BACKGROUND: Haemophilus influenzae (Hi) can cause severe disease in children. This study aimed to identify risk factors related to invasive Hi disease in Alaska children and evaluate carriage in people around them. METHODS: From 2005 to 2011, we investigated episodes of invasive, typeable Hi disease in Alaska children <10 years old. Three age-matched control children were enrolled for each case-patient. We evaluated oropharyngeal Hi carriage in people in close contact with Hi case-patients (contacts) as well as control children and their household members. Individual and household risk factors for illness and carriage were evaluated using questionnaires and chart reviews. RESULTS: Thirty-eight of 44 (86%) children with invasive, typeable Hi disease were recruited: 20 Hi serotype a (53%), 13 serotype b (Hib) (34%) and 5 serotype f (13%). Children with the invasive Hi disease were more likely than controls to have underlying health problems (67% vs. 24%, P = 0.001), other carriers of any Hi in their household (61% vs. 15%, P < 0.001), and inadequate Hib vaccination (26% vs. 9%, P = 0.005). People who carried Hi were younger than noncarriers (mean 12.7 vs. 18.0 years, P = 0.008). The carriage was clustered within case-patient households, with carriage in 19% of household contacts, while only 6.3% of nonhousehold contacts and 5.5% of noncontacts carried the Hi serotype of interest ( P < 0.001). CONCLUSIONS: Factors associated with invasive Hi disease in children included underlying health problems, household carriage and inadequate Hib vaccination. The high level of carriage in case-patient households is important to consider when evaluating treatment and prophylaxis strategies.

BACKGROUND: The duration of protection from hepatitis B vaccination in children and adults is not known. In 1981, we used three doses of plasma-derived hepatitis B vaccine to immunize a cohort of 1578 Alaska Native adults and children from 15 Alaska communities who were 6 months or older. METHODS: We tested persons for anti-HBs levels 35 years after receiving the primary series. Those with levels <10 mIU/ml received 1 booster dose of recombinant hepatitis B vaccine 2-4 weeks later and were then evaluated on the basis of anti-HBs measurements 30 days post-booster. RESULTS: Among the 320 recruited, 112 persons had not participated in the 22 nor 30-year follow-up study (Group 1) and 208 persons had participated but were not given an HBV booster dose (Group 2). Among the 112 persons in Group 1 who responded to the original primary series, 53 (47.3%) had an anti-HBs level ≥10 mIU/ml. Among group 1, 73.7% (28/38) of persons available for a booster dose responded to it with an anti-HBs level ≥10 mIU/ml at 30 days. Initial anti-HBs level after the primary series was correlated with higher anti-HBs levels at 35 years. Among 8 persons who tested positive for anti-HBc, none tested positive for HBsAg nor HBV DNA. CONCLUSIONS: Based on anti-HBs level ≥10 mIU/ml at 35 years and a 73.7% booster dose response, we estimate 86% of participants had evidence of protection 35 years later. Booster doses are not needed in the general population at this time.

OBJECTIVE: In the United States, HPV vaccination is routinely recommended at age 11 or 12 years; the series can be started at age 9. We conducted a cohort study to assess long-term immunogenicity of quadrivalent HPV vaccine (4vHPV) in an American Indian/Alaska Native (AI/AN) Indigenous population. METHODS: During 2011-2014, we enrolled AI/AN girls and boys aged 9-14 years, who were vaccinated with a 3-dose series of 4vHPV. Serum specimens were collected at five time points: immediately prior to doses 2 and 3, and at one month, one year, and two years after series completion. Antibody testing was performed using a multiplex virus-like-particle-IgG ELISA for 4vHPV types (HPV 6/11/16/18). RESULTS: Among 477 children (405 girls/72 boys) completing the 3-dose series, median age at enrollment was 11.2 years. Of the 477, 72 (15%) were tested before dose 2 and 70 (15%) before dose 3. Following series completion, 435 (91%) were tested at one month, 382 (80%) at one year, and 351 (74%) at two years. All tested participants had detectable antibody to 4vHPV types at all time points measured. Geometric mean concentrations (GMCs) for 4vHPV types at one month and two years post-series completion were 269.9 and 32.7 AU/ml for HPV6, 349.3 and 42.9 AU/ml for HPV11, 1240.2 and 168.3 IU/ml HPV16, and 493.2 and 52.2 IU/ml for HPV18. Among children tested after each dose, GMCs after doses 1 and 2 were 3.9 and 32.2 AU/ml for HPV6, 5.3 and 45.6 AU/ml for HPV11, 20.8 and 187.9 IU/ml for HPV16; and 6.6 and 49.7 IU/ml for HPV18. No serious adverse events were reported. CONCLUSION: All AI/AN children developed antibodies to all 4vHPV types after vaccination. GMCs rose after each dose, then decreased to a plateau over the subsequent two years. This cohort will continue to be followed to determine duration of antibody response.

