Background: A large body of evidence suggests that fine particulate matter (PM) air pollution is a cause of cardiovascular disease, but little is known in particular about the cardiovascular effects of indoor air pollution from household use of solid fuels in developing countries. RESPIRE (Randomized Exposure Study of Pollution Indoors and Respiratory Effects) was a randomized trial of a chimney woodstove that reduces wood smoke exposure.Objectives: We tested the hypotheses that the stove intervention, compared with open fire use, would reduce ST-segment depression and increase heart rate variability (HRV).a) between-groups comparisons based on randomized stove assignment, and b) before-and-after comparisons within control subjects who used open fires during the trial and received chimney stoves after the trial. Electrocardiogram sessions that lasted 20 hr were repeated up to three times among 49 intervention and 70 control women 38–84 years of age, and 55 control subjects were also assessed after receiving stoves. HRV and ST-segment values were assessed for each 30-min period. ST-segment depression was defined as an average value below –1.00 mm. Personal fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] exposures were measured for 24 hr before each electrocardiogram.Methods: We used two complementary study designs: 2.5 exposure means were 266 and 102 μg/m3 during the trial period in the control and intervention groups, respectively. During the trial, the stove intervention was associated with an odds ratio of 0.26  for ST-segment depression. We found similar associations with the before-and-after comparison. The intervention was not significantly associated with HRV.Results: PMConclusions: The stove intervention was associated with reduced occurrence of nonspecific ST-segment depression, suggesting that household wood smoke exposures affect ventricular repolarization and potentially cardiovascular health. Most of2.5 and carbon monoxide (The RESPIRE (Randomized Exposure Study of Pollution Indoors and Respiratory Effects) project, the first randomized controlled trial to investigate the health effects of reducing air pollution exposures over a period of many months in a general population, installed improved chimney woodstoves in households using open wood fires for cooking in highland villages  in rural Guatemala . The intmonoxide , 2010. Tmonoxide . Becausemonoxide , we alsoStudy population. The study area for the RESPIRE project comprised 23 rural villages spread over an area of about 94 km2 in the towns of San Lorenzo and Comitancillo, San Marcos, in the western highland region of Guatemala, home to a primarily agricultural indigenous population living at an elevation of 2,200–3,000 m above sea level. A baseline survey of these villages in 2002 showed that nearly all households used solid biomass fuels (primarily wood and crop residues) for cooking, and most burned these fuels indoors with open fires. Eligibility criteria for the RESPIRE project included exclusive use of open fires for cooking. Households (n = 534) were recruited and randomized into control and intervention groups from October 2002 through May 2003  and control (open fire) groups, we recruited for the cardiovascular substudy women who cooked daily, were > 38 years of age, lived in one of 19 villages closest to the study headquarters, and were generally the grandmothers of children in the acute lower respiratory infection study . ResponsAt the end of the trial, the control households received the chimney stove, which allowed a before-and-after comparison.Measurements. Baseline subject characteristics, such as age, ownership of assets , exposure to SHS, and use of a wood-fired sauna for bathing, were attained before randomization.2.5 during the 24 hr before each Holter session by asking the participants to wear air samplers that included an Apex pump with flow set to 1.5 L/min , a Triplex Sharp-Cut Cyclone for particle size selection  with inlet clipped above waste height, and a 37-mm Teflon filter inside a metal filter holder  value. We defined an ischemic episode by transient ST-segment depression > 1.0 mm (0.1 mV) compared with the resting baseline , lasting ≥ 1 min, separated by ≥ 5 min from other episodes, and with horizontal or downward-sloping ST-segment morphology. We also calculated 30-min average ST-segment values as a measure of nonspecific changes in ventricular repolarization, and we created a dichotomous variable for whether this value was below –1.0 mm (–0.1 mV), regardless of the slope of the ST-segment.HRV, also calculated over 30-min intervals, was measured as standard deviation of normal-to-normal intervals (SDNN) and low-frequency  and high-frequency  components of variability. Average heart rate was also recorded for each 30-min interval.A questionnaire conducted before and after each electrocardiogram monitoring session was used to collect information on recent exposures, such as use of a wood-fired sauna. Daily average temperature, relative humidity, and rainfall were collected by a weather station near the center of the study area.Statistical analyses. To estimate the geometric mean and 95% confidence intervals (CIs) of personal PM2.5 exposure by study group and period, we log-transformed the PM2.5 measures and used mixed models with random intercepts for subjects to provide more accurate CIs that account for correlation among repeated measures.p < 0.05.We fitted logistic regression models for the occurrence of 30-min average ST-segment depression and linear regression models for the natural-log–transformed measures of HRV. To account for correlation among repeated measures, we assessed the intervention effects using generalized estimating equations in SAS PROC GENMOD , selecting autoregressive covariance within subjects and reporting sandwich estimators of variance. Statistical significance was defined as a priori, namely, age, body mass index (BMI), ever smoking, SHS, ownership of a wood-fired sauna, recent use of wood-fired sauna, an asset index as a measure of socioeconomic status, and time of day. The asset index is the sum of binary indicators for having a bicycle, a radio, and a television.The between-groups study design compares the control and intervention groups during the trial period. Although randomization is expected to produce two comparable groups, because of the small sample size and postintervention selection, we adjusted for potential between-subjects confounders selected The before-and-after study design estimates the within-subject effect of the intervention among control subjects by comparing ECG data collected before and after adoption of the chimney stoves. People serve as their own controls, so these estimates can only be biased by factors that vary over time, and we adjusted for several time-varying covariates, including age, day of week, season (wet/dry), daily average temperature and relative humidity, daily rainfall, interactions of weather variables with season, recent use of wood-fired sauna, and time of day.3 and tested for interaction between these age and BMI groups and the stove intervention. Because the difference in mean personal PM2.5 exposure between the groups appeared to be less during the first 3 months of the trial compared with the rest of the trial, we tested for an interaction between the stove intervention and study period . All interactions were tested by adding a term for the product of the two variables to the models.Sensitivity analyses for ST-segment depression included adjusting for average heart rate during the 30-min intervals and modeling the counts of 30-min intervals with ST values ≤ –1.0 mm per Holter session as a Poisson variable using generalized linear mixed models (SAS PROC GLIMMIX). To assess potential bias due to varying numbers of observations per subject, we repeated the between-groups and before-and-after analyses for ST-segment and HRV using only each subject’s last Holter session during the corresponding study period. We also evaluated all associations with the stove intervention within age groups < 52 and ≥ 52 years and within BMI groups < 25 and ≥ 25 kg/m3; these two important predictors of ST-segment depression were similar, on average, in the two groups. The women in this study lived at an elevation of around 2,600 m above sea level, on average. Most women in both groups had none or only one of the assets included in the index used as a surrogate for socioeconomic status , and the proportion of women from households with access to electricity was around 70% in both groups. Percentages of women who reported ever smoking or other sources of household air pollution, such as wood-fired saunas, kerosene lamps, and SHS exposure, were also similar between the two study groups.2.5 exposure in the control group was 266 μg/m3 , and the average in the intervention group was 102 μg/m3 . The mixed-model–estimated geometric means of personal PM2.5 during the trial period were 179 and 65 μg/m3 for control and intervention groups, respectively, equivalent to a 64% reduction  associated with the chimney-stove intervention compared with the open-fire group. In the before-and-after comparison, the estimated geometric means were 187 and 112 μg/m3  before and after the stove intervention, respectively, equivalent to a somewhat smaller 40%  reduction in personal PM2.5 after introduction of the chimney stove in control households. The intervention group had been cooking with the chimney stove for 293 days on average  when we took measures during the trial period, whereas control households had been using the improved stoves for 63 days  on measurement occasions after the trial period.We maintained a substantial exposure contrast throughout the trial, although the contrast may have been slightly less during the first few months . The aveWe evaluated the ST-segments for transient horizontal or down-sloping depression, consistent with myocardial ischemia, but only 36 of these events occurred, and most were among only three subjects. There were too few of these events to warrant statistical analyses, so the models we present focus on the nonspecific outcome of 30-min average ST-segments below –1.0 mm, regardless of slope.The mean ST-segment values were approximately 0.10 mm lower, and there were almost three times more 30-min periods with average ST-segment values ≤ –1.0 mm, among the control group than among the intervention group . These n3) in both study designs. For the between-groups comparison, we found that the association between stove and ST-segment depression was significantly greater after the first 3 months of follow-up , when the odds of ST-segment depression in the chimney-stove intervention group was 0.16 times lower than in the control group .In both the between-groups and before-and-after study designs, we found similar results after either adjusting for heart rate, using a Poisson model for the rate of ST-segment depression, or including only one Holter session per subject . The oddp = 0.053), but the association was weaker after adjustment for confounders . The before-and-after comparison did not change appreciably when we restricted it to each subject’s first Holter session per study period, and we found no evidence of an interaction with age group or BMI (data