Clinical Implementation of Routine Whole-genome Sequencing for Hospital Infection Control of Multi-drug Resistant Pathogens.

BACKGROUND: Prospective whole-genome sequencing (WGS)-based surveillance may be the optimal approach to rapidly identify transmission of multi-drug resistant (MDR) bacteria in the healthcare setting. METHODS: We prospectively collected methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Acinetobacter baumannii (CRAB), extended-spectrum beta-lactamase (ESBL-E), and carbapenemase-producing Enterobacterales (CPE) isolated from blood cultures, sterile sites, or screening specimens across three large tertiary referral hospitals (2 adult, 1 paediatric) in Brisbane, Australia. WGS was used to determine in silico multi-locus sequence typing (MLST) and resistance gene profiling via a bespoke genomic analysis pipeline. Putative transmission events were identified by comparison of core genome single nucleotide polymorphisms (SNPs). Relevant clinical meta-data were combined with genomic analyses via customised automation, collated into hospital-specific reports regularly distributed to infection control teams. RESULTS: Over 4 years (April 2017 to July 2021) 2660 isolates were sequenced. This included MDR gram-negative bacilli (n = 293 CPE, n = 1309 ESBL), MRSA (n = 620), and VRE (n = 433). A total of 379 clinical reports were issued. Core genome SNP data identified that 33% of isolates formed 76 distinct clusters. Of the 76 clusters, 43 were contained to the 3 target hospitals, suggesting ongoing transmission within the clinical environment. The remaining 33 clusters represented possible inter-hospital transmission events or strains circulating in the community. In 1 hospital, proven negligible transmission of non-multi-resistant MRSA enabled changes to infection control policy. CONCLUSIONS: Implementation of routine WGS for MDR pathogens in clinical laboratories is feasible and can enable targeted infection prevention and control interventions.

Genomic Investigation Reveals Contaminated Detergent as the Source of an Extended-Spectrum-ß-Lactamase-Producing Klebsiella michiganensis Outbreak in a Neonatal Unit.

Klebsiella species are problematic pathogens in neonatal units and may cause outbreaks, for which the sources of transmission may be challenging to elucidate. We describe the use of whole-genome sequencing (WGS) to investigate environmental sources of transmission during an outbreak of extended-spectrum-ß-lactamase (ESBL)-producing Klebsiella michiganensis colonizing neonates. Ceftriaxone-resistant Klebsiella spp. isolated from neonates (or their mothers) and the hospital environment were included. Short-read sequencing (Illumina) and long-read sequencing (MinION; Oxford Nanopore Technologies) were used to confirm species taxonomy, to identify antimicrobial resistance genes, and to determine phylogenetic relationships using single-nucleotide polymorphism profiling. A total of 21 organisms (10 patient-derived isolates and 11 environmental isolates) were sequenced. Standard laboratory methods identified the outbreak strain as an ESBL-producing Klebsiella oxytoca, but taxonomic assignment from WGS data suggested closer identity to Klebsiella michiganensis Strains isolated from multiple detergent-dispensing bottles were either identical or closely related by single-nucleotide polymorphism comparison. Detergent bottles contaminated by K. michiganensis had been used for washing milk expression equipment. No new cases were identified once the detergent bottles were removed. Environmental reservoirs may be an important source in outbreaks of multidrug-resistant organisms. WGS, in conjunction with traditional epidemiological investigation, can be instrumental in revealing routes of transmission and guiding infection control responses.

Effect of population breast screening on breast cancer mortality up to 2005 in England and Wales: an individual-level cohort study.