BACKGROUND: In Alaska, while introduction of 13-valent pneumococcal conjugate vaccine led to declines in invasive pneumococcal disease, carriage prevalence remained stable because of replacement with non-vaccine serotypes. We assessed antibiotic non-susceptibility of carried pneumococci during serotype redistribution, determined the contributions of within-serotype shifts, and assessed factors that could explain changes in non-susceptibility. METHODS: Each year from 2008 to 2015, at multiple sites in Alaska, we collected nasopharyngeal swabs and completed surveys for a convenience sample of participants. Pneumococcal serotyping and antimicrobial susceptibility testing for penicillin and erythromycin were performed. We described changes in non-susceptibility of isolates from 2008-2011 to 2012-2015, and assessed the contributions of serotype redistribution and within-serotype changes in non-susceptibility by comparing observed data to modeled data removing either factor. We used weighted logistic regression to assess whether reported risk factors could explain changes over time in non-susceptibility within serotypes. RESULTS: From 2008-2011 to 2012-2015, the overall proportion of isolates non-susceptible to penicillin or erythromycin increased by 3%, from 23% (n = 1,183) to 26% (n = 1,589; P < 0.05). However, a decrease of 3% would be expected if serotype redistribution occurred without within-serotype changes in non-susceptibility. Standardization by either factor produced hypothetical data significantly different to observed data. Within serotypes, the average annual increase in odds of non-susceptibility to penicillin or erythromycin was 1.08 (95% CI 1.05-1.11). Recent antibiotic exposure, urban residence and increased household size of participants predicted isolate non-susceptibility but did not explain the increase over time. DISCUSSION: An overall increase in non-susceptibility of carried pneumococcal isolates to penicillin or erythromycin resulted from increases in non-susceptibility within serotypes, which outweighed a protective effect of serotype redistribution. Characterization of emerging resistant clones within carried non-vaccine serotypes, including risk factors for colonization and disease, would support disease prevention efforts and inform vaccine strategies.

BACKGROUND: Alaska Native (AN) infants are at risk for severe disease due to respiratory syncytial virus (RSV) and influenza. Maternal immunization protects young infants through transplacental antibody transfer. RSV- and influenza-specific transplacental antibody transfer in mother-infant pairs has not previously been evaluated in the AN population. METHODS: Serum samples collected during pregnancy and at birth from AN mother-infant pairs in the Yukon-Kuskokwim Delta region (YKD) of Alaska (2000-2011; n = 75) and predominantly white pairs in Seattle, Washington (2014-2016; n = 57), were tested for RSV and influenza antibody using a microneutralization and hemagglutination inhibition assay, respectively, and compared between sites. RESULTS: Mean RSV antibody concentrations in pregnant women in YKD and Seattle were similar (log2 RSV antibody 10.6 vs 10.7, P = .86), but cord blood RSV antibody concentrations were significantly lower in infants born to mothers in YKD compared with Seattle (log2 RSV antibody 11.0 vs 12.2, P < .001). Maternal and cord blood influenza antibody concentrations were lower for women and infants in YKD compared with Seattle for all 4 influenza antigens tested (all P < .05). The mean cord to maternal RSV antibody transfer ratio was 1.15 (standard deviation [SD], 0.13) in mother-infant pairs in Seattle compared with 1.04 (SD, 0.08) in YKD. Mean cord blood to maternal antibody transfer ratios for influenza antigens ranged from 1.22 to 1.42 in Seattle and from 1.05 to 1.59 in YKD. CONCLUSIONS: Though the transplacental antibody transfer ratio was high (>1.0) for both groups, transfer ratios for RSV antibody were significantly lower in AN mother-infant pairs. Further studies are needed to elucidate the impact of lower transplacental antibody transfer on infant disease risk in rural Alaska.Alaska Native and continental US mother-infant pairs have high transplacental antibody transfer ratios (>1.0) for influenza and respiratory syncytial virus, but anti-respiratory syncytial virus antibody levels are significantly lower in Alaska Native pairs than in those from the continental US.

