The World Health Organization's Immunization and Vaccines-related Implementation Research Advisory Committee (IVIR-AC) serves to independently review and evaluate vaccine-related research to maximize the potential impact of vaccination programs. From 28 June - 1 July 2024, IVIR-AC was convened for an ad hoc meeting to discuss new evidence on criteria for rubella vaccine introduction and the risk of congenital rubella syndrome. This report summarizes background information on rubella virus transmission and the burden of congenital rubella syndrome, meeting structure and presentations, proceedings, and recommendations.

This cross-sectional study systematically examines the contributions of COVID-19 and other underlying causes of death to the widened gender life expectancy gap from 2010 to 2021. | eng

BACKGROUND: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients. OBJECTIVES: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission. PATIENTS/METHODS: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, VT, USA) between 2010-19 and the validation cohorts people admitted to Hennepin County Medical Center (Minneapolis, MN, USA), University of Michigan Medical Center (Ann Arbor, MI, USA), and Harris Health Systems (Houston, TX, USA). Individuals with VTE at admission, <18-years old, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to selected candidate HA-VTE risk factors for final inclusion in the RAM. RESULTS: The development cohort included 60,633 admissions and 227 HA-VTE and the validation cohorts 111,269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t-statistics ≥1.5 were included in the RAM: prior history of VTE, low hemoglobin, elevated creatinine, active cancer, hyponatremia, elevated red cell distribution width, and malnutrition. The AUC and calibration slope were 0.72 and 1.10. The AUC and calibration slopes were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems. The RAM performed well stratified by age, sex, and race. CONCLUSIONS: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE.

Specific organochlorines (OCs) have been associated with non-Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g., dichlorodiphenyltrichloroethane [DDT], hexachlorocyclohexane [HCH]) are different from Western populations. We evaluated NHL risk and prediagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl congeners in a case-control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid-adjusted OC levels and NHL risk. Median levels of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), the primary DDT metabolite, and β-HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher β-HCH levels both overall (3rd vs. 1st tertile OR = 1.8, 95%CI = 1.0-3.2; p(trend) = 0.049) and after excluding cases diagnosed within 2 years of blood collection (3rd vs. 1st tertile OR = 2.0, 95%CI = 1.1-3.9; p(trend) = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p'-DDE. Our findings provide support for an association between β-HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p'-DDE do not support an association.

An author's name was misspelled in the byline on page 1420. “Keri N. Atlhoff” should read “Keri N. Althoff.” The error has been corrected in the published article.

BACKGROUND: Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. METHODS: We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. RESULTS: We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region. INTERPRETATION: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission.

We aimed to describe frequency of COVID-19 exposure risk factors among patients presenting for medical care at an urban, public hospital serving mostly uninsured/Medicare/Medicaid clients and risk factors associated with SARS-CoV-2 infection. Consenting, adult patients seeking care at a public hospital from August to November 2020 were enrolled in this cross-sectional investigation. Saliva, anterior nasal and nasopharyngeal swabs were collected and tested for SARS-CoV-2 using RT-PCR. Participant demographics, close contact, and activities ≤14 days prior to enrollment were collected through interview. Logistic regression was used to identify risk factors associated with testing positive for SARS-CoV-2. Among 1,078 participants, 51.8% were male, 57.0% were aged ≥50 years, 81.3% were non-Hispanic Black, and 7.6% had positive SARS-CoV-2 tests. Only 2.7% reported COVID-19 close contact ≤14 days before enrollment; this group had 6.79 adjusted odds of testing positive (95%CI = 2.78-16.62) than those without a reported exposure. Among participants who did not report COVID-19 close contact, working in proximity to ≥10 people (adjusted OR = 2.17; 95%CI = 1.03-4.55), choir practice (adjusted OR = 11.85; 95%CI = 1.44-97.91), traveling on a plane (adjusted OR = 5.78; 95%CI = 1.70-19.68), and not participating in an essential indoor activity (i.e., grocery shopping, public transit use, or visiting a healthcare facility; adjusted OR = 2.15; 95%CI = 1.07-4.30) were associated with increased odds of testing positive. Among this population of mostly Black, non-Hispanic participants seeking care at a public hospital, we found several activities associated with testing positive for SARS-CoV-2 infection in addition to close contact with a case. Understanding high-risk activities for SARS-CoV-2 infection among different communities is important for issuing awareness and prevention strategies.

