Plasma Proteomic Signature Predicts Myeloid Neoplasm Risk.

PURPOSE: Clonal hematopoiesis (CH) is thought to be the origin of myeloid neoplasms (MN). Yet, our understanding of the mechanisms driving CH progression to MN and clinical risk prediction of MN remains limited. The human proteome reflects complex interactions between genetic and epigenetic regulation of biological systems. We hypothesized that the plasma proteome might predict MN risk and inform our understanding of the mechanisms promoting MN development. EXPERIMENTAL DESIGN: We jointly characterized CH and plasma proteomic profiles of 46,237 individuals in the UK Biobank at baseline study entry. During 500,036 person-years of follow-up, 115 individuals developed MN. Cox proportional hazard regression was used to test for an association between plasma protein levels and MN risk. RESULTS: We identified 115 proteins associated with MN risk, of which 30% (N = 34) were also associated with CH. These were enriched for known regulators of the innate and adaptive immune system. Plasma proteomics improved the prediction of MN risk (AUC = 0.85; P = 5×10-9) beyond clinical factors and CH (AUC = 0.80). In an independent group (N = 381,485), we used inherited polygenic risk scores (PRS) for plasma protein levels to validate the relevance of these proteins toMNdevelopment. PRS analyses suggest that most MN-associated proteins we identified are not directly causally linked toMN risk, but rather represent downstream markers of pathways regulating the progression of CH to MN. CONCLUSIONS: These data highlight the role of immune cell regulation in the progression of CH to MN and the promise of leveraging multi-omic characterization of CH to improveMN risk stratification. See related commentary by Bhalgat and Taylor, p. 3095.

Stabilizing the Proteomes of Acute Myeloid Leukemia Cells: Implications for Cancer Proteomics.

Previous work has shown that inhibition of abundant myeloid azurophil granule-associated serine proteases (ELANE [neutrophil elastase], PRTN3 [protease 3], and CTSG [Cathepsin G]) is required to stabilize some proteins in myeloid cells. We therefore hypothesized that effective inhibition of these proteases may be necessary for quantitative proteomic analysis of samples containing myeloid cells. To test this hypothesis, we thawed viably preserved acute myeloid leukemia cells from cryovials in the presence or the absence of diisopropyl fluorophosphate (DFP), a cell-permeable and irreversible serine protease inhibitor. Global proteomic analysis was performed, using label-free and isobaric peptide-labeling quantitation. The presence of DFP resulted in an increase of tryptic peptides (14-57%) and proteins (9-31%). In the absence of DFP, 11 to 31% of peptide intensity came from nontryptic peptides; 52 to 75% had cleavage specificity consistent with activities of ELANE-PRTN3. Treatment with DFP reduced the intensity of nontryptic peptides to 4-8% of the total. ELANE inhibition was 95%, based on diisopropyl phosphate modification of active site serine residue. Overall, the relative abundance of 20% of proteins was significantly altered by DFP treatment. These results suggest that active myeloid serine proteases, released during sample processing, can skew quantitative proteomic measurements. Finally, significant ELANE activity was also detected in Clinical Proteomics Tumor Analysis Consortium datasets of solid tumors (many of which have known myeloid infiltration). In the pancreatic cancer dataset, the median percentage of nontryptic intensity detected across patient samples was 34%, with many patient samples having more than half of their detected peptide intensity from nontryptic cleavage events consistent with ELANE-PRTN3 cleavage specificity. Our study suggests that in vitro cleavage of proteins by myeloid serine proteases may be relevant for proteomic studies of any tumor that contains infiltrating myeloid cells.

Proteomic and phosphoproteomic landscapes of acute myeloid leukemia.

We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow-derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and related signaling proteins. PML-RARA-initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis.

Active Interaction Mapping Reveals the Hierarchical Organization of Autophagy.

We have developed a general progressive procedure, Active Interaction Mapping, to guide assembly of the hierarchy of functions encoding any biological system. Using this process, we assemble an ontology of functions comprising autophagy, a central recycling process implicated in numerous diseases. A first-generation model, built from existing gene networks in Saccharomyces, captures most known autophagy components in broad relation to vesicle transport, cell cycle, and stress response. Systematic analysis identifies synthetic-lethal interactions as most informative for further experiments; consequently, we saturate the model with 156,364 such measurements across autophagy-activating conditions. These targeted interactions provide more information about autophagy than all previous datasets, producing a second-generation ontology of 220 functions. Approximately half are previously unknown; we confirm roles for Gyp1 at the phagophore-assembly site, Atg24 in cargo engulfment, Atg26 in cytoplasm-to-vacuole targeting, and Ssd1, Did4, and others in selective and non-selective autophagy. The procedure and autophagy hierarchy are at http://atgo.ucsd.edu/.