Background: The first HPV vaccines licensed targeted two HPV types responsible for most cervical cancers. A 9-valent vaccine (9vHPV), targeting 5 additional types, was introduced in 2016 and is currently the only HPV vaccine available in the United States. Previous studies demonstrated high rates of HPV infection in Alaska Native (AN) women. We sought to measure prevalence of high risk HPV types in AN women undergoing colposcopy and to determine those preventable by vaccination. Methods: For this cross-sectional study, we recruited women who were undergoing colposcopy for clinical indications at Alaska Native Medical Center to obtain cervical brush biopsy samples. Specimens were shipped to Atlanta, Georgia for DNA extraction, HPV detection, and typing using L1 PCR with type-specific hybridization to detect 37 HPV types. Results: Four hundred eighty eight specimens from 489 women were tested. At least one HPV type was found in 458 (94%) specimens. Of 458 participants who were HPV positive, 332 (72%) had two or more types. At least one type targeted by 9vHPV was detected in 95% of participants with CIN 3 (21/22), 82% with CIN 2 (37/45), and 65% with CIN 1 (119/184). (p < 0.001) HPV 16 or 18 were detected in 77% (17/22) with CIN 3, 53% (24/45) with CIN 2, and 36% (67/184) with CIN 1. (p < 0.001). Conclusions: A substantial proportion of AN women attending colposcopy clinic had evidence of HPV 16/18 infection, as well as other high risk types targeted by 9vHPV. At least one 9vHPV type was detected in 62% of the participants overall, and 95% of participants with CIN3. AN women are expected to benefit from vaccination against HPV 16/18, and will have greater benefit from 9vHPV. Information from this study could be used to develop public health strategies to increase vaccine uptake, or to track HPV genotype prevalence over time.

INTRODUCTION: Alaska Native (AN) children from the Yukon Kuskokwim (YK) Delta region have high rates of chronic suppurative lung disease (CSLD), including bronchiectasis. We characterized the clinical progress of an AN adolescent cohort with CSLD/bronchiectasis, and estimated bronchiectasis prevalence trends in this region. METHODS: The original cohort comprised 41 AN children (originally aged 0.5-8 years) with CSLD/bronchiectasis, recruited between 2005 and 2008, with follow-up in 2015-2016. Clinical assessments, lung function, radiography, medical chart review, and spirometry were obtained. We also conducted data queries of bronchiectasis diagnoses in YK individuals born between 1990 and 2010 to estimate prevalence. RESULTS: Thirty-four (83%) of the original cohort aged 7.3-17.6 years were reviewed, of whom 14 (41%) had high-resolution computed tomography (HRCT)-confirmed bronchiectasis, eight (24%) had no evidence of bronchiectasis on HRCT scans, while 12 (35%) had not undergone HRCT scans. Annual lower respiratory tract infection (LRTI) frequency decreased with age, although 27 (79%) still had respiratory symptoms, including all with HRCT-confirmed bronchiectasis, who were also more likely than those without confirmed bronchiectasis to have recent wheeze (80 vs 25%, P = 0.005), auscultatory crackles (60 vs 0%, P < 0.001), and lower mean forced expiratory volume in 1-second/forced vital capacity ratio (73 vs 79%, P = 0.03). The bronchiectasis prevalence for YK AN people born during 2000-2009 was 7 per 1000 births, which was lower than previously reported. CONCLUSION: Despite reduced LRTI frequency, most AN children with CSLD/bronchiectasis had symptoms/signs of underlying lung disease as they entered adolescence. Close clinical follow-up remains essential for managing these patients as they transition to adulthood.

