Efficient management of new patient referrals to a breast service: the safe introduction of an advanced nurse practitioner-led telephone breast pain service.

INTRODUCTION: There has been an almost 100% increase in referrals to breast cancer diagnostic clinics in the past decade. Breaching of the two-week cancer referral target is now commonplace, potentially delaying diagnoses of breast malignancy in many women. Almost one in five of these referrals are women with mastalgia, not a symptom linked to breast cancer. The objective of the study was the safe introduction of an advanced nurse practitioner-led telephone service for women with mastalgia to improve the service for women and create capacity for those with "red flag" breast symptoms. METHODS: Referrals to clinic were triaged, women with mastalgia only were directed to a telephone-based assessment clinic and symptoms evaluated using a multidisciplinary created proforma. RESULTS: Within 23 months, 1,427 women were assessed in the breast pain telephone assessment clinic: 863 (61%) were aged over 40 and 564 (39%) aged under 40. A total of 1,238 underwent telephone assessment. Reassurance and discharge only was needed for 365 (26%). The aetiology of pain was identified as musculoskeletal in 1,104/1,238 (89%) of patients, with only 39/1,238 (3.2%) identified as having true breast pain. Additional symptoms were mentioned by 264 women (18%) during the consultation; all immediately redirected back to a diagnostic clinic. Mammography was undertaken in 609 women (43%). Seven women (0.6%) were diagnosed with a breast malignancy. Patient survey indicated that 93% of patients were satisfied with the care received and 97% said they would recommend the service to a family member or friend. CONCLUSIONS: Although face-to-face assessments for breast pain remain the standard practice in many breast units, data indicating the safety of a telephone assessment clinic, along with high levels of patient satisfaction, question whether services can be delivered differently.

The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.

OBJECTIVE: To establish the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women referred to colposcopy with persistent high-risk human papillomavirus (hrHPV) cytology-negative screening sample according to hrHPV genotype, age at referral and colposcopic performance. DESIGN: Prospective cohort study. SETTING: Single colposcopy clinic linked to a population-based screening programme. POPULATION: Women referred with persistent hrHPV cytology-negative routine screening samples. METHODS: Prospective study with descriptive statistics from a single colposcopy unit between June 2014 and July 2019. MAIN OUTCOME MEASURES: Prevalence of hrHPV genotypes and CIN2+, positive predictive value for colposcopic impression, and inadequate colposcopic examinations. RESULTS: A total of 3107 women were referred. Prevalence of CIN2+ was highest for persistent HPV16 infections (10.7%) compared with HPV18 (3.6%) or HPVO (4.7%). Prevalence of CIN2+ declined with age (25-34 years 14.2% to 55-64 years 1.1%) whereas the percentage of women with an inadequate colposcopic examination increased (25-34 years 0.9% to 55-64 years 29.5%). High-grade colposcopic impression fell over time during the study from 16.1 to 5.1%. The positive predictive value for colposcopic impression of CIN2+ was affected by hrHPV genotype (57.3% for HPV16 versus 32.1% for nonHPV16). The adjunctive use of electrical impedance spectroscopy detected an extra 42 cases of CIN2+, which was irrespective of hrHPV genotype. CONCLUSIONS: Primary hrHPV cervical screening increases detection of CIN2+; however, low specificity results in more women being referred to colposcopy with a low prevalence of CIN2+. Colposcopy performs poorly in some groups, particularly with HPVO infections and women over 50 years of age. An appropriate threshold for referral to colposcopy in primary hrHPV screening has not been established. TWEETABLE ABSTRACT: Low prevalence of CIN2+ in HPV-positive negative cytology samples. HPV genotype, age and prevalence of CIN2+ affect colposcopic performance.

Resource use in the last three months of life by lung cancer patients in southern Ontario.