BACKGROUND: Population breast screening has been implemented in the UK for over 25 years, but the size of benefit attributable to such programmes remains controversial. We have conducted the first individual-based cohort evaluation of population breast screening in the UK, to estimate the impact of the NHS breast screening programme (NHSBSP) on breast cancer mortality. METHODS: We followed 988 090 women aged 49-64 years in 1991 resident in England and Wales, who because of the staggered implementation of the NHSBSP, included both invited subjects and an uninvited control group. Individual-level breast screening histories were linked to individual-level mortality and breast cancer incidence data from national registers. Risk of death from breast cancer was investigated by incidence-based mortality analyses in relation to intention to screen and first round attendance. Overdiagnosis of breast cancer following a single screening round was also investigated. RESULTS: Invitation to NHSBSP screening was associated with a reduction in breast cancer mortality in 1991-2005 of 21% (RR=0.79, 95% CI: 0.73-0.84, P<0·001) after adjustment for age, socioeconomic status and lead-time. Breast cancer deaths among first invitation attenders were 46% lower than among non-attenders (RR=0.54, 95% CI: 0.51-0·57, P<0.001) and 32% lower following adjustment for age, socioeconomic status and self-selection bias (RR=0.68, 95% CI: 0.63-0·73, P<0.001). There was little evidence of overdiagnosis associated with invitation to first screen. CONCLUSIONS: The results indicate a substantial, statistically significant reduction in breast cancer mortality between 1991 and 2005 associated with NHSBSP activity. This is important in public health terms.

Reducing the socioeconomic gradient in uptake of the NHS bowel cancer screening Programme using a simplified supplementary information leaflet: a cluster-randomised trial.

BACKGROUND: Uptake of colorectal cancer screening is low in the English NHS Bowel Cancer Screening Programme (BCSP). Participation in screening is strongly associated with socioeconomic status. The aim of this study was to determine whether a supplementary leaflet providing the 'gist' of guaiac-based Faecal Occult Blood test (gFOBt) screening for colorectal cancer could reduce the socioeconomic status (SES) gradient in uptake in the English NHS BCSP. METHODS: The trial was integrated within routine BCSP operations in November 2012. Using a cluster randomised controlled design all adults aged 59-74 years who were being routinely invited to complete the gFOBt were randomised based on day of invitation. The Index of Multiple Deprivation was used to create SES quintiles. The control group received the standard information booklet ('SI'). The intervention group received the SI booklet and the Gist leaflet ('SI + Gist') which had been designed to help people with lower literacy engage with the invitation. Blinding of hubs was not possible and invited subjects were not made aware of a comparator condition. The primary outcome was the gradient in uptake across IMD quintiles. RESULTS: In November 2012, 163,525 individuals were allocated to either the 'SI' intervention (n = 79,104) or the 'SI + Gist' group (n = 84,421). Overall uptake was similar between the intervention and control groups (SI: 57.3% and SI + Gist: 57.6%; OR = 1.02, 95% CI: 0.92-1.13, p = 0.77). Uptake was 42.0% (SI) vs. 43.0% (SI + Gist) in the most deprived quintile and 65.6% vs. 65.8% in the least deprived quintile (interaction p = 0.48). The SES gradient in uptake was similar between the study groups within age, gender, hub and screening round sub-groups. CONCLUSIONS: Providing supplementary simplified information in addition to the standard information booklet did not reduce the SES gradient in uptake in the NHS BCSP. The effectiveness of the Gist leaflet when used alone should be explored in future research. TRIAL REGISTRATION: ISRCTN74121020 , registered: 17/20/2012.

Pooled Open Blocks Shorten Wait Times for Nonelective Surgical Cases.

OBJECTIVE: Assess the impact of the implementation of a data-driven scheduling strategy that aimed to improve the access to care of nonelective surgical patients at Massachusetts General Hospital (MGH). BACKGROUND: Between July 2009 and June 2010, MGH experienced increasing throughput challenges in its perioperative environment: approximately 30% of the nonelective patients were waiting more than the prescribed amount of time to get to surgery, hampering access to care and aggravating the lack of inpatient beds. METHODS: This work describes the design and implementation of an "open block" strategy: operating room (OR) blocks were reserved for nonelective patients during regular working hours (prime time) and their management centralized. Discrete event simulation showed that 5 rooms would decrease the percentage of delayed patients from 30% to 2%, assuming that OR availability was the only reason for preoperative delay. RESULTS: Implementation began in January 2012. We compare metrics for June through December of 2012 against the same months of 2011. The average preoperative wait time of all nonelective surgical patients decreased by 25.5% (P < 0.001), even with a volume increase of 9%. The number of bed-days occupied by nonurgent patients before surgery declined by 13.3% whereas the volume increased by 4.5%. CONCLUSIONS: The large-scale application of an open-block strategy significantly improved the flow of nonelective patients at MGH when OR availability was a major reason for delay. Rigorous metrics were developed to evaluate its performance. Strong managerial leadership was crucial to enact the new practices and turn them into organizational change.

