Peter O'Rourke

Laparoscopic sacral colpopexy versus total vaginal mesh for vaginal vault prolapse: a randomized trial

OBJECTIVE To compare the laparoscopic sacral colpopexy and total vaginal mesh for vaginal vault prolapse. STUDY DESIGN Women with symptomatic stage ≥2 vault prolapse were randomly allocated the laparoscopic sacral colpopexy (53) or total vaginal mesh (55). Primary outcome measures were objective success rates at pelvic organ prolapse quantification sites individually and collectively. Secondary outcome measures included perioperative outcomes, patient satisfaction, quality of life outcomes, complications, and reoperations. RESULTS The laparoscopic sacral colpopexy group had a longer operating time, reduced inpatient days, and quicker return to activities of daily living as compared with the total vaginal mesh group. At the 2-year review, the total objective success rate at all vaginal sites was 41 of 53 (77%) for laparoscopic sacral colpopexy as compared with 23 of 55 (43%) in total vaginal mesh (P < .001). Reoperation rate was significantly higher after the vaginal mesh surgery 12 of 55 (22%) as compared with laparoscopic sacral colpopexy 3 of 53 (5%) (P = .006). CONCLUSION At 2 years, the laparoscopic sacral colpopexy had a higher satisfaction rate and objective success rate than the total vaginal mesh with lower perioperative morbidity and reoperation rate.

Prevalence and stability of antibodies to the BK and JC polyomaviruses: A long-term longitudinal study of Australians

Serology has been used to indicate past infection by the human polyomaviruses BK virus (BKV) and JC virus (JCV), because the site of primary infection is not established fully. Little is known about BKV and JCV antibody stability over time. We investigated BKV and JCV seroprevalence and antibody stability over time in an Australian population-based study. Serum was collected from 458 adults participating in a longitudinal skin cancer study in Queensland in 1992, 1993 and 1996, and 117 people had a fourth sample collected in 2003. Serum samples were analysed for BKV and JCV VP1 antibodies by multiplex detection using the Luminex platform. The seroprevalence for BKV and JCV over 4.5 years was 97 and 63 %, respectively. The BKV seroprevalence was 99 % in 25-60-year-olds, and 94 % in people older than 60 years. JCV seroprevalence was around 60 % in people younger than 50 years, 68 % in people 50-70 years of age and 64 % in people older than 70 years. BKV seroprevalence was very stable over 11 years, with 96 % of people staying seropositive and 2 % remaining seronegative. JCV antibody status over time was less stable; 57 % of participants remained seropositive and 31 % seronegative. The same proportion of people (4 % each) seroconverted, seroreverted or had fluctuating JCV antibody levels. These results confirm the previously believed stability of polyomavirus antibodies, with BKV antibodies being highly stable and JCV antibodies moderately so. Thus, a single measure can be used as a reasonable indicator of long-term antibody status in epidemiological studies aiming to understand associations between polyomaviruses and disease.

Cough-generated aerosols of Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic fibrosis

Background: Pseudomonas aeruginosa is the most common bacterial pathogen in patients with cystic fibrosis (CF). Current infection control guidelines aim to prevent transmission via contact and respiratory droplet routes and do not consider the possibility of airborne transmission. It was hypothesised that subjects with CF produce viable respirable bacterial aerosols with coughing. Methods: A cross-sectional study was undertaken of 15 children and 13 adults with CF, 26 chronically infected with P aeruginosa. A cough aerosol sampling system enabled fractioning of respiratory particles of different sizes and culture of viable Gram-negative non-fermentative bacteria. Cough aerosols were collected during 5 min of voluntary coughing and during a sputum induction procedure when tolerated. Standardised quantitative culture and genotyping techniques were used. Results: P aeruginosa was isolated in cough aerosols of 25 subjects (89%), 22 of whom produced sputum samples. P aeruginosa from sputum and paired cough aerosols were indistinguishable by molecular typing. In four cases the same genotype was isolated from ambient room air. Approximately 70% of viable aerosols collected during voluntary coughing were of particles ⩽3.3 μm aerodynamic diameter. P aeruginosa, Burkholderia cenocepacia, Stenotrophomonas maltophilia and Achromobacter xylosoxidans were cultivated from respiratory particles in this size range. Positive room air samples were associated with high total counts in cough aerosols (p = 0.003). The magnitude of cough aerosols was associated with higher forced expiratory volume in 1 s (r = 0.45, p = 0.02) and higher quantitative sputum culture results (r = 0.58, p = 0.008). Conclusion: During coughing, patients with CF produce viable aerosols of P aeruginosa and other Gram-negative bacteria of respirable size range, suggesting the potential for airborne transmission.