Self-collected specimens can expand access to SARS-CoV-2 testing. At a large inner-city hospital 1,082 participants self-collected saliva and anterior nasal swab (ANS) samples before healthcare workers collected nasopharyngeal swab (NPS) samples on the same day. To characterize patient preferences for self-collection, this investigation explored ability, comfort, and ease of ANS and saliva self-collection for SARS-CoV-2 testing along with associated patient characteristics, including medical history and symptoms of COVID-19. With nearly all participants successfully submitting a specimen, favorable ratings from most participants (at least >79% in ease and comfort), and equivocal preference between saliva and ANS, self-collection is a viable SARS-CoV-2 testing option.

There are no studies comparing the prognosis for mature T-cell lymphoma (TCL) in people with human immunodeficiency virus (PWH) to people without HIV (PWoH) and to AIDS-defining B-cell lymphomas (A-BCL) in the modern antiretroviral therapy (ART) era. NA-ACCORD and COMPLETE are cohorts that enroll patients diagnosed with HIV and TCL, respectively. In our study 52, 64, 101, 500 and 246 PWH with histological confirmation of TCL, primary CNS, Burkitt's, diffuse large B-cell lymphoma (DLBCL) and Hodgkin's lymphoma (HL) respectively and 450 TCL without HIV were eligible for analysis. At the time of TCL diagnosis, Anaplastic large-cell lymphoma (ALCL) was the most common TCL subtype within PWH. While PWH with TCL diagnosed between 1996-2009, experienced a low 5-year survival probability at 0.23 (95% CI: 0.13, 0.41), we observed a marked improvement in their survival when diagnosed between 2010-2016 (0.69; 95% CI: 0.48, 1; p=0.04) in contrast to TCL among PWoH (0.45; 95% CI: 0.41, 0.51; p=0.53). Similarly, PWH with ALCL diagnosed between 1996-2009 were associated with a conspicuously inferior 5-year survival probability (0.17; 95% CI: 0.07, 0.42) and consistently lagged behind A-BCL subtypes such as Burkitt's (0.43; 95% CI:0.33, 0.57; p=0.09) and DLBCL (0.17; 95% CI: 0.06, 0.46; p=0.11) and behind HL (0.57; 95% CI: 0.50, 0.65; p <0.0001). Despite a small number, those diagnosed between 2010-2016, experienced a remarkable improvement in survival (0.67; 95% CI: 0.3, 1) in comparison to PWoH (0.76; 95% CI: 0.66, 0.87; p=0.58). Thus, our analysis confirms improved overall survival for aggressive B and T-cell malignancies among PWH in the last decade.

We evaluated the performance of self-collected anterior nasal swab (ANS) and saliva samples compared with healthcare worker-collected nasopharyngeal swab specimens used to test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We used the same PCR diagnostic panel to test all self-collected and healthcare worker-collected samples from participants at a public hospital in Atlanta, Georgia, USA. Among 1,076 participants, 51.9% were men, 57.1% were >50 years of age, 81.2% were Black (non-Hispanic), and 74.9% reported >1 chronic medical condition. In total, 8.0% tested positive for SARS-CoV-2. Compared with nasopharyngeal swab samples, ANS samples had a sensitivity of 59% and saliva samples a sensitivity of 68%. Among participants tested 3-7 days after symptom onset, ANS samples had a sensitivity of 80% and saliva samples a sensitivity of 85%. Sensitivity varied by specimen type and patient characteristics. These findings can help physicians interpret PCR results for SARS-CoV-2.

BACKGROUND: The natural history and clinical progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can be better understood using combined serological and reverse transcription polymerase chain reaction (RT-PCR) testing. METHODS: Nasopharyngeal swabs and serum were collected at a single time-point from patients at an urban, public hospital August - November 2020 and tested for SARS-CoV-2 using RT-PCR, viral culture, and anti-Spike pan-Ig antibody testing. Participant demographics and symptoms were collected through interview. Chi-squared and Fisher's exact tests were used to identify associations between RT-PCR and serology results with presence of viable virus and frequency of symptoms. RESULTS: Among 592 participants, 129 (21.8%) had evidence of SARS-CoV-2 infection by RT-PCR or serology. Presence of SARS-CoV-2 antibodies was strongly associated with lack of viable virus (p-value=0.016). COVID-19 symptom frequency was similar for patients testing RT-PCR positive/seronegative and patients testing RT-PCR positive/seropositive. Patients testing RT-PCR positive/seronegative reported headaches, fatigue, diarrhea and vomiting at rates not statistically significantly different from those testing RT-PCR negative/seropositive. CONCLUSIONS: While patients testing SARS-CoV-2 seropositive were unlikely to test positive for viable virus and were therefore low-risk for forward transmission, COVID-19 symptoms were common. Paired SARS-CoV-2 RT-PCR and antibody testing provides more nuanced understanding of patients' COVID-19 status.

