Azithromycin and Doxycycline Resistance Profiles of U.S. Mycoplasma genitalium Strains and Their Association with Treatment Outcomes.

Mycoplasma genitalium is a sexually transmitted bacterium associated with nongonococcal urethritis (NGU) in men and cervicitis, endometritis, and pelvic inflammatory disease in women. Effective treatment is challenging due to the inherent, and increasingly acquired, antibiotic resistance in this pathogen. In our treatment trial conducted from 2007 to 2011 in Seattle, WA, we demonstrated poor efficacy of azithromycin (AZM) and doxycycline (DOX) against M. genitalium among men with NGU. In the present study, we cultured M. genitalium from 74 of 80 (92.5%) PCR-positive men at enrollment (V-1) and defined the MICs of AZM (N = 56 isolates) of DOX (N = 62 isolates). Susceptibility to AZM was bimodal; MICs were >8 µg/ml (44.6%) and <0.004 µg/ml (55.4%) for these isolates. The association of MIC with treatment efficacy was determined for men initially treated with either AZM (N = 30) or DOX (N = 24). Men treated with AZM were more likely to experience microbiologic treatment failure (P < 0.001) if infected with isolates that had AZM MICs of >8 µg/ml (18/18 men) than those with isolates that had AZM MICs of <0.004 µg/ml (1/12 men). Clinical treatment failure also was more likely to occur (P = 0.002) with AZM MICs of >8 µg/ml (12/18 men) than with AZM MICs of <0.004 µg/ml (1/12 men). In contrast, DOX MICs ranged from <0.125 to 2 µg/ml and were not correlated with microbiologic (P = 0.71) or clinical treatment (P = 0.41) failure, demonstrating no relationship between DOX MICs and treatment efficacy. Given the rapid spread of AZM resistance and the emergence of quinolone resistance, the current second-line therapy, monitoring MICs and evaluating other potential treatments for M. genitalium will be critical.

Factors Associated With Nonaccidental Trauma Evaluation Among Patients Below 36 Months Old Presenting With Femur Fractures at a Level-1 Pediatric Trauma Center.

BACKGROUND: In 2009, the American Academy of Orthopedic Surgeons published clinical practice guidelines (CPGs) on the treatment of pediatric diaphyseal femur fractures, which recommended a nonaccidental trauma (NAT) evaluation for all patients below 36 months of age. A recent study of these guidelines found <50% clinical compliance with this treatment recommendation. We aimed to identify areas for improvement in compliance with this guideline. METHODS: A retrospective review was performed of all patients presenting to a single pediatric tertiary care hospital with a diaphyseal femur fracture from January 2007 to June 2013 who were below 36 months old. Medical records were reviewed for documentation of a NAT evaluation, patient characteristics, presence of other fractures or injuries, and hospital of presentation. Radiographs were reviewed for fracture pattern. Statistical analysis was performed to assess for differences overall and before and after CPG publication. RESULTS: During the study period, 281 children below 36 months presented with femur fractures; 41% were evaluated for NAT. Overall, the following factors were significantly associated with receipt of a NAT evaluation: younger age (P<0.001), transfer from an outside facility (P=0.027), and identification of another fracture (P=0.004). Before publication of the CPG, nonwhite patients were much more likely to undergo NAT evaluation compared with white patients (43% vs. 19%; P=0.014). After publication of the CPGs, this differential disappeared (43% vs. 47%; P=0.685). Fracture pattern and patient sex did not influence receipt of NAT evaluation. CONCLUSIONS: We found poor utilization of NAT evaluation for patients below 36 months old presenting with femur fracture. Despite CPG publication, only modest improvements in this evaluation occurred over the study period, with less than half of all patients being evaluated. Younger children, patients transferred from other institutions, and patients presenting with concomitant fractures were more likely to undergo NAT evaluation. Compliance with the CPG may be improved by focusing on older children, patients who initially present to tertiary care centers, and those with an isolated femur fracture. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Child and teacher acceptability of school-based echocardiographic screening for rheumatic heart disease in Uganda.