Biological efficacy and stability of diluted ticarcillin-clavulanic acid in the topical treatment of Pseudomonas aeruginosa infections.

Topical compounded Timentin(®) diluted with an inactive vehicle has been reported to be effective in the treatment of otitis externa caused by Pseudomonas aeruginosa. The aims of this study were to determine the biological efficacy of Timentin(®) (ticarcillin and clavulanic acid) when diluted in the carrier vehicle Methopt(®) against P. aeruginosa and to determine the efficacy and stability of Timentin(®) aqueous stock concentrate solution. Timentin(®) stock concentrate was tested against four P. aeruginosa isolates on days 0, 7, 14, 21 and 28; then after 2, 3, 4, 5, 6, 9 and 12 months of storage at 4 or -20°C. The diluted Timentin(®)-Methopt(®) solutions were tested against all isolates after 0, 2, 4, 6, 8, 10, 12, 14, 17, 21, 24 and 28 days of storage at 24 or 4°C. Minimal inhibitory concentration (MIC) levels for all strains were determined using the broth microdilution method. The MIC of the stock solution remained relatively constant and acceptable throughout the study when stored at -20°C and was also acceptable for shorter time periods (6-9 months) when stored at 4°C. The MIC for the diluted Timentin(®)-Methopt(®) solution remained relatively constant and acceptable throughout the study for all four bacterial strains, with no difference between the solutions stored at 4 or 24°C. The results of this study indicate that storage of the Timentin(®) stock solution at -20°C does not compromise efficacy for at least 12 months and that Timentin(®) diluted in Methopt(®) was stable for 28 days when stored at either 4 or 24°C.

Sexually transmitted infections and hepatitis in men with a history of incarceration.

BACKGROUND: Men entering correctional facilities have high rates of human immunodeficiency virus, sexually transmitted infections (STI), and hepatitis. Many prisons offer screening, treatment, and vaccination services; however, little is known about the rates of these infections in men after release to the community. METHODS: Young men were recruited from prisons in Mississippi, Rhode Island, and Wisconsin as part of a human immunodeficiency virus/STI/hepatitis intervention study. Participants were offered screening for Neisseria gonorrhoeae (GC), Chlamydia trachomatis, trichomoniasis, syphilis, hepatitis B (HBV) and C (HCV) 6 months after release. Logistic regression was performed to identify associations with prevalent infections. RESULTS: Of 248 eligible men, 178 (71.8%) participated. Their mean age was 22.5 years, and 92% reported multiple lifetime incarcerations. At 6-month postrelease, 79% reported unprotected vaginal or anal sex, and 26% tested positive for 1 or more infections (GC, 1%; C. trachomatis, 12%; trichomoniasis, 8%; syphilis, 0%; HCV, 6%; HBV, 1%). Of all, 55% were susceptible to HBV infection. Active STI (GC, C. trachomatis, or trichomoniasis) was associated with less education (odds ratios [OR], 2.25; P < 0.05). HCV infection was associated with injection drug use (OR, 69.70; P < 0.05) and being white (OR, 7.54; P < 0.05). HBV susceptibility was associated with older age (OR, 3.02; P < 0.05), more education (OR, 2.39; P < 0.05), or incarceration in Mississippi (OR, 6.69; P < 0.05) or Rhode Island (OR, 2.84; P < 0.05). CONCLUSIONS: Effective screening and prevention programs are needed for this population before and after release from custody to prevent acquisition and further transmission of these infections.

Occult bacterial lower urinary tract infections in cats-urinalysis and culture findings.

Bacterial urinary tract infections (UTIs) can be detected in feline urine submitted for urinalysis and culture as part of the diagnostic workup for a variety of conditions. Our aim was to investigate urinalysis and culture findings in urine specimens from cats with no history of lower urinary tract signs. Study inclusion criteria required cystocentesis specimens from cats with no history of lower urinary tract signs, inappropriate urination, or previous UTI (including pyelonephritis). Of 132 specimens, 38 were culture positive and 94 were culture negative. Culture positive urine specimens were more likely to come from older female cats (p=0.03, p<0.001, respectively) and they had higher pH (p=0.001), erythrocyte (p=0.013) and leukocyte counts (p=0.003) than culture negative urine specimens. Gram-negative infected specimens (n=15) had lower urine specific gravity and higher leukocyte counts than Gram-positive infected specimens (n=21; p=0.0012, p=0.005, respectively) and culture negative specimens (p=0.003, p<0.0001, respectively). Urine protein:creatinine ratio was higher in Gram-negative infected urine than in culture negative urine (p=0.013). Enterococcus faecalis was the most commonly isolated bacteria (19 of a total of 44 isolates; 43.2%) and E. coli phylogenetic group B2 was the most common Gram-negative isolate (14 of a total of 44 isolates; 31.8%). We conclude that feline bacterial urinary tract infections can occur in cats without lower urinary tract signs, particularly older females and that they are associated with high urine erythrocyte and leukocyte counts.