not shown).To the best of our knowledge, RESPIRE was the first randomized controlled trial of an intervention to reduce air pollution exposures in a general population under normal conditions , 2010. RTo our knowledge, this is the first study to investigate associations between electrocardiogram measurements and wood smoke or any long-term  air pollution exposure. Our findings add to the growing evidence that pollutants from combustion of biomass produce many health impacts similar to those from fossil fuels and tobacco smoke . The pub2.5 originating from local combustion sources , which was much higher than ambient levels associated with HRV in previous studies . If participation was also associated with ST-segment depression or HRV, selection bias may have produced study groups that were not comparable. We found, however, that the study groups were similar according to all baseline covariates we analyzed . Moreove2.5, but there are two important limitations that should be addressed in future studies. The first is that the few personal exposure measures we took do not allow accurate estimation of each subject’s typical exposure during the trial or of their time-resolved exposures over several days before electrocardiogram sessions. Based on analyses of child exposures in RESPIRE, which had similar between- and within-subjects variance components (data not shown), The exposure assessment strategy we employed was successful for estimating the average effect of the stove intervention on personal PMThe clinical significance of 30-min average ST-segment values below –1 mm in this population is unclear. The classical definition of ST-segment depression indicative of overt ischemia requires an episode that is reversible and ST-segments that are horizontal or downward sloping, usually assessed during exercise stress testing . HoweverTo our knowledge, the RESPIRE trial was the first study to examine the association between exposure to wood smoke from household stoves and an electrocardiographic outcome. The risk of ST-segment depression associated with use of traditional open fires may have health implications for the nearly 3 billion people living in rural areas of less developed countries who rely on solid biomass fuels. Household air pollution in developing countries is already estimated to be a leading risk factor for disease globally, because of evidence of respiratory effects , and our


Cryptococcal meningitis (CM) causes significant morbidity and mortality globally; however, recent national trends have not been described. Incidence and trends for CM-associated hospitalizations in 18 states were estimated using the Agency for Healthcare and Research Quality (AHRQ) State Inpatient Databases (SID) datasets for 1997 through 2009. We identified 30,840 hospitalizations coded for CM, of which 21.6% were among HIV-uninfected patients. CM in-hospital mortality was significant (12.4% for women and 10.8% for men) with a total of 3,440 deaths over the study period. Co-morbidities of CM coded at increased frequency in HIV-uninfected CM hospitalized populations included hydrocephalus and acute/chronic renal failure as well as possible predispositions including transplantation, combined T and B cell defects, Cushing’s syndrome, liver disease and hypogammaglobulinemia. Median hospitalization costs were significant for CM and higher for HIV-uninfected patients . Cryptococcal meningitis remains a disease with significant morbidity and mortality in the U.S. and the relative burden among persons without HIV infection is increasing. Cryptococcal meningitis (CM) is a disease with significant morbidity and mortality that afflicts both immunecompetent and immune compromised hosts. Globally, approximately 1 million AIDS-related cases of cryptococcosis occur annually with more than 600,000 associated deaths, predominantly within the developing world where anti-retroviral therapy is less available www.hcup-us.ahrq.gov). These data illustrate a complex epidemiology, with a moderate decline in HIV-related CM and a persistence of non-HIV CM. Given that non-HIV CM is becoming a more significant subpopulation in the U.S. CM patient burden, we also conducted a national analysis of CM co-morbidities in the HIV-uninfected population to better understand possible risk factors and complications within this heterogeneous population.Prior to the AIDS epidemic, cryptococcal infection was reported in less than 500 patients globally in the decade of the 1950’s This analysis was performed using the State Inpatient Databases (SID). In 2010, SID encompassed approximately 95% of U.S. hospital discharges from 44 states. Our study period included the years 1997 through 2009 and was limited to the 18 states that reported continuously during this period, containing information from over 200 million discharges. These 18 states represent over 50% of the total US population. Data were extracted as described The study population included all hospitalizations with a discharge diagnosis code for CM as either the principal diagnosis or any of 9 secondary diagnoses. This approach of using multiple secondary diagnoses was used to reduce bias due to secular trends in documentation and coding priorities as recently described in studies of pneumonia Associations among categorical variables were assessed using the Chi-square test  and the Wilcoxon test was used for non-parametric comparisons, with statistical significance assessed at p<0.05. Poisson regression was used to estimate trends in hospitalizations and in-hospital mortality, using the Annual Percent Change (APC) to quantify the rate. Significance of relative prevalence of co-morbidities using Chi-square was determined as p<0.0001, to adjust for multiple comparisons (200 ICD-9 codes compared) using a Bonferroni correction. Statistical analysis was performed using SAS version 9.2  and Prism ver. 5.0 (Graphpad Software).A total of 30,840 CM hospitalizations were documented over the 13 year period, with a total of 1827 hospitalizations recorded in the most current year (2009). Of those, 24,151 (79.4%) were associated with HIV and 6,689 (21.6%) were not associated with an ICD-9-CM code for HIV/AIDS (042). Based on state population data from the U.S. census in the mid-study year 2003, our analysis included approximately 53.5% of the country’s population during that period. Extrapolating our data to a US population of 307 million in the last study year (2009), we estimated approximately 3,400 hospitalizations associated with CM annually in the US for the most current year for which data was available.Rates of HIV-related CM were higher in states with a higher prevalence of HIV infection such as NY, Florida, Maryland and Georgia , althougCM hospitalizations decreased in the HIV-infected patient population during the study period with a high of 16.6 hospitalizations/million total population in 1997 to 7.7 in 2009 (53.6% decline) with the annual percentage change (APC) showing a significant decline of -5.8%  over the time period . This isWe identified a total of 3,440 CM-associated deaths over the 13 year study period with 338 deaths from CM in the first study year, decreasing to 177 deaths in 2009, with an extrapolated total estimate in the US of 330 deaths in 2009. The incidence of in-hospital mortality decreased over the study period in both the HIV-infected  and HIV-uninfected patients  , althougUsing the SID database, we calculated relative prevalence (RP) of co-morbid conditions, comparing the proportion of hospitalizations with selected comorbid conditions among those with CM to those without. A number of well-known sequelae of CM were identified as significant after adjustment for multivariable comparisons including hydrocephalus (RP: 51) The median cost of CM for HIV-uninfected patients was estimated to be $16,803 and $15,708 for HIV-infected patients. This includes only hospitalization costs and does not include outpatient, rehabilitation or lost income estimates. In addition, highest hospitalization costs were found in NY, CT, NJ and MD with an average cost of $17,200 to a low of $12,100 per hospitalization in WA and OR. Hospitalizations were also higher in patients who did not survive, vs. those who did survive . Based on an estimated number of hospitalizations of 3400 for CM, approximately USD $54 million were spent per year on these direct hospitalization-associated costs associated with CM in the U.S. in 2009.Cryptococcus is present in bird droppings, decaying wood and soil Here we present nationally-representative population-based estimates for incidence of CM hospitalizations over a 13-year period. These findings from the SID represent the largest epidemiological study of CM in the U.S to include both HIV-infected and uninfected patients representing data from approximately 200 million hospital admissions from both academic and community hospitals. We found a declining incidence of CM hospitalizations associated with HIV as reported earlier In-hospital mortality decreased over the study period for both HIV-infected and HIV-uninfected patients. This improvement is likely multifactorial and may include advancements in supportive care of critically ill hospitalized patients, as well as the development of less toxic formulations of Amphotericin B, allowing more patients to complete therapy C. gattii disease Our study estimated the frequency of co-morbidities for CM-associated hospitalizations of HIV-uninfected patients in the most recent two years that data was available (2008–2009). Co-morbidities disproportionately represented among HIV-uninfected CM patients  includedwww.dartmouthatlas.org) which could be due to regional differences in referral patterns or rates of intensive care utilization The present studies also found that CM is associated with a significant financial burden with HIV-uninfected patients having a greater cost than HIV-infected patients. This relationship was found previously in a study using the Maryland Hospitalization Discharge Data Set (MDHDDS) conducted in 1997 Cryptococcus, such that we have not included in our incidence estimates of other manifestations of cryptococcosis such as lung, bone or localized skin disease which may be particularly true of infections due to C. gattii which have high rates of lung disease without meningitis (29). Restrictions in the study to 18 states due to lack of continuous reporting in the remainder may have influenced overall estimated prevalence estimates if there were unrecognized large deviations in prevalence throughout the U.S. Finally, because such data represent hospital discharges rather than individually-identified patients Large administrative databases such as the SID offer unique opportunities to develop nationally representative estimates of infections among hospitalized patients that can complement more detailed single center studies In summary, these studies show the persistence of cryptococcosis in the post-ART era, with an increasing burden of the disease in HIV-uninfected individuals. While the overall incidence of cryptococcosis is decreasing, the epidemiology is complex and changing and it remains an important threat, especially in the HIV-uninfected, emphasizing a continued need for more effective control and treatment strategies in the U.S.


