Bacteriophage Therapy for Pan-Drug-Resistant Pseudomonas aeruginosa in Two Persons With Cystic Fibrosis.

Cystic fibrosis (CF) is an important monogenic disease that affects more than 70 000 people worldwide. Defects of the CF transmembrane conductance regulator gene lead to dehydrated viscous secretions that result in chronic bacterial colonization. This leads to frequent recurrent lung infections called pulmonary exacerbations, lung inflammation, and resulting structural lung damage called bronchiectasis. Pseudomonas aeruginosa in particular is a common pathogen in persons with CF associated with increased pulmonary exacerbations, long-term lung function decline, and reduced survival. In addition, P. aeruginosa commonly develops antibiotic resistance and forms biofilms, making it difficult to treat. Here, we report the details of two patients with CF with pan-drug-resistant P. aeruginosa who were treated with a novel therapeutic strategy, bacteriophages. These cases highlight the need for further research and development of this treatment modality, including pediatric clinical trials.

Phage therapy in a lung transplant recipient with cystic fibrosis infected with multidrug-resistant Burkholderia multivorans.

BACKGROUND: There is increased interest in bacteriophage (phage) therapy to treat infections caused by antibiotic-resistant bacteria. A lung transplant recipient with cystic fibrosis and Burkholderia multivorans infection was treated with inhaled phage therapy for 7 days before she died. METHODS: Phages were given via nebulization through the mechanical ventilation circuit. Remnant respiratory specimens and serum were collected. We quantified phage and bacterial deoxyribonucleic acid (DNA) using quantitative polymerase chain reaction, and tested phage neutralization in the presence of patient serum. We performed whole genome sequencing and antibiotic and phage susceptibility testing on 15 B. multivorans isolates. Finally, we extracted lipopolysaccharide (LPS) from two isolates and visualized their LPS using gel electrophoresis. RESULTS: Phage therapy was temporally followed by a temporary improvement in leukocytosis and hemodynamics, followed by worsening leukocytosis on day 5, deterioration on day 7, and death on day 8. We detected phage DNA in respiratory samples after 6 days of nebulized phage therapy. Bacterial DNA in respiratory samples decreased over time, and no serum neutralization was detected. Isolates collected between 2001 and 2020 were closely related but differed in their antibiotic and phage susceptibility profiles. Early isolates were not susceptible to the phage used for therapy, while later isolates, including two isolates collected during phage therapy, were susceptible. Susceptibility to the phage used for therapy was correlated with differences in O-antigen profiles of an early versus a late isolate. CONCLUSIONS: This case of clinical failure of nebulized phage therapy highlights the limitations, unknowns, and challenges of phage therapy for resistant infections.

Inhaled Bacteriophage Therapy for Multi-Drug Resistant Achromobacter.

The rise of antimicrobial resistant (AMR) bacteria is a global public health threat. AMR Achromobacter bacteria pose a challenging clinical problem, particularly for those with cystic fibrosis (CF) who are predisposed to chronic bacterial lung infections. Lytic bacteriophages (phages) offer a potential alternative to treat AMR infections, with the possible benefit that phage selection for resistance in target bacteria might coincide with reduced pathogenicity. The result is a genetic "trade-off," such as increased sensitivity to chemical antibiotics, and/or decreased virulence of surviving bacteria that are phage resistant. Here, we show that two newly discovered lytic phages against Achromobacter were associated with stabilization of respiratory status when deployed to treat a chronic pulmonary infection in a CF patient using inhaled (nebulized) phage therapy. The two phages demonstrate traits that could be generally useful in their development as therapeutics, especially the possibility that the phages can select for clinically useful trade-offs if bacteria evolve phage resistance following therapy. We discuss the limitations of the current study and suggest further work that should explore whether the phages could be generally useful in targeting pulmonary or other Achromobacter infections in CF patients.

Surgical management of suspected gallbladder cancer: The role of intraoperative frozen section for diagnostic confirmation.