Background: End-of-life cancer care involves multidisciplinary teams working in various settings. Evaluating the quality of care and the feedback from such processes is an important aspect of health care quality improvement. Our retrospective cohort study reviewed health care use by lung cancer patients at end of life, their reasons for visiting the emergency department (ed), and feedback from regional health care professionals. Methods: We assessed 162 Ontario patients with small-cell and relapsed or advanced non-small-cell lung cancer. Demographics, disease characteristics, and resource use were collected, and the consenting caregivers for patients with ed visits were interviewed. Study results were disseminated, and feedback about barriers to care was sought. Results: Median patient age was 69 years; 73% of the group had non-small-cell lung cancer; and 39% and 69% had received chemotherapy and radiation therapy respectively. Median overall survival was 5.6 months. In the last 3 months of life, 93% of the study patients had visited an oncologist, 67% had telephoned their oncology team, 86% had received homecare, and 73% had visited the ed. Death occurred for 55% of the patients in hospital; 23%, at home; and 22%, in hospice. Goals of care had been documented for 68% of the patients. Homecare for longer than 3 months was associated with fewer ed visits (80.3% vs. 62.1%, p = 0.022). Key themes from stakeholders included the need for more resources and for effective communication between care teams. Conclusions: Use of acute-care services and rates of death in an acute-care facility are both high for lung cancer patients approaching end of life. In our study, interprofessional and patient-provider communication, earlier connection to homecare services, and improved access to community care were highlighted as having the potential to lower the need for acute-care resources.

Prevalence of high-grade cervical intraepithelial neoplasia in women with persistent high-risk HPV genotypes and negative cytology.

INTRODUCTION: Primary HPV screening will be implemented into the English Cervical Screening Programme by 2019. Its impact upon women referred to colposcopy, with negative cytology but persistently positive high-risk HPV (hrHPV), remains unreported from UK Sentinel sites. HPV primary screening was introduced in Sheffield, UK in April 2013; this paper reports its impact on the service. METHODS: A retrospective cohort study was performed from June 2014 to July 2016 at the Jessop Wing Colposcopy Unit, Sheffield. UK. Data were obtained from the pathology and colposcopy databases and cross-referenced with case-notes and pathology results for women referred with persistently positive hrHPV, cytology negative samples. Patient demographics, hrHPV genotype, biopsy rates, histological diagnoses, management, and outcomes were collected and baseline statistics performed. RESULTS: During the study 1076 women were seen. Most frequent hrHPV genotypes were: hrHPV other, 41%; and HPV16, 33%. The majority (72%) were found to have normal colposcopy; 28% had an abnormal colposcopic assessment (11% low-grade; 11% high-grade; 6% inadequate). The majority were discharged (83%) and only 5% underwent LLETZ. No cancers were detected. High-grade cervical intraepithelial neoplasia (CIN) was found in 7%; overall risk of CIN2 was 1/29; 1/30 for CIN3. Presence of HPV16 was associated with a significantly higher risk of high-grade CIN; 1/9. CONCLUSION: This is the first study to report results for women referred to colposcopy with cytology negative, persistently positive hrHPV. Disease prevalence is low, although women with HPV16 have a significantly higher likelihood of high-grade disease compared to other HPV subtypes.

Transforming activity and therapeutic targeting of C-terminal-binding protein 2 in Apc-mutated neoplasia.