Introduction Rheumatic heart disease causes substantial morbidity in children in low-income countries. School-based echocardiographic screening has been suggested as a means to identify children with latent disease; however, little is known about the experience of children and teachers participating in screenings. The aim of our study was to assess students' and teachers' experience of school-based echocardiographic screening and identify areas for improvement. Materials and methods A school-based echocardiographic screening programme was conducted in five schools in Northern Uganda in 2013. After 8 months, an age- and gender-stratified population that included 5% of the participating students and teachers completed a questionnaire via an in-person interview. Responses were reviewed by question and coded to identify key themes. RESULTS: A total of 255 students (mean 10.7 years; 48% male) and 35 teachers participated in our study. In total, 95% of the students and 100% of the teachers were happy to have participated in the screening; however, students reported feeling scared (35%) and nervous (48%) during the screening process. Programmatic strengths included the following: knowing one's health status, opportunity to receive treatment, and staff interactions. Although 43% of the patients did not suggest a change with open-ended questioning, concerns regarding privacy, fear of the screening process, and a desire to include others in the community were noted. Discussion School-based echocardiographic rheumatic heart disease screening was well received by students and teachers. Future programmes would likely benefit from improved pre-screening education regarding the screening process and diagnosis of rheumatic heart disease. Furthermore, education of teachers and students could improve screening perception and establish realistic expectations regarding the scope of screening.

Health and wealth in Mesoamerica: findings from Salud Mesomérica 2015.

BACKGROUND: Individual income and poverty are associated with poor health outcomes. The poor face unique challenges related to access, education, financial capacity, environmental effects, and other factors that threaten their health outcomes. METHODS: We examined the variation in the health outcomes and health behaviors among the poorest quintile in eight countries of Mesoamerica using data from the Salud Mesomérica 2015 baseline household surveys. We used multivariable logistic regression to measure the association between delivering a child in a health facility and select household and maternal characteristics, including education and measures of wealth. RESULTS: Health indicators varied greatly between geographic segments. Controlling for other demographic characteristics, women with at least secondary education were more likely to have an in-facility delivery compared to women who had not attended school (OR: 3.20, 95 % confidence interval [CI]: 2.56-3.99, respectively). Similarly, women from households with the highest expenditure were more likely to deliver in a health facility compared to those from the lowest expenditure households (OR 3.06, 95 % CI: 2.43-3.85). Household assets did not impact these associations. Moreover, we found that commonly-used definitions of poverty do not align with the disparities in health outcomes observed in these communities. CONCLUSIONS: Although poverty measured by expenditure or wealth is associated with health disparities or health outcomes, a composite indicator of health poverty based on coverage is more likely to focus attention on health problems and solutions. Our findings call for the public health community to define poverty by health coverage measures rather than income or wealth. Such a health-poverty metric is more likely to generate attention and mobilize targeted action by the health communities than our current definition of poverty.

Frequent vaccination missed opportunities at primary care encounters contribute to underimmunization.

OBJECTIVE: To examine missed opportunities to administer an eligible vaccination (MOs) and their contribution to underimmunization in contemporary pediatric practices. STUDY DESIGN: This study was a retrospective analysis from 42 diverse pediatric practices located throughout the US. Medical records of 50 randomly selected children 3-18 months of age per practice were reviewed in Spring 2013. Immunization status for age and MOs were assessed as of each encounter and as of March 1, 2013. RESULTS: Of 2076 eligible patients, 72.7% (95% CI 67.6-77.9) were up-to-date with receipt of standard vaccines. Most children (82.4%; 95% CI 78.3-85.9) had at least 1 MO, and 37.8% (95% CI 30.0-46.2) had at least one MO to administer an overdue vaccination. After adjustment, risk of underimmunization was 3.5 times greater for patients who had ever experienced an MO for an overdue vaccination compared with those who had not (adjusted relative risk = 3.5; 95% CI 2.8-4.3). If all age-appropriate vaccinations had been administered at the last recorded encounter, 45.5% (95% CI 36.8-54.5) of the underimmunized patients would have been up to date at the time of assessment. CONCLUSION: MOs were common and contributed substantially to underimmunization in this contemporary sample of diverse primary care practice settings.