OBJECTIVES: Burden of pneumococcal disease depends on the prevalence and invasive disease potential of serotypes. We aimed to estimate the invasive disease potential of serotypes in children under 5 years of age by combining data from different settings with routine immunisation with pneumococcal conjugate vaccines (PCV). METHODS: We conducted a systematic review, supplemented by unpublished data, to identify data on the frequency of pneumococcal serotypes in carriage and invasive pneumococcal disease (IPD). We estimated the invasive disease potential of serotypes as the ratio of IPD in relation to carriage (odds ratio and 95%CI) compared with 19A (reference serotype) by meta-analysis. We report results based on a random effects model for children aged 0-23, 24-29, and 0-59 months and by invasive clinical syndromes. RESULTS: In comparison with 19A, serotypes 1, 7F, and 12F had a significantly higher invasive disease potential in children aged 0-23 and 0-59 months for all IPD and clinical syndromes (OR>5). Several non-vaccine types (NVTs) (6C, 15A, 15BC, 16F, 23B, in these two age groups) had a lower invasive disease potential than 19A (OR 0*1-0*3). NVTs 8, 12F, 24F, and 33F were at the upper end of the invasiveness spectrum. CONCLUSIONS: There is substantial variation among pneumococcal serotypes in their potential to cause IPD and disease presentation, which is influenced by age and time after PCV introduction. Surveillance of IPD and carriage is critical to understand the expected effectiveness of current PCVs (in the longer term) and guide the development of future vaccines.

PURPOSE: Results of a study evaluating the impact of an antimicrobial stewardship program (ASP) on clinical outcomes in patients hospitalized for community-acquired pneumonia (CAP) are reported. METHODS: A retrospective records review was conducted at a 400-bed hospital to identify patients admitted over 3 years with CAP documented as a primary or secondary diagnosis. Clinical and medication-use outcomes during a 1-year baseline period and in the first and second years after ASP implementation (post-ASP years 1 and 2) were analyzed. A local CAP guideline was implemented around the beginning of post-ASP year 2. RESULTS: The mean hospital length of stay declined from 7.24 days in the baseline period to 5.71 days in post-ASP year 1 (p = 0.011) and 5.52 days in post-ASP year 2 (p = 0.008). Mean inpatient antimicrobial days of therapy (DOT) declined from 5.68 days in the baseline period to 5.08 days (p = 0.045) and 4.99 days (p = 0.030) in post-ASP years 1 and 2, respectively. Mean DOT per 100 total days of antimicrobial therapy declined from 9.69 days in the baseline period to 8.85 days in post-ASP year 1 (p = 0.019) and 8.38 days in post-ASP year 2 (p = 0.001). CONCLUSION: ASP implementation was associated with specific clinical benefits in patients with CAP, including decreased length of stay, decreased durations of antimicrobial therapy, and a shift in utilization to a primary regimen shown to produce superior clinical outcomes.

In the United States, the incidence of hepatitis A virus (HAV) infection has been reduced through universal childhood vaccination. However, the duration of immunogenicity for the hepatitis A vaccine is not known. We report on the 22 year follow-up time point of a cohort of Alaska children who were randomized to three different vaccine schedules: A) 0,1,2 months; B) 0,1,6 months; and C) 0,1,12 months. Among 46 participant available for follow-up, 40 (87%) maintained protective levels of anti-hepatitis A antibody. These results indicate that a supplemental booster dose is not yet necessary at or before the 22-year time point. This article is protected by copyright. All rights reserved.