To assess transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a detention facility experiencing a coronavirus disease outbreak and evaluate testing strategies, we conducted a prospective cohort investigation in a facility in Louisiana, USA. We conducted SARS-CoV-2 testing for detained persons in 6 quarantined dormitories at various time points. Of 143 persons, 53 were positive at the initial test, and an additional 58 persons were positive at later time points (cumulative incidence 78%). In 1 dormitory, all 45 detained persons initially were negative; 18 days later, 40 (89%) were positive. Among persons who were SARS-CoV-2 positive, 47% (52/111) were asymptomatic at the time of specimen collection; 14 had replication-competent virus isolated. Serial SARS-CoV-2 testing might help interrupt transmission through medical isolation and quarantine. Testing in correctional and detention facilities will be most effective when initiated early in an outbreak, inclusive of all exposed persons, and paired with infection prevention and control.

BACKGROUND: COVID-19 continues to cause significant morbidity and mortality worldwide. Correctional and detention facilities are at high risk of experiencing outbreaks. We aimed to evaluate cohort-based testing among detained persons exposed to laboratory-confirmed cases of SARS-CoV-2 in order to identify presymptomatic and asymptomatic cases. METHODS: During May 1-19, 2020, two testing strategies were implemented in 12 tiers or housing units of the Cook County Jail in Chicago, Illinois. Detained persons were approached to participate in serial testing (n=137) tests at 3 time points over 14 days (day 1, day 3-5, and day 13-14). The second group was offered a single test and interview at the end of a 14-day quarantine period (day 14 group) (n=87). RESULTS: A total of 224 detained persons were approached for participation and of these 194 (87%) participated in at least one interview, and 172 (77%) had at least one test. Of the 172 tested, 19 were positive for SARS-CoV-2. In the serial testing group, 17 (89%) new cases were detected, sixteen (84%) on day 1, one (5%) on days 3-5, and none on days 13-14; and, in day 14 group, two (11%) cases were identified. More than half (12/19; 63%) of the newly identified cases were pre-symptomatic or asymptomatic. CONCLUSION: Our findings highlight the utility of cohort-based testing promptly after initiating quarantine within a housing tier. Cohort-based testing efforts identified new SARS-CoV-2 asymptomatic and presymptomatic infections that may have been missed by symptom screening alone.

Epilepsy is more common among children and adults living in households at lowest incomes. Like those living with any complex chronic condition, people with epilepsy need quality healthcare to improve their health and social outcomes. The purpose of this study was to use the latest national data to provide updated estimates of the percentages of adults aged 18-64years with active epilepsy who were uninsured in 2010, 2013, 2015, and 2017 and to examine changes in health insurance coverage during these years. We analyzed nationally representative samples of adults (aged 18-64years) from the 2010, 2013, 2015, and 2017 National Health Interview Survey (NHIS). We used a validated epilepsy surveillance case definition to classify adults as having active epilepsy during 2010 and 2013 (n=507) and during 2015 and 2017 (n=582). We used the NHIS recode variables available in each year that account for a series of questions posed to respondents to confirm coverage and that ultimately classify respondents with different healthcare coverage types. Overall, the percentage of uninsured adults among respondents aged 18-64years with active epilepsy decreased by more than half (59%), from 17.7% (95% confidence interval [CI]=13.6%-22.7%) in 2010 and 2013 to 7.3% (95% CI=4.8%-10.7%) in 2015 and 2017. The decrease in the percentage of uninsured adults with active epilepsy after 2010 and 2013 was balanced by a similar increase in public insurance coverage and private insurance coverage in 2015 and 2017. Epilepsy stakeholders can ensure that all uninsured adults with epilepsy obtain access to health insurance coverage. National Health Interview Survey data on epilepsy, when available, can be used to monitor trends in insurance status in the new decade.