Efficacy of standard therapies against Ureaplasma species and persistence among men with non-gonococcal urethritis enrolled in a randomised controlled trial.

OBJECTIVE: Ureaplasma urealyticum biovar 2 (UU-2), but not Ureaplasma parvum (UP), has been associated with non-gonococcal urethritis (NGU), but little is known about species-specific responses to standard therapies. We examined species-specific treatment outcomes and followed men with treatment failure for 9 weeks. METHODS: From May 2007 to July 2011, men aged ≥16 attending a sexually transmitted disease (STD) clinic in Seattle, Washington, with NGU (urethral discharge or urethral symptoms plus ≥5 polymorphonuclear leucocytes /high-powered field) enrolled in a double-blind, randomised trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice a day ×7 days) + placebo azithromycin. Ureaplasma were detected in culture followed by species-specific PCR. Outcomes were assessed at 3, 6 and 9 weeks. At 3 weeks, men with persistent Ureaplasma detection received 'reverse therapy' (e.g., active doxycycline if they first received active azithromycin). At 6 weeks, persistently positive men received moxifloxacin (400 mg×7 days). RESULTS: Of 490 men, 107 (22%) and 60 (12%) were infected with UU-2 and UP, respectively, and returned at 3 weeks. Persistent detection was similar for UU-2-infected men initially treated with azithromycin or doxycycline (25% vs. 31%; p=0.53), but differed somewhat for men with UP (45% vs. 24%; p=0.11). At 6 weeks, 57% of UU-2-infected and 63% of UP-infected men who received both drugs had persistent detection. Failure after moxifloxacin occurred in 30% and 36%, respectively. Persistent detection of UU-2 or UP was not associated with signs/symptoms of NGU. CONCLUSIONS: Persistent detection after treatment with doxycycline, azithromycin and moxifloxacin was common for UU and UP, but not associated with persistent urethritis. TRIAL REGISTRATION NUMBER: NCT00358462.

Validation of a new predictive risk model: measuring the impact of the major modifiable risks of death for patients and populations.

BACKGROUND: Modifiable risks account for a large fraction of disease and death, but clinicians and patients lack tools to identify high risk populations or compare the possible benefit of different interventions. METHODS: We used data on the distribution of exposure to 12 major behavioral and biometric risk factors inthe US population, mortality rates by cause, and estimates of the proportional hazards of risk factor exposure from published systematic reviews to develop a risk prediction model that estimates an adult's 10 year mortality risk compared to a population with optimum risk factors. We compared predicted risk to observed mortality in 8,241 respondents in NHANES 1988-1994 and NHANES 1999-2004 with linked mortality data up to the end of 2006. RESULTS: Predicted risk showed good discrimination with an area under the receiver operating characteristic (ROC) curve of 0.84 (standard error 0.01) for women and 0.84 (SE 0.01) for men. Across deciles of predicted risk, mortality was accurately predicted in men ((Χ (2) statistic = 12.3 for men, p=0.196) but slightly overpredicted in the highest decile among women (Χ (2) statistic = 22.8, p=0.002). Mortality risk was highly concentrated; for example, among those age 30-44 years, 5.1 % (95 % CI 4.1 % - 6.0 %) of the male and 5.9 % (95 % CI 4.8 % - 6.9 %) of the female population accounted for 25 % of the risk of death. CONCLUSION: The risk model accurately predicted mortality in a representative sample of the US population and could be used to help inform patient and provider decision-making, identify high risk groups, and monitor the impact of efforts to improve population health.

Salud Mesoamérica 2015 Initiative: design, implementation, and baseline findings.