Mapping functional transcription factor networks from gene expression data.

A critical step in understanding how a genome functions is determining which transcription factors (TFs) regulate each gene. Accordingly, extensive effort has been devoted to mapping TF networks. In Saccharomyces cerevisiae, protein-DNA interactions have been identified for most TFs by ChIP-chip, and expression profiling has been done on strains deleted for most TFs. These studies revealed that there is little overlap between the genes whose promoters are bound by a TF and those whose expression changes when the TF is deleted, leaving us without a definitive TF network for any eukaryote and without an efficient method for mapping functional TF networks. This paper describes NetProphet, a novel algorithm that improves the efficiency of network mapping from gene expression data. NetProphet exploits a fundamental observation about the nature of TF networks: The response to disrupting or overexpressing a TF is strongest on its direct targets and dissipates rapidly as it propagates through the network. Using S. cerevisiae data, we show that NetProphet can predict thousands of direct, functional regulatory interactions, using only gene expression data. The targets that NetProphet predicts for a TF are at least as likely to have sites matching the TF's binding specificity as the targets implicated by ChIP. Unlike most ChIP targets, the NetProphet targets also show evidence of functional regulation. This suggests a surprising conclusion: The best way to begin mapping direct, functional TF-promoter interactions may not be by measuring binding. We also show that NetProphet yields new insights into the functions of several yeast TFs, including a well-studied TF, Cbf1, and a completely unstudied TF, Eds1.

Communicable diseases prioritized for surveillance and epidemiological research: results of a standardized prioritization procedure in Germany, 2011.

INTRODUCTION: To establish strategic priorities for the German national public health institute (RKI) and guide the institute's mid-term strategic decisions, we prioritized infectious pathogens in accordance with their importance for national surveillance and epidemiological research. METHODS: We used the Delphi process with internal (RKI) and external experts and a metric-consensus approach to score pathogens according to ten three-tiered criteria. Additional experts were invited to weight each criterion, leading to the calculation of a median weight by which each score was multiplied. We ranked the pathogens according to the total weighted score and divided them into four priority groups. RESULTS: 127 pathogens were scored. Eighty-six experts participated in the weighting; "Case fatality rate" was rated as the most important criterion. Twenty-six pathogens were ranked in the highest priority group; among those were pathogens with internationally recognised importance (e.g., Human Immunodeficiency Virus, Mycobacterium tuberculosis, Influenza virus, Hepatitis C virus, Neisseria meningitides), pathogens frequently causing large outbreaks (e.g., Campylobacter spp.), and nosocomial pathogens associated with antimicrobial resistance. Other pathogens in the highest priority group included Helicobacter pylori, Respiratory Syncytial Virus, Varicella zoster virus and Hantavirus. DISCUSSION: While several pathogens from the highest priority group already have a high profile in national and international health policy documents, high scores for other pathogens (e.g., Helicobacter pylori, Respiratory syncytial virus or Hantavirus) indicate a possible under-recognised importance within the current German public health framework. A process to strengthen respective surveillance systems and research has been started. The prioritization methodology has worked well; its modular structure makes it potentially useful for other settings.

Strengthening systems for communicable disease surveillance: creating a laboratory network in Rwanda.

BACKGROUND: The recent emergence of a novel strain of influenza virus with pandemic potential underscores the need for quality surveillance and laboratory services to contribute to the timely detection and confirmation of public health threats. To provide a framework for strengthening disease surveillance and response capacities in African countries, the World Health Organization Regional Headquarters for Africa (AFRO) developed Integrated Disease Surveillance and Response (IDSR) aimed at improving national surveillance and laboratory systems. IDSR emphasizes the linkage of information provided by public health laboratories to the selection of relevant, appropriate and effective public health responses to disease outbreaks. METHODS: We reviewed the development of Rwanda's National Reference Laboratory (NRL) to understand essential structures involved in creating a national public health laboratory network. We reviewed documents describing the NRL's organization and record of test results, conducted site visits, and interviewed health staff in the Ministry of Health and in partner agencies. Findings were developed by organizing thematic categories and grouping examples within them. We purposefully sought to identify success factors as well as challenges inherent in developing a national public health laboratory system. RESULTS: Among the identified success factors were: a structured governing framework for public health surveillance; political commitment to promote leadership for stronger laboratory capacities in Rwanda; defined roles and responsibilities for each level; coordinated approaches between technical and funding partners; collaboration with external laboratories; and use of performance results in advocacy with national stakeholders. Major challenges involved general infrastructure, human resources, and budgetary constraints. CONCLUSIONS: Rwanda's experience with collaborative partnerships contributed to creation of a functional public health laboratory network.