In China, injection drug use is a major transmission route for HIV and hepatitis C virus (HCV) infection. Timely HIV and HCV testing among drug users is vital to earlier diagnosis, linkage to care, and retention. This study aimed to examine HIV and hepatitis C virus (HCV) testing delays at methadone clinics in Guangdong Province, China, and identify individual-level and clinic-level factors associated with delayed testing. Data from 13,270 individuals at 45 methadone clinics in Guangdong were abstracted from a national web-based surveillance database. A two-level binomial logit model was used to examine the association between individual- and clinic-level factors and delayed HIV and HCV testing, defined as receiving a test seven or more days after initial entry into the methadone system. Among 10,046 patients tested for HIV, 1882 (18.7%) had delayed testing; among 10,404 patients tested for HCV, 1542 (14.8%) had delayed testing. Among delayed testers, the median time to HCV testing was significantly longer than the median time to HIV testing . In the multivariate analysis, the likelihood of delayed HIV testing was higher among individuals with high school or greater education  and individuals enrolled at clinics with more patients . The likelihood of delayed HCV testing was higher among women  and employed individuals . Delayed testing for HIV and HCV is common among patients at methadone clinics in Guangdong, with many patients experiencing delays of two or more months. Structural interventions are needed to expedite testing once individuals enter the methadone maintenance program. Timely HIV testing among most-at-risk populations is vital to earlier diagnosis, linkage to care, and retention. Although HIV testing is currently accessible in a variety of health care settings in many countries, delayed diagnosis continues to be a common problem worldwide In China, late HIV diagnosis continues to play a substantial role in late access to ART In China, where injection drug use is a major transmission route for HIV and HCV infection affects nearly half of injection drug users Individual-level factors, such as younger age and lower educational status, that might influence patients’ initial willingness to undergo testing can lead to delays in HIV and HCV testing. Additionally, clinic-level factors–staffing, intake protocols, and quality of pre-test counseling–can contribute to testing delays. Most studies of expedited HIV testing have focused on improving individual test-seeking behavior This study was approved by the Health Bureau of Guangdong Province and the Ethics Review Committee at Sun Yat-sen University. Written informed consent was provided by clinical directors who answered the questionnaire. All patients gave their written consent for their information to be stored in the national web-based administrative database and allowed to use for research.A national unified web-based HIV/AIDS information system has been established by the Chinese Centers for Disease Control and Prevention (CDC). Details of this system have been described elsewhere According to national guidelines, providers at methadone clinics routinely conduct HIV and HCV testing when clients register at methadone clinics and enter results into the web-based management database 6/L or AIDS-defining illnesses are initiated on standardized first-line treatment regimens that typically consist of three antiretroviral drugs Individuals who test positive for HIV or HCV at methadone clinics are referred by clinic staff to outside health care facilities for further evaluation and treatment. HIV- and HCV-infected patients are treated according to national guidelines Of the people living with HIV in China who were infected through injecting drug use, 84.2% live in six of the country’s 33 provinces/autonomous regions, including Guangdong Province Our primary outcome was delayed testing, a dichotomous outcome defined as receiving an HIV or HCV test seven or more days after initial entry into the methadone system, which was based on the date the blood sample was collected. This cutoff was chosen because according to national guidelines seven days is the threshold for considering someone a drop-out from the methadone maintenance program Individual-level socio-demographic and clinical characteristics included in the analysis were sex, age , marital status , education completed , employment status , and drug injecting experience , HIV infection status , HCV infection status , and years of heroin use . Clinic-level factors included were economic region , administrative level , affiliated institution , number of nurses and physicians employed , number of clients , integration of voluntary HIV counseling services , clinic finances , and distance between the clinic and most clients’ residences .Data were collected during November and December 2008. All individual characteristics were obtained from the web-based management system. Clinical staff downloaded the data and removed all identifying information. Clinic characteristics were obtained through a self-administered questionnaire completed by the director of each methadone clinic.Four clinics were opened less than one month prior to the study and were not included in the analysis. A total of 13,442 individuals were registered in the remaining 45 methadone clinics in Guangdong Province at the time of study. 172 (1.28%) individuals were excluded from the analysis because they had three or more individual-level variables missing from their dataset.First, we calculated the percentage of patients who had not yet been tested for HIV and HCV at 3 days, 5 days, 7 days, 15 days, and 1 month, among individuals who eventually underwent testing, and examined the time trend. Second, we examined the univariate associations between individual-level and clinic-level characteristics and delayed HIV and HCV testing. Group comparisons were examined with chi-square tests at the individual level and with nonparametric Kruskal-Wallis tests at the clinic level.We observed clustering of observations at the clinic level and decided to use multilevel modeling in order to examine the interactions between individual- and clinic-level factors. A two-level binomial logit model was used to estimate the effect of individual- and clinic-level factors on delayed HIV and HCV testing. The form and interpretation of the model are described elsewhere Data from 13,270 individuals at 45 clinics were analyzed. The majority of individuals were male (93.9%) and heroin users (99.6%), and 82.6% were between 20 and 40 years old. Most individuals had completed nine years or less of school and were unemployed at the time of the survey .Among the 13,270 individuals analyzed, 10,046 (75.7%) had an HIV test and 10,404 (78.4%) underwent HCV testing. Among those who ultimately were tested, 1882 (18.7%) had delayed HIV testing and 1542 (14.8%) had delayed HCV testing. Among delayed testers, the median time to HIV testing was 54 days  and the median time to HCV testing was 73 days . More individuals had delayed HIV test uptake compared to HCV test uptake Click here for additional data file.Table S1Clinic-level characteristics associated with delayed HIV and HCV testing at methadone clinics in Guangdong Province (N = 45).(DOC)Click here for additional data file.Table S2Multivariate analysis of factors associated with delayed HIV testing at methadone clinics .(DOC)Click here for additional data file.Table S3Multivariate analysis of factors associated with delayed HCV testing at methadone clinics .(DOC)Click here for additional data file.


Pneumocystis. Absolute lymphocyte count in our hospital is available immediately. In contrast, it can take 48 hours or longer to obtain more specific CD-4 counts and AIDS enzyme-linked immunosorbent assay (ELISA) serology. The association of lymphopenia with ultimate diagnosis of AIDS and Pneumocystis supports immediate empiric treatment for pneumocystis carinii pneumonia (PCP) in our highly HIV prevalent hospital.This is a retrospective review of patients admitted to an inner city community hospital with community-acquired pneumonia who were ultimately diagnosed with AIDS and  Although the number of newly diagnosed HIV patients with or without AIDS is declining in North America, the prevalence in Maryland has never been higher, a direct result of increased life expectancy (1) . As recePneumocystis was diagnosed by clinical criteria and/or bronchial lavage. Absolute lymphocyte count on admission was considered to be low if measured at 1.0 or less in the initial complete blood count (CBC).We established a database of all HIV-positive admissions to our hospital over a 4-year period, reviewed each individual chart, and set aside the new cases. New AIDS cases were defined as patients non-HIV-positive on admission, who had no prior medical record of being HIV-positive, who were subsequently diagnosed with HIV, and a low CD-4 count. A clinical diagnosis of community-acquired pneumonia was made on admission by history, physical examination, and chest x-ray; Pneumocystis pneumonia. The next highest frequency of AIDS indicating disease was systemic candidiasis (four of the 40 new cases of AIDS had candidiasis). Absolute lymphocyte counts for the 40 newly diagnosed AIDS patients are listed in Pneumocystis had their lactate dehydrogenase (LDH) levels tested, and their levels were found to be elevated. CD-4 counts arrived at an average of 44 hours post-admission, similar to the HIV enzyme-linked immunosorbent assay (ELISA) test.From 2006 to 2009, there were 2,786 admissions to our hospital who were ultimately identified as HIV positive. Of these, there were 64 new cases of HIV; 40 of which had progressed to AIDS at the time of diagnosis. From these 40 new cases of AIDS, 32 (80%) were ultimately diagnosed with The attack on CD-4 lymphocytes by HIV leads to disease progression . At certPneumocystis should nevertheless be pursued because it remains a potentially fatal illness (Although HIV prevalence in our hospital remains high, new cases are quite rare. Only 2% of our database was diagnosed for the first time during this time frame, as over a 4-year period, 64 patients were admitted with newly diagnosed HIV. In a patient denying high-risk behavior, early attention to diagnose  illness . As we h