BACKGROUND: Helicobacter pylori is one of the most common human infections in the world, and studies in Alaska Native people, as well as other Indigenous peoples, have shown a high prevalence of this gastric infection. This study was undertaken to determine the prevalence of H. pylori infection by urea breath test (UBT) and anti- H. pylori IgG among Alaskans living in four regions of the state and to identify factors associated with infection. METHODS: A convenience sample of persons > 6 months old living in five rural and one urban Alaskan community were recruited from 1996 to 1997. Participants were asked about factors possibly associated with infection. Sera were collected and tested for anti- H. pylori IgG antibodies; a UBT was administered to participants > 5 years old. RESULTS: We recruited 710 people of whom 571 (80%) were Alaska Native and 467 (66%) were from rural communities. Rural residents were more likely to be Alaska Native compared with urban residents (P < .001). Of the 710 people, 699 (98%) had a serum sample analyzed, and 634 (97%) persons > 5 years old had a UBT performed. H. pylori prevalence was 69% by UBT and 68% by anti- H. pylori IgG. Among those with a result for both tests, there was 94% concordance. Factors associated with H. pylori positivity were Alaska Native racial status, age >/= 20 years, rural region of residence, living in a crowded home, and drinking water that was not piped or delivered. CONCLUSIONS: Helicobacter pylori prevalence is high in Alaska, especially in Alaska Native persons and rural residents. Concordance between UBT and serology was also high in this group. Two socioeconomic factors, crowding and drinking water that was not piped or delivered, were found to be associated with H. pylori positivity.

Alaska Native children experience high rates of lower respiratory tract infections (LRTIs) and lung conditions, which are associated with substandard indoor air quality (IAQ). We conducted an intervention of home remediation and education to assess the impact on IAQ, respiratory symptoms and LRTI visits. We enrolled households of children 1-12 years of age with lung conditions. Home remediation included improving ventilation and replacing leaky woodstoves. We provided education about IAQ and respiratory health. We monitored indoor airborne particles (PM2.5), CO2, relative humidity and volatile organic compounds (VOCs), and interviewed caregivers about children's symptoms before, and for 1 year after intervention. We evaluated the association between children's respiratory visits, symptoms and IAQ indicators using multiple logistic regression. A total of 60 of 63 homes completed the study. VOCs decreased (coefficient = -0.20; p < 0.001); however, PM2.5 (coeff. = -0.010; p = 0.89) did not decrease. Burning wood for heat, VOCs and PM2.5 were associated with respiratory symptoms. After remediation, parents reported decreases in runny nose, cough between colds, wet cough, wheezing with colds, wheezing between colds and school absences. Children had an age-adjusted decrease in LRTI visits (coefficient = -0.33; p = 0.028). Home remediation and education reduced respiratory symptoms, LRTI visits and school absenteeism in children with lung conditions.

BACKGROUND: American Indian/Alaska Native (AI/AN) children have experienced higher otitis media (OM) outpatient visit rates than other United States (US) children. To understand recent trends, we evaluated AI/AN OM rates before and after 13-valent pneumococcal conjugate vaccine introduction. METHODS: We analyzed outpatient visits listing OM as a diagnosis among AI/AN children <5 years of age from the Indian Health Service National Patient Information Reporting System for 2010-2013. OM outpatient visits for the general US child population < 5 years of age were analyzed using the National Ambulatory Medical Care and National Hospital Ambulatory Care Surveys for 2010-2011. RESULTS: The 2010-2011 OM-associated outpatient visit rate for AI/AN children (63.5 per 100/year) was similar to 2010-2011 rate for same-aged children in the general US population (62.8), and decreased from the 2003-2005 AI/AN rate (91.4). Further decline in AI/AN OM visit rates were seen for 2010-2011 to 2012-2013 (p-value<0.0001). The AI/AN infant OM visit rate (130.5) was 1.6 fold higher than the US infant population. For 2010-2011, the highest AI/AN OM visit rate for <5 year olds was from Alaska (135.0). CONCLUSION: AI/AN < 5 year old OM visits declined by one-third from 2003-2005 to 2010-2011 to a rate similar to the US general population <5 years. However, the AI/AN infant OM rate remained higher than the US infant population. The highest AI/AN < 5 year old OM rate occurred in Alaska.