Prevalence and factors affecting home blood pressure documentation in routine clinical care: a retrospective study.

BACKGROUND: Home blood pressure (BP) is closely linked to patient outcomes. However, the prevalence of its documentation has not been examined. The objective of this study was to analyze the prevalence and factors affecting documentation of home BP in routine clinical care. METHODS: A retrospective study of 142,973 encounters of 9,840 hypertensive patients with diabetes from 2000 to 2005 was performed. The prevalence of recorded home BP and the factors associated with its documentation were analyzed. We assessed validity of home BP information by comparing the difference between home and office BP to previously published prospective studies. RESULTS: Home BP was documented in narrative notes for 2.08% of encounters where any blood pressure was recorded and negligibly in structured data (EMR flowsheets). Systolic and diastolic home BP in narrative notes were lower than office BP readings by 9.6 and 2.5 mm Hg, respectively (p < 0.0001 for both), consistent with prospective data. Probability of home BP documentation increased by 23.0% for each 10 mm Hg of office systolic BP (p < 0.0001), by 6.2% for each $10,000 in median income of zip code (p = 0.0055), and by 17.7% for each decade in the patient's age (p < 0.0001). CONCLUSIONS: Home BP readings provide a valid representation of the patient's condition, yet are seldom documented despite their potential utility in both patient care and research. Strong association between higher patient income and home BP documentation suggests that the cost of the monitors may be a limiting factor; reimbursement of home BP monitoring expenses should be pursued.

Polyparasite helminth infections and their association to anaemia and undernutrition in Northern Rwanda.

BACKGROUND: Intestinal schistosomiasis and soil-transmitted helminth (STH) infections constitute major public health problems in many parts of sub-Saharan Africa. In this study we examined the functional significance of such polyparasite infections in anemia and undernutrition in Rwandan individuals. METHODS: Three polyparasite infection profiles were defined, in addition to a reference profile that consisted of either no infections or low-intensity infection with only one of the focal parasite species. Logistic regression models were applied to data of 1,605 individuals from 6 schools in 2 districts of the Northern Province before chemotherapeutic treatment in order to correctly identify individuals who were at higher odds of being anaemic and/or undernourished. FINDINGS: Stunted relative to nonstunted, and males compared to females, were found to be at higher odds of being anaemic independently of polyparasite infection profile. The odds of being wasted were 2-fold greater for children with concurrent infection of at least 2 parasites at M+ intensity compared to those children with the reference profile. Males compared to females and anaemic compared to nonanaemic children were significantly more likely to be stunted. None of the three polyparasite infection profiles were found to have significant effects on stunting. CONCLUSION: The present data suggest that the levels of polyparasitism, and infection intensities in the Rwandan individuals examined here may be lower as compared to other recent similar epidemiological studies in different regions across sub-Saharan Africa. Neither the odds of anaemia nor the odds of stunting were found to be significantly different in the three-polyparasite infection profiles. However, the odds of wasting were higher in those children with at least two parasites at M+ intensity compared to those children with the reference profile. Nevertheless, despite the low morbidity levels indicated in the population under study here, we recommend sustainable efforts for the deworming of affected populations to be continued in order to support the economic development of the country.

Healthcare-associated infections in pediatric cancer patients: results of a prospective surveillance study from university hospitals in Germany and Switzerland.