BACKGROUND: Preoperative diagnosis for suspected gallbladder cancers is challenging, with a risk of overtreating benign disease, for example, xanthogranulomatous cholecystitis, with radical cholecystectomies. We retrospectively evaluated the surgeon's intraoperative assessment alone, and with the addition of intraoperative frozen sections, for suspected gallbladder cancers from a tertiary hepatobiliary multidisciplinary team (MDT). METHODS: MDT patients with complex gallbladder disease were included. Collated data included demographics, MDT discussion, operative details, and patient outcomes. RESULTS: A total of 454 patients with complex gallbladder disease were reviewed, 48 (10.6%) were offered radical surgery for suspected cancer. Twenty-five underwent frozen section that led to radical surgery in 6 (25%). All frozen sections were congruent with final histopathology but doubled the operating time (p < 0.0001). Both the surgeon's subjective and additional frozen section's objective assessment, allowed for de-escalation of unnecessary radical surgery, comparing favourably to a 13.0% cancer diagnosis among radical surgery historically. CONCLUSIONS: The MDT process was highly sensitive in identifying gallbladder cancers but lacked specificity. The surgeon's intraoperative assessment is paramount in suspected cancers, and deescalated unnecessary radical surgery. Intraoperative frozen section was a safe and viable adjunct at a cost of resources and operative time.

Hydrogen peroxide vapor decontamination of N95 respirators for reuse.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has led to global shortages of N95 respirators. Reprocessing of used N95 respirators may provide a higher filtration crisis alternative, but whether effective sterilization can be achieved for a virus without impairing respirator function remains unknown. We evaluated the viricidal efficacy of Bioquell vaporized hydrogen peroxide (VHP) on contaminated N95 respirators and tested the particulate particle penetration and inhalation and exhalation resistance of respirators after multiple cycles of VHP. METHODS: For this study, 3M 1870 N95 respirators were contaminated with 3 aerosolized bacteriophages: T1, T7, and Pseudomonas phage phi-6 followed by 1 cycle of VHP decontamination using a BQ-50 system. Additionally, new and unused respirators were sent to an independent laboratory for particulate filter penetration testing and inhalation and exhalation resistance after 3 and 5 cycles of VHP. RESULTS: A single VHP cycle resulted in complete eradication of bacteriophage from respirators (limit of detection 10 PFU). Respirators showed acceptable limits for inhalation/exhalation resistance after 3 and 5 cycles of VHP. Respirators demonstrated a filtration efficiency >99 % after 3 cycles, but filtration efficiency fell below 95% after 5 cycles of HPV. CONCLUSION: Bioquell VHP demonstrated high viricidal activity for N95 respirators inoculated with aerosolized bacteriophages. Bioquell technology can be scaled for simultaneous decontamination of a large number of used but otherwise intact respirators. Reprocessing should be limited to 3 cycles due to concerns both about impact of clinical wear and tear on fit, and to decrement in filtration after 3 cycles.

Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration.

BACKGROUND AND AIMS: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration. APPROACH AND RESULTS: Wild-type and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two-thirds partial hepatectomy. Using translational noninvasive imaging techniques, CDDO-Me was shown to enhance the rate of restoration of liver volume (MRI) and improve liver function (multispectral optoacoustic imaging of indocyanine green clearance) in wild-type, but not Nrf2 null, mice following partial hepatectomy. Using immunofluorescence imaging and whole transcriptome analysis, these effects were found to be associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic adaptation in the remnant liver tissue. Similar processes were modulated following exposure of primary human hepatocytes to CDDO-Me, highlighting the potential relevance of our findings to patients. CONCLUSIONS: Our results indicate that pharmacological activation of Nrf2 is a promising strategy for enhancing functional liver regeneration. Such an approach could therefore aid the recovery of patients undergoing liver surgery and support the treatment of acute and chronic liver disease.

Successful Treatment of a Recalcitrant Staphylococcus epidermidis Prosthetic Knee Infection with Intraoperative Bacteriophage Therapy.