BACKGROUND: In 2015, Singapore had the first and only reported foodborne outbreak of invasive disease caused by the group B Streptococcus (GBS; Streptococcus agalactiae). Disease, predominantly septic arthritis and meningitis, was associated with sequence type (ST)283, acquired from eating raw farmed freshwater fish. Although GBS sepsis is well-described in neonates and older adults with co-morbidities, this outbreak affected non-pregnant and younger adults with fewer co-morbidities, suggesting greater virulence. Before 2015 ST283 had only been reported from twenty humans in Hong Kong and two in France, and from one fish in Thailand. We hypothesised that ST283 was causing region-wide infection in Southeast Asia. METHODOLOGY/PRINCIPAL FINDINGS: We performed a literature review, whole genome sequencing on 145 GBS isolates collected from six Southeast Asian countries, and phylogenetic analysis on 7,468 GBS sequences including 227 variants of ST283 from humans and animals. Although almost absent outside Asia, ST283 was found in all invasive Asian collections analysed, from 1995 to 2017. It accounted for 29/38 (76%) human isolates in Lao PDR, 102/139 (73%) in Thailand, 4/13 (31%) in Vietnam, and 167/739 (23%) in Singapore. ST283 and its variants were found in 62/62 (100%) tilapia from 14 outbreak sites in Malaysia and Vietnam, in seven fish species in Singapore markets, and a diseased frog in China. CONCLUSIONS: GBS ST283 is widespread in Southeast Asia, where it accounts for a large proportion of bacteraemic GBS, and causes disease and economic loss in aquaculture. If human ST283 is fishborne, as in the Singapore outbreak, then GBS sepsis in Thailand and Lao PDR is predominantly a foodborne disease. However, whether transmission is from aquaculture to humans, or vice versa, or involves an unidentified reservoir remains unknown. Creation of cross-border collaborations in human and animal health are needed to complete the epidemiological picture.

PURPOSE: The lifetime risk of renal damage in children with spina bifida is high but only limited baseline imaging data are available for this population. We evaluated a large prospective cohort of infants with spina bifida to define their baseline imaging characteristics. MATERIALS AND METHODS: The UMPIRE Protocol for Young Children with Spina Bifida is an iterative quality improvement protocol that follows a cohort of newborns at 9 United States centers. Using descriptive statistics, we report the initial baseline imaging characteristics, specifically regarding renal bladder ultrasound, cystogram and dimercaptosuccinic acid nuclear medicine scan. RESULTS: Data on 193 infants from 2015 to 2018 were analyzed. Renal-bladder ultrasound was normal in 55.9% of infants, while 40.4% had Society for Fetal Urology grade 1 to 2 hydronephrosis in at least 1 kidney, 3.7% had grade 3 to 4 hydronephrosis in either kidney and 21.8% had grade 1 or higher bilateral hydronephrosis. There was no vesicoureteral reflux in 84.6% of infants. A third of enrolled infants underwent dimercaptosuccinic acid nuclear medicine renal scan, of whom 92.4% had no renal defects and 93.9% had a difference in differential function of less than 15%. CONCLUSIONS: The majority of infants born with spina bifida have normal baseline imaging characteristics and normal urinary tract anatomy at birth. This proactive protocol offers careful scheduled surveillance of the urinary tract with the goal of lifelong maintenance of normal renal function and healthy genitourinary development.

BACKGROUND: Dried blood spots (DBS), collected universally from newborns in the U.S., could be used as a matrix for the detection of cytomegalovirus (CMV) infection in infants. However, sensitivity to detect CMV in DBS as compared to saliva and urine is variable across studies largely due to the DNA extraction method. Thermal shock, a widely used DNA extraction method, is highly sensitive for the detection of CMV in DBS, however, the processing time required is not practical for high-throughput testing. OBJECTIVE: To determine if rapid and cost-effective DNA extraction methods amenable to newborn screening (NBS) could achieve the same sensitivity as the thermal shock method. STUDY DESIGN: DBS were prepared from CMV positive blood samples from 20 organ transplant recipients. Three DNA extraction methods were compared for relative yield and sensitivity of detection of CMV DNA: thermal shock, KOH Tris buffer, and DNA Extract All. CMV DNA was detected by real-time quantitative polymerase chain reaction (qPCR). RESULTS: The KOH Tris and DNA Extract All methods gave higher yields and sensitivity of CMV detection in DBS than thermal shock, which were significantly greater when viral loads were </= 10,000 copies/ml blood. Both methods gave faster turnaround times than thermal shock and would be better suited for NBS. CONCLUSIONS: The choice of DNA extraction method greatly influences the ability to detect low levels of CMV DNA in DBS. Moreover, development of highly sensitive yet rapid methods for CMV detection could help facilitate future newborn screening of CMV in DBS.