BACKGROUND: Pediatric cancer patients face an increased risk of healthcare-associated infection (HAI). To date, no prospective multicenter studies have been published on this topic. METHODS: Prospective multicenter surveillance for HAI and nosocomial fever of unknown origin (nFUO) with specific case definitions and standardized surveillance methods. RESULTS: 7 pediatric oncology centers (university facilities) participated from April 01, 2001 to August 31, 2005. During 54,824 days of inpatient surveillance, 727 HAIs and nFUOs were registered in 411 patients. Of these, 263 (36%) were HAIs in 181 patients, for an incidence density (ID) (number of events per 1,000 inpatient days) of 4.8 (95% CI 4.2 to 5.4; range 2.4 to 11.7; P < 0.001), and 464 (64%) were nFUO in 230 patients. Neutropenia at diagnosis correlated significantly with clinical severity of HAI. Of the 263 HAIs, 153 (58%) were bloodstream infections (BSI). Of the 138 laboratory-confirmed BSIs, 123 (89%) were associated with use of a long-term central venous catheter (CVAD), resulting in an overall ID of 2.8 per 1,000 utilization days (95% CI 2.3 to 3.3). The ID was significantly lower in Port-type than in Hickman-type CVADs. The death of 8 children was related to HAI, including six cases of aspergillosis. The attributable mortality was 3.0% without a significant association to neutropenia at time of NI diagnosis. CONCLUSION: Our study confirmed that pediatric cancer patients are at an increased risk for specific HAIs. The prospective surveillance of HAI and comparison with cumulative multicenter results are indispensable for targeted prevention of these adverse events of anticancer treatment.

Skeletal self-repair: stress fracture healing by rapid formation and densification of woven bone.

UNLABELLED: Stress fractures of varying severity were created using a rat model of skeletal fatigue loading. Periosteal woven bone formed in proportion to the level of bone damage, resulting in the rapid recovery of whole bone strength independent of stress fracture severity. INTRODUCTION: A hard periosteal callus is a hallmark of stress fracture healing. The factors that regulate the formation of this woven bone callus are poorly understood. Our objective was to produce stress fractures of varying severity and to assess the woven bone response and recovery of bone strength. MATERIALS AND METHODS: We used the forelimb compression model to create stress fractures of varying severity in 192 adult rats. Forelimbs were loaded in fatigue until the displacement reached 30%, 45%, 65%, or 85% of fracture. The osteogenic responses of loaded and contralateral control ulnas were assessed 7 and 14 days after loading using pQCT, microCT, mechanical testing, histomorphometry, and Raman spectroscopy. RESULTS: Loading stimulated the formation of periosteal woven bone that was maximal near the ulnar midshaft and transitioned to lamellar bone away from the midshaft. Woven bone area increased in a dose-response manner with increasing fatigue displacement. Whole bone strength was partially recovered at 7 days and fully recovered at 14 days, regardless of initial stress fracture severity. The density of the woven bone increased by 80% from 7 to 14 days, caused in part by a 30% increase in the mineral:collagen ratio of the woven bone tissue. CONCLUSIONS: Functional healing of a stress fracture, as evidenced by recovery of whole bone strength, occurred within 2 wk, regardless of stress fracture severity. Partial recovery of strength in the first week was attributed to the rapid formation of a collar of woven bone that was localized to the site of bone damage and whose size depended on the level of initial damage. Complete recovery of strength in the second week was caused by woven bone densification. For the first time, we showed that woven bone formation occurs as a dose-dependent response after damaging mechanical loading of bone.

SurvNet electronic surveillance system for infectious disease outbreaks, Germany.

In 2001, the Robert Koch Institute (RKI) implemented a new electronic surveillance system (SurvNet) for infectious disease outbreaks in Germany. SurvNet has captured 30,578 outbreak reports in 2001-2005. The size of the outbreaks ranged from 2 to 527 cases. For outbreaks reported in 2002-2005, the median duration from notification of the first case to the local health department until receipt of the outbreak report at RKI was 7 days. Median outbreak duration ranged from 1 day (caused by Campylobacter) up to 73 days (caused by Mycobacterium tuberculosis). The most common settings among the 10,008 entries for 9,946 outbreaks in 2004 and 2005 were households (5,262; 53%), nursing homes (1,218; 12%), and hospitals (1,248; 12%). SurvNet may be a useful tool for other outbreak surveillance systems because it minimizes the workload of local health departments and captures outbreaks even when causative pathogens have not yet been identified.

Outbreak of Chlamydia pneumoniae infection in a Japanese nursing home, 1999-2000.