A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs.

Background Critical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection. Methods and Findings A prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether–lumefantrine (A/L) or atovaquone-proguanil (A/P). In the first cohort (n = 6) where volunteers received ∼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6). In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, n = 6; A/P, n = 7) The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120–4786 and 7–40 respectively; p<0.01). Conclusions This system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials. Trial Registration: ClinicalTrials.gov NCT01055002

Metastatic progression of breast cancer: insights from 50 years of autopsies

There remain no clear guidelines for the optimal management of patients with metastatic breast cancer. To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer. We reviewed clinical, treatment and pathological aspects of all cases and, additionally, pathological features and biomarker expression (ER, PgR, HER2, EGFR, p53, Ki67, c‐Kit, CK AE1/AE3) were assessed in detail for the primary tumour and matched metastases for 55 of the cases. Genomes of the primary tumour and multiple metastases were analysed by array‐based comparative genomic hybridization for six cases##. 945 metastatic deposits were identified, with a median of four/patient. The most common organs involved were lung/pleura (80%), bone (74%), liver (71%) and non‐axillary lymph nodes (55%). Major findings included: (a) patients with CNS metastases were more likely to have bone metastases (p < 0.013); (b) younger age was associated with metastasis to the liver (≤ 49 years; p < 0.001) and to gynaecological organs (≤ 49 years; p = 0.001); (c) surgical excision of the primary tumour was associated with metastasis to the liver (p = 0.002); and (d) ER and PgR showed down‐regulation during progression in a non‐random manner, particularly in lung/pleura (ER; p < 0.001), liver and bone metastases. Genomic analysis revealed DNA copy number variation between the primary tumour and metastases (e.g. amplification of 2q11.2–q12.1 and 10q22.2–q22.3) but little variation between metastases from the same patient. In summary, the association of CNS and bone metastases, liver and gynaecological metastases in young women and the risk of liver metastases following surgery have important implications for the management of patients with breast cancer. Clonal heterogeneity of the primary tumour is important in developing metastatic propensity and the change in tumour phenotype during progression/colonization highlights the importance of sampling metastatic disease for optimal treatment strategies.

Obesity and steatosis influence serum and hepatic inflammatory markers in chronic hepatitis C

Obesity and fatty liver are commonly observed among patients with chronic hepatitis C virus (HCV) and are risk factors for increased hepatic fibrosis. Obesity is accompanied by a low‐grade, chronic inflammatory response that may contribute to pathogenesis of obesity‐related comorbidities. To assess whether obesity and steatosis potentiate expression of inflammatory markers in chronic HCV, serum protein and hepatic messenger RNA (mRNA) levels of c‐reactive protein (CRP), interleukin‐6 (IL‐6), and tumor necrosis factor‐alpha (TNF‐α) were measured in 171 patients with chronic HCV. The relationships of body mass index, steatosis, histological features of inflammation and fibrosis with serum and hepatic levels of these factors were determined. In comparison with lean patients, overweight and obese subjects had increased circulating (P < 0.001) and hepatic (P = 0.003) CRP, and there was a significant correlation between serum protein and hepatic CRP mRNA levels (rs= 0.51, P < 0.001). Obesity (P = 0.001) and steatosis (P < 0.001) were associated with increased circulating but not hepatic IL‐6, and a weak correlation was seen between serum protein and hepatic IL‐6 mRNA levels (rs= 0.29, P = 0.003). An independent relationship was seen between hepatic TNF‐α mRNA levels and higher total inflammatory score (P < 0.001) and stage of fibrosis (P = 0.037). Subjects with HCV genotype 3 had lower hepatic TNF‐α mRNA levels compared with subjects with genotype 1 (P = 0.017), but there was no relationship between serum TNF‐α protein and hepatic TNF‐α mRNA levels. Conclusion: In patients with chronic HCV, obesity and steatosis are associated with increased expression of selected inflammatory markers; however, circulating levels of IL‐6 and TNF‐α do not reflect hepatic expression. Hepatic TNF‐α was associated with both increased inflammatory activity and hepatic fibrosis, providing support for the key role of this pro‐inflammatory cytokine in liver injury in chronic HCV. (HEPATOLOGY 2008;48:80–87.)