BACKGROUND: Health has improved markedly in Mesoamerica, the region consisting of southern Mexico and Central America, over the past decade. Despite this progress, there remain substantial inequalities in health outcomes, access, and quality of medical care between and within countries. Poor, indigenous, and rural populations have considerably worse health indicators than national or regional averages. In an effort to address these health inequalities, the Salud Mesoamérica 2015 Initiative (SM2015), a results-based financing initiative, was established. METHODS: For each of the eight participating countries, health targets were set to measure the progress of improvements in maternal and child health produced by the Initiative. To establish a baseline, we conducted censuses of 90,000 households, completed 20,225 household interviews, and surveyed 479 health facilities in the poorest areas of Mesoamerica. Pairing health facility and household surveys allows us to link barriers to care and health outcomes with health system infrastructure components and quality of health services. RESULTS: Indicators varied significantly within and between countries. Anemia was most prevalent in Panama and least prevalent in Honduras. Anemia varied by age, with the highest levels observed among children aged 0 to 11 months in all settings. Belize had the highest proportion of institutional deliveries (99%), while Guatemala had the lowest (24%). The proportion of women with four antenatal care visits with a skilled attendant was highest in El Salvador (90%) and the lowest in Guatemala (20%). Availability of contraceptives also varied. The availability of condoms ranged from 83% in Nicaragua to 97% in Honduras. Oral contraceptive pills and injectable contraceptives were available in just 75% of facilities in Panama. IUDs were observed in only 21.5% of facilities surveyed in El Salvador. CONCLUSIONS: These data provide a baseline of much-needed information for evidence-based action on health throughout Mesoamerica. Our baseline estimates reflect large disparities in health indicators within and between countries and will facilitate the evaluation of interventions and investments deployed in the region over the next three to five years. SM2015's innovative monitoring and evaluation framework will allow health officials with limited resources to identify and target areas of greatest need.

Suboptimal adherence to doxycycline and treatment outcomes among men with non-gonococcal urethritis: a prospective cohort study.

OBJECTIVE: Doxycycline, one of two recommended therapies for non-gonococcal urethritis (NGU), consists of a 7-day course of therapy (100 mg BID). Since suboptimal adherence may contribute to poor treatment outcomes, we examined the association between self-reported imperfect adherence to doxycycline and clinical and microbiologic failure among men with NGU. METHODS: Men aged ≥16 years with NGU attending a Seattle, WA, sexually transmitted diseases clinic were enrolled in a double-blind, parallel-group superiority trial from January 2007 to July 2011. Men were randomised to active doxycycline/placebo azithromycin or placebo doxycycline/active azithromycin. Imperfect adherence was defined as missing ≥1 dose in 7 days. Urine was tested for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), and Ureaplasma urealyticum-biovar 2 (UU-2) using nucleic acid amplification tests. Clinical failure (symptoms and ≥5 PMNs/HPF or discharge) and microbiologic failure (positive tests for CT, MG, and/or UU-2) were determined after 3 weeks. RESULTS: 184 men with NGU were randomised to active doxycycline and provided data on adherence. Baseline prevalence of CT, MG and UU-2 was 26%, 13% and 27%, respectively. 28% of men reported imperfect adherence, and this was associated with microbiologic failure among men with CT (aRR=9.33; 95% CI 1.00 to 89.2) and UU-2 (aRR=3.08; 95% CI 1.31 to 7.26) but not MG. Imperfect adherence was not significantly associated with clinical failure overall or for any specific pathogens, but it was more common among imperfectly adherent men with CT (aRR=2.63; 0.93-7.41, p=0.07). CONCLUSIONS: Adherence may be important for microbiologic cure of select pathogens. Factors other than adherence should be considered for CT-negative men with persistent NGU.

Aspirin use and knowledge in the community: a population- and health facility based survey for measuring local health system performance.