OBJECTIVE: To identify risk factors for infection and severe illness due to Chlamydia pneumoniae. METHODS: To identify risk factors for infection, we conducted a case-control study among nursing home residents who had onset of symptoms during December 1, 1999, to February 20, 2000. To identify risk factors for severe illness among nursing home residents, we conducted a retrospective cohort study. SETTING: A nursing home providing long-term and day care services for elderly patients in Japan.Participants. Fifty-nine residents and 41 staff members of a nursing home. RESULTS: The attack rates for respiratory illness were 53% (31 of 59) among residents and 22% (9 of 41) among staff. Infection was confirmed in 15 resident and 2 staff case patients by isolation of C. pneumoniae from nasal swab specimens. Fifteen resident case patients developed severe illness (ie, bronchitis, pneumonia, and hypoxia); one case patient died. The median age of resident case patients was 87 years. We could identify neither the source of the outbreak nor significant risk factors for infection and severe illness in residents. However, residents with a higher level of physical activity were more likely to become infected, whereas older residents (aged more than 85 years) and those with a lower level of physical activity were more likely to develop severe illness (P>.05). Contact with residents was a risk factor for infection in staff (relative risk, undefined; P=.04). CONCLUSIONS: C. pneumoniae can cause large outbreaks of infection and severe illness among elderly persons, and its transmission is likely to be enhanced by close contacts among people in nursing homes. Therefore, early detection of an outbreak by means of better surveillance, and subsequent isolation of patients, may be effective control measures.

Restricted use of glycopeptides in paediatric cancer patients with fever and neutropenia.

Until now, studies confirming the safety of glycopeptide restriction in the empirical treatment of prolonged fever and neutropenia included only nine children. In an open-label observational study, the use of teicoplanin in paediatric oncology patients was investigated. A period of unrestricted use (2001-2003) was compared with a second period (2004) following implementation of a restrictive treatment guideline. Empirical first-line treatment consisted of piperacillin/tazobactam; in 2004, fosfomycin was added after 72 h as the second-line combination instead of teicoplanin. In total, 213 episodes (n=163 in 2001-2003; n=50 in 2004) managed with teicoplanin or fosfomycin (only 2004) were eligible. Empirical treatment of fever of unknown origin with teicoplanin was reduced by 97%. In 2004, the mean length of stay was 0.4 days shorter, no infection-related death occurred and no vancomycin-resistant enterococci were detected. Restriction of empirical glycopeptides is safe in paediatric cancer patients after first-line treatment with piperacillin/tazobactam. Fosfomycin appears to offer a feasible and cost-saving alternative in second-line combination therapy.

Severe cutaneous reactions to sulfadoxine-pyrimethamine and trimethoprim-sulfamethoxazole in Blantyre District, Malawi.

We estimated the frequency of clinically diagnosed Stevens-Johnson syndrome and toxic epidermal necrolysis associated with sulfadoxine-pyrimethamine (SP) and trimethoprim-sulfamethoxazole (CTX) in Blantyre District, Malawi. Cases were detected by passive surveillance at 22 health centers from March 2001 through September 2002. Denominators were estimated from the Malawi national census for Blantyre District and the frequency of SP and CTX use reported in five household surveys. Crude rates of adverse reactions were estimated to be 1.2 per 100,000 exposures for SP and 1.5 per 100,000 exposures for CTX. Rates were higher in adults (1.7 cases per 100,000 SP exposures and 2.6 cases per 100,000 CTX exposures) and in persons positive for human immunodeficiency virus (4.9 cases per 100,000 SP exposures and 8.4 cases per 100,000 CTX exposures). Infrequent treatment doses with SP are associated with a low risk of an adverse cutaneous reaction, and SP can be recommended for treatment of malaria in areas where P. falciparum is susceptible.

Understanding recent increases in the incidence of sexually transmitted infections in men having sex with men: changes in risk behavior from risk avoidance to risk reduction.

OBJECTIVE: The objective of this study was to explore risk behavior and routes of transmission in men having sex with men (MSM) with newly diagnosed sexually transmitted infections (STIs). METHODS: A questionnaire on clinical diagnosis and manifestation site for acute STIs was completed by physicians participating in a sentinel study. Patients contributed information on sexual risk behavior and the likely route of STI transmission. RESULTS: Three hundred fifty-six diagnosis forms and 169 matching patient questionnaires could be analyzed. The most frequent diagnosis was syphilis (n = 147; 33% primary syphilis with ulcer localization 71% genital, 22% anorectal, and 8% oral; 67% secondary syphilis), followed by gonorrhea (n = 136; 59% genital, 34% rectal, 7% pharyngeal) and Chlamydia trachomatis infection (n = 51; 48% genital, 48% rectal, 4% pharyngeal). In 12 patients, more than one infection was diagnosed, and 2 or 3 sites were affected in 11 patients. Approximately 60% of infections were acquired by genital-oral and oral-anal practices. Unprotected anal intercourse (UAI) was reported more often by HIV-positive men (mostly receptive) and men with high partner numbers. CONCLUSION: High partner numbers, an important role of genital-oral sexual practices for the transmission of STIs, and relatively high frequencies of mostly receptive UAI in HIV-positive men are all contributing to increasing STI incidences among MSM.