Effect of population breast screening on breast cancer mortality to 2005 in England and Wales: A nested case-control study within a cohort of one million women.

Objectives To evaluate the effectiveness of the NHS breast screening programme (NHSBSP) on breast cancer mortality in England and Wales and to compare findings with a cohort analysis of the same underlying population. Methods A nested case-control study within a cohort of 959,738 women in England and Wales aged 49-64 who were eligible for routine NHSBSP screening during 1991-2005. Cases who died from breast cancer in 1991-2005 were matched to controls without breast cancer at the case diagnosis date and alive when the case died. Risk of breast cancer mortality associated with intention to screen (ITS) (7047 cases/28,188 controls) and screening attendance (4707 cases/9413 controls) was examined. Bias was minimised in accordance with currently advocated best practice. Odds ratios (ORs) were calculated using conditional logistic regression. Results were compared with findings from an incidence-based breast cancer mortality cohort analysis. Results ITS was associated with a 21% breast cancer mortality reduction (OR = 0.79, 95% confidence interval [CI]: 0.71-0.88, P < 0.001). Attendance ≤5 years before diagnosis was associated with a 47% reduction in breast cancer mortality after self-selection correction (OR = 0.53, 95% CI: 0.46-0.62, P < 0.001). Breast cancer mortality reduction associated with ITS was 21% in both the case-control and cohort analyses, but the impact of attendance was marginally greater in the case-control analysis (36% vs. 32%). Conclusions Case-control studies designed and analysed according to current best practice guidelines offer an effective means of evaluating population breast screening.

Geographic Variations in Arthritis Prevalence, Health-Related Characteristics, and Management - United States, 2015.

PROBLEM/CONDITION: Doctor-diagnosed arthritis is a common chronic condition affecting an estimated 23% (54 million) of adults in the United States, greatly influencing quality of life and costing approximately $300 billion annually. The geographic variations in arthritis prevalence, health-related characteristics, and management among states and territories are unknown. Therefore, public health professionals need to understand arthritis in their areas to target dissemination of evidence-based interventions that reduce arthritis morbidity. REPORTING PERIOD: 2015. DESCRIPTION OF SYSTEM: The Behavioral Risk Factor Surveillance System is an annual, random-digit-dialed landline and cellular telephone survey of noninstitutionalized adults aged ≥18 years residing in the United States. Self-reported data are collected from the 50 states, the District of Columbia, Guam, and Puerto Rico. Unadjusted and age-standardized prevalences of arthritis, arthritis health-related characteristics, and arthritis management were calculated. County-level estimates were calculated using a validated statistical modeling method. RESULTS: In 2015, in the 50 states and the District of Columbia, median age-standardized prevalence of arthritis was 23.0% (range: 17.2%-33.6%). Modeled prevalence of arthritis varied considerably by county (range: 11.2%-42.7%). In 13 states that administered the arthritis management module, among adults with arthritis, the age-standardized median percentage of participation in a self-management education course was 14.5% (range: 9.1%-19.0%), being told by a health care provider to engage in physical activity or exercise was 58.5% (range: 52.3%-61.9%), and being told to lose weight to manage arthritis symptoms (if overweight or obese) was 44.5% (range: 35.1%-53.2%). Respondents with arthritis who lived in the quartile of states with the highest prevalences of arthritis had the highest percentages of negative health-related characteristics (i.e., arthritis-attributable activity limitations, arthritis-attributable severe joint pain, and arthritis-attributable social participation restriction; ≥14 physically unhealthy days during the past 30 days; ≥14 mentally unhealthy days during the past 30 days; obesity; and leisure-time physical inactivity) and the lowest percentage of leisure-time walking. INTERPRETATION: The prevalence, health-related characteristics, and management of arthritis varied substantially across states. The modeled prevalence of arthritis varied considerably by county. PUBLIC HEALTH ACTION: The findings highlight notable geographic variability in prevalence, health-related characteristics, and management of arthritis. Targeted use of evidence-based interventions that focus on physical activity and self-management education can reduce pain and improve function and quality of life for adults with arthritis and thus might reduce these geographic disparities.

Prevalence of bacterial species in cats with clinical signs of lower urinary tract disease: recognition of Staphylococcus felis as a possible feline urinary tract pathogen.

This study investigated the prevalence of bacterial pathogens of the urinary tract in Australian cats. Urine was collected by cystocentesis and subjected to urinalysis, bacterial culture and susceptibility testing. A total of 126 isolates were obtained from 107 culture-positive cats. Escherichia coli was most commonly isolated (37.3% of isolates) with the majority of isolates showing susceptibility to the 14 antimicrobials tested. Just over a quarter of isolates (27.0%) were Enterococcus faecalis, which showed resistance to cephalosporins and clindamycin. Staphylococcus felis, a previously unreported feline urinary tract pathogen which was susceptible to all antimicrobial agents tested, comprised 19.8% of the isolates. S. felis was significantly associated with urine that had a higher specific gravity (p=0.011) and pH (p=0.006) and was more likely to contain crystals (p=0.002) than urine from which other bacterial species were isolated. This is the first published study that associates the isolation of S. felis with clinical signs of lower urinary tract disease in cats.

Clinical efficacy and palatability of pradofloxacin 2.5% oral suspension for the treatment of bacterial lower urinary tract infections in cats.

BACKGROUND: Pradofloxacin is a 3rd generation veterinary fluoroquinolone designed to restrict the emergence of antimicrobial resistance during therapy. HYPOTHESIS: Pradofloxacin 2.5% oral suspension is a safe, efficacious, and palatable treatment for bacterial urinary tract infections (UTI) in cats. ANIMALS: Seventy-eight cats presented with lower urinary tract signs and were positive on bacterial culture of urine. METHODS: Cats were allocated into 3 treatment groups depending on bacterial susceptibility results: pradofloxacin (n = 27), doxycycline (n = 23), or amoxicillin-clavulanic acid (n = 28). All antimicrobials were presented in palatable liquid form. Posttreatment urine specimens were collected after completion of the course of treatment and submitted for bacterial culture and sensitivity. Owners were questioned before and after treatment about their experiences with administering oral medication to their cats. RESULTS: Posttreatment urine culture was negative in all cats in the pradofloxacin group, but there were 3 treatment failures in each of the other groups. Owners' perceptions of the difficulty of administering oral medication to their cats was more positive posttreatment than pretreatment (P = .001; P < .001). There was no difference in palatability among the treatment groups (P > .05). CONCLUSIONS AND CLINICAL IMPORTANCE: We conclude that pradofloxacin 2.5% oral suspension is a highly effective and safe antimicrobial treatment for bacterial lower urinary tract infection in cats, and that the palatable formulation optimizes owner compliance. These findings make pradofloxacin a useful addition to the veterinary formulary.

Annual Incidence of Knee Symptoms and Four Knee Osteoarthritis Outcomes in the Johnston County Osteoarthritis Project.

OBJECTIVE: To estimate annual incidence rates (IRs) of knee symptoms and 4 knee osteoarthritis (OA) outcomes (radiographic, symptomatic, severe radiographic, and severe symptomatic), overall and stratified by sociodemographic characteristics and knee OA risk factors. METHODS: We analyzed baseline (1991-1997) and first followup (1999-2003) data (n = 1,518) from the Johnston County Osteoarthritis Project. Participants were African American and white adults, ages ≥45 years, living in Johnston County, North Carolina, US. Knee symptoms were pain, aching, or stiffness on most days in a knee. Radiographic OA was Kellgren/Lawrence grade ≤2 (severe radiographic ≥3) in at least 1 knee. Symptomatic OA was defined as symptoms in a radiographically affected knee; severe symptomatic OA was defined as severe symptoms and severe radiographic OA. RESULTS: The median followup time was 5.5 years. Average annual IRs were 6% for symptoms, 3% for radiographic OA, 2% for symptomatic OA, 2% for severe radiographic OA, and 0.8% for severe symptomatic OA. Across outcomes, IRs were highest among those with the following baseline characteristics: age ≥75 years, obese, a history of knee injury, or an annual household income ≤$15,000. CONCLUSION: The annual onset of knee symptoms and 4 OA outcomes in Johnston County was high. This may preview the future of knee OA in the US and underscores the urgency of clinical and public health collaborations that reduce risk factors for, and manage the impact of, these outcomes. Inexpensive, convenient, and proven strategies (e.g., physical activity, self-management education courses) complement clinical care and can reduce pain and improve quality of life for people with arthritis.

Illicit substance use, sexual risk, and HIV-positive gay and bisexual men: differences by serostatus of casual partners.

OBJECTIVE: To examine the use of alcohol and illicit drugs among HIV-positive gay and bisexual men and to determine substance-use-related predictors of unprotected sex with casual partners who were HIV negative, HIV positive, or whose serostatus was unknown. DESIGN: Cross-sectional assessment of baseline data from a behavioral intervention. METHODS: From 1999 to 2001, we recruited 1168 HIV-positive gay and bisexual men in New York City and San Francisco and determined the prevalence of drinking and drug use, as well as the use of substances with sex. We then examined associations between substance use variables and risky sexual behaviors with casual partners by partner serostatus. RESULTS: Substance use was common, and the use of "party drugs" [e.g. methamphetamine, nitrate inhalants (poppers), ketamine, and gamma hydroxybutyrate] was most often associated with sexual risk in multivariate models. Substance use before or during sex was not associated with risk with HIV-negative partners, but was associated with risk with HIV-positive and unknown-serostatus partners. CONCLUSION: Substance use before or during sex was not associated with risk with HIV-negative partners, suggesting that disclosure by HIV-negative sexual partners of HIV-positive men may be important. Being a user of particular party drugs was associated with recent risk with HIV-negative partners. With partners whose serostatus was unknown, the use of certain party drugs and using substances in the context of sex was associated with risk, possibly as a result of reliance on assumptions of seroconcordance. This same pattern was seen for HIV-positive casual partners. These data have intervention implications for both HIV-positive and HIV-negative men.

Psychosocial correlates of transmission risk behavior among HIV-seropositive gay and bisexual men.

OBJECTIVES: We sought to identify the determinants of sexual transmission risk behavior by HIV-positive individuals. We examined social cognitive theory (SCT) variables, which have been found to mediate the effectiveness of HIV risk reduction interventions. We also sought to identify contextual influences that might contribute to initial levels of SCT factors such as self-efficacy. METHOD: In the present study, a series of social cognitive variables and a number of factors hypothesized to influence self-efficacy were assessed among participants at baseline in the Seropositive Urban Men's Intervention Trial. Variables tested for their effects on self-efficacy included hedonistic and self-evaluative outcome expectancies, sexual compulsivity, a history of childhood sexual abuse, drug use, and race. Models predicting condom use during anal sex with partners of HIV-negative or unknown status were tested separately for main partners and for non-main partners. RESULTS: Self-efficacy was associated with condom use in both analyses. Contextual influences on condom use with main partners were fewer and operated mostly via effects on self-efficacy. Influences on condom use with non-main partners exerted both direct effects on condom use and effects mediated by self-efficacy. Drug use was predictive of condom use with non-main, but not main, partners. DISCUSSION: The present results support the approach of addressing both standard SCT factors, and when possible contextual factors in interventions for HIV-positive men.

Influence of annual mammography from age 40 on breast cancer pathology.

The objective of this study was to determine the influence of annual mammography on pathology features of breast cancers in an invited population. We conducted a randomized trial of 53,890 invited and 106,971 control United Kingdom women who were recruited only from those aged 40 years, with central review of cancer histology. We compare the invasive cancer distribution for the categories of size, histological type, grade, and node status in subgroups of the invited population with that of controls. Among 1287 cancers identified in the total population through the end of December 1999, there are major differences among prevalence, incidence, interval, and lapsed-attender and nonattender subgroups for the distribution of cancer numbers in categories of chosen qualitative histological features. These reflect the biases known to affect a population exposed to screening. Comparing cancers from the unbiased group of the invited population with controls shows significant differences in distributions for size, grade, and node status but not histological type. Multivariate logistic regression shows significant reduction (odds ratio, 0.73; P = 0.043) in node-positive status for the unbiased group. We conclude that annual mammography from age 40 years significantly reduces size and positive-node status of invasive cancers in the invited population. The potential for phenotypic drift of grade emphasizes the relevance of screen detection of all grades at sizes smaller than 10 mm.

Implications of pathologist concordance for breast cancer assessments in mammography screening from age 40 years.

Three pathologists reviewed slides and reports of cancers arising in both the study and control populations of the U.K. trial of annual mammography screening from age 40 years. A total of 875 cases were scored independently as noninvasive, microinvasive, or invasive cancer, with the last also evaluated for histology grade, type, and lymphatic vascular invasion. Of these, 870 (99.2%) were confirmed malignant, 1 case had cytology only, and 5 were judged by all reviewers as benign. Reviewer complete concordance for the three classes of malignancy was achieved in 826 (95%) and majority agreement in 31 (3.6%) of 870 with complete data. All three readers recorded grade in 736 cancers, giving a kappa statistic of 0.69, 0.52, and 0.66 for grades I, II, and III, respectively, and 0.61 overall. Agreement that the cancer was special type or not was obtained in 671 (89.0%) with complete concordance in the nature of the type in 504 and majority view in 167; another 58 (7.7%) were characterised as "part special" pattern, with type disagreement in 23 (3%). The kappa statistic for single type subcategories in those cancers was substantial, at 0.68 overall. This improved to 0.76 for the last 230 invasive cancers after the pathologists agreed more explicit criteria for type discrimination. There was almost perfect agreement between original and review diagnosis of breast malignancy for both noninvasive/microinvasive and invasive cancer (kappa 0.84 and 0.91, respectively), justifying confidence in the diagnosis of breast cancer by U.K. pathologists. The specialists agreed substantially on qualitative histology features of type and grade of cancers, and improved further for typing by defining criteria. These consensus data, along with invasive size and node status, are reliable for use as surrogate measures of outcome, and to enhance interpretation of effect, when the trial case population sources are disclosed.

Canine model for investigating the impact of oral enrofloxacin on commensal coliforms and colonization with multidrug-resistant Escherichia coli.

A model was developed in dogs to determine the impact of oral enrofloxacin administration on the indigenous coliform population in the gastrointestinal tract and subsequent disposition to colonization by a strain of multidrug-resistant Escherichia coli (MDREC). Dogs given a daily oral dose of 5 mg enrofloxacin kg(-1) for 21 consecutive days showed a significant decline in faecal coliforms to levels below detectable limits by 72 h of administration. Subsequently, faecal coliforms remained suppressed throughout the period of enrofloxacin dosing. Upon termination of antibiotic administration, the number of excreted faecal coliforms slowly returned over an 8-day period, to levels comparable to those seen prior to antibiotic treatment. Enrofloxacin-treated dogs were more effectively colonized by MDREC, evidenced by a significantly increased count of MDREC in the faeces (7.1 +/- 1.5 log(10) g(-1)) compared with non-antibiotic-treated dogs (5.2 +/- 1.2; P = 0.003). Furthermore, antibiotic treatment also sustained a significantly longer period of MDREC excretion in the faeces (26.8 +/- 10.5 days) compared with animals not treated with enrofloxacin (8.5 +/- 5.4 days; P = 0.0215). These results confirm the importance of sustained delivery of an antimicrobial agent to maintain and expand the colonization potential of drug-resistant bacteria in vivo, achieved in part by reducing the competing commensal coliforms in the gastrointestinal tract to below detectable levels in the faeces. Without in vivo antimicrobial selection pressure, commensal coliforms dominated the gastrointestinal tract at the expense of the MDREC population. Conceivably, the model developed could be used to test the efficacy of novel non-antibiotic strategies aimed at monitoring and controlling gastrointestinal colonization by multidrug-resistant members of the Enterobacteriaceae that cause nosocomial infections.

Overseeing research on therapeutic cloning: a private ethics board responds to its critics.

Advanced Cell Technology's Ethics Advisory Board has been called window dressing for a corporate marketing plan. But the scientists and managers have paid attention, and the lawyers have gone along.