenting with AEC on cervical cytology. METHODS: A seven-year retrospective study examining clinical outcomes of women with AEC on a screening cervical smear. Cytology and histology results were extracted from the Western Australia Cervical Screening Registry, and time-to-event analysis was used to predict the odds of having or developing in situ and invasive neoplasia. RESULTS: AEC was reported in index smears from 0.093% (584/622754) women during the study period. No follow-up was available in 35 AEC cases. Sixty-five of the remaining 549 women (11.8%) had, or developed, high-grade cervical dysplasia within five years of their index AEC diagnosis. Endometrial cancer was diagnosed in 21 women and cervical cancer in four women during the follow-up period. CONCLUSION: Cytologic demonstration of AEC requires careful gynaecologic evaluation, particularly in younger women who may be found to have either high-grade squamous (CIN) or glandular (ACIS) lesions, while in older women, the possibility of endometrial neoplasia needs to be considered.