International outbreak of Salmonella Oranienburg due to German chocolate.

BACKGROUND: This report describes a large international chocolate-associated Salmonella outbreak originating from Germany. METHODS: We conducted epidemiologic investigations including a case-control study, and food safety investigations. Salmonella (S.) Oranienburg isolates were subtyped by the use of pulsed-field gel electrophoresis (PFGE). RESULTS: From 1 October 2001 through 24 March 2002, an estimated excess of 439 S. Oranienburg notifications was registered in Germany. Simultaneously, an increase in S. Oranienburg infections was noted in other European countries in the Enter-net surveillance network. In a multistate matched case-control study in Germany, daily consumption of chocolate (matched odds ratio [MOR]: 4.8; 95% confidence interval [CI]: 1.3-26.5), having shopped at a large chain of discount grocery stores (MOR: 4.2; CI: 1.2-23.0), and consumption of chocolate purchased there (MOR: 5.0; CI: 1.1-47.0) were associated with illness. Subsequently, two brands from the same company, one exclusively produced for that chain, tested positive for S. Oranienburg. In two other European countries and in Canada chocolate from company A was ascertained that also contained S. Oranienburg. Isolates from humans and from chocolates had indistinguishable PFGE profiles. No source or point of contamination was identified. Epidemiological identification of chocolate as a vehicle of infections required two months, and was facilitated by proxy measures. CONCLUSIONS: Despite the use of improved production technologies, the chocolate industry continues to carry a small risk of manufacturing Salmonella-containing products. Particularly in diffuse outbreak-settings, clear associations with surrogates of exposure should suffice to trigger public health action. Networks such as Enter-net have become invaluable for facilitating rapid and appropriate management of international outbreaks.

Nosocomial Serratia marcescens outbreak in Osaka, Japan, from 1999 to 2000.

OBJECTIVES: To investigate and control an outbreak of bloodstream infections (BSIs) caused by Serratia marcescens and to identify risk factors for respiratory colonization or infection with S. marcescens. DESIGN: Epidemiologic investigation, including review of medical and laboratory records, procedural investigations, pulsed-field gel electrophoresis (PFGE) typing of environmental and patient isolates, statistical study, and recommendation of control measures. PATIENTS AND SETTING: All patients admitted to a 380-bed, secondary-care hospital in Osaka Prefecture, Japan, from July 1999 through June 2000 (study period). RESULTS: Seventy-one patients were colonized or infected with S. marcescens; 3 patients who developed primary BSIs on the same ward within 5 days in June 2000 had isolates with indistinguishable PFGE patterns and indwelling intravenous catheters for more than 5 days. On multivariate analysis, among 36 case-patients with positive sputum specimens and 95 control-patients, being bedridden (odds ratio [OR], 15.91; 95% confidence interval [CI95], 4.17-60.77), receiving mechanical ventilation (OR, 7.86; CI95, 2.27-27.16), being older than 80 years (OR, 3.12; CI95, 1.05-9.27), and receiving oral cleaning care (OR, 3.10; CI95, 1-9.58) were significant risk factors. S. marcescens was isolated from the fluid tanks of three nebulizers and a liquid soap dispenser. The hospital did not have written infection control standards, and many infection control practices were found to be inadequate (eg, respiratory equipment was used without disinfection between patients). CONCLUSIONS: Poor hospital hygiene and the lack of standard infection control measures contributed to infections hospital-wide. Recommendations to the hospital included adoption of written infection control policies.

Cost of illness in the 1993 waterborne Cryptosporidium outbreak, Milwaukee, Wisconsin.

To assess the total medical costs and productivity losses associated with the 1993 waterborne outbreak of cryptosporidiosis in Milwaukee, Wisconsin, including the average cost per person with mild, moderate, and severe illness, we conducted a retrospective cost-of-illness analysis using data from 11 hospitals in the greater Milwaukee area and epidemiologic data collected during the outbreak. The total cost of outbreak-associated illness was 96.2 million US dollars: 31.7 million US dollars in medical costs and 64.6 million US dollars in productivity losses. The average total costs for persons with mild, moderate, and severe illness were 116 US dollars, 47 US dollars, and 7,808 US dollars, respectively. The potentially high cost of waterborne disease outbreaks should be considered in economic decisions regarding the safety of public drinking water supplies.