Overexpression of the transcriptional coregulators C-terminal binding proteins 1 and 2 (CtBP1 and 2) occurs in many human solid tumors and is associated with poor prognosis. CtBP modulates oncogenic gene expression programs and is an emerging drug target, but its oncogenic role is unclear. Consistent with this oncogenic potential, exogenous CtBP2 transformed primary mouse and human cells to anchorage independence similarly to mutant H-Ras. To investigate CtBP's contribution to in vivo tumorigenesis, Apcmin/+ mice, which succumb to massive intestinal polyposis, were bred to Ctbp2+/- mice. CtBP interacts with adenomatous polyposis coli (APC) protein, and is stabilized in both APC-mutated human colon cancers and Apcmin/+ intestinal polyps. Ctbp2 heterozygosity increased the median survival of Apcmin/+ mice from 21 to 48 weeks, and reduced polyp formation by 90%, with Ctbp2+/- polyps exhibiting reduced levels of ß-catenin and its oncogenic transcriptional target, cyclin D1. CtBP's potential as a therapeutic target was studied by treating Apcmin/+ mice with the CtBP small-molecule inhibitors 4-methylthio-2-oxobutyric acid and 2-hydroxy-imino phenylpyruvic acid, both of which reduced polyposis by more than half compared with vehicle treatment. Phenocopying Ctbp2 deletion, both Ctbp inhibitors caused substantial decreases in the protein level of Ctbp2, as well its oncogenic partner ß-catenin, and the effects of the inhibitors on CtBP and ß-catenin levels could be modeled in an APC-mutated human colon cancer cell line. CtBP2 is thus a druggable transforming oncoprotein critical for the evolution of neoplasia driven by Apc mutation.

Urethral Foreign Bodies: Clinical Presentation and Management.

OBJECTIVE: To review a single institution's 15-year experience with urethral foreign bodies, including evaluation, clinical findings, and treatment. MATERIALS AND METHODS: In total, 27 patients comprising 35 episodes of inserted urethral foreign bodies were reviewed at Cook County Hospital between 2000 and 2015. Retrospective chart review was performed to describe the clinical presentation, rationale for insertion, management, recidivism, and sequelae. RESULTS: Median patient age was 26 (range 12-60). Twenty-six patients (97 %) were male, 1 was female (3%). Items inserted included pieces of plastic forks, spoons, metal screws and aluminum, pieces of cardboard or paper, staples, writing utensils such as pens and pencils, as well as coaxial cable and spray foam sealant. Reported reasons for insertion were self-stimulation, erectile enhancement, and attention seeking. Presenting symptoms included dysuria, gross hematuria, urinary retention, urinary tract infection, and penile discharge. The most common technique for removal was manual extraction with extrinsic pressure (n = 19, 54%). Other methods include endoscopic retrieval (n = 8, 23%), open cystotomy (n = 1, 3%), and voiding to expel the foreign body (n = 7, 20%). Postremoval complications included urinary tract infection (n = 7), sepsis (n = 4), urethral false passage (n = 5), laceration (n = 5), and stricture (n = 1). CONCLUSION: We present the largest single-institutional series of urethral foreign bodies to date. Urethral foreign body insertion is a relatively rare occurrence and, commonly, is a recurrent behavior. Urethral trauma related to foreign body insertion is associated with significant risk of infection and urethral injury with long-term sequelae.

Does LLETZ excision margin status predict residual disease in women who have undergone post-treatment cervical cytology and high-risk human papillomavirus testing?

OBJECTIVE: This study looks at the importance of large loop excision of the transformation zone (LLETZ) excision margins and residual cervical intraepithelial neoplasia (CIN) in women undertaking high-risk human papillomavirus (hrHPV) test of cure (TOC). METHODS: A retrospective cohort study with interval analysis performed June 2007 and June 2012 on all women undertaking treatment for CIN and subsequent hrHPV TOC 6 months post LLETZ. RESULTS: Final analysis group comprised 2093 women treated by LLETZ (1396 completely excised; 697 incompletely excised). 298 out of 1794 women (13%) were hrHPV positive at TOC. Thirty-six women who failed TOC and attended colposcopy had residual CIN. No statistically significant difference existed between the completely and incompletely excised groups with regards to the detection of residual CIN at 6 months post-treatment. There was no correlation of margins of excision with hrHPV status at TOC. The overall cure rate at TOC was 98%. CONCLUSIONS: TOC pathways recommend subsequent follow-up in primary care. This study identified no safety issues with TOC pathways. We can no longer assess histological failure rates at 12 months; we, therefore, recommend that this measure of treatment failure be redefined for post TOC women. It seems time to question the benefits of routine excision margins reporting, in the absence of invasion, for treated CIN. Future reporting needs to be reconsidered by the Royal College of Pathologists.

Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes.

BACKGROUND: The ability to perform comprehensive profiling of cancers at high resolution is essential for precision medicine. Liquid biopsies using shed exosomes provide high-quality nucleic acids to obtain molecular characterization, which may be especially useful for visceral cancers that are not amenable to routine biopsies. PATIENTS AND METHODS: We isolated shed exosomes in biofluids from three patients with pancreaticobiliary cancers (two pancreatic, one ampullary). We performed comprehensive profiling of exoDNA and exoRNA by whole genome, exome and transcriptome sequencing using the Illumina HiSeq 2500 sequencer. We assessed the feasibility of calling copy number events, detecting mutational signatures and identifying potentially actionable mutations in exoDNA sequencing data, as well as expressed point mutations and gene fusions in exoRNA sequencing data. RESULTS: Whole-exome sequencing resulted in 95%-99% of the target regions covered at a mean depth of 133-490×. Genome-wide copy number profiles, and high estimates of tumor fractions (ranging from 56% to 82%), suggest robust representation of the tumor DNA within the shed exosomal compartment. Multiple actionable mutations, including alterations in NOTCH1 and BRCA2, were found in patient exoDNA samples. Further, RNA sequencing of shed exosomes identified the presence of expressed fusion genes, representing an avenue for elucidation of tumor neoantigens. CONCLUSIONS: We have demonstrated high-resolution profiling of the genomic and transcriptomic landscapes of visceral cancers. A wide range of cancer-derived biomarkers could be detected within the nucleic acid cargo of shed exosomes, including copy number profiles, point mutations, insertions, deletions, gene fusions and mutational signatures. Liquid biopsies using shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling.

Dietary patterns and cognitive decline in an Australian study of ageing.

The aim of this paper was to investigate the association of three well-recognised dietary patterns with cognitive change over a 3-year period. Five hundred and twenty-seven healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing completed the Cancer Council of Victoria food frequency questionnaire at baseline and underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months follow-up. Individual neuropsychological test scores were used to construct composite scores for six cognitive domains and a global cognitive score. Based on self-reported consumption, scores for three dietary patterns, (1) Australian-style Mediterranean diet (AusMeDi), (2) western diet and (3) prudent diet were generated for each individual. Linear mixed model analyses were conducted to examine the relationship between diet scores and cognitive change in each cognitive domain and for the global score. Higher baseline adherence to the AusMeDi was associated with better performance in the executive function cognitive domain after 36 months in apolipoprotein E (APOE) ɛ4 allele carriers (P<0.01). Higher baseline western diet adherence was associated with greater cognitive decline after 36 months in the visuospatial cognitive domain in APOE ɛ4 allele non-carriers (P<0.01). All other results were not significant. Our findings in this well-characterised Australian cohort indicate that adherence to a healthy diet is important to reduce risk for cognitive decline, with the converse being true for the western diet. Executive function and visuospatial functioning appear to be particularly susceptible to the influence of diet.

High-risk HPV platforms and test of cure: should specific HPV platforms more suited to screening in a 'test of cure' scenario be recommended?

OBJECTIVE: When the Sheffield screening laboratory changed the high-risk human papillomavirus (hrHPV) platforms from hybrid capture 2(®) (HC2; Digene Ltd) and to cobas 4800(®) (Roche) an unexpected and substantial increase in the number of cytology-negative/hrHPV-positive test-of-cure (ToC) samples after large loop excision of the transformation zone (LLETZ) was noted. We explore the potential reasons for these increased rates and discuss the implications this may have on the English NHS cervical screening programme (CSP). METHODS: A retrospective cohort study with interval analysis between June 2007 and June 2012. RESULTS: ToC was performed on 1530 women with HC2 and 396 with cobas 4800: 95.1% and 92.4% of women had negative cytology at ToC in the HC2 and cobas4800 testing period, respectively. Of these 13.9% and 27.8% tested positive for hrHPV in the HC2 and cobas 4800 group, respectively (P = <0.0001). No clinically significant increase in the number of cases of cervical intraepithelial neolpasia (CIN) was detected by the cobas4800 test in spite of doubling the number of cytology-negative/hrHPV-positive ToC samples. CONCLUSIONS: As far as we are aware, this is the first study reporting potential differences between different HPV platforms currently available in the English programme. The immediate impact of this increase in rates of hrHPV detection with cobas4800 is an increased number of colposcopy referrals to our service. The NHSCSP needs to assess whether this increase is acceptable and, if not, whether specific HPV platforms more suited to screening in a ToC scenario should be recommended.