Here, we present a case of a 79-year-old female with a recalcitrant Staphylococcal epidermidis prosthetic knee infection that was successfully treated with a single dose of adjuvant intra-articular bacteriophage therapy after debridement and implant retention surgery. The bacteriophage used in this case, PM448, is the first ɛ2 bacteriophage to be used in vivo. Currently the patient is without evidence of clinical recurrence and, interestingly, the patient had also suffered from debilitating aplastic anemia for over 2 years, which is recovering since receiving adjuvant bacteriophage therapy.

Bacteriophage therapy for infections in CF.

Pseudomonas aeruginosa and Staphylococcus aureus are bacterial pathogens frequently associated with pulmonary complications and disease progression in cystic fibrosis (CF). However, these bacteria increasingly show resistance to antibiotics, necessitating novel management strategies. One possibility is bacteriophage (phages; bacteria-specific viruses) therapy, where lytic phages are administered to kill target bacterial pathogens. Recent publications of case reports of phage therapy to treat antibiotic-resistant lung infections in CF have garnered significant attention. These cases exemplify the renewed interest in phage therapy, an older concept that is being newly updated to include rigorous collection and analysis of patient data to assess clinical benefit, which will inform the development of clinical trials. As outcomes of these trials become public, the results will valuable gauge the potential usefulness of phage therapy to address the rise in antibiotic-resistant bacterial infections. In addition, we highlight the further need for basic research to accurately predict the different responses of target bacterial pathogens when phages are administered alone, sequentially, or as mixtures (cocktails), and whether within-cocktail interactions among phages hold consequences for the efficacy of phage therapy in patient treatment.

Effects on Mouse Food Consumption After Exposure to Bedding from Sick Mice or Healthy Mice.

Control mice housed in the same room as mice with pancreatic ductal adenocarcinoma (PDAC) demonstrate decreased food intake coincident with the cachexia experienced by the mice with PDAC. Mice are considered an empathetic species, and we hypothesized that the reduced food intake in normal mice was an "empathy state" that was mediated by olfactory cues. Naïve male and female C57BL/6 mice were exposed to soiled bedding from mice experiencing PDAC induced cachexia or from control mice in the PDAC study. Body weight, food intake, and food spillage were measured across 48 h. Statistically significant differences in food consumption were found at various time points in both positive and negative directions for the 2 bedding conditions, and the direction of effect was opposite for males and females. Although analysis of data from previous PDAC studies showed differences in food spillage between PDAC mice and their controls, in this study we found no correlation between food consumption and food spillage based on bedding type. Disruption of food intake due to the "empathy state" requires testing larger numbers of animals to attain appropriate statistical power, which is contrary to the goal of using fewer animals. Empathy effects require careful consideration of sample size and cautious interpretation of results. This study also highlights the importance of sex as a biologic variable and why quantifying food spillage is important in studies of food intake.

Phage steering of antibiotic-resistance evolution in the bacterial pathogen, Pseudomonas aeruginosa.

BACKGROUND AND OBJECTIVES: Antimicrobial resistance is a growing global concern and has spurred increasing efforts to find alternative therapeutics. Bacteriophage therapy has seen near constant use in Eastern Europe since its discovery over a century ago. One promising approach is to use phages that not only reduce bacterial pathogen loads but also select for phage resistance mechanisms that trade-off with antibiotic resistance-so called 'phage steering'. METHODOLOGY: Recent work has shown that the phage OMKO1 can interact with efflux pumps and in so doing select for both phage resistance and antibiotic sensitivity of the pathogenic bacterium Pseudomonas aeruginosa. We tested the robustness of this approach to three different antibiotics in vitro (tetracycline, erythromycin and ciprofloxacin) and one in vivo (erythromycin). RESULTS: We show that in vitro OMKO1 can reduce antibiotic resistance of P. aeruginosa (Washington PAO1) even in the presence of antibiotics, an effect still detectable after ca.70 bacterial generations in continuous culture with phage. Our in vivo experiment showed that phage both increased the survival times of wax moth larvae (Galleria mellonella) and increased bacterial sensitivity to erythromycin. This increased antibiotic sensitivity occurred both in lines with and without the antibiotic. CONCLUSIONS AND IMPLICATIONS: Our study supports a trade-off between antibiotic resistance and phage sensitivity. This trade-off was maintained over co-evolutionary time scales even under combined phage and antibiotic pressure. Similarly, OMKO1 maintained this trade-off in vivo, again under dual phage/antibiotic pressure. Our findings have implications for the future clinical use of steering in phage therapies. Lay Summary: Given the rise of antibiotic-resistant bacterial infection, new approaches to treatment are urgently needed. Bacteriophages (phages) are bacterial viruses. The use of such viruses to treat infections has been in near-continuous use in several countries since the early 1900s. Recent developments have shown that these viruses are not only effective against routine infections but can also target antibiotic resistant bacteria in a novel, unexpected way. Similar to other lytic phages, these so-called 'steering phages' kill the majority of bacteria directly. However, steering phages also leave behind bacterial variants that resist the phages, but are now sensitive to antibiotics. Treatment combinations of these phages and antibiotics can now be used to greater effect than either one independently. We evaluated the impact of steering using phage OMKO1 and a panel of three antibiotics on Pseudomonas aeruginosa, an important pathogen in hospital settings and in people with cystic fibrosis. Our findings indicate that OMKO1, either alone or in combination with antibiotics, maintains antibiotic sensitivity both in vitro and in vivo, giving hope that phage steering will be an effective treatment option against antibiotic-resistant bacteria.

SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions.

We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.

The impact of an operative note proforma at a paediatric surgical centre.

RATIONALE, AIMS AND OBJECTIVES: With expectations for standardization and evidence-based practice, the Royal College of Surgeons (RCS) published the 'Good Surgical Practice' in 2008. The document sets standards for operative records anticipating improved documentation, audits, medico-legal review and quality and safety of handover. We evaluated (1) documentation against RCS standards; (2) whether RCS standards are applicable to and adequate for paediatric surgery; and (3) the impact of a standardized operative proforma. METHODS: All general surgery and urology admissions during July 2011 and August 2012 were retrospectively reviewed using 23 set criteria. An operative note proforma was introduced in February 2012. Results were compared and statistically analysed using two-tailed Fisher's exact test, with Bonferroni correction where appropriate (SPSS 20.0, IBM SPSS Statistics, Armonk, NY, USA). RESULTS: There were 345 children admitted; 63.2% underwent an operation (119 in 2011 versus 99 in 2012); 55% of operations were day cases. The initial audit noted poor documentation in 7 of 23 criteria. Following introduction of the operative note proforma, documentation improved significantly: patient identifiers by 12.3%, procedure time 43.3%, assistant's name 31.9%, procedure type 21.4%, closure 6.2%, anaesthetist's name 15.9%, anaesthetic type 56.8% and surgeons grade 65.8% (P<0.05). Subgroup analysis in the latter cohort shows most of these effects to be related to the use of the proforma rather than education alone (P<0.05). Quality of documentation was better by consultants versus trainees in 2 of 23 criteria (P<0.05). CONCLUSION: We have demonstrated a simple and cost-effective way of improving the quality of operative documentation, in line with guidelines set out by the RCS, in a climate of increasing economic austerity.

Localization techniques for guided surgical excision of non-palpable breast lesions.