BACKGROUND: Little is known about the relationship between cardiovascular risk, disease and actual use of aspirin in the community. METHODS: The Measuring Disparities in Chronic Conditions (MDCC) study is a community and health facility-based survey designed to track disparities in the delivery of health interventions for common chronic diseases. MDCC includes a survey instrument designed to collect detailed information about aspirin use. In King County, WA between 2011 and 2012, we surveyed 4633 white, African American, or Hispanic adults (45% home address-based sample, 55% health facility sample). We examined self-reported counseling on, frequency of use and risks of aspirin for all respondents. For a subgroup free of CAD or cerebral infarction that underwent physical examination, we measured 10-year coronary heart disease risk and blood salicylate concentration. RESULTS: Two in five respondents reported using aspirin routinely while one in five with a history of CAD or cerebral infarction and without contraindication did not report routine use of aspirin. Women with these conditions used less aspirin than men (65.0% vs. 76.5%) and reported more health problems that would make aspirin unsafe (29.4% vs. 21.2%). In a subgroup undergoing phlebotomy a third of respondents with low cardiovascular risk used aspirin routinely and only 4.6% of all aspirin users had no detectable salicylate in their blood. CONCLUSIONS: In this large urban county where health care delivery should be of high quality, there is insufficient aspirin use among those with high cardiovascular risk or disease and routine aspirin use by many at low risk. Further efforts are needed to promote shared-decision making between patients and clinicians as well as inform the public about appropriate use of routine aspirin to reduce the burden of atherosclerotic vascular disease.

Randomized trial of a health communication intervention for parents of children with asthma.

OBJECTIVE: To determine if a health communication intervention targeting parents of high-risk, urban, minority children with asthma could (i) improve parental perceptions of connectedness to and communication with their child's primary care providers (PCP) and (ii) decrease reliance on emergency departments (EDs) and other urgent care services for their child's asthma-related care. METHODS: The design was a single blind, parallel groups, randomized controlled trial. Parents were recruited from an ED-based asthma clinic serving primarily low-income, minority children in Washington, DC. The intervention involved face-to-face education on effective communication followed by a single booster call. Standardized instruments were administered to assess primary care connectedness and healthcare utilization at baseline and 2- and 6-months post-enrollment. RESULTS: A total of 150 parents of children 1-12 years old were randomized (77 intervention and 73 usual care), and 137 (91%) were successfully followed for six months. Only at the two-month follow-up time-point, parents in the intervention group were significantly more likely to identify a PCP as the main source of their child's asthma care (adjusted odds ratio: 12.6, 95% confidence interval: 1.1-142.1) and to report a significant reduction in ED visits for asthma care (adjusted incidence rate ratio: 0.3, 95% confidence interval: 0.1-0.8). There was no significant effect on parent communication self-efficacy or number of PCP visits. CONCLUSIONS: A brief, in-person health communication intervention for parents of high-risk children with asthma resulted in improved identification of PCPs as the usual source of asthma care and reduced reliance on EDs for asthma care, albeit only for two months post-intervention.

Standard treatment regimens for nongonococcal urethritis have similar but declining cure rates: a randomized controlled trial.

BACKGROUND: Azithromycin or doxycycline is recommended for nongonococcal urethritis (NGU); recent evidence suggests their efficacy has declined. We compared azithromycin and doxycycline in men with NGU, hypothesizing that azithromycin was more effective than doxycycline. METHODS: From January 2007 to July 2011, English-speaking males ≥16 years, attending a sexually transmitted diseases clinic in Seattle, Washington, with NGU (visible urethral discharge or ≥5 polymorphonuclear leukocytes per high-power field [PMNs/HPF]) were eligible for this double-blind, parallel-group superiority trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice daily for 7 days) + placebo azithromycin. Urine was tested for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Ureaplasma urealyticum biovar 2 (UU-2), and Trichomonas vaginalis (TV) using nucleic acid amplification tests. Clinical cure (<5 PMNs/HPF with or without urethral symptoms and absence of discharge) and microbiologic cure (negative tests for CT, MG, and/or UU-2) were determined after 3 weeks. RESULTS: Of 606 men, 304 were randomized to azithromycin and 302 to doxycycline; CT, MG, TV, and UU-2 were detected in 24%, 13%, 2%, and 23%, respectively. In modified intent-to-treat analyses, 172 of 216 (80%; 95% confidence interval [CI], 74%-85%) receiving azithromycin and 157 of 206 (76%; 95% CI, 70%-82%) receiving doxycycline experienced clinical cure (P = .40). In pathogen-specific analyses, clinical cure did not differ by arm, nor did microbiologic cure differ for CT (86% vs 90%, P = .56), MG (40% vs 30%, P = .41), or UU-2 (75% vs 70%, P = .50). No unexpected adverse events occurred. CONCLUSIONS: Clinical and microbiologic cure rates for NGU were somewhat low and there was no significant difference between azithromycin and doxycycline. Mycoplasma genitalium treatment failure was extremely common. Clinical Trials Registration.NCT00358462.