A blood-based predictor for neocortical Aß burden in Alzheimer's disease: results from the AIBL study.

Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aß (extracellular ß-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aß accumulation, therefore, providing a platform for developing a population-based screen.

Adherence to a Mediterranean diet and Alzheimer's disease risk in an Australian population.

The Mediterranean diet (MeDi), due to its correlation with a low morbidity and mortality for many chronic diseases, has been widely recognised as a healthy eating model. We aimed to investigate, in a cross-sectional study, the association between adherence to a MeDi and risk for Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large, elderly, Australian cohort. Subjects in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing cohort (723 healthy controls (HC), 98 MCI and 149 AD participants) completed the Cancer Council of Victoria Food Frequency Questionnaire. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of AD and MCI status in multinominal logistic regression models that were adjusted for cohort age, sex, country of birth, education, apolipoprotein E genotype, total caloric intake, current smoking status, body mass index, history of diabetes, hypertension, angina, heart attack and stroke. There was a significant difference in adherence to the MeDi between HC and AD subjects (P < 0.001), and in adherence between HC and MCI subjects (P < 0.05). MeDi is associated with change in Mini-Mental State Examination score over an 18-month time period (P < 0.05) in HCs. We conclude that in this Australian cohort, AD and MCI participants had a lower adherence to the MeDi than HC participants.

The multidisciplinary colposcopy meeting: recommendations for future service provision and an analysis of clinical decision making.

OBJECTIVE: In 2004 the NHS Cervical Screening Programme (NHSCSP) recommended that multidisciplinary meetings should be incorporated into patient management. No data has been provided since then regarding its functionality or benefits. We aim to address this issue. DESIGN: Retrospective review. SETTING: Jessop Wing colposcopy multidisciplinary meeting (MDM), Sheffield, UK. POPULATION: All women referred to the MDM from September 2003 to September 2009. METHODS: Retrospective review of the colposcopy database (Sept 2003-Sept 2009), cross-referenced with multidisciplinary team (MDT) letters, patient notes and the hospital results reporting system. Baseline statistics were used for data analysis. MAIN OUTCOME MEASURES: Indications for MDT referral; concordance rates from cytopathology and histopathology review; concordance rates between MDT treatment decisions and final patient management. RESULTS: A total of 535 cases were discussed at 62 MDT meetings during the allocated study period. Discrepancy between referral cytology and cervix punch biopsy was the most common referral (49%). Cytology and histology review concurred with the initial reports in 75.8 and 97.8% of cases, respectively; the MDT decision was concordant with the final patient management in 97% of cases. The main reason for discordance (67%) resulted from patient factors. CONCLUSIONS: When significant discrepancies exist between colposcopy, cytology and histopathology, then MDT discussion seems pertinent as MDT discussion can lead to the avoidance of over-treatment. To improve timeliness of treatment, MDT meetings should occur at least monthly. The results of each case discussion should be recorded in the patient case notes, the minutes of each meeting should be circulated to all MDT members and a letter describing MDT recommendations must be sent to the colposcopist responsible for patient care.

Eradication programme for bovine viral diarrhoea virus in Orkney 2001 to 2008.