BACKGROUND: This paper aims to demonstrate how systems modeling methodology of Group Model Building (GMD) can be applied for exploring and reaching consensus on non-communicable disease (NCD) management. This exercise was undertaken as a first step for developing a quantitative simulation model for generating credible estimates to make an investment case for the prevention and management of NCDs. METHODS: Stakeholder engagement was facilitated through the use of a Group Model Building (GMB) approach. This approach combines various techniques in order to gain a whole system perspective. RESULTS: A conceptual qualitative model framework that connects prevention-via risk factors reduction-screening and treatment of non-communicable diseases (NCDs) was developed with stakeholders that draws on stakeholders personal experiences, beliefs, and perceptions through a moderated interactions to gain in-depth understanding of NCDs management. CONCLUSION: Managing NCDs in Cambodia will require concerted effort to tackle NCD risk factors, identifying individuals with NCDs through screening and providing adequate and affordable consistent care to improve health and outcomes of NCDs.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), bedaquiline (0.10, 0.05 to 0.14), and clofazimine (0.06, 0.01 to 0.10). There was a significant association between reduced mortality and use of linezolid (-0.20, -0.23 to -0.16), levofloxacin (-0.06, -0.09 to -0.04), moxifloxacin (-0.07, -0.10 to -0.04), or bedaquiline (-0.14, -0.19 to -0.10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I(2) method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

BACKGROUND: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. METHODS: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (</=6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. FINDINGS: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2.8, 95% CI 1.1-7.3), but no significant effect on mortality (aOR 0.7, 0.4-1.1) or acquired rifampicin resistance (aOR 0.1, 0.0-1.2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0.4, 0.2-0.7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. INTERPRETATION: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. FUNDING: World Health Organization and Canadian Institutes of Health Research.

As funding for malaria control increased considerably over the past 10 years resulting in the expanded coverage of malaria control interventions, so did the need to measure the impact of these investments on malaria morbidity and mortality. Members of the Roll Back Malaria (RBM) Partnership undertook impact evaluations of malaria control programs at a time when there was little guidance in terms of the process for conducting an impact evaluation of a national-level malaria control program. The President's Malaria Initiative (PMI), as a member of the RBM Partnership, has provided financial and technical support for impact evaluations in 13 countries to date. On the basis of these experiences, PMI and its partners have developed a streamlined process for conducting the evaluations with a set of lessons learned and recommendations. Chief among these are: to ensure country ownership and involvement in the evaluations; to engage stakeholders throughout the process; to coordinate evaluations among interested partners to avoid duplication of efforts; to tailor the evaluation to the particular country context; to develop a standard methodology for the evaluations and a streamlined process for completion within a reasonable time; and to develop tailored dissemination products on the evaluation for a broad range of stakeholders. These key lessons learned and resulting recommendations will guide future impact evaluations of malaria control programs and other health programs.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Relative cost-effectiveness of home visits and telephone contacts in preventing early childhood caries. Koh R, Kularantna S, Gordon LG, Barnett AG, Walsh LJ, Seow WK. Community Dent Oral Epidemiol 2015;43:560-8. SOURCE OF FUNDING: National Health and Medical Research Council of Australia (government) and Australian Centre for Health Services Innovation (nonprofit). TYPE OF STUDY/DESIGN: Markov model and Monte Carlo simulation where parameters are obtained from longitudinal intervention study, program data, and published data.

INTRODUCTION: Care of children with spina bifida (SB) has significantly advanced over the last half-century, resulting in gains in longevity and quality of life for affected children and caregivers. Bladder dysfunction is the norm in SB patients and may result in infection, renal scarring, and chronic kidney disease. However, the optimal urologic management for SB-related bladder dysfunction is unknown. METHODS: In 2012, Centers for Disease Control and Prevention (CDC) convened a working group composed of pediatric urologists, nephrologists, epidemiologists, methodologists, community advocates, and CDC personnel to develop a protocol to optimize urologic care of children with SB from the newborn period through 5 years of age. RESULTS: An iterative quality-improvement protocol was selected; in this model, participating institutions agree to prospectively treat all newborns with SB using a single consensus-based protocol. Over the course of the 5-year study period, study outcomes are routinely assessed and the protocol adjusted as needed in order to optimize patient and process outcomes. Primary study outcomes include urinary tract infections (UTI), renal scarring, renal function, and bladder characteristics. The protocol specifies the timing and use of testing (e.g., ultrasonography, urodynamics) and interventions (e.g., intermittent catheterization, prophylactic antibiotics, antimuscarinic medications). Starting in 2014, the CDC began funding nine study sites to implement and evaluate the protocol. CONCLUSIONS: The CDC Urologic and Renal Protocol for the Newborn and Young Child with Spina Bifida began accruing patients in 2015. Assessment in the first 5 years will focus on UTIs, renal function, renal scarring, and clinical process improvements.