Asymptomatic urethritis is common and is associated with characteristics that suggest sexually transmitted etiology.

We evaluated 236 asymptomatic men for urethritis, assessed sexual behaviors, and tested urine for pathogens. Asymptomatic urethritis was present in 38 (16.1%). Of these, nearly half (42.1%) had a previously unrecognized discharge on examination; only 18.4% had a known pathogen. Correlates included black race, anal intercourse, and number of sex partners.

Bacterial vaginosis-associated bacteria in men: association of Leptotrichia/Sneathia spp. with nongonococcal urethritis.

BACKGROUND: Approximately 45% of nongonococcal urethritis cases have no identified etiology. Novel bacteria recently associated with bacterial vaginosis (BV) in women may be involved. We evaluated the association of idiopathic nongonococcal urethritis and 5 newly described BV-associated bacteria (BVAB). METHODS: Heterosexual men 16 years or older attending a sexually transmitted disease clinic in Seattle, Washington, from May 2007 to July 2011 and negative for Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium, and Ureaplasma urealyticum-biovar2 were eligible. Cases had urethral discharge or 5 or more polymorphonuclear leukocytes per high-power field in urethral exudates. Controls had no urethral discharge and less than 5 polymorphonuclear leukocytes per high-power field. Urine was tested for Atopobium spp., BVAB-2, BVAB-3, Megasphaera spp., and Leptotrichia/Sneathia spp. using quantitative taxon-directed polymerase chain reaction. RESULTS: Cases (n = 157) and controls (n = 102) were of similar age, education, and income, and most were white. Leptotrichia/Sneathia spp. was significantly associated with urethritis (24/157 [15.3%] vs. 6/102 [5.9%], P = 0.03). BVAB-2 was more common in cases than in controls (7/157 [4.5%] vs. 1/102 [1.0%], P = 0.15), and BVAB-3 (n = 2) and Megasphaera spp. (n = 1) were only detected in men with urethritis, but these bacteria were found only in men who also had Leptotrichia/Sneathia spp. Atopobium spp. was not associated with urethritis. The quantity of bacteria did not differ between cases and controls. Among treated cases, doxycycline was more effective than azithromycin for clinical cure of men with Leptotrichia/Sneathia spp. (9/10 vs. 7/12, P = 0.16) and BVAB-2 (3/3 vs. 0/3, P = 0.10). CONCLUSIONS: Leptotrichia/Sneathia spp. may be urethral pathogens or contribute to a pathogenic microbiota that can also include BVAB-2, BVAB-3, and Megasphaera spp. Doxycycline may be more effective than azithromycin against these newly identified bacteria.

Medication Adherence, Health Care Utilization, and Spending Among Privately Insured Adults With Chronic Conditions in the United States, 2010-2016.

BACKGROUND: Chronic conditions are common and costly for older Americans and for the health system. Adherence to daily maintenance medications may improve patient health and lead to lower health care spending. METHODS: To identify predictors of adherence and to quantify associations with health care utilization and spending among older adults with chronic conditions, we conducted a longitudinal retrospective analysis using the OptumLabs Data Warehouse. This database of deidentified administrative claims includes medical and eligibility information for more than 200 million commercial and Medicare Advantage enrollees. We identified adults age 50+ years initiating treatment for atrial fibrillation (N = 33,472), chronic obstructive pulmonary disease (COPD; N = 44,130), diabetes (N =76,726), and hyperlipidemia (N= 249,391) between January 2010 and December 2014. We assessed adherence, health care utilization, and spending during the first 2 years of treatment. RESULTS: During the first year of treatment, 13%-53% of each condition cohort was adherent (proportion of days covered ≥0.80). White race, Midwest residence, and having fewer comorbidities consistently and independently predicted adherence among enrollees initiating treatment for chronic obstructive pulmonary disease, diabetes, and hyperlipidemia. Male sex and higher net worth were also independently associated with adherence among commercial enrollees with these conditions. Patients in most condition cohorts who were adherent to treatment had significantly lower odds of hospitalization or emergency department use compared to patients who were not adherent. Additional spending on pharmacy claims by patients who were adherent was not consistently offset by lower spending on medical claims over a 2-year horizon. CONCLUSIONS: Although many patient factors are strongly associated with medication adherence, the problem of non-adherence is common across all groups and may increase risk of adverse health outcomes.