The strategies used and the results obtained in Orkney's bovine viral diarrhoea virus (BVDV) eradication programme over eight years (2001 to 2008) are presented and discussed. The venture was undertaken by local veterinary practices and the Orkney Livestock Association (OLA) with the financial support of the Orkney Islands Council. Participation is voluntary; the programme comprises screening of youngstock, a whole-herd test if required, elimination of persistently infected animals and strict biosecurity measures and/or vaccination. BVDV-free herds are certified, and certification is updated annually by retesting the youngstock. The programme aims to minimise economic losses, thereby increasing the competitiveness of the Orcadian cattle industry and to improve animal health and welfare by eliminating virus circulation. Information from databases of the Scottish Agricultural College, Biobest Laboratories and OLA show that despite a significant reduction in the overall prevalence of BVDV on Orkney during the initial stages of the eradication programme, there has been little progress made since 2006 and that some difficulties have been encountered, with herd BVDV breakdowns following initial eradication. These results highlight the need for continued motivation of farmers, strict application of biosecurity measures and/or systematic vaccination of all seronegative breeding animals.

High-risk HPV detection in specimens collected in SurePath preservative fluid: comparison of ambient and refrigerated storage.

OBJECTIVE: With moves to introduce human papillomavirus (HPV) triage at sentinel sites in England, it is essential that optimal storage and transport conditions are determined for efficient HPV detection using residual liquid-based cytology specimens. METHODS: Two cytology laboratories with comparable workloads sent residual cervical cytology specimens collected in BD Surepath Preservative Fluid to the Specialist Virology Centre for HPV testing. Storage and transport of specimens was at ambient (site A) or refrigerated (site R) temperatures. The effect of temperature on the ability to detect high-risk human papillomavirus (HR-HPV) using Digene Hybrid Capture 2 High-Risk HPV DNA Test (hc2) and Roche AMPLICOR HPV Test (AMPLICOR) was assessed. All specimens with discordant results were tested using Roche Linear Array HPV Genotyping test. RESULTS: A total of 796 residual cytology specimens, with cytology ranging from normal to severe dyskaryosis, were provided (399 from site A and 397 from site R). Ambient storage and transit of cervical specimens in SurePath medium did not appear to affect significantly the suitability of the specimen for HPV testing, as measured by the concordance of the HR-HPV screening assays for ambient versus refrigerated specimens and by the proportion of specimens which tested invalid. CONCLUSION: Residual cytology specimens in SurePath medium, stored and transported at ambient temperature, appear suitable for HR-HPV detection by AMPLICOR beyond the manufacturer's recommended time and potentially up to four weeks.

The metabolic effects of pregnancy in cystic fibrosis.

OBJECTIVE: Our purpose was to determine glucose tolerance in pregnant women with cystic fibrosis (CF) and to relate glucose tolerance to insulin sensitivity, hepatic glucose production, and protein turnover. METHODS: We studied 8 CF women during pregnancy (CFPreg). Results were compared with those from 9 pregnant controls (PregCont) and 8 nonpregnant CF women (CFCont). The following metabolic studies were conducted: oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp, stable isotope infusion of [1-13C]leucine and [6,6-2H2]glucose for measurement of whole body protein turnover and hepatic glucose production (HGP), respectively. Indirect calorimetry was used to measure resting energy expenditure (REE), and food intake was measured by 3-day food journals. Fat-free mass was measured by total body potassium 40K scan. RESULTS: All but one CFPreg developed diabetes by the end of the second trimester and had significantly lower insulin secretion and more insulin resistance than PregCont. Hepatic glucose production was significantly higher and suppression by insulin was less in CF subjects, and protein breakdown was significantly higher. Insulin resistance and HGP increased during pregnancy similarly in CFPreg and PregCont groups. CONCLUSION: Pregnancy in CF is associated with decreased insulin sensitivity and high HGP, in addition to inherent decreased insulin secretion. Pregnancy in CF is also associated with increased protein turnover and less response to insulin's anticatabolic effect. These changes appear to predispose the pregnant CF women to early development of diabetes and poor weight gain.

Mini-open medial reefing and arthroscopic lateral release for the treatment of recurrent patellar dislocation: a medium-term follow-up.