MRSA outbreak was controlled with daily hexachlorophene showers and hygiene education. Staphylococcus aureus (MRSA) skin and soft tissue infection (SSTI) occurred in a college football team from August to September 2003. Eleven case-players were identified, and boils were the most common sign. Linemen had the highest attack rate (18%). Among 99 (93% of team) players with cultured specimens, 8 (8%) had positive MRSA nasal cultures. All available case-players' MRSA isolates characterized had the community-associated pulsed-field type USA300. A case-control study found that sharing bars of soap and having preexisting cuts or abrasions were associated with infection. A carrier-control study found that having a locker near a teammate with an SSTI, sharing towels, and living on campus were associated with nasal carriage. Successful outbreak control measures included daily hexachlorophene showers and hygiene education.An outbreak of community-associated methicillin-resistant  Staphylococcus aureus (CA-MRSA) strains have been a cause of SSTI outbreaks among athletes participating in football, wrestling, rugby, soccer, fencing and canoeing  and fewer resistance genes to non β-lactam antimicrobial drugs than healthcare-associated MRSA strains  received reports of 2 college football players (players X and Y) on team A hospitalized for SSTIs due to MRSA, which was later identified as a community-associated strain (USA300) . No otheTeam A was a college football program with 107 players on the roster at the time of the outbreak. The team practiced and played 11 of their 13 games on grass fields. Players began their football season with training camp from August 5 to 18, 2003. In camp, players were sequestered and lived together, in suites of 4 per dormitory, to foster camaraderie among teammates. Rigorous practices were held twice daily in the hot, summer weather.Case-players were defined as team A members with MRSA culture-confirmed SSTIs or SSTIs presumably caused by the USA300 strain in the outbreak period August 5 to September 5, 2003. Because we suspected that disease exposure occurred during camp, we chose the study period from the start of training camp to ≈2 weeks after the end. Our experience with other SSTI outbreaks found that in most persons lesions develop within 2 weeks postexposure to CA-MRSA. To find case-players, we reviewed the trainer's treatment log to identify players with skin lesions who required medical or surgical interventions. We asked the staff to conduct skin inspections of all players. Players were encouraged to report any skin lesion. In addition, we queried the student health center to determine if these infections were prevalent on campus.As soon as the current outbreak was recognized, a returning player (player X) was suspected to be the source of infection. Player X had 1 of the 2 cases of CA-MRSA SSTIs discovered in 2002. His locker was directly across from the index case-player, and he was a roommate, during camp, of another case-player. Trainers obtained a nasal culture from player X on August 25. On September 3, trainers obtained cultures from the anterior nares of 99 available team members for a nasal carriage study.SmaI and EagI restriction enzymes . We also characterized a sample of methicillin-susceptible Staphylococcus aureus (MSSA) isolates from players' nasal cultures.MRSA isolates from case-players and nasal carriers were characterized by using pulsed-field gel electrophoresis (PFGE) with the  enzymes ,13. PFGE enzymes . This stOn the basis of anecdotal reports of players sleeping in the locker room on used towels and delaying treatment of cuts and abrasions, we hypothesized that poor hygiene habits and compromised skin integrity might predispose players to infection. We designed a standard questionnaire to collect data on player demographics, living situation, football activities, exposure to persons with skin infections, hygiene practices, histories of skin lesions, and clinical symptoms. Trained health department employees administered the questionnaires in person.We conducted unmatched case-control and carrier-control studies. Controls were selected by jersey numbers, by using a random-number generator, from asymptomatic teammates without nasal carriage of MRSA. Teammates with positive nasal cultures for MRSA were considered carriers. Carrier-players were defined as carriers with matching PFGE pattern to the USA300 strain. We excluded non-USA300 carriers who might represent the background prevalence of MRSA in the community. Players who were not available for interviews were not included. Bivariate analysis was completed by using Fisher exact test in Epi Info version 3.3 . Statistical significance was defined as p values <0.05. Because of the small sample size and zero-valued cells, similar risk factors from the bivariate analysis were grouped into categories. Multivariate analysis was completed by using the conditional exact test in SAS version 8 .Upon recognition of the outbreak on August 25, team A instituted daily hexachlorophene showers for all players, increased the frequency of cleaning the facilities and athletic gear, disinfected the whirlpool tubs, provided more towels, and posted hand-hygiene signs in the locker room. Once nasal culture results were available, team physicians attempted to decolonize carriers with intranasal mupirocin . We recoWe identified 11 case-players out of 107 team members for an attack rate of 10%. Cases were diagnosed during or within 2 weeks of the end of training camp . The firStaphylococcus aureus, among which 8 (8%) were positive for MRSA, including player X. Player Y's nasal culture was negative. The median age of carriers was 20 years (range 18–21 years), and median tenure on the team was 2.5 years (range 1–5 years). MRSA carriage was highest in linemen (38%). We identified 1 case-player with nasal carriage of MRSA. However, trainers obtained nasal cultures after all case-players had begun antimicrobial treatment. Locker room assignments showed clustering of case-players and carrier-players, notably the proximity of the potential source player (player X) to the index case-player  of 107 team members. Twenty-six (26%) cultures were positive for e-player . Among MFour (57%) of seven MRSA isolates from culture-confirmed case-players were available for PFGE analysis. All were indistinguishable from each other, the USA300 strain found in Los Angeles County, and the isolates from 2 cases (players X and Y) in 2002. We denoted this genotype as strain A. Of 6 (75%) available MRSA isolates from 8 carriers, 4 (67%) were indistinguishable from strain A. Two carriers had unique MRSA genotypes (strains B and C) with ≥7 bands difference between them and between strain A. Strains A, B, and C, player X and Y's isolates, demonstrate community-associated antimicrobial susceptibility phenotypes . Among 5Ten of 11 case-players were enrolled in the study; 1 was unavailable for interview. During camp, case-players were 15 times more likely than controls to have shared bars of soap with teammates and more likely to have had preexisting cuts or abrasions .Five of 6 carrier-players were available for interviews. Carrier-players were 60 times more likely than controls to have had a locker adjacent to or across from a teammate with an SSTI and 47 times more likely to have shared towels with teammates . CarrierPotential risk factors were grouped into 3 categories: "sharing" (sharing soap/towels with teammates), "skin injury" , and "close contact" . Multivariate analysis including these categories indicated that sharing was a significant risk factor for CA-MRSA infection  and carriage .Daily hexachlorophene showers were in use from August 25 to September 19. No new infections were reported during the 4 weeks after the discontinuation of the hexachlorophene showers. From October 20 to November 9, MRSA SSTI developed in 4 players: a lineman with a chin abscess, a linebacker (player Y from 2002) with an elbow boil, a quarterback (player Z) with folliculitis on a leg, and a tight end with a gluteal boil. Three MRSA isolates (except from the tight end) were available for PFGE; all matched strain A. The lineman in this cluster shared bars of soap with his roommate, a case-player.Because of ongoing disease transmission and to identify potential reservoirs of MRSA, all 28 staff and student trainers and managers were nasally cultured on November 3; 11 (39%) were positive for MSSA. None was positive for MRSA. On November 22, we observed an official game. Previously unidentified lapses in hygiene practices occurred on the sidelines. We observed that student trainers reused hand towels between players, and players shared towels among themselves. Subsequently, the team switched to single-use towels on the sidelines. No new infections were reported for the remainder of the 2003 season. In the following season (August–December 2004), no MRSA SSTI outbreak occurred on team A. However, player Z had a recurrence of MRSA pustules on the forearm and leg in October 2004. He responded to outpatient treatment with doxycycline, rifampin, and incision and drainage of the lesions. His MRSA isolate was not available for PFGE. Throughout the last 3 football seasons, we received no reports of SSTI outbreaks among opposing athletes after playing this team.This report is the first of recurring CA-MRSA SSTIs in a football team during consecutive seasons. From 2 cases in 2002 to an outbreak involving 11 players in 2003 and then 1 case in 2004, we have shown that eradicating these infections is difficult once they become established in a football team. Infections were likely propagated year to year from previously infected players, and they appear to be susceptible to recurring colonization and infection themselves.Consistent with other reports, our findings implicate sharing personal items and improper wound care as risk factors for CA-MRSA infections ,18. WhilLinemen were identified as a high-risk subgroup. They engage in frequent and aggressive skin-to-skin contact during games, similar to hand-to-hand combat maneuvers as reported in a military MRSA outbreak . In addiTwo recent reported CA-MRSA outbreaks in football teams detected no nasal carriage in their combined cohort of 182 football players ,18. In cCrowded living conditions during training camp appear to facilitate the acquisition of CA-MRSA, which then propagates in on-campus housing. Investigators of an outbreak among military recruits found an association between having a roommate with an SSTI and MRSA infection . ConsequUnique to our investigation are 1 confirmed and 2 presumed community-associated strains of MRSA. We presented laboratory results indicating that the outbreak strain was likely the USA300 genotype. Since we do not have PFGE results from 6 case-players, different strains could have caused those infections. However, a multiclonal outbreak is unlikely, since other MRSA SSTI outbreaks in Los Angeles County among soccer players, men who have sex with men, jail inmates, and newborns have been exclusively due to the USA300 strain (Selection bias of case-players and controls is a limitation of this study. Enrollment of players with uncultured infections and those without PFGE results introduces the possibility of misdiagnosis and misclassification. Most football teams assign jersey numbers on the basis of field position. Therefore, our control selection method might not have captured a representative sample of the team. However, the distribution of field positions among controls and the entire team appears similar . The smaAs CA-MRSA strains become more prevalent in the community , SSTIs w


A history of prolonged and excessive consumption of alcohol increases the risk for infections. The goal of this study was to investigate circulating white blood cells (WBC) differentiated by flow cytometry and neutrophil CD64 expression in excessive alcohol drinkers versus abstinent or moderate drinkers, and in those with or without infection, in medical patients admitted to the intensive care unit (ICU).All patients admitted between September 2009 and March 2010 with an ICU-stay of 3 days or more were eligible for inclusion. Upon admission, hematological exams were conducted by flow cytometry.P = 0.002). Four groups of patients were defined: not-at-risk drinkers with no infection (n = 66); not-at-risk drinkers with infection (n = 112); at-risk drinkers with no infection (n = 53); and at-risk drinkers with infection (n = 50). Whilst the presence of infection significantly reduced levels of noncytotoxic and cytotoxic T lymphocytes and significantly increased levels of CD16– monocytes in not-at-risk drinkers, with variation related to infection severity, infection had no effect on any of the variables assessed in at-risk drinkers. Post-hoc comparisons showed that B-lymphocyte, noncytotoxic, and cytotoxic T lymphocyte and CD16– counts in at-risk drinkers were similar to those in not-at-risk drinkers with infection and significantly lower than those in not-at-risk drinkers without infection. Neutrophil CD64 index varied significantly between groups, with variations related to infection, not previous alcohol consumption.Overall, 281 adult were included, with 37% identified as at-risk drinkers. The only significant difference found in circulating WBC between at-risk and not-at-risk drinkers was a lower number of B lymphocytes in at-risk drinkers (These results show that chronic alcohol exposure has an impact on the immune response to infection in critically ill medical patients. The absence of significant variations in circulating WBC seen in at-risk drinkers according to the severity of infection is suggestive of