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Genome-wide association studies (GWAS) have mapped risk alleles for at least ten distinct cancers to a small region of 63,000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele specific effects on DNA methylation were seen for a subset of risk loci indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Current trends in US population growth, age distribution, and disease dynamics foretell rises in the prevalence of chronic diseases and other chronic conditions. These trends include the rapidly growing population of older adults, the increasing life expectancy associated with advances in public health and clinical medicine, the persistently high prevalence of some risk factors, and the emerging high prevalence of multiple chronic conditions. Although preventing and mitigating the effect of chronic conditions requires sufficient measurement capacities, such measurement has been constrained by lack of consistency in definitions and diagnostic classification schemes and by heterogeneity in data systems and methods of data collection. We outline a conceptual model for improving understanding of and standardizing approaches to defining, identifying, and using information about chronic conditions in the United States. We illustrate this model's operation by applying a standard classification scheme for chronic conditions to 5 national-level data systems.

In response to the 2009 H1N1 pandemic and subsequent vaccination program, the Department of Health and Human Services and collaborators developed the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) Program as a demonstration project to detect rare adverse events rapidly. The program monitored three million people who had received the H1N1 vaccine by linking data from large private health plans and from public immunization registries that had originally not been designed to share data, and on a larger scale than had been previously attempted. The program generated safety data in two weeks rather than three to six months-the standard time frame achievable using health plan data. PRISM substantially contributed to the understanding of the safety of H1N1 vaccines. Its use in the case of H1N1 highlights the necessity of proactive planning, scalable infrastructure, and public-private partnerships in tracking adverse events after vaccination in epidemics. It also illustrates how data could be integrated to produce policy-relevant information for other medical products.

IN THIS YEAR-IN-REVIEW ARTICLE, we review | 52 of 55 articles published on tuberculosis (TB) in the | International Journal of Tuberculosis and Lung Disease from August through December 2011, complementing the 104 summarized by Chang and Nuermberger,1 and using the same categories (Table 1). We | also summarize 33 of 36 non-TB articles for the entire year (Table 2). | ACTIVE TB | Epidemiology | There was diversity in six epidemiological publications. | Over 8 years, one Madrid hospital showed an overall | incidence of disease of 1.9 cases per 100 person-years | in a retrospective cohort of 1824 human immunodefi ciency virus (HIV) infected patients receiving ART; | 19% had TST-positive results, with an increased risk | of progression to disease (odds ratio [OR] 4.4). Baseline CD4 count was a factor only in patients with tuberculin skin test (TST) negative results, elevating the | risk 16-fold.2 A 2-year Polish hospital-based survey | affi rmed that the current genotyping triage methodology, the combination of 15-loci MIRU-VNTR (mycobacterial interspersed repetitive units-variable number of tandem repeats) typing with spoligotyping for | primary analysis, with insertion sequence 6110-RFLP | (restriction fragment length polymorphism) typing | reserved as a fi nal step, is suffi cient for disaggregating epidemiologically linked clusters.3 A 5-month | nationwide Mongolian survey among new and previously treated sputum smear-positive TB patients demonstrated striking emergence of multidrug-resistant | (MDR) disease among those previously treated: 28% | vs. 1.4% among new cases. MDR-TB among new | cases had risen slightly from 1.0% in 1999, in a survey excluding retreatment cases.4

BACKGROUND: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. METHODS AND FINDINGS: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1-6.0]), ofloxacin (aOR: 2.5 [1.6-3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3-2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7-4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7-4.3]), ofloxacin (aOR: 2.3 [1.3-3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4-2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4-6.0]). CONCLUSIONS: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. (Please see later in the article for the Editors' Summary.)