BACKGROUND: Breast cancer is the most common form of cancer and the second leading cause of death amongst women in Europe. Amongst five invasive cancers per 1000 women detected in screening, 2.7 were < 15 mm in diameter; and others reported that over one third of excised breast lesions were clinically occult. The challenge is to accurately locate small non-palpable lesions intraoperatively for optimal therapeutic outcome. A secondary important goal is to remove the smallest amount possible of healthy glandular tissue for optimal cosmesis. Currently the most widely adopted approach (80% in one survey) in guided breast-conserving surgery for excising non-palpable breast lesions is wire-guided localization (WGL). With the clinical setting shifting towards earlier non-palpable breast lesions being detected through screening, we investigated whether the current standard in assisting surgical excision of these lesions, WGL, yields the best therapeutic outcome for women with breast cancer. OBJECTIVES: To assess the therapeutic outcomes of any new form of guided surgical intervention for non-palpable breast lesions against wire-guided localization, the current gold standard. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's (CBCG) Specialized Register, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal from the earliest available date up to 30 March 2015. We also handsearched recent conference proceedings and sought information from experts in the field. SELECTION CRITERIA: Two review authors, BC and RJ, independently screened by title and abstract the studies we had identified through the search strategy; when this was inconclusive, they examined the full-text article for inclusion. We resolved any discrepancies regarding eligibility by discussion with a third review author, RA. DATA COLLECTION AND ANALYSIS: Three review authors, BC, JW, and RJ, independently extracted data using a standardized data sheet. We performed all analyses using Review Manager (RevMan) or the R meta package, and in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. We reported results via a graphical assessment using forest plots showing the study estimates. We considered and discussed additional subgroup and sensitivity analyses. MAIN RESULTS: We identified 11 randomized controlled trials (RCTs) that met the inclusion criteria of this Cochrane review and included eight trials in the meta-analyses. Six RCTs compared radioguided occult lesion localization (ROLL) versus WGL, and two RCTs compared radioactive iodine ((125)I) seed localization (RSL) versus WGL. Of the three remaining trials, one RCT compared cryo-assisted techniques (CAL) versus WGL, one compared intraoperative ultrasound-guided lumpectomy (IOUS) versus WGL, and one compared modified ROLL technique in combination with methylene dye (RCML) versus WGL. Of the trials we included in the meta-analysis, there were a total of 1273 participants with non-palpable breast lesions (627 participants (WGL); 443 participants (ROLL); and 203 participants (RSL)). The participant population varied considerably between included trials, which included participants with both non-palpable benign and malignant lesions, and varied in defining clear margins. The included trials did not report any long-term outcomes.In general, the outcomes of WGL, ROLL and RSL were comparable.ROLL demonstrated favourable results in successful localization (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.16 to 2.28; 869 participants; six trials), positive excision margins (RR 0.74, 95% CI 0.42 to 1.29; 517 participants; five trials), and re-operation rates (RR 0.51, 95% CI 0.21 to 1.23; 583 participants; four trials) versus WGL, but none were statistically significant. WGL was significantly superior to RSL in successfully localizing non-palpable lesions (RR 3.85, 95% CI 1.21 to 12.19; 402 participants; two trials). However, for successful excision, ROLL and RSL have comparable outcomes versus WGL (ROLL versus WGL: RR 1.00, 95% CI 0.99 to 1.01; 871 participants; six trials; RSL versus WGL: RR 1.00, 95% CI 0.99 to 1.01; 402 participants; two trials). These findings were similar in that RSL demonstrated favourable results over WGL in positive tumour margins (RR 0.67, 95% CI 0.43 to 1.06; 366 participants; two trials), and re-operation rates (RR 0.80, 95% CI 0.48 to 1.32; 305 participants; one trial) but neither reached statistical significance. In contrast, WGL had fewer postoperative complications to both ROLL (RR 1.18, 95% CI 0.71 to 1.98; 642 participants; four trials) and RSL (RR 1.51, 95% CI 0.75 to 3.03; 305 participants; one trial), although this was also not statistically significant.The overall quality of evidence was good. The main risk of bias amongst included studies consisted of incomplete data sets, selective reporting, and allocation concealment. Interpretation and applicability of this meta-analysis was hindered by the mixed indication of diagnostic versus therapeutic purposes when undertaking WGL, ROLL, or RSL, leading to a high level of mixed pathology in numerous trials. Other limitations include underpowered studies, lack of data in standardized format for meta-analysis, lack of complete data amongst the trials, and absence of long-term data. AUTHORS' CONCLUSIONS: Owing to a lack of trials in certain localization techniques, we could only draw conclusions about ROLL and RSL versus WGL. There is no clear evidence to support one guided technique for surgically excising a non-palpable breast lesion over another. Results from this Cochrane review support the continued use of WGL as a safe and tested technique that allows for flexibility in selected cases when faced with extensive microcalcification. ROLL and RSL could be offered to patients as a comparable replacement for WGL as they are equally reliable. Other techniques such as IOUS, RCML, and CAL are of academic interest, but recommendation for routine use in the clinical environment and oncological outcomes require further validation. The results of this Cochrane review also stress the need for more fully powered RCTs to evaluate the best technique according to the comprehensive criteria described, with a more consistent and standardized approach in outcome reporting.