altered immune response. A history of prolonged and excessive consumption of alcohol increases the risk for infections -3. Not sin vitro and in animal models [+ Th1 : Th2 ratio before and after surgery. In addition, the cytotoxic lymphocyte CD8+ : Tc1/Tc2 ratio was depressed preoperatively and remained depressed for 5 days. However, the impact of chronic alcohol consumption has not been as well described in critically ill medical patients [Immune alterations related to chronic alcohol exposure have been extensively studied l models ,12,14-18l models -21. In tpatients ,8,22,23.The development of flow cytometry, its feasibility, and the increase in the number of cell surface-clustered domains identifiable by specific antibodies provides the opportunity to study alterations in the numbers of various circulating white blood cells (WBC) in large populations.To further elucidate immune alterations associated with chronic alcohol exposure, we performed a study to assess differences between not-at-risk and at-risk drinkers with respect to circulating WBC and neutrophil CD64 expression in critically ill medical patients and the influence of coexisting infection on presentation to the ICU.A prospective, observational cohort study was performed in the ICU at Hôpital Pontchaillou from September 15, 2010 to March 15, 2011. This ICU is a mixed 21-bed ICU admitting mostly medical patients in a 1,950-bed teaching hospital. In 2006, 31% of the patients admitted to this ICU were identified as at-risk drinkers, based on National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria ,25. NonaAssessments to determine alcohol consumption and categorization as at-risk or not-at-risk drinkers were similar to those used in a previous study . PatientAt-risk and not-at-risk drinkers were classified according to criteria defined by the NIAAA. An at-risk drinker was defined as someone who had >14 drinks per week or more than 4 drinks per occasion for men aged ≤65 years, and as 7 drinks per week or more than 3 drinks per occasion for all women or men aged >65 years. Not-at-risk drinkers comprised abstainers  and moderate drinkers  ,27,28. PTwo intensivists and two specialists of infectious diseases retrospectively reviewed medical records and classified patients as not having systemic inflammatory response syndrome (SIRS) or sepsis, or as having SIRS, sepsis, severe sepsis, or septic shock at the time of admission to the ICU according to the consensus definitions . Infecti2 were defined as underweight [Dental hygiene was grossly assessed by the same physician (AGa) for all patients and arbitrarily considered as “poor” when there was visual evidence of at least two untreated caries at examination. A tooth was classified as carious if there was evidence of cavity. Patients with body mass index <18.5 kg/merweight .Upon admission the following data were recorded: age, gender, body mass index, Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment, presence of alcoholic liver cirrhosis, and, when available, serum levels of γ-glutamyl transferase (GGT), mean corpuscular volume (MCV), aspartate aminotransferase, and alanine aminotransferase. Current smoking also was considered.+) and CD16-negative (CD16–) monocytes, and immature granulocytes. Blood samples were performed at the time of ICU admission. Details of the flow cytometer used, data management, and routine application of flow cytometry have been published elsewhere [In addition to the five types of circulating WBC classically differentiated by standard cytology , we took the opportunity of routine flow cytometric evaluation  using autogating software  provided by the clinical hematology laboratory of our hospital to differentiate B lymphocytes, cytotoxic T lymphocytes, noncytotoxic T lymphocytes, natural killer lymphocytes, CD16-positive ; 3 patients were readmitted; 4 patients suffered from postchemotherapy aplasia; and 11 patients were admitted after acute alcohol consumption with a blood alcohol level >1 g/dL. In addition, nine patients were missed, and technical problems occurred in the laboratory for three patients. Among the 281 patients who were evaluated, 103 (37%) were classified as at-risk drinkers, of whom 3 patients (3%) had been at-risk drinkers for <5 years, 20 (19%) for 5–10 years, and 80 (78%) for >10 years. No patient was admitted with the diagnosis of acute alcoholic hepatitis.P = 0.002). To assess the effect of severe alcohol abuse in at-risk drinkers, we distinguished the patients with a daily intake of five or more drinks per day from those with a daily intake fewer than five drinks per day. The median number of circulating B lymphocytes was 0.117 × 109/ L (0.03-0.14) in patients consuming ≥5 drinks per day and 0.145 × 109/ L (0.08-0.18) in patients consuming <5 drinks par day (P = 0.04 after comparison).At-risk drinkers were predominantly males, were more frequently current smokers, and were more likely to have poor dental hygiene compared with not-at-risk drinkers Table . Not-at-P = 0.15 after comparison). The median duration of symptoms was suggestive that infection before admission did not significantly differ between groups  in not-at-risk drinkers versus 3 days  in at-risk drinkers, P = 0.19). The two groups of patients were similar with respect to the site of infection the pathogens involved, and systemic inflammatory response (Table Sixty-five (58%) of the 112 not-at-risk drinkers with infection received antibiotics before admission to the ICU, whereas 35 (70%) of the 50 at-risk drinkers with infection received antibiotics . Post-hoc comparisons showed that for B lymphocytes, noncytotoxic and cytotoxic T lymphocytes, and CD16– counts obtained for at-risk drinkers were similar to those in not-at-risk drinkers with infection and were significantly lower than those in not-at-risk drinkers with no infection  and infection  were independently associated with noncytotoxic lymphocyte counts but not previous treatment with antibiotics , current smoking , and poor dental state .At-risk drinking and infection were not found to be independent predictors of circulating B lymphocytes, cytotoxic T lymphocytes, and CD16– and CD16+ monocytes) varied significantly according to infection severity.In the group of at-risk drinkers, none of the subsets of circulating WBC counts varied significantly after comparisons between patients with no SIRS or sepsis, patients with SIRS, patients with sepsis, and those with severe sepsis or septic shock Figure , indicatNeutrophil CD64 index varied significantly by severity of infection in both at-risk and not-at-risk drinkers, being obviously higher in those with severe sepsis or septic shock in both patient groups Figure .– monocytes in at-risk drinkers, with or without infection, were similar to those in not-at-risk drinkers with infection and significantly lower than those in not-at-risk drinkers without infection. When severity of infection was considered, none of the subsets of circulating WBC studied varied significantly in at-risk drinkers. Neutrophil CD64 index varied significantly by severity of infection both in at-risk and not-at-risk drinkers.This prospective, observational study performed on a large population of critically ill patients assessed upon admission to the ICU, and distinguished according to the presence or absence of infection, shows that previous alcohol consumption has an impact on counts of circulating WBC involved in both innate and adaptive immunity. The only difference in circulating WBC counts between at-risk and not-at-risk drinkers was in B lymphocytes, which were significantly lower in at-risk drinkers. We found that B lymphocytes, cytotoxic T lymphocytes, noncytotoxic T lymphocytes, and CD16in vitro and in vivo studies [Because individuals with a history of alcohol abuse are more likely to develop severe pneumonia leading to ICU admission, the effect of chronic alcohol exposure on immunity of the lung has been assessed in many  studies ,12. In p studies ,34. Parain vitro by mitogens, and blunts CD4+ and CD8+ lymphocytes [The low WBC counts in at-risk drinkers observed in our study are in accordance with published data showing that chronic alcohol exposure results in hyporesponsiveness of neutrophils to chemotactic signals, reduces delayed hypersensitivity response of isolated lymphocytes after stimulation phocytes ,12,14,35Various abnormalities in circulating neutrophils also have been described with chronic alcohol consumption, ranging from an increase in the number of these cells in the peripheral blood to neutropenia in those with the most severe form of infection or severe underlying hepatic disease . For ourIn the present study, most of the at-risk drinkers had been exposed to alcohol for many years. The low circulating B-lymphocyte count found in at-risk drinkers is in agreement with results from previous studies showing that the number of peripheral blood B cells is diminished after long-term alcohol consumption. Laslo et al. ,37 previ– monocytes. However, for these subsets of WBC, multivariate analysis failed to demonstrate that at-risk drinking was an independent predictor when infection was included in the model. Because our findings suggest that at-risk drinkers admitted to the ICU with infection are less prompt to develop intense immune response than not-at-risk drinkers, we believe that systematic and accurate identification of patients with prior alcohol misuse will lead to improved care for these patients. In addition, our results suggest that neutrophil CD64 index may help physicians to diagnose infection in at-risk drinkers.Results listed in Table Whilst our study has some strengths, including a large number of patients and a long history of alcohol consumption in most of the at-risk drinkers, our study also has some limitations. The impact of alcohol exposure on the functionality of WBC was not assessed, except for neutrophils by looking at CD64 expression. Also, serum levels of immunoglobulins and cytokines were not analyzed in this study, whereas previous authors have shown that, at the onset of infection and during early septic shock, chronic alcoholic patients had lower plasma levels of proinflammatory interleukins than nonalcoholic patients . PatientPatients were not screened for illicit drugs and assessment of blood alcohol was not systematically performed; therefore, we cannot exclude that acute alcohol consumption was unrecognized in some patients. In human studies focusing on defects in the immune system associated with alcohol abuse, it is important to differentiate between acute and chronic alcohol exposure, and the presence or absence of acute hepatitis or liver cirrhosis. Acute alcohol consumption has effects on inflammatory cell activation opposite to those seen with chronic alcohol consumption ,10. In tOur results show that, similar to findings in trauma and postoperative patients, chronic alcohol exposure has an impact on the immune response to infection in critically ill patients. In accordance with animal and experimental data, the absence of significant variations of circulating WBC seen in at-risk drinkers according to the severity of infection is suggestive of reduced immune response in patients chronically exposed to alcohol. On the other hand, neutrophil CD64 expression did not appear to be affected by chronic alcohol exposure.– At-risk drinkers had a lower number of B lymphocytes at admission to the ICU.– At-risk drinkers exhibited less variation in circulating WBC in response to infection than nonalcoholic patients.– CD64 expression did not appear to be affected by chronic alcohol exposure.The authors declare that they have no competing interests.AG, MR, AGr and YLT conceived the study protocol, participated in its designed and drafted the manuscript. MR, FU and TF carried out the cytometry. ES, LC and SM recorded data and helped draft the manuscript. AG and CC performed statistical analysis, CC helped interpret the data. All authors read and approved the final manuscript.


Background. Chlamydia infections often follow an asymptomatic course but may damage the reproductive tract. Chlamydia antibodies in serum are used as markers for past infections and can relate to tubal pathology and infertility. This “proof of principle” study aimed to assess whether Chlamydia antibodies are detectable in easier to obtain, noninvasive, vaginal mucosa samples and relate to current or past infection. Methods. We compared outcomes of Chlamydia IgG and IgA antibody tests in serum and vaginal mucosal swabs in (a) 77 women attending a fertility clinic, of whom 25 tested positive for serum-IgG and (b) 107 women visiting an STI centre, including 30 Chlamydia PCR-positive subjects. Results. In the STI clinic, active Chlamydia infections were linked to serum-IgG and serum-IgA (P < 0.001) and mucosa-IgA (P < 0.001), but not mucosa-IgG. In the fertility clinic, mucosa-IgG had stronger correlations with serum-IgG (P = 0.02) than mucosa-IgA (P = 0.06). Women with tubal pathology or Chlamydia history more commonly had serum-IgG and mucosa-IgA (both P < 0.001), whereas this link was weaker for mucosa-IgG (P = 0.03). Conclusion. Chlamydia IgG and IgA are detectable in vaginal mucosal material. Serum-IgG had stronger associations with current or past infections. Mucosa-IgA also showed associations with (past) infection and complications. IgA presence in vaginal mucosa warrants further epidemiological studies. Chlamydia trachomatis is a common sexually transmitted infection among adolescents. In women, lower genital tract infections (cervicitis) may ascend to the upper genital tract and cause pelvic inflammatory disease (PID), potentially leading to tubal pathology and subsequent infertility [ertility , 2. Chlaertility , which mertility .Various immunological markers have been studied for their ability to indicate an individual's history of Chlamydia infection and increased probability for late complications –8. In inproof of principle” study was to assess the usefulness of the application of the CAT-test on mucosal swabs for identification of women who have or have had an infiltrating Chlamydia infection that could be the cause of late complications. We hypothesized that local, mucosal IgG antibodies can persist in the lower genital tract mucosa for a long time (similar to IgG in serum), while IgA antibodies may disappear in the course of time, provided that the infection is cleared. IgA antibodies in serum are assumed to reflect chronic inflammation and have been shown to be useful in the serodiagnosis of tubal factor infertility caused by C. trachomatis [The further aim of the current “chomatis , 12. Antchomatis , 21. HenIn this study, we compared (A) the correlation between the outcomes of the serum-IgG CAT and the mucosa-CAT in a group of women at risk for late complications (attending a fertility clinic) and (B) the correlation between the presence of Chlamydia DNA (PCR) in vaginal swabs and the outcomes of the serum-CAT and mucosa-CAT (IgG and IgA), in women at risk for a current infection (attending an STI clinic).We performed a comparative diagnostic study, in two groups of patients.(A) Women attending the fertility clinic of the University Medical Center in Groningen (UMCG) in January and February 2012: healthy, 20 to 40-year-old women, who had a serum IgG CAT  taken within the previous year(s) as part of their fertility workup received a written request to participate. After consent was given, they received a short questionnaire on past Chlamydia infections or PID and a test-kit with a vaginal swab for self-collection. Further relevant data were obtained from the medical records at a later stage in the clinical investigations. Recruitment continued until a number of 25 serum-CAT-positive and 50 serum-CAT-negative women was reached. In total, 85 agreed to participate and for 79 of them, complete questionnaire data and samples were obtained (93%), while results of serological CAT were available for 77 women (from current or previous clinic visits). Of the 77 women, 52 had serum-CAT-negative results and 25 serum-CAT-positive results for Chlamydia IgG antibodies, in accordance with the sampling plan. Mucosa-CAT results (IgG and IgA) were obtained for all 79 women who returned the swab (see (B) Women attending the sexually transmitted infection (STI) clinic in The Hague between September 2011 and February 2012: this study population consisted of women of all ages, who were tested for Chlamydia DNA as part of their STI consultation and consented to the use of their (anonymously stored) remaining sample material from serum and swab for further STI-related research. During consultation, standard information on the person's background and sexual behaviour and risk factors was collected and entered into an electronic patient database for STI surveillance. Recruitment continued until results for 30 PCR-positive and 70 PCR-negative women were obtained. In total, sample material from 117 women was analysed. Results of swabs were available for 115 women and serum results for 102 women; one woman with serum results only was excluded from analysis. Of the remaining 116 women, 33 were PCR positive for Chlamydia and 83 PCR-negative . Serum samples and material collected by vaginal swabs were analysed with Medac Ct IgG/IgA ELISA test  in the Laboratory of Immunogenetics, VU University Amsterdam. Tests were performed according to manufacturers' instructions. This Medac test uses a species-specific synthetic peptide based on the major outer membrane protein (MOMP) as an antigen, ensuring minimum cross-reactivity with Chlamydia pneumonia , 23. PerThe qualitative results of serum- and mucosa-CAT were compared with each other and with PCR results and proportions with positive IgG/IgA calculated. At the STI clinic, some test results remained “equivocal” , because the samples could not be submitted to a confirmation test ; these samples were excluded from further calculations.In order to evaluate the agreement of the mucosa-CAT results to the outcomes of PCR and serum-CAT, we calculated Kappa-values for mucosa IgG and IgA versus PCR (in the STI clinic only) and versus IgG in serum (both for the fertility and the STI clinic). We searched for potential relations between IgG or IgA CAT-test outcomes and (determinants of) current and past Chlamydia infection and sequelae thereof . In the STI clinic, the question combined history of Chlamydia, gonorrhoea, or syphilis diagnosis in the past 2 years, but in this setting and in the age group of heterosexual women, such a previous STI is most likely to be a Chlamydia episode . All anaThe women in the fertility clinic had a median age of 32 years (IQR 28–36 yrs.) at the time of the questionnaire. Fifty-four of 79 (68%) women reported to have been tested for STI in the past and 13 of these 54 (24%) reported a history of Chlamydia; one woman reported a past PID. Clinical data from the women's medical records (6 months later) showed that nine women were diagnosed with tubal pathology and four had experienced an extrauterine pregnancy, while 12 women had become pregnant spontaneously and 56 women had no tubal damage-related diagnosis .The women at the STI clinic had a median age of 22 years (IQR 22–25 yrs.). The majority (113/116) had heterosexual relationships and three were bi-/homosexual; 40 of 116 (34%) reported to have had one partner in the last 6 months, 28 (24%) had 2 partners, and 47 (41%) had three partners or more; 106/116 (91%) had a Dutch background and 10 had non-Dutch background. As a reason for their visit, 24 (21%) mentioned STI-related complaints and 11 (9.5%) were notified to get tested by a sex-partner. Among 33 Chlamydia positives, two had a gonorrhoea infection as well.In the group of women recruited in the STI clinic, IgG was detected in 36% and IgA in 14% of the sera, while in the mucosal swabs this was 39% (IgG) and 19% (IgA). In the selected group of women in the fertility clinic, IgG was detected in 44% and IgA in 10% of the mucosal swabs; IgG in serum was reported in 32% of women (selection aimed to include 25 positives).(A) Women in the STI Clinic. Of the women with a current, PCR-confirmed, Chlamydia infection in the STI clinic, the large majority (94%) had IgG antibodies and one-third (38%) had IgA antibodies in the serum, while only 10% of women without infection had IgG and 6% IgA in the serum. The correlation between the result of PCR tests was high for IgG presence in serum  and modest for IgA . The vaginal swab material of PCR-positive women tested positive for IgG in 48% of cases and for IgA in 41% of cases, while these values were 35% and 10% in PCR-negative women . Comparing the results of serum-CAT and mucosa-CAT (P = 0.001) and 0.130 (P = 0.2) for IgG.ve women ; here Igcosa-CAT  showed tn = 10) often also had IgA antibodies in the swab (6/10); most serum-IgA-negative women also had no IgA in the swab . The association between serum-IgA and swab IgA was most visible in PCR-negative women (P = 0.18).Women who tested serum-IgA-positive (ve women . There wn = 11) had a higher chance to have detectable serum-IgG than women with no prior STI history , but their chance to have a mucosa-IgG was lower  had a higher chance to have a positive IgG in serum than women who had no complaints . Similar differences were seen for women who reported not to have used a condom at the last sexual contact (n = 31) compared to those who did  and borderline for serum-IgG (P = 0.06), but not for mucosa-IgG or -IgA presence. Women with a non-Dutch background (n = 10), mucosal CAT results were more often positive for IgG (70%) and IgA (60%) than among Dutch women , whereas there was no significant difference in the proportion serum-CAT positives.Women with a history of STI ((B) Women in the Fertility Clinic. Among women with serum-IgG, 64% also had IgG antibodies in the vaginal mucosa, while 35% of the seronegative women tested positive for mucosa-IgG (P = 0.015). Mucosa-IgA was found in 20% of the women with serum-IgG and in 6% of the serum-negatives (P = 0.055).cosa-IgG . The Kapegatives , resultiN = 9) more often tested positive on serum-IgG (89%) than women without tubal pathology  and more often for mucosa-IgA , but not for mucosa-IgG (56% versus 43%). Similarly, women with a history of Chlamydia infection  more often had serum-IgG and mucosa-IgA and -IgG than those without such a history .Women diagnosed with a reported tubal pathology diagnosis  were linked to both serum-IgG  and seruAltogether, IgG in serum was the best predictor for a current or probable past Chlamydia infection (combining PCR-confirmed current infection with a history of STI) in the STI clinic and also the best predictor for “Chlamydia and related complications”  in the fertility clinic. IgA in swabs showed high specificity for tubal pathology in the fertility clinic and Kappa values were consistently higher for IgA than IgG in swab see .Chlamydia antibody testing can detect local IgG and IgA in vaginal mucosal swab material from women with a current Chlamydia infection or probable exposure in the past. The correlations between local anti-Chlamydia antibodies and systemic antibodies or (past) Chlamydia infection were however not unambiguous and warrant further prospective studies. IgG antibodies in serum were the best predictor of a current or potential past Chlamydia infection, in both groups under study: women at the STI clinic and in the fertility clinic. Serum-IgG results were not exchangeable with the results of antibody tests in vaginal mucosa in a straightforward way; however, mucosa-IgA showed a modest association with (past) Chlamydia infection but a stronger association, also compared to serum-IgG, with tubal pathology as a potential long-term complication thereof. Combining results on systemic and mucosal immunological responses seems promising to get more insights into the pathogenesis of Chlamydia.It is known that up to 80% of the Chlamydia infections in women are asymptomatic , and the Chlamydia trachomatis infections [Our study was unique in exploring the added value of using mucosal (self) swabs to identify markers for adverse outcomes of Ct infections. On the other hand, as this was a small exploratory study, only preliminary conclusions can be drawn; further research and test validation are recommended. Due to the small and selective sample, the estimation of (adjusted) risk factors .Our data suggest that local IgA antibodies might have a stronger discriminative value than local IgG, as IgA presence in the vaginal mucosa was associated with tubal pathology and history of Chlamydia infection in women in the fertility clinic and it correlated to current Chlamydia infection and to the presence of IgG in serum in the group of women in the STI clinic. Provided that the mucosal CAT test has a high specificity, larger population-based studies and further prospective cohort studies are needed to assess to what extent and when IgA in vaginal (self-)swabs could be of value as a biomarker, on its own or in combination with other immunological host-related markers, indicating which women have a higher chance to develop late sequelae from Chlamydia infections.


Patient-reported outcomes are measured in many epidemiologic studies using self- or interviewer-administered questionnaires. While in some studies differences between these administration formats were observed, other studies did not show statistically significant differences important to patients. Since the evidence about the effect of administration format is inconsistent and mainly available from cross-sectional studies our aim was to assess the effects of different administration formats on repeated measurements of patient-reported outcomes in participants with AIDS enrolled in the Longitudinal Study of Ocular Complications of AIDS.We included participants enrolled in the Longitudinal Study of Ocular Complications in AIDS (LSOCA) who completed the Medical Outcome Study [MOS] -HIV questionnaire, the EuroQol, the Feeling Thermometer and the Visual Function Questionnaire (VFQ) 25 every six months thereafter using self- or interviewer-administration. A large print questionnaire was available for participants with visual impairment. Considering all measurements over time and adjusting for patient and study site characteristics we used linear models to compare HRQL scores  between administration formats. We defined adjusted differences of ≥0.2 standard deviations [SD]) to be quantitatively meaningful.We included 2,261 participants  with a median of 43.1 years of age at enrolment who provided data on 23,420 study visits. The self-administered MOS-HIV, Feeling Thermometer and EuroQol were used in 70% of all visits and the VFQ-25 in 80%. For eight domains of the MOS-HIV differences between the interviewer- and self- administered format were < 0.1 SD. Differences in scores were highest for the social and role function domains but the adjusted differences were still < 0.2 SD. There was no quantitatively meaningful difference between administration formats for EuroQol, Feeling Thermometer and VFQ-25 domain scores. For ocular pain (VFQ-25), we found a statistically significant difference of 3.5 , which did, however, not exceed 0.2 SD. For all instruments scores were similar for the large and standard print formats with all adjusted differences < 0.2 SD.Our large study provides evidence that administration formats do not have a meaningful effect on repeated measurements of patient-reported outcomes. As a consequence, longitudinal studies may not need to consider the effect of different administration formats in their analyses. Patient-reported outcomes (PRO) are measured in studies using information that is provided directly by study participants. Probably most commonly, PROs are used as outcome measures in epidemiologic studies and clinical trials -5. But PPRO instruments are either completed by study participants' themselves (self-administered) or administered by an interviewer. Self-administered PRO questionnaires offer the advantage of not requiring research staff as interviewers and participants to complete the questionnaire at their own pace. It may be offered as a paper- and pencil method both at the study site or at home (mail) or through web-based applications. Interviewer-administered PRO questionnaires are more resource intensive but offer additional control over the quality of the measurement. Interviewers may administer the questionnaires face-to-face or over the telephone. In many epidemiologic studies, both self- and interviewer-administered questionnaires are available to accommodate preferences, physical impairment or literacy of participants ,10.In a study, the format of questionnaire administration often varies between participants but it may also vary within participants from one follow-up to another. The evidence on the effects of different administration formats on PRO scores is inconsistent. A number of studies  found that the administration format had an effect on PRO scores for some or all of the domains ,11-19. IMost studies comparing different administration formats were relatively small and considered only one or two measurements ,11-19. Tst 2009. LSOCA is one of the largest prospective observational studies of persons with AIDS. Study participants have AIDS diagnoses according to the 1993 Centers for Disease Control and Prevention case surveillance definition of AIDS. Over the course of the study, recruitment has been performed at 19 clinical centers across the United States, located in urban areas with sizable HIV-infected populations. The current number of active study sites is 13 , IQR 1.9-4.7). Overall, 83.0% of participants received HAART at enrollment.We included 2,261 participants in the analysis. The patient population was predominantly male (81%) with a median age of 43 years (interquartile range [IQR] 38-49), of non-hispanic white (46%) or black ethnicity (36%). At enrollment, 409 participants (18%) had been diagnosed with AIDS for one year or less (incident AIDS) and 1,852 participants (82%) for more than a year. Median CD4+ T cell count at enrollment was 174 cells/μL (IQR 61-339), median nadir CD4+ T cell count was 31 cells/μL (IQR 10-91) and median HIV RNA  level was 2.9 . Of the 2,261 patients, 929 (41%) completed their first (baseline) questionnaires via interview and 1,332 (59%) completed it via self-administration. In 6,910 (30%) visits the HRQL questionnaires were interviewer-administered and in 224 (1%) visits participants used the self-administered version with large print letters. These percentages changed with follow-up  started with the self-administered MOS-HIV, EuroQol and Feeling Thermometer whereas 531 participants (23%) started with the interviewer-administered format. 1,265 (56%) never switched the administration format of the MOS-HIV, EuroQol and Feeling Thermometer, 335 (15%) switched permanently and 661 (29%) switched intermittently. Of the 1,096 participants who completed the VFQ-25 989 (90%) never switched administration format, 93 (9%) switched permanently and 14 (1%) switched intermittently.For eight domains of the MOS-HIV, we did not find statistically significant differences between the interviewer- and self- administered formats Table . For the465 participants who started with self-administration and switched at least once to interviewer-administered questionnaires were available for the sensitivity analysis. We did not find any statistically significant differences between scores of the MOS-HIV, Feeling Thermometer, EuroQol and VFQ-25 from the last study visit before the switch (self-administered) to scores obtained at the first visit where interviewer administration was chosen. All differences were below the thresholds for a meaningful difference.For all domains of the MOS-HIV, the Feeling Thermometer and EuroQol the scores were similar for the large and standard print formats and we did not find statistically significant differences Tables  and 3. AIn our analysis of more than 23,000 clinic visits of participants with AIDS, different administration formats of generic or disease-specific PRO instruments did not have a meaningful effect on HRQL scores measured repeatedly over time. Differences between all scores of the interviewer- and self-administered questionnaires were below our predefined threshold for a quantitatively meaningful difference. Also, the use of the large print format did not have an impact on HRQL scores.We defined a meaningful difference between administration formats to be ≥0.2 SD, which corresponds to a small but potentially important difference as first defined by Cohen . Other sThe results of studies comparing different administration formats, including ours, are heterogeneous. Some studies found scores indicating less impairment with interviewer- than with self-administered questionnaires ,11-19, wIf an effect of administration format is present investigators should be concerned with a potential effect that may alter inferences in two ways. First, different administration formats may introduce additional measurement variability, which makes the detection of small but important associations or effects more difficult. Sample size requirements to detect a certain difference in PRO could be larger if different administration formats are used because of greater standard deviations and because effect estimates are likely to be attenuated by additional  measurement error ,10. SecoFor example, one could be interested in comparing HRQL between HIV-infected persons with and without AIDS Figure . Let us We see two solutions to address this issue. One solution would be to restrict the administration format strictly to one mode of administration. Since this may be unrealistic in many studies a second solution would be to record the administration format at each study visits and check for an independent effect of administration format on PRO scores as we did in this study. Intuitively, investigators may think that one should adjust the effect estimate for administration format, which has also been proposed in the literature . HoweverStrengths of our analysis include the large sample size and the repeated administrations of PRO instruments over time. Thereby, our analysis represents the typical cohort study settings for which there is little evidence on the effects of administration formats and we have little reason to assume that the results of our study are specific to patients with AIDS only. Another strength is the adjustment for patient and study site characteristics that could have confounded the comparisons. However, a limitation of our study is the lack of randomization for administration format so that some residual confounding might still be present. Also, since the VFQ-25 and the large print format were introduced rather recently the sample size was smaller for investigating the effects of administration format on VFQ-25 scores or of the large versus standard print.Our large study provides evidence that administration formats do not have a meaningful effect on repeated measurements of PRO. As a consequence, longitudinal studies may not need to consider different administration formats in their analyses. However, if investigators find an effect of administration format they should not adjust for the administration format but consider using one of the methods available for correcting systematic measurement error.The authors declare that they have no competing interests.MP, AA, MVN, CM designed the study. MP, AA, MVN undertook the statistical analyses. MP wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.


Attention Deficit Hyperactivity Disorder (ADHD) is becoming an increasingly commonly diagnosed and treated childhood illness. Untreated ADHD is recognised as an independent risk factor for suicide-related events and deliberate self-harm and is reported more commonly in these populations. With the treatment of ADHD it is thus crucial to understand further any associations between pharmacological treatments and suicide-related events. Specific data for suicide-related events with stimulants have not been publically reported. Suicidal tendencies are, however, a contraindication to the treatment of patients with methylphenidate. Clinicians and patients may be helped by a meta-analytic comparison of suicide-related events in comparative randomised double-blind atomoxetine and methylphenidate clinical trials.Suicide-related events retrospectively mapped to the suicide-related event assessment instrument recommended by the FDA, the Columbia Classification Algorithm for Suicide Assessment (C-CASA), were evaluated in five double-blind placebo controlled comparative studies of atomoxetine and methylphenidate (n = 1024) of 6 to 9 weeks duration. The Mantel-Haenszel risk ratio and Mantel-Haenszel incidence differences have been calculated.In total there were 5 suicide-related events, atomoxetine (ATX) 3/559 and methylphenidate (MPH) 2/465. There were no suicide attempts nor completed suicides. Meta-analysis finds no difference of a difference in risk between ATX and MPH with a Mantel-Haenszel risk ratio of 0.52 .In the only reported meta-analysis of comparative suicide-related events between atomoxetine and methylphenidate, no significant evidence of a difference in risk has been found. These data may be informative to clinicians and patients when developing clinical guidelines. Atomoxetine was first licensed in Europe in 2004 and is currently the only non-stimulant medication licensed in Europe for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. As of January 2012 there are six other medications in the UK also licensed, with some available in other European countries, for ADHD, of which five are methylphenidate formulations and dexamphetamine. There is good evidence that the rates of both diagnosis and treatment of ADHD have been increasing over the last decade. During 1999–2006 the prevalence of prescribing of ADHD medications in the age group 15–21 in the UK increased 6.23 fold [In a paediatric population there is a clear focus on the safety of medications and this is paramount when considering suicidality. Suicide-related events are a broad term that encompasses suicidal ideation, behaviours, attempts and completed suicides. ADHD is an illness with which comorbid depression and anxiety are commonly found and knowledge regarding the incidence of self-harm in the adolescent group is now available . Recent The next relevant clinical question relates to the association of ADHD treatments with suicidality. In 2008 from a meta-analysis of suicide-related events from randomised clinical trials in atomoxetine patients, there was a clear conclusion that, although uncommon, suicidal ideation was significantly more common in paediatric ADHD patients receiving atomoxetine than placebo . For metBecause suicide-related events are so rare, individual clinical trials are too small to collect data on either the incidence of such events or comparative incidence rates . This isThere are a number of studies comparing atomoxetine and methylphenidate. A recent non-inferiority meta-analysis considering core ADHD symptoms included 7 direct comparative atomoxetine and methylphenidate clinical trials of at least 6 weeks duration (n = 1368) reporting no efficacy differences in responder rates . Meta-anIn 2010 the FDA recommended that in all trials in psychiatric populations an assessment instrument mapping to the Columbia Classification Algorithm for Suicide Assessment (C-CASA) should be routinely used -18. C-CAAn analysis of suicide-related events identified in paediatric randomised controlled double-blind ADHD clinical studies involving both atomoxetine and methylphenidate undertaken by Eli Lilly  was conducted -22. TablThe FDA has defined an approach that classifies adverse events relating to suicidality in set categories -18:Code 1 = Completed suicideCode 2 = Suicide attemptCode 3 = Preparatory acts toward imminent suicidal behaviourCode 4 = Suicidal ideationCode 5 = Self-injurious behaviour, intent unknownCode 6 = Fatal event. Not enough informationCode 7 = Self-injurious behavior, no suicidal intentCode 8 = other: accident, psychiatric, medicalCode 9 = Not enough information Each study was searched for suicide related events using the Lilly clinical trial and serious adverse event databases as per FDA defined guidance for all events occurring during the double-blind phase or within 1 day of stopping treatment in these trials.The following text string terms were used:accident, asphyxiation attempt, burn, cut, drown, firearm, gas, gun, hang, hung, immolate, injure, jump, monoxide, mutilate, overdose, poison, self damage, self, harm, self inflict, self injury, shoot, slash, suffocation, suicPatient summaries were reviewed blinded by two Eli Lilly medical staff with training and expertise in adverse event reporting and pharmacovigilance, at least one a physician. With any discrepancy a third reviewer was used. Cases were then mapped to the relevant FDA codes. Data was collected during the trial into case report forms with subsequent further additional data collected and incorporated into a patient narrative.Meta-analytic comparisons were made using the Mantel-Haenszel risk ratio. Two variables were reported: (1) the Mantel-Haenszel risk ratio (MHRR) which estimates the percentage risk of the specific adverse event amongst ATX treated patients over the percentage among methylphenidate treated patients; and (2) the Mantel-Haenszel incidence difference (MHID) which estimates the percentage risk of the specific adverse event amongst ATX treated patients minus the percentage among methylphenidate treated patients in percentage units.There are 7 comparator trials of atomoxetine and methylphenidate, 5 of which are randomised double blind and included in the analysis. Open label studies were excluded. Summaries of the characteristics of the 5 included studies, all of which were funded by Eli Lilly, are detailed in Table This analysis of the 5 acute randomised double-blind paediatric controlled trials of ATX and MPH of 6–9 weeks duration finds that the risk of suicide-related events as assessed using FDA methodology finds no evidence of a difference in risk between atomoxetine and methylphenidate. To our knowledge this is the only comparator data-set in existence comparing suicide-related events between these two common treatments for ADHD. ,10,23. AA summary of these meta-analysis data was published in 2008 as part of an analysis of cases of suicide-related events with ATX in clinical trials . Two recThere are limitations however in making any finite conclusions as data derived from clinical studies are often short-term and may not be reflective of longer-term outcomes. Open-ended, rather than event-specific, adverse event solicitation may also miss suicide-related events, especially suicidal ideation. The use of the Columbia Suicide Severity Rating Scale (C-SSRS) and Columbia Classification Algorithm for Suicide Assessment (C-CASA) in clinical trials was not mandated at the time of performing these trials but is however now mandatory for ADHD medications. Suicide-related events are uncommon in a clinical trial and hence the usage of large databases to collect data over longer periods in larger cohorts may be informative . Data onIn other defined cohorts, suicide-related events data on ATX have been reported over the last 2 years -30. The Suicide-related events may be associated with the ingestion of ADHD medications ,24. The This meta-analysis and current data support that suicide-related events are measurable in an ADHD treated cohort but that there is no current evidence of any significant differential risk between ATX and MPH, however this is the only systematic evidence currently available on suicide-related events in patients receiving psychostimulants and data from ongoing clinical trials may be helpful in defining further this comparison . It is aClinicians have no current reason to solely choose their treatments on the basis of any presumption of differential risk of suicide-related events. The usage of Columbia Suicide Severity Rating Scale (C-SSRS) and Columbia Classification Algorithm for Suicide Assessment (C-CASA) in clinical trials where appropriate, when used prospectively may further help to define any suicidal risk in clinical trials . Longer-The risk of suicide associated with ADHD must not be underestimated. A recent birth cohort study reported that 1.9% of an ADHD cohort (mean age diagnosis 10 years) were deceased  at follow-up (mean age 27 years), with the standardised mortality ratio for suicide as an individual cause of death elevated 4.83 (95% CI 1.14–20.46) when compared with a control cohort . A recenCB and NS are employees and stockholders of Eli Lilly and Company who manufacture atomoxetine.CB and NS conceived the project. The first draft was written by CB and subsequent revisions by CB and NS. Both authors read and approved the final manuscript.