BACKGROUND: Stroke is a critical public health issue in the United States and globally. System models to optimally capture stroke incidence in rural and culturally diverse communities are needed. The epidemiological transition to a western lifestyle has been associated with an increased burden of vascular risk factors among Alaska Native (AN) people. The burden of stroke in AN communities remains understudied. METHODS: The Alaska Native Stroke Registry (ANSR) was designed to screen and capture all stroke cases between 2005 and 2009 through its integration into the existing single-payer Alaska Tribal Health System infrastructure. Registry staff received notification each time stroke International Classification of Diseases, Ninth Revision codes (430-436) were initiated anywhere in the system. Trained chart abstractors reviewed medical records to document incident strokes among AN patients, which were adjudicated. RESULTS: Between October 2005 and October 2009, over 2100 alerts were screened identifying 514 unique stroke cases, of which 372 were incident strokes. The average annual incidence of stroke (per 100,000) among AN adults was 190.6: 219.2 in men and 164.7 in women. Overall, the ischemic stroke incidence rate was 148.5 per 100,000 with men (184.6) having higher ischemic rates per 100,000 than women (118.3). Men have higher rates of ischemic stroke at all ages, whereas older women experienced higher rates of hemorrhagic strokes over the age of 75 years. CONCLUSIONS: We report a high rate of overall stroke, 190.6 per 100,000. The ANSR methods and findings have implications for other indigenous populations and for global health populations currently undergoing similar epidemiological transitions.

Hepatitis A vaccine is recommended for children ≥1 year old to prevent hepatitis A virus (HAV) infection. However the duration of vaccine-induced immunity is unknown. We evaluated a cohort of Alaska Native persons 20 years after HAV vaccination. Children aged 3-6 years had been previously randomized to receive 3 doses of HAV vaccine (360 ELISA units/dose) at: A) 0,1,2 months; B) 0,1,6 months; and C) 0,1,12 months. We measured anti-HAV antibody concentrations every 2-3 years; described geometric mean concentrations (GMC) and the proportion with protective antibody (≥20 mIU mL-1) over time; and modelled change in GMC using fractional polynomial regression. Of 144 participants, after 20 year 52 (36.1%) were available for follow-up (17, 18, 17 children in Groups A, B and C, respectively). Overall, 46 (88.5%) of 52 available participants had anti-HAV antibody concentrations ≥20mIU mL-1 and overall GMC was 107 mIU mL-1. Although GMC levels were lower in Group A (60; CI 34-104) than in Group B (110; CI 68-177), or Group C (184; CI 98-345) (B versus C: p=0.168; A versus B/C: p=0.011), there was no difference between groups after adjusting for peak antibody levels post vaccination (p=0.579). Models predicted geometric mean concentrations of 124 mIU mL-1 after 25 years, and 106 mIU mL-1 after 30 years. HAV vaccine provides protective antibody levels 20 years after childhood vaccination. Lower antibody levels in Group A may be explained by a lower initial peak response. Our results suggest a booster vaccine dose is unnecessary for at least 25-30 years.

Sirs, We appreciate the interest in our study from Professors Chen and Liaw and the opportunity to provide additional information.1 As we acknowledged in our paper, the wide confidence intervals for our risk estimates resulting from the relatively small number of case- and control-patients developing HCC were an important limitation to our study.2 Thus, it is possible that we failed to detect a real reduction in HCC risk because of insufficient statistical power. As requested, we recalculated the risk for developing HCC after excluding the 2 case-patients who received antiviral treatment before HBsAg seroclearance and the 32 control-patients who had received antiviral treatment. After adjusting for age at cohort entry and initial anti-hepatitis B e antibody status, we did not detect a difference in HCC risk among case-compared with control-patients after excluding patients who had received antiviral treatment (adjusted hazard ratio: 0.7; 95% confidence interval: 0.2–2.7). The effect of age at HBsAg seroclearance on risk for HCC is complex and could be partly related to the specific HBV genotypes represented in a population. It has been demonstrated that the duration of hepatitis B e antigen persistence and the risk for HCC is substantially higher for persons with HBV genotype C compared with other genotypes.3,4 The majority of patients in the study indicating an increased risk for HCC among persons aged ≥50 years at the time of HBsAg seroclearance were infected with HBV genotype C.5,6 In contrast, the majority of patients in our study population were infected with HBV genotype D. Therefore, the risk for HCC associated with a later age of HBsAg seroclearance among Alaska Native persons compared with other geographic regions is unclear because of differences in the prevalence of HBV genotypes. Furthermore, the age at HBsAg seroclearance should not affect our interpretation of the relative risk for HCC between case- and control-patients because the majority of participants acquired HBV infection in early childhood and our analysis adjusted for case-patients’ HBsAg duration prior to seroclearance. We also speculated in our paper that ongoing low-level HBV DNA replication with continued integration into the host hepatocyte could have contributed to persistent HCC risk after HBsAg seroclearance. Further study is necessary to determine the relative importance of HBV viremia early in the course of disease versus persistence of viremia after HBsAg clearance in the development of HCC.

OBJECTIVES: To evaluate the hepatocellular carcinoma (HCC) risk in Alaska Native children and young adults with hepatitis B virus (HBV). STUDY DESIGN: Retrospective analysis of a population-based cohort of Alaska Native persons with HBV followed during 1982-2012. All individuals with HBV were offered HCC screening regardless of age using alpha-fetoprotein every 6 months; persons with an elevated alpha-fetoprotein or persons at high-risk for HCC, such as cirrhosis, family history of HCC, were offered ultrasound. We calculated the HCC incidence/1000 person-years from date of cohort entry until death, diagnosis of HCC, or attaining the age of 40 years (males) or 50 years (females). RESULTS: We followed 1083 subjects with HBV (56% male) comprising 5 genotypes (A2 [12.5%], B6 [1.7%], C [5.3%], D [49.7%], F1 [18.6%], unknown [12.4%]) for a median of 23.4 years/person. We observed 22 HCC cases (incidence/1000 person-years follow-up: 1.0); 19 HCC cases among persons with genotype F1. There was no significant difference in HCC incidence between males (1.4) and females (0.6). The HCC incidence was significantly higher for persons with genotype F1 (4.4) compared with genotype A2 (0.4) and D (0.2) and remained higher among persons with HBV genotype F1 excluding persons with HCC family history/cirrhosis (1.9). CONCLUSIONS: Alaska Native children and young adults with HBV genotype F1 are at high risk for HCC and should receive HCC surveillance. For males <40 years of age and females <50 years of age with HBV in regions of the world with a high genotype F prevalence, testing/confirming genotype F can identify persons who could benefit from HCC surveillance.

Here we describe the relationships between serotypes, genotypes, and antimicrobial susceptibility among isolates causing invasive pneumococcal disease in Alaskan children during the pneumococcal conjugate vaccine (PCV) era. From 2001 to 2013 we received 271 isolates representing 33 serotypes. The most common serotypes were 19A (29.5%, n= 80), 7F (12.5%, n= 34), 15B/C (6.3%, n= 17), and 22F (4.8%, n= 13). Multilocus sequence typing identified 11 clonal complexes (CC) and 45 singletons. Five CCs accounted for 52% (141/271) of the total: CC199 (21% [n= 57], serotypes 19A, 15B/C), CC191 (12.2% [n= 33], serotype 7F), CC172 (10.3% [n= 28], serotypes 19A, 23A, 23B), CC433 (4.4% [n= 12], serotype 22F), and CC100 (4.4% [n= 12], serotype 33F). The proportion of isolates nonsusceptible to erythