OBJECTIVE: Using an innovative data sharing model, we assessed the impacts of the COVID-19 pandemic on the health of people who inject drugs (PWID). DESIGN: The PWID Data Collaborative was established in 2021 to promote data sharing across PWID studies in North America. Contributing studies submitted aggregate data on 23 standardized indicators during four time periods: pre-pandemic (Mar 2019 - Feb 2020), early-pandemic (Mar 2020 - Feb 2021), mid-pandemic (Mar 2021 - Feb 2022), and late pandemic (Mar 2022 - Feb 2023). METHODS: We present study-specific and meta-analyzed estimates for the percentage of PWID who took medications for opioid use disorder, received substance use treatment, shared syringes or injection equipment, had a mental health condition, had been incarcerated, or had experienced houselessness. To examine change over time across indicators, we fit a random effects meta-regression model to prevalence estimates using time as a moderator. RESULTS: Thirteen studies contributed estimates to the Data Collaborative on these indicators, representing 6,213 PWID interviews. We observed minimal change across prevalence of the six indicators between the pre-pandemic (March 2019 - February 2020) and three subsequent time periods, overall or within individual studies. Considerable heterogeneity was observed across study- and time-specific estimates. CONCLUSIONS: Limited pandemic-related change observed in indicators of PWID health is likely a result of policy and supportive service-related changes and may also reflect resilience among service providers and PWID themselves. The Data Collaborative is an unprecedented data sharing model with potential to greatly improve the quality and timeliness of data on the health of PWID.

BACKGROUND: During shortages, elastomeric half-mask respirators (EHMRs) are an alternative to reusing N95 filtering facepiece respirators but require between-use disinfection. The objectives of this study were to (a) measure microbial reductions on EHMR surfaces under laboratory conditions by a standardized procedure using wipes impregnated with health care disinfectants and to (b) measure microbial reductions on EHMRs disinfected by volunteer health care providers. METHOD: We inoculated EHMR (Honeywell model RU8500) surfaces with Pseudomonas aeruginosa, Bacillus atrophaeus spores, and bacteriophages MS2 and Φ6, and disinfected them using two wipes with hydrogen peroxide (HP), alcohols, and quaternary ammonium compounds (QACs). Then, we randomized 54 volunteer subjects into three groups (Group 1: two wipes with instructions, Group 2: five wipes with instructions, Group 3: no instructions or set number of wipes) and used 0.5% HP wipes without precleaning on EHMRs inoculated with Raoultella terrigena and MS2. FINDINGS: The laboratory study demonstrated that all organisms achieved at least 4 log(10) median reductions (HP>QAC/alcohol>QAC>QAC/saline). Pseudomonas was highly susceptible to HP and QAC/alcohol and Φ6 to all disinfectants. MS2 reduction was highest using HP and lowest using QAC/saline. Bacillus was least susceptible. The volunteer study showed a 3 to 4 log(10) average reductions of bacteria and virus; Raoultella reductions were greater than MS2, with variability within and between subjects. Conclusions: HP disinfectant wipes used in laboratory and by volunteers reduce bacteria and viruses on EHMRs by 3 to 4 log(10) on average. IMPLICATIONS FOR PRACTICE: Commercially available hospital disinfectant wipes reduce bacteria and viruses on EHMRs and can fill the need for between-use disinfection. HP and combination QAC/alcohol have the greatest efficacy under our test conditions.

BACKGROUND: New elastomeric half mask respirator (EHMR) models without exhalation valves (EVs) or with exhalation valve filters (EVFs) are facilitating expanded use in health settings to reduce workers' exposure to airborne hazards while acting as source control to prevent pathogen spread. The physical comfort of new models has not been assessed in comparison to previously used EHMRs with EVs. METHODS: Researchers assessed 1,962 healthcare and emergency medical service personnels' self-reported adverse experiences from two cohorts while wearing EHMR models with EVs (Cohort 1, n=1,080) and without EVs or with EVFs (Cohort 2, n=882). Fisher's Exact Test identified differences between the cohorts accounting for organizational factors when possible. RESULTS: Cohort 1 respondents experienced communication challenges and discomfort when wearing the EHMR >1 hour statistically significantly more often than Cohort 2. Cohort 2 respondents reported statistically significantly more instances of difficulty breathing, moisture buildup, being uncomfortable to wear <1 hour, and being uncomfortably warm. CONCLUSIONS: Discomfort is prevalent among end users and more often among those wearing EHMRs without an EV/with an EVF. As EHMR research and development advances, prevalence in use may increase for emergency and routine situations. Organizations may not only need guidance about respirator selection but also model-specific selection.

BACKGROUND: Reusable elastomeric half-mask respirators (EHMR) are an alternative to address shortages of disposable respirators. While respirator discomfort has been noted as a barrier to adherence to wearing an N95 filtering facepiece respirator (FFR) among health care personnel (HCP), few have examined EHMR comfort while providing patient care, which was the purpose of this study. METHOD: Among a cohort of 183 HCP, we prospectively examined how HCP rated EHMR tolerability using the Respirator Comfort, Wearing Experience, and Function Instrument (R-COMFI) questionnaire at Study Week 2 and Week 10. At the completion of the study (Week-12), HCP compared EHMR comfort with their prior N95 FFR use. Overall R-COMFI scores and three subscales (comfort, wear experience, and function) were examined as well as individual item scores. FINDINGS: The HCP reported an improved overall R-COMFI score (lower score more favorable, 30.0 vs. 28.7/47, respectively) from Week 2 to Week 10. Many individual item scores improved or remained low over this period, except difficulty communicating with patients and coworkers. The overall R-COMFI scores for the EHMR were more favorable than for the N95 FFR (33.7 vs. 37.4, respectively), with a large proportion of workers indicating their perception that EHMR fit better, provided better protection, and they preferred to wear it in pandemic conditions compared with the N95 FFR. CONCLUSION/APPLICATION TO PRACTICE: Findings suggest that the EHMR is a feasible respiratory protection device with respect to tolerance. EHMRs can be considered as a possible alternative to the N95 FFR in the health care setting. Future work is needed in the EHMR design to improve communication.

BACKGROUND: During public health emergencies, demand for N95® filtering facepiece respirators (N95 FFRs) can outpace supply. Elastomeric half mask respirators (EHMRs) are a potential alternative that are reusable and provide the same or higher levels of protection. This study sought to examine the practical aspects of EHMR use among healthcare personnel (HCP). METHODS: Between September and December 2021, 183 HCP at two tertiary referral centers participated in this three-month EHMR deployment, wearing the EHMR whenever respiratory protection was required according to hospital protocols (i.e., when an N95 FFR would typically be worn) and responding to surveys about their experience. RESULTS: Participants wore EHMRs typically 1-3 hours per shift, reported disinfecting the respirator after 85% of removals, and reported high confidence in using the EHMR following the study. EHMRs caused minimal interference with patient care tasks, though they did inhibit communication. DISCUSSION: HCP who had not previously worn an EHMR were able to wear it as an alternative to an N95 FFR without much reported interference with their job tasks and with high disinfection compliance. CONCLUSION: This study highlights the feasibility of deployment of EHMRs during a public health emergency when an alternative respirator option is necessary.

Diagnostic limitations challenge management of clinically indistinguishable acute infectious illness globally. Gene expression classification models show great promise distinguishing causes of fever. We generated transcriptional data for a 294-participant (USA, Sri Lanka) discovery cohort with adjudicated viral or bacterial infections of diverse etiology or non-infectious disease mimics. We then derived and cross-validated gene expression classifiers including: 1) a single model to distinguish bacterial vs. viral (Global Fever-Bacterial/Viral [GF-B/V]) and 2) a two-model system to discriminate bacterial and viral in the context of noninfection (Global Fever-Bacterial/Viral/Non-infectious [GF-B/V/N]). We then translated to a multiplex RT-PCR assay and independent validation involved 101 participants (USA, Sri Lanka, Australia, Cambodia, Tanzania). The GF-B/V model discriminated bacterial from viral infection in the discovery cohort an area under the receiver operator curve (AUROC) of 0.93. Validation in an independent cohort demonstrated the GF-B/V model had an AUROC of 0.84 (95% CI 0.76-0.90) with overall accuracy of 81.6% (95% CI 72.7-88.5). Performance did not vary with age, demographics, or site. Host transcriptional response diagnostics distinguish bacterial and viral illness across global sites with diverse endemic pathogens.

In 2022, 13.5% of adults aged ≥18 years felt very tired or exhausted most days or every day in the past 3 months, and this percentage declined with age. Among men, the percentage was highest among those aged 18–44 years (11.0%), followed by those aged 45–64 years (9.7%) and ≥65 years (8.9%). Among women, the decline in the percentage with age was steeper, decreasing from 20.3% (18–44 years), to 15.3% (45–64 years), to 11.5% (≥65 years). The percentage of adults who felt tired or exhausted most days or every day was higher for women compared with men in each age group.

BACKGROUND: Disposable N95 respirator shortages during the COVID-19 and 2009 H1N1 influenza pandemics highlighted the need for reusable alternatives, such as elastomeric half-mask respirators (EHMRs). Two US medical organizations deployed reusable EHMRs during the COVID-19 response. In addition to wipe-based disinfection following patient care episodes expected per local policies at both organizations, postshift centralized cleaning and disinfection (C&D) was expected at one site (A), permitting shared-pool EHMR use, and optional at the other (Site B), where EHMRs were issued to individuals. Using a survey, we evaluated disinfection practices reported by EHMR users and predictors of disinfection behaviors and perceptions. METHODS: Surveys assessed EHMR disinfection practices, occupational characteristics, EHMR use frequency, training, and individual-issue versus shared-pool EHMR use. RESULTS: Of 1080 EHMR users completing the survey, 76% reported that they disinfect the EHMR after each patient encounter, which was the expected practice at both sites. Increasing EHMR use, recall of disinfection training, and work in intensive care or emergency settings significantly influenced higher reporting of this practice. 36% of respondents reported using centralized C&D, although reporting was higher at the site (A) where this was expected (53%). Confidence in cleanliness of the EHMR following centralized C&D was not influenced by individual versus shared-pool EHMR issue. CONCLUSIONS: Most EHMR users reported adherence with expected post-care individual-based disinfection of EHMRs but did not necessarily use standardized, centralized C&D. Future efforts to limit reliance on behavior related to respirator disinfection may improve EHMR implementation in healthcare to avert dependence on single-use, disposable N95 respirators.

BACKGROUND: A major concern among healthcare experts is a shortage of N95 filtering facepiece respirators (FFRs) during a pandemic. If the supply of N95 FFRs becomes limited, reusable elastomeric half-mask respirators (EHMRs) may be used to protect healthcare workers. The focus of this study was to evaluate the effects on filter performance of wiping decontamination for EHMR P100 filter cartridges. METHODS: The filter cartridge exterior of EHMR Honeywell, Moldex, and MSA models was wiped using quaternary ammonium and sodium hypochlorite wipes. These filter cartridge properties were assessed including observational analysis and filter performance tests. These wiping and assessing procedures were repeated after each set of wiping cycles (50, 100, 150, 200, and 400 cycles) to determine the effects of wiping decontamination. RESULTS: For sodium hypochlorite wipes, Honeywell, Moldex, and MSA models passed the NIOSH liquid particulate penetration criteria for all wiping cycles from 50 to 400 (penetrations < 0.014%). For quaternary ammonium wipes, filter penetrations of Moldex failed (penetrations >0.03%) after 150 cycles, while the filter penetrations of Honeywell and MSA passed for all wiping cycles (penetrations ≤ 0.013%). CONCLUSIONS: Wiping decontamination methods using sodium hypochlorite and quaternary ammonium wipes could be considered as promising decontamination candidates for Honeywell, Moldex, and MSA reuse, except for the wiping number selection for Moldex (< 150 cycles) when using the quaternary ammonium wipe.

BACKGROUND: Availability of personal protective equipment (PPE) and its effective use may influence safety climate perceptions among health care personnel (HCP). It is unclear how health care organizations can leverage the effective use of respiratory protection to engage in continuous improvement of their safety climate, which can inform opportunities for employee education and engagement. METHODS: After using an elastomeric half mask respirator (EHMR) as their primary form of respiratory protection for several months, 1,080 HCP provided feedback in an electronic survey about respiratory protection training, confidence in EHMR use, barriers during use, and perceived safety climate. Ordinal logistic regressions were used as nonlinear models to test relationships between these variables. FINDINGS: We observed that an increase in user confidence (p < .013), training content (p < .001), training formats (p < .001), and a decrease in EHMR barriers (p < .001) were associated with a statistically significant increase in proactive safety climate. In the second model, an increase in user confidence (p < .006) and training content (p < .001), and a decrease in barriers (p < .001), was associated with a statistically significant increase in compliant safety climate. CONCLUSIONS/APPLICATION TO PRACTICE: HCP EHMR confidence was positively associated with safety climate perceptions, underscoring the value of competency building by respiratory protection leaders prior to implementation. Because fewer barriers experienced while using an EHMR were associated with a more positive perception of safety climate, it is important to first communicate with end users about potential barriers and, second, to continue research with end users and manufacturers to improve the design of EHMRs moving forward.

OBJECTIVE: This study evaluated healthcare workers' (HCW) knowledge and confidence in using elastomeric half-mask respirator (EHMR) attributes known to influence usage. METHODS: HCW were surveyed regarding their EHMR donning and doffing experience. Respondents were categorized into competency categories based on their scores. Category differences were analyzed using chi square and multiple logistic regression. RESULTS: 72% showed high levels of EHMR donning and doffing knowledge and confidence (mastery); however, 21% had greater confidence than knowledge (misinformed). Respiratory therapists had greater odds of mastery than other HCW (p < .05), while those working in medical/surgical and pediatric units had greater odds of doubt than other HCW (p < .01). CONCLUSION: While most HCW show high knowledge and confidence with EHMR use strategies to confirm respirator use competency may ensure greater HCW protection.

The National Institute for Occupational Safety and Health's methods and requirements for air-purifying respirator breathing resistance in 42 CFR Part 84 do not include work of breathing. The International Organization for Standardization Technical Committee 94, Subcommittee 15 utilized work of breathing to evaluate airflow resistance for all classes of respiratory protective devices as part of their development of performance standards regarding respiratory protective devices. The objectives of this study were: (1) to evaluate the relationship between the International Organization for Standardization's work of breathing measurements and the National Institute for Occupational Safety and Health's breathing resistance test results; (2) to provide scientific bases for standard development organizations to decide if work of breathing should be adopted; and (3) to establish regression equations for manufacturers and test laboratories to estimate work of breathing measurements using breathing resistance data. A total of 43 respirators were tested for work of breathing at minute ventilation rates of 10, 35, 65, 105, and 135 liters per minute. Breathing resistance obtained at a constant flow rate of 85 liters per minute per National Institute of Occupational Safety and Health protocol was correlated to each of the parameters (total work of breathing, inhalation, and exhalation) obtained from the work of breathing tests. The ratio of work of breathing exhalation to work of breathing inhalation for all air-purifying respirators is similar to the ratio of exhalation to inhalation resistance when tested individually. The ratios were about 0.8 for filtering facepiece respirators, 0.5 for half-masks, and 0.25 for full-facepiece respirators. The National Institute for Occupational Safety and Health's breathing resistance is close to work of breathing's minute ventilation of 35 liters per minute, which represents the common walking/working pace in most workplaces. The work of breathing and the National Institute of Occupational Safety and Health's breathing resistance were found to be strongly and positively correlated (r values of 0.7-0.9) at each work rate for inhalation and exhalation. In addition, linear and multiple regression models (R-squared values of 0.5-0.8) were also established to estimate work of breathing using breathing resistance. Work of breathing was correlated higher to breathing resistance for full-facepiece and half-mask elastomeric respirators than filtering facepiece respirators for inhalation. For exhalation, filtering facepiece respirators were correlated much better than full-facepiece and half-mask elastomeric respirators. Therefore, the National Institute for Occupational Safety and Health's breathing resistance may reasonably be used to predict work of breathing for air-purifying respirators. The results could also be used by manufacturers for product development and evaluation.

Recently, total inward leakage (TIL) for filtering facepiece and elastomeric half-mask respirators (EHRs) was measured according to the International Organization for Standardization (ISO) test method standard 16900-1:2014 that showed larger TIL for corn oil aerosol than for NaCl aerosol. Comparison of TIL measured for different aerosols for higher protection level respirators is lacking. The objective of this study was to determine TIL for EHRs, full-facepiece respirators, and loose-fitting and tight-fitting powered air-purifying respirators (PAPRs) using NaCl and corn oil aerosols to compare. TIL was measured for two models each of EHRs, full-facepiece respirators, and loose-fitting and tight-fitting PAPRs. After fit testing with a PortaCount (TSI, St. Paul, MN) using the Occupational Safety and Health Administration (OSHA) protocol, eight subjects were tested in the NaCl aerosol chamber first and then in the corn oil aerosol chamber, while another eight subjects tested in the reverse order. Subjects were randomly assigned to one of the two groups. TIL was measured as a ratio of mass-based aerosol concentrations inside the mask to the test chamber while the subjects performed ISO 16900-1-defined exercises using continuous sampling methods. The concentration of corn oil aerosol was measured with one light scattering photometer, alternately, and NaCl aerosol was measured using two flame photometers. Results showed the geometric mean TIL for EHR was significantly (p < 0.05) larger for corn oil aerosol than for NaCl aerosol. EHR models equipped with P100 filters showed relatively smaller TIL values than the same models with N95 filters showing that TIL was inversely related to filter efficiency. Interestingly, TIL was significantly (p < 0.05) larger for NaCl aerosol than for corn oil aerosol for PAPRs, but not for full-facepiece respirators. TIL was inversely related to fit factors of respirator types. Overall, filter efficiency and faceseal leakage determine TIL. The relative trends in TIL for the two aerosols' test methods differ between respirator types indicating that generalization of TIL for respirator types may not be appropriate when using different test agents.

Background: Black mothers in the United States have shorter breastfeeding (BF) durations and less exclusive breastfeeding (EBF) than others. The factors underlying these disparities require investigation. Methods: Using longitudinal data from a CDC-sponsored birth cohort in Cincinnati, Ohio, we analyzed the factors mediating racial disparity in BF outcomes. Study mothers were enrolled in prenatal clinics associated with two large birth hospitals. Analysis was restricted to racial groups with sufficient numbers in the cohort, non-Hispanic Black (n = 92) and White (n = 113) mothers, followed to at least 6 months postpartum. Results: Black mothers were 25 times more likely to reside in socioeconomically deprived neighborhoods and 20 times more likely to have an annual household income <$50,000/year than White mothers (p < 0.001). The gap in EBF for 6 weeks was 45 percentage points by racial group (13%-Black mothers versus 58%-White mothers, p < 0.001); in any BF at 6 months was 37 percentage points (28%-Black mothers versus 65%-White mothers, p < 0.001); and in mothers meeting their own intention to BF at least 6 months was 51 percentage points (29%-Black mothers versus 80%-White mothers, p < 0.001). Racial disparity in EBF at 6 weeks was mediated in logistic regression models by inequities in socioeconomic position, maternal hypertension, and BF intention. Racial disparities in BF at 6 months or meeting 6-month BF intention were mediated by inequities in socioeconomic position, maternal obesity, and EBF at 6 weeks. Not all BF disparities could be explained by models used in these analyses. Conclusions: Efforts to lessen BF disparities should address the underlying structural inequities that disproportionately affect Black mothers and children, should incorporate maternal health, and focus on breastfeeding exclusivity and duration. Few Black mothers achieved EBF at 6 weeks, which contributed to disparity in BF duration. Greater attention to Black mother-infant pairs is a public health priority.

As part of development of performance standards, the International Organization for Standardization (ISO) technical committee, ISO/TC 94/SC 15 Respiratory protective devices (RPD), adopted work of breathing (WOB) to evaluate airflow resistance for all designs (classes) of respiratory protective devices. The interests of the National Institute for Occupational Safety and Health's (NIOSH) National Personal Protective Technology Laboratory (NPPTL) are to compare the proposed WOB method and results for current RPD with those for present resistance methods. The objectives here were to assemble a method to meet the ISO SC15 standards, validate operation and conformance, and assess repeatability of WOB measurements for RPD. WOB method implementation and use followed standards ISO 16900-5:2016 and ISO 16900-12:2016. Volume-averaged total work of breathing (WOBT/VT where VT is tidal volume) determined for standard orifices was analyzed for variation and bias. After fabrication and assembly, the method gave preliminary verification orifice results that met ISO requirements and were equivalent to those from other laboratories. Evaluation of additional results from RPD testing showed tidal volume and frequency determined compliance. Appropriate adjustments reduced average absolute bias to 1.7%. Average coefficient of variation for WOBT/VT was 2.3%. Over 97% of results obtained during significant use over time met specifications. WOBT/VT for as-received air-purifying and supplied-air RPD were repeatable (p<0.05). WOBT/VT for unsealed half mask air-purifying RPD was an average of 31% lower compared to sealed. When experimental parameters were appropriately adjusted, the ISO WOB method implemented by NIOSH NPPTL consistently provided ISO-compliant verification WOBT/VT. Results for appropriately sealed RPD were reproducible.

Endocrine and metabolism disrupting chemicals (EDCs/MDCs) have been associated with environmental liver diseases including toxicant-associated steatohepatitis (TASH). TASH has previously been characterized by hepatocellular necrosis, disrupted intermediary metabolism, and liver inflammation. Polychlorinated biphenyls (PCBs) are environmental EDCs/MDCs associated with the genesis and progression of steatohepatitis in animal models and human liver injury in epidemiology studies. The cross-sectional Anniston Community Health Survey (ACHS) investigates ortho-substituted PCB exposures and health effects near a former PCB manufacturing complex. The rates of obesity, diabetes, and dyslipidemia were previously determined to be high in ACHS. In this study, 738 ACHS participants were categorized by liver disease status using the serum cytokeratin 18 biomarker. Associations between PCB exposures and mechanistic biomarkers of intermediary metabolism, inflammation, and hepatocyte death were determined. The liver disease prevalence was high (60.2%), and 80.7% of these individuals were categorized as having TASH. Sex and race/ethnicity differences were noted. TASH was associated with increased exposures to specific PCB congeners, insulin resistance, dyslipidemia, pro-inflammatory cytokines, and liver necrosis. These findings are consistent with PCB-related steatohepatitis. SigmaPCBs was inversely associated with insulin resistance/production, leptin, and hepatocyte apoptosis, while other adipocytokines were increased. This is possibly the largest environmental liver disease study applying mechanistic biomarkers ever performed and the most comprehensive analysis of PCBs and adipocytokines. It provides insight into the mechanisms of PCB-related endocrine and metabolic disruption in liver disease and diabetes. In the future, associations between additional exposures and liver disease biomarkers will be evaluated in the ACHS and follow-up ACHS-II studies.

Introduction The purpose of this article is to present the collective experiences of six federally-funded critical congenital heart disease (CCHD) newborn screening implementation projects to assist federal and state policy makers and public health to implement CCHD screening. Methods A qualitative assessment and summary from six demonstration project grantees and other state representatives involved in the implementation of CCHD screening programs are presented in the following areas: legislation, provider and family education, screening algorithms and interpretation, data collection and quality improvement, telemedicine, home and rural births, and neonatal intensive care unit populations. Results The most common challenges to implementation include: lack of uniform legislative and statutory mandates for screening programs, lack of funding/resources, difficulty in screening algorithm interpretation, limited availability of pediatric echocardiography, and integrating data collection and reporting with existing newborn screening systems. Identified solutions include: programs should consider integrating third party insurers and other partners early in the legislative/statutory process; development of visual tools and language modification to assist in the interpretation of algorithms, training programs for adult sonographers to perform neonatal echocardiography, building upon existing newborn screening systems, and using automated data transfer mechanisms. Discussion Continued and expanded surveillance, research, prevention and education efforts are needed to inform screening programs, with an aim to reduce morbidity, mortality and other adverse consequences for individuals and families affected by CCHD.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

While therapeutic drugs are routinely self-administered by patients, there is little precedent for self-vaccination. Convenient self-vaccination may expand vaccination coverage and reduce administration costs. Microneedle patches are in development for many vaccines, but no reports exist on usability or acceptability. We hypothesized that naive patients could apply patches and that self-administered patches would improve stated intent to receive an influenza vaccine. We conducted a randomized, repeated measures study with 91 venue-recruited adults. To simulate vaccination, subjects received placebo microneedle patches given three times by self-administration and once by the investigator, as well as an intramuscular injection of saline. Seventy participants inserted patches with thumb pressure alone and the remainder used snap-based devices that closed shut at a certain force. Usability was assessed by skin staining and acceptability was measured with an adaptive-choice analysis. The best usability was seen with the snap device, with users inserting a median value of 93-96% of microneedles over three repetitions. When a self-administered microneedle patch was offered, intent to vaccinate increased from 44% to 65% (CI: 55-74%). The majority of those intending vaccination would prefer to self-vaccinate: 64% (CI: 51-75%). There were no serious adverse events associated with use of microneedle patches. The findings from this initial study indicate that microneedle patches for self-vaccination against influenza are usable and may lead to improved vaccination coverage.

Microsporidia are increasingly recognized as opportunistic pathogens in immunocompromised organ transplant recipients (OTR). Disseminated infection due to Encephalitozoon sp. is reported mainly in human immunodeficiency virus (HIV)-positive patients and rarely in HIV-negative OTR. The clinical spectrum ranges from keratoconjunctivitis, to pneumonitis, to acute kidney injury. The kidney is a common site for disseminated infection; however, specialized techniques are required for definitive diagnosis. We report the first case of disseminated Encephalitozoon cuniculi infection in an HIV-negative lung transplant recipient diagnosed on renal biopsy. Five months after transplant, he presented with fever and a lung infiltrate and developed acute kidney injury. Renal biopsy showed granulomatous interstitial nephritis with gram-positive rod-shaped organisms with a "belt-like stripe" in tubular epithelial cells. Electron microscopy, polymerase chain reaction, and mammalian cell cultures of the urine sediment confirmed E. cuniculi infection. Retrospective review of a previous lung biopsy showed similar organisms. On the basis of electron microscopy findings, the patient was treated with albendazole, and immunosuppressive therapy was reduced. However, the patient expired due to Aspergillus pneumonia and disseminated E. cuniculi infection. Microsporidia should be considered in cases of fever of unknown origin and/or multiorgan infection in HIV-negative OTR when other causes have been excluded, as successful treatment requires early detection.

Quality assurance (QA) is a systematic process to monitor and improve clinical laboratory practices. The fundamental components of a laboratory QA program include providing a functional and safe laboratory environment, trained and competent personnel, maintained equipment, adequate supplies and reagents, testing of appropriate specimens, internal monitoring of quality, accurate reporting, and external quality assessments. These components are necessary to provide accurate and precise CD4 T-cell counts, an essential test to evaluate start of and monitor effectiveness of antiretroviral therapy for HIV-infected patients. In recent years, CD4 testing has expanded dramatically in resource-limited settings. Information on a CD4 QA program as described in this article will provide guidelines not only for clinical laboratory staff but also for managers of programs responsible for supporting CD4 testing. All agencies involved in implementing CD4 testing must understand the needs of the laboratory and provide advocacy, guidance, and financial support to established CD4 testing sites and programs. This article describes and explains the procedures that must be put in place to provide reliable CD4 determinations in a variety of settings.

An original evidence review examined screening and diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) and the subsequent outcomes in a population of newly diagnosed cases of colorectal cancer (CRC). This supplementary evidence review focuses on five issues of further interest to the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG), as summarized below. | | Clarifying how to define the clinical disorder—Lynch syndrome. In this supplementary review, Lynch syndrome refers to individuals with a predisposition to CRC and certain other malignancies as a result of a germline mismatch repair (MMR) gene mutation—including those with an existing cancer and those who have not yet developed cancer. This definition allows planned analyses of clinical validity and utility to be more straightforward. Several recent editorials and publications recommend that the ambiguous term HNPCC be abandoned and that this clarified definition of Lynch syndrome should be used instead. | Removing family history from consideration as a preliminary test. A previous evidence review showed that screening performance of both the Amsterdam and the Bethesda criteria to identify individuals with Lynch syndrome were highly heterogeneous, possibly due to differences among the populations tested. In a general population, Amsterdam criteria are associated with relatively low sensitivity (28–45%), but high specificity (99%), whereas Bethesda criteria are associated with higher sensitivity (73–91%), but at the cost of lower specificity (82–77%). Neither provides the necessary high sensitivity/specificity in a reliable and consistent manner. There are also gaps in knowledge relating to the time required to collect family history, the consistency with which it is collected, and the accuracy of the information. These shortcomings have led us to remove family history from consideration as a preliminary test in individuals newly diagnosed with CRC. However, family history may still be an important component of CRC risk assessment in the general population. | Documenting the clinical validity of DNA-based preliminary tests. Because of rapid advances in knowledge and technology regarding molecular testing and Lynch syndrome, we generally limited this review to publications from 2003 and later. Although not formally studied, this is a likely reason why several of our estimates differ from those provided in an earlier evidence report. There was “Adequate” (a formal EWG term) evidence showing the sensitivity of microsatellite instability (MSI) testing to be about 89% (for mutations in the MMR genes MLH1 and MSH2), with a lower sensitivity of about 77% for MSH6 mutations. Sensitivity was higher when three or more mononucleotide markers were included in the panel. Specificity was estimated to be 90.2%, with an adequate level of evidence. There was also good evidence showing the sensitivity of immunohistochemical (IHC) testing to be 83%, regardless of the underlying MMR gene involved. Specificity was more variable with a central estimate of 88.8%, and an adequate level of evidence. Inadequate evidence was available to determine the distribution of mutations in the MMR genes, but the limited data suggest 32% will be in MLH1, 38% in MSH2, 14% in MSH6, and 15% in PMS2. Adequate evidence was available to estimate sensitivity (69%) and specificity (point estimate of 100%) for identifying Lynch syndrome using a specific mutation in the BRAF gene among those with absent IHC staining for MLH1. An alternative to BRAF mutation testing might be direct testing of MLH1 methylation status, but this was not evaluated. | Benefits and harms to probands and relatives with Lynch syndrome. Between 2 and 12 first-degree relatives of probands (newly diagnosed CRC cases with Lynch syndrome, or index cases) can be contacted, based on resources and methodology. There was adequate evidence to document uptake of counseling among these first-degree relatives who were contacted (52%) and subsequently targeted for MMR gene mutation testing (95%). Adequate evidence was found showing the risk of CRC by age 70 to be approximately 45% for men and 35% for women among relatives with Lynch syndrome. This is lower than earlier estimates, because of the more severe family histories included in earlier studies. Among relatives with Lynch syndrome, risks for endometrial cancer by 70 years of age are variable and range from as low as 31% to as high as 64%. Some of the higher estimates, however, may be subject to family history bias. The U.S. Multisociety Task Force on Colorectal Cancer recommends colonoscopy every 1 or 2 years for first-degree relatives of individuals diagnosed with Lynch syndrome, and uptake among this group is about 80%. The most serious adverse events associated with colonoscopy in the general population are bleeding (1.1/1000 individuals), perforation (3.3/1000), and death (0.08/1000). Adequate evidence on the effectiveness of routine colonoscopy in relatives with Lynch syndrome is available from a controlled trial in Finland and from an observational cohort study in the Netherlands. Evidence, overall, was rated as Level IIb. By using an intention to treat analysis, the Finnish study reported that CRC incidence was reduced by 62%, with no deaths among those undergoing surveillance, compared with nine in the control group. Other less direct studies suggest efficacy of periodic colonoscopy. Adequate evidence exists that 63% of women will adhere to endometrial cancer surveillance. Inadequate data are available to document that transvaginal ultrasound and endometrial biopsy can reduce the incidence of endometrial cancer. Hysterectomy and bilateral salpingo-oophorectomy are effective in reducing the risk for endometrial cancer, but uptake is low (19%) and it has not been the standard of care to recommend this procedure. | Economic modeling of programmatic costs and costs per Lynch syndrome detected using four different testing strategies. Data from this supplementary review, along with other published information, were used to perform a cost-consequences analysis. Rather than looking at health outcomes, this type of analysis focuses on the direct consequences of testing. In this analysis, the costs per Lynch syndrome case detected were determined for four strategies that represent a wide range of possible testing/diagnostic scenarios. The list of strategies is not intended to be exhaustive but to provide examples. It is assumed that the initial test in each of the four strategies described below would have 67% uptake so that detection rates for Lynch syndrome can be compared between strategies. Subsequent actions are modeled at rates found in the literature (e.g., uptake of counseling and testing among their relatives). Total program costs (preliminary testing, counseling, diagnostic testing, contacting relatives and targeted testing) are computed assuming a cohort of 150,000 newly diagnosed CRC cases with a 3% prevalence of Lynch syndrome. | Strategy 1. Individuals with newly diagnosed CRC (probands) would have MMR gene sequencing/deletion testing for MLH1, MSH2, and MSH6. This strategy will have the highest sensitivity for Lynch syndrome (about 85% or 2537 of the 3000 cases), and cost about $111,000 (90% CI, $83,000–$148,000) per proband with Lynch syndrome detected. If relatives of the proband are included in the analysis as well, the cost per adult with Lynch detected is reduced to about $72,000 (90% CI, $49,000–$101,000). Costs are reduced when relatives are included because they require only counseling and targeted testing for the family mutation. Total program costs for this strategy are about $281 million. | Strategy 2. All probands would have quality MSI testing; those with high instability would have sequencing/deletion testing for the three MMR genes. This strategy will have a lower overall detection rate (73% or 2198 cases) because the MSI is not high in all individuals with Lynch syndrome. The cost per proband with Lynch syndrome detected is $47,000 (90% CI, $33,000 –$64,000). When relatives are included, the cost per case detected is reduced to $31,000 (90% CI, $20,000 –$44,000). Total program costs are about $104 million. | Strategy 3. All probands would have quality IHC testing; those with negative staining would have sequencing/deletion testing for the some of the three MMR genes. This strategy will have a slightly lower overall detection rate (70% or 2105 cases), compared with Strategy 2, because IHC testing seems to be slightly less reliable when identifying probands with Lynch syndrome. The cost per Lynch syndrome proband detected is $21,000 (90% CI, $14,000–$29,000). When relatives are included, the cost per case detected is reduced to $14,000 (90% CI, $9,000–$20,000). The lower costs are because IHC testing provides information about which MMR gene(s) are likely to contain the mutation, thereby reducing testing costs for the probands. Total program costs are about $46 million. | Strategy 4. Strategy 3 is modified so that probands with an IHC MLH1 negative stain are all tested for the specific BRAF mutation. If that mutation is not found, the individual continues on for MMR gene(s) testing. If the mutation is found, no further testing (sequencing) is required as the chance of having Lynch syndrome is very low. The overall detection rate remains at about 70% (or 2097 cases), as the sensitivity of BRAF mutation testing is close to 100%. The cost per Lynch syndrome proband detected is $19,000 (90% CI, $13,000–$26,000). When relatives are included, the cost per case detected is reduced to $13,000 (90% CI, $8,000–$18,000). Total program costs are about $41 million.