Clinical reasoning: the relative contribution of identification, interpretation and hypothesis errors to misdiagnosis.

The aim of this study was to identify and describe the types of errors in clinical reasoning that contribute to poor diagnostic performance at different levels of medical training and experience. Three cohorts of subjects, second- and fourth- (final) year medical students and a group of general practitioners, completed a set of clinical reasoning problems. The responses of those whose scores fell below the 25th centile were analysed to establish the stage of the clinical reasoning process—identification of relevant information, interpretation or hypothesis generation—at which most errors occurred and whether this was dependent on problem difficulty and level of medical experience. Results indicate that hypothesis errors decrease as expertise increases but that identification and interpretation errors increase. This may be due to inappropriate use of pattern recognition or to failure of the knowledge base. Furthermore, although hypothesis errors increased in line with problem difficulty, identification and interpretation errors decreased. A possible explanation is that as problem difficulty increases, subjects at all levels of expertise are less able to differentiate between relevant and irrelevant clinical features and so give equal consideration to all information contained within a case. It is concluded that the development of clinical reasoning in medical students throughout the course of their pre-clinical and clinical education may be enhanced by both an analysis of the clinical reasoning process and a specific focus on each of the stages at which errors commonly occur.

The clinical reasoning characteristics of diagnostic experts

The aim of this study was to identify and describe the clinical reasoning characteristics of diagnostic experts. A group of 21 experienced general practitioners were asked to complete the Diagnostic Thinking Inventory (DTI) and a set of 10 clinical reasoning problems (CRPs) to evaluate their clinical reasoning. Both the DTI and the CRPs were scored, and the CRP response patterns of each GP examined in terms of the number and type of errors contained in them. Analysis of these data showed that six GPs were able to reach the correct diagnosis using significantly less clinical information than their colleagues. These GPs also made significantly fewer interpretation errors but scored lower on both the DTI and the CRPs. Additionally, this analysis showed that more than 20% of misdiagnoses occurred despite no errors being made in the identification and interpretation of relevant clinical information. These results indicate that these six GPs diagnose efficiently, effectively and accurately using relatively few clinical data and can therefore be classified as diagnostic experts. They also indicate that a major cause of misdiagnoses is failure to properly integrate clinical data. We suggest that increased emphasis on this step in the reasoning process should prove beneficial to the development of clinical reasoning skill in undergraduate medical students.

Prognostic indicators for open globe injury

Background:  The purpose of the study is to identify factors predictive of outcome after open globe injury in 273 patients admitted to the Royal Brisbane Hospital, Queensland, Australia between 1992 and 2003.

Infant to staff ratios and risk of mortality in very low birthweight infants

Objectives: To assess the effect that infant to staff ratios, in the first three days of life, have on the survival to hospital discharge of very low birthweight infants (<1500 g), having adjusted for initial risk and unit workload. Design: In a retrospective analysis of a cohort of patients, the number of infants per nurse per shift were averaged for the first three days after admission and related to risk of mortality by logistic regression analysis. Infant to staff ratio was divided into terciles of low (1.16–1.58), medium (1.59–1.70), and high (1.71–1.97) infants per staff member. Subjects: 692 very low birthweight infants admitted to the Intensive Care Nursery, Royal Women’s Hospital, Brisbane over a four year period from January 1996 to December 1999. Main outcome measures: Survival to hospital discharge, adjusted for initial risk using the Clinical Risk Index for Babies (CRIB) score, and adjusted for unit workload using dependency scores. Results: There were 80 deaths among the 692 babies analysed for the study period. The odds of mortality, adjusted for initial risk and infant dependency scores (unit workload), were improved by 82% when an infant/staff ratio of greater than 1.71 occurred, suggesting improved survival with the highest infant/staff ratio. The low and medium staffing levels corresponded with similar odds ratios for mortality. Conclusions: Infants exposed to higher infant to staff ratios have an improved adjusted risk of survival to hospital discharge.