Sequence variation and immunogenicity of the Mycoplasma genitalium MgpB and MgpC adherence proteins during persistent infection of men with non-gonococcal urethritis.

Mycoplasma genitalium is a sexually transmitted bacterial pathogen that infects men and women. Antigenic variation of MgpB and MgpC, the immunodominant adherence proteins of M. genitalium, is thought to contribute to immune evasion and chronic infection. We investigated the evolution of mgpB and mgpC sequences in men with non-gonococcal urethritis persistently infected with M. genitalium, including two men with anti-M. genitalium antibodies at enrollment and two that developed antibodies during follow-up. Each of the four patients was persistently infected with a different strain type and each patient produced antibodies targeting MgpB and MgpC. Amino acid sequence evolution in the variable regions of MgpB and MgpC occurred in all four patients with changes observed in single and multiple variable regions over time. Using the available crystal structure of MgpC of the G37 type strain we found that predicted conformational B cell epitopes localize predominantly to the variable region of MgpC, amino acids that changed during patient infection lie in these epitopes, and variant amino acids are in close proximity to the conserved sialic acid binding pocket. These findings support the hypothesis that sequence variation functions to avoid specific antibodies thereby contributing to persistence in the genital tract.

Conducting an investigator-initiated randomized double-blinded intervention trial in acute decompensation of inborn errors of metabolism: Lessons from the N-Carbamylglutamate Consortium.

Organic acidemias and urea cycle disorders are ultra-rare inborn errors of metabolism characterized by episodic acute decompensation, often associated with hyperammonemia, resulting in brain edema and encephalopathy. Retrospective reports and translational studies suggest that N-carbamylglutamate (NCG) may be effective in reducing ammonia levels during acute decompensation in two organic acidemias, propionic and methylmalonic acidemia (PA and MMA), and in two urea cycle disorders, carbamylphosphate synthetase 1 and ornithine transcarbamylase deficiency (CPSD and OTCD). We established the 9-site N-carbamylglutamate Consortium (NCGC) in order to conduct two randomized double-blind, placebo-controlled trials of NCG in acute hyperammonemia of PA, MMA, CPSD and OTCD. Conducting clinical trials is challenging in any disease, but poses unique barriers and risks in the ultra-rare disorders. As the number of clinical trials in orphan diseases increases, evaluating the successes and opportunities for improvement in such trials is essential. We summarize herein the design, methods, experiences, challenges and lessons from the NCGC-conducted trials.

Trends and Disparities in Osteoporosis Screening Among Women in the United States, 2008-2014.

BACKGROUND: The United States Preventive Services Task Force recommends universal osteoporosis screening among women ages 65+ and targeted screening of younger women, but historically, adherence to these evidence-based recommendations has been suboptimal. METHODS: To describe contemporary patterns of osteoporosis screening, we conducted a retrospective analysis using the OptumLabs™ Data Warehouse, a database of de-identified administrative claims, which includes medical and eligibility information for over 100 million Medicare Advantage and commercial enrollees. Study participants included 1,638,454 women ages 50+ with no prior history of osteoporosis diagnosis, osteoporosis drug use, or hip fracture. Osteoporosis screening during the most recent 2-year period of continuous enrollment was assessed via medical claims. Patient sociodemographics, comorbidities, and utilization of other services were also determined using health insurance files. RESULTS: Overall screening rates were low: 21.1%, 26.5%, and 12.8% among women ages 50-64, 65-79, and 80+ years, respectively. Secular trends differed significantly by age (P <.001). Between 2008 and 2014, utilization among women ages 50-64 years declined 31.4%, changed little among women 65-79, and increased 37.7% among women 80+ years. Even after accounting for socioeconomic status, health status, and health care utilization patterns, non-Hispanic black women were least likely to be screened, whereas non-Hispanic Asian and Hispanic women were most likely to undergo screening. Marked socioeconomic gradients in screening probabilities narrowed substantially over time, decreasing by 44.5%, 71.9%, and 59.7% among women ages 50-64, 65-79 and 80+ years, respectively. CONCLUSIONS: Despite significant changes in utilization of osteoporosis screening among women ages 50-64 and 80+, in line with national recommendations, tremendous deficiencies among women 65+ remain.

Osteoporosis-Related Health Services Utilization Following First Hip Fracture Among a Cohort of Privately-Insured Women in the United States, 2008-2014: An Observational Study.

Timely identification and treatment of osteoporosis following hip fracture is recommended to mitigate future fracture risk, yet prior work has demonstrated a disconnect between evidence-based recommendations and real-world implementation. We sought to describe contemporary patterns of osteoporosis screening and initiation of pharmacotherapy following hip fracture based on medical and pharmacy claims in the OptumLabs™ Data Warehouse. From a national sample, we identified 8349 women aged 50+ years enrolled in private commercial or Medicare Advantage plans with no prior history of osteoporosis diagnosis, osteoporosis pharmacotherapy, or hip fracture who experienced a hip fracture between 2008 and 2013. Just 17.1% and 23.1% of these women had evidence of osteoporosis assessment and/or treatment within 6 or 12 months of their fractures, respectively. Women aged 80+ years were one-third less likely to utilize recommended services within 6 months, compared to those aged 50 to 79 years (13.8% versus 20.8%; p < 0.001). Utilization of bone mass measurement increased significantly among women aged 65+ years over the study period (p < 0.001) while declining among those aged 50 to 64 years (p = 0.2). In contrast, rates of osteoporosis pharmacotherapy remained steady among women aged 50 to 64 years (p = 0.8) yet declined among women aged 65 to 79 years and aged 80+ years (p = 0.07 and p = 0.004, respectively). Accounting for differences in all measured characteristics, receipt of primary care was the strongest and most consistent predictor of osteoporosis assessment or treatment following fracture. © 2017 American Society for Bone and Mineral Research.

Strategies for Improving Vaccine Delivery: A Cluster-Randomized Trial.

OBJECTIVE: New emphasis on and requirements for demonstrating health care quality have increased the need for evidence-based methods to disseminate practice guidelines. With regard to impact on pediatric immunization coverage, we aimed to compare a financial incentive program (pay-for-performance [P4P]) and a virtual quality improvement technical support (QITS) learning collaborative. METHODS: This single-blinded (to outcomes assessor), cluster-randomized trial was conducted among unaffiliated pediatric practices across the United States from June 2013 to June 2014. Practices received either the P4P or QITS intervention. All practices received a Vaccinator Toolkit. P4P practices participated in a tiered financial incentives program for immunization coverage improvement. QITS practices participated in a virtual learning collaborative. Primary outcome was percentage of all needed vaccines received (PANVR). We also assessed immunization up-to-date (UTD) status. RESULTS: Data were analyzed from 3,147 patient records from 32 practices. Practices in the study arms reported similar QI activities (∼6 to 7 activities). We found no difference in PANVR between P4P and QITS (mean ± SE, 90.7% ± 1.1% vs 86.1% ± 1.3%, P = 0.46). Likewise, there was no difference in odds of being UTD between study arms (adjusted odds ratio 1.02, 95% confidence interval 0.68 to 1.52, P = .93). In within-group analysis, patients in both arms experienced nonsignificant increases in PANVR. Similarly, the change in adjusted odds of UTD over time was modest and nonsignificant for P4P but reached significance in the QITS arm (adjusted odds ratio 1.28, 95% confidence interval 1.02 to 1.60, P = .03). CONCLUSIONS: Participation in either a financial incentives program or a virtual learning collaborative led to self-reported improvements in immunization practices but minimal change in objectively measured immunization coverage.