BACKGROUND: Although recurrent patellar dislocations are not uncommon, their pathophysiology and treatment are controversial. HYPOTHESIS: Stabilization of recurrent patellar dislocations can be successfully managed with a mini-open approach. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-two patients (23 knees) underwent a mini-open medial reefing and arthroscopic lateral release for the treatment of recurrent patellar dislocations with an average follow-up of 4.4 years (range, 1.4-14 years). The average age at the first dislocation was 15 years (range, 5-26 years), and the average age at surgery was 23 years (range, 12-65 years). RESULTS: There was 1 postoperative dislocation (4%) and 1 recurrent subluxation (4%). The average Kujala knee score was 88.2 +/- 13.5, with overall good scores in each category. The lowest scores involved squatting (5.7), abnormal painful kneecap movements (subluxations) (7.1), and jumping (7.9). Overall, there was a statistically significant improvement in the Tegner score from 3.7 +/- 1.8 before surgery to 6.9 +/- 2.0 after surgery (P < .001). Six knees (26%) were rated subjectively as excellent, 15 (65%) as good, 2 (9%) as fair, and 0 (0%) as poor. All 22 patients (100%) stated that the procedure was worthwhile. Radiographically, there was a statistically significant improvement in the congruence angle (normal, -8.0 degrees +/- 6.0 degrees) from 15.7 degrees +/- 12.6 degrees (range, 0.0 degrees to +44.0 degrees) before surgery to -11.5 degrees +/- 8.7 degrees (range, -20.0 degrees to +10.0 degrees) after surgery (P < .001) and in the lateral patellofemoral angle (normal, >0 degrees) from -0.2 degrees +/- 6.4 degrees (range, -10 degrees to +8 degrees) before surgery to 7.9 degrees +/- 2.6 degrees (range, 0.0 degrees to +11.0 degrees) after surgery (P < .001). CONCLUSION: Our mini-open technique provides anatomical restoration with limited morbidity and cosmetically appealing results. Furthermore, our redislocation rates compare favorably with traditional, more extensile open approaches.

Airway hyperresponsiveness to bradykinin induced by allergen challenge in actively sensitised Brown Norway rats.

The mechanism(s) of bradykinin-induced bronchoconstriction was investigated in the Brown Norway (BN) rat model of allergic asthma. Bronchoconstrictor responses to i.v. bradykinin in BN rats were maximally augmented 24 h following challenge with allergen and declined at later time points. Histological evaluation of the inflammatory status of the lungs after ovalbumin (OA) challenge showed a marked inflammatory response, which was maximal at 24 h and declined thereafter. However, pretreatment with budesonide did not inhibit the augmented bronchoconstrictor response to bradykinin 24 h after allergen challenge. The selective B1 receptor agonist, Lys-[desArg9]-BK had no bronchoconstrictor effects, whereas the selective B2 receptor antagonist, HOE 140, abolished the response to bradykinin in OA-challenged animals. The augmented response to bradykinin was not affected by methysergide, indomethacin, disodium cromoglycate, iralukast, the 5-lipoxygenase inhibitor, CGS8515, or the NK2 receptor antagonist, SR48968. It was, however, partially inhibited by atropine both in saline- and OA-challenged animals. Pretreatment with captopril and thiorphan markedly potentiated responses to bradykinin both in saline- and OA-challenged animals. Thus, augmentation of the bronchoconstrictor response to bradykinin occurs in actively sensitised BN rats 24 h after challenge with OA and is associated with marked pulmonary inflammation. The response is entirely B2 receptor mediated and approximately 50% of the response is cholinergic. However, mast cell activation, the products of the cyclooxygenase or 5-lipoxygenase pathways and tachykinins are not involved. Peptidase inhibition mimics the effect of allergen challenge on the bronchoconstrictor response to bradykinin and it remains possible that the mechanism of the augmented response to bradykinin following allergen challenge involves downregulation of peptidase activity as a consequence of the inflammatory response.