Exploiting antitumor immunity to overcome relapse and improve remission duration.

Cancer survivors often relapse due to evolving drug-resistant clones and repopulating tumor stem cells. Our preclinical study demonstrated that terminal cancer patient's lymphocytes can be converted from tolerant bystanders in vivo into effective cytotoxic T-lymphocytes in vitro killing patient's own tumor cells containing drug-resistant clones and tumor stem cells. We designed a clinical trial combining peginterferon α-2b with imatinib for treatment of stage III/IV gastrointestinal stromal tumor (GIST) with the rational that peginterferon α-2b serves as danger signals to promote antitumor immunity while imatinib's effective tumor killing undermines tumor-induced tolerance and supply tumor-specific antigens in vivo without leukopenia, thus allowing for proper dendritic cell and cytotoxic T-lymphocyte differentiation toward Th1 response. Interim analysis of eight patients demonstrated significant induction of IFN-γ-producing-CD8(+), -CD4(+), -NK cell, and IFN-γ-producing-tumor-infiltrating-lymphocytes, signifying significant Th1 response and NK cell activation. After a median follow-up of 3.6 years, complete response (CR) + partial response (PR) = 100%, overall survival = 100%, one patient died of unrelated illness while in remission, six of seven evaluable patients are either in continuing PR/CR (5 patients) or have progression-free survival (PFS, 1 patient) exceeding the upper limit of the 95% confidence level of the genotype-specific-PFS of the phase III imatinib-monotherapy (CALGB150105/SWOGS0033), demonstrating highly promising clinical outcomes. The current trial is closed in preparation for a larger future trial. We conclude that combination of targeted therapy and immunotherapy is safe and induced significant Th1 response and NK cell activation and demonstrated highly promising clinical efficacy in GIST, thus warranting development in other tumor types.

Surveillance after treatment for cervical intraepithelial neoplasia: outcomes, costs, and cost-effectiveness.

OBJECTIVE: To estimate outcomes and costs of surveillance strategies after treatment for high-grade cervical intraepithelial neoplasia (CIN). METHODS: A hypothetical cohort of women was evaluated after treatment for CIN 2 or 3 using a Markov model incorporating data from a large study of women treated for CIN, systematic reviews of test accuracy, and individual preferences. Surveillance strategies included initial conventional or liquid-based cytology, human papillomavirus testing, or colposcopy 6 months after treatment, followed by annual or triennial cytology. Estimated outcomes included CIN, cervical cancer, cervical cancer deaths, life expectancy, costs, cost per life-year, and cost per quality-adjusted life-year. RESULTS: Conventional cytology at 6 and 12 months, followed by triennial cytology, was least costly. Compared with triennial cytology, annual cytology follow-up reduced expected cervical cancer deaths by 73% to 77% and had an average incremental cost per life-year gained of $69,000 to $81,000. For colposcopy followed by annual cytology, the incremental cost per life-year gained ranged from $70,000 to more than $1 million, depending on risk. Between-strategy differences in mean additional life expectancy per woman were less than 4 days; differences in mean incremental costs per woman were as high as $822. In the cost-utility analysis, colposcopy at 6 months followed by annual cytology had an incremental cost per quality-adjusted life-year of less than $5,500. Human papillomavirus testing or liquid-based cytology added little to no improvement to life-expectancy with higher costs. CONCLUSION: Annual conventional cytology surveillance reduced cervical cancers and cancer deaths compared with triennial cytology. For high risk of recurrence, a strategy of colposcopy at 6 months increased life expectancy and quality-adjusted life expectancy. Human papillomavirus testing and liquid-based cytology increased costs, but not effectiveness, compared with traditional approaches.

Screening for breast cancer: an update for the U.S. Preventive Services Task Force.

BACKGROUND: This systematic review is an update of evidence since the 2002 U.S. Preventive Services Task Force recommendation on breast cancer screening. PURPOSE: To determine the effectiveness of mammography screening in decreasing breast cancer mortality among average-risk women aged 40 to 49 years and 70 years or older, the effectiveness of clinical breast examination and breast self-examination, and the harms of screening. DATA SOURCES: Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2008), MEDLINE (January 2001 to December 2008), reference lists, and Web of Science searches for published studies and Breast Cancer Surveillance Consortium for screening mammography data. STUDY SELECTION: Randomized, controlled trials with breast cancer mortality outcomes for screening effectiveness, and studies of various designs and multiple data sources for harms. DATA EXTRACTION: Relevant data were abstracted, and study quality was rated by using established criteria. DATA SYNTHESIS: Mammography screening reduces breast cancer mortality by 15% for women aged 39 to 49 years (relative risk, 0.85 [95% credible interval, 0.75 to 0.96]; 8 trials). Data are lacking for women aged 70 years or older. Radiation exposure from mammography is low. Patient adverse experiences are common and transient and do not affect screening practices. Estimates of overdiagnosis vary from 1% to 10%. Younger women have more false-positive mammography results and additional imaging but fewer biopsies than older women. Trials of clinical breast examination are ongoing; trials for breast self-examination showed no reductions in mortality but increases in benign biopsy results. LIMITATION: Studies of older women, digital mammography, and magnetic resonance imaging are lacking. CONCLUSION: Mammography screening reduces breast cancer mortality for women aged 39 to 69 years; data are insufficient for older women. False-positive mammography results and additional imaging are common. No benefit has been shown for clinical breast examination or breast self-examination.

Periodontal health of older men: the MrOS dental study.

OBJECTIVE: The purpose of this study was to evaluate the prevalence and severity of periodontitis in men of 65+ years and identify demographic and lifestyle factors associated with its presence. METHODS: Participants were recruited from the Osteoporotic Fractures in Men Study, a longitudinal study of risk factors for fractures in older men. Dental measures included clinical attachment loss (CAL), pocket depth (PD), calculus, plaque and bleeding on a random half-mouth, plus a questionnaire regarding access to care, symptoms and previous diagnosis. RESULTS: 1210 dentate men completed the dental visit. Average age was 75 years, 39% reported some graduate school education, 32% smoked 20 + pack years and 88% reported their overall health as excellent/good. In terms of periodontal health, 38% had sub-gingival calculus, 53% gingival bleeding, 82% CAL > or =5 mm and 34% PD > or =6 mm. The prevalence of severe periodontitis was 38%. Significant demographic and lifestyle factors associated with severe periodontitis in multivariate analyses included age > or =75 (OR 1.4, 95% CI 1.1-1.7) non-white race (OR 1.9, 95% CI 1.3-2.8), less than an annual dental visit (OR 1.5, 95% CI 1.1-2.0), and 20 + pack years (OR 2.1, 95% CI 1.6-2.7). CONCLUSION: A high proportion of healthy older men have evidence of periodontal destruction which could, given the growing ageing population, have a significant impact on the dental profession's ability to provide preventive and therapeutic care. The population at highest risk of periodontitis in MrOS is older minority men who smoke and do not have annual dental visits.

Posttreatment human papillomavirus testing for recurrent cervical intraepithelial neoplasia: a systematic review.

OBJECTIVE: We conducted a systematic review to evaluate the characteristics of human papillomavirus testing, particularly Hybrid Capture 2, in follow-up evaluations after treatment for cervical intraepithelial neoplasia for the detection of residual or recurrent cervical intraepithelial neoplasia grade >/= 2. STUDY DESIGN: Medline was searched for relevant studies that were published between 1992 and September 2007. Of the 1107 citations that were identified, 20 articles met the inclusion criteria. RESULTS: Studies that used polymerase chain reaction testing were too heterogeneous to combine. We identified 5 studies that performed both Hybrid Capture 2 and colposcopy. Pooled sensitivity for Hybrid Capture 2 was 90.7% (95% CI, 75.4-96.9%), and pooled specificity was 74.6% (95% CI, 60.4-85.0%). Pooled sensitivity for cervical cytologic testing was 76.6% (95% CI, 62.0-86.8%), and pooled specificity was 89.7% (95% CI, 22.7-99.6%). CONCLUSION: Hybrid Capture 2 testing can identify approximately 91% of women with residual or recurrent cervical intraepithelial neoplasia grade >/= 2; however, approximately 30% of women would undergo colposcopy in follow-up evaluation.

The effect of antireflux surgery on esophageal carcinogenesis in patients with barrett esophagus: a systematic review.

OBJECTIVE: To determine whether patients with Barrett esophagus who undergo antireflux surgery differ from medically treated patients in incidence of esophageal adenocarcinoma and probability of disease regression/progression. SUMMARY BACKGROUND DATA: Barrett esophagus is a risk factor for the development of esophageal adenocarcinoma. A question exists as to whether antireflux surgery reduces this risk. METHODS: Query of PubMed (1966 through October 2005) using predetermined search terms revealed 2011 abstracts, of which 100 full-text articles were reviewed. Twenty-five articles met selection criteria. A review of article references and consultation with experts revealed additional articles for inclusion. Studies that enrolled adults with biopsy-proven Barrett esophagus, specified treatment-type rendered, followed up patients with endoscopic biopsies no less than12 months of instituting therapy, and provided adequate extractable data. The incidence of adenocarcinoma and the proportion of patients developing progression or regression of Barrett esophagus and/or dysplasia were extracted. RESULTS: In surgical and medical groups, 700 and 996 patients were followed for a total of 2939 and 3711 patient-years, respectively. The incidence rate of esophageal adenocarcinoma was 2.8 (95% confidence interval, 1.2-5.3) per 1000 patient-years among surgically treated patients and 6.3 (3.6-10.1) among medically treated patients (P = 0.034). Heterogeneity in incidence rates in surgically treated patients was observed between controlled studies and case series (P = 0.014). Among controlled studies, incidence rates were 4.8 (1.7-11.1) and 6.5 (2.6-13.8) per 1000 patient-years in surgical and medical patients, respectively (P = 0.320). Probability of progression was 2.9% (1.2-5.5) in surgical patients and 6.8% (2.6-12.1) in medical patients (P = 0.054). Probability of regression was 15.4% (6.1-31.4) in surgical patients and 1.9% (0.4-7.3) in medical patients (P = 0.004). CONCLUSIONS: Antireflux surgery is associated with regression of Barrett esophagus and/or dysplasia. However, evidence suggesting that surgery reduces the incidence of adenocarcinoma is largely driven by uncontrolled studies.

The effectiveness of primary care-based interventions to promote breastfeeding: systematic evidence review and meta-analysis for the US Preventive Services Task Force.

PURPOSE: We wanted to systematically review whether primary care-based interventions improve initiation and duration of breastfeeding. METHODS: Studies were found by searching MEDLINE (1966-2001), Health-STAR, the Cochrane Database of Systematic Reviews, the National Health Service Centre for Reviews and Dissemination Databases, and bibliographies of identified trials and review articles. Studies were included if they originated in the primary care setting and were conducted in a developed country, written in English, and contained a concurrent control group. RESULTS: Thirty randomized and nonrandomized controlled trials and 5 systematic reviews of breastfeeding counseling were included. Educational programs had the greatest effect of any single intervention on both initiation (difference 0.23; 95% confidence interval [CI], 0.12-0.34) and short-term duration (difference 0.39; 95% CI, 0.27-0.50). Support programs conducted by telephone, in person, or both increased short-term (difference 0.11; 95% CI, 0.03-0.19) and long-term duration (difference 0.08; 95% CI, 0.02-0.16). In contrast, written materials such as pamphlets did not significantly increase breastfeeding. Data were insufficient to determine whether the combination of education with support was more effective than education alone. CONCLUSIONS: Educational programs were the most effective single intervention. One woman would breast-feed for up to 3 months for every 3 to 5 women attending breastfeeding educational programs. Future research and policy should focus on translating these findings into more widespread practice in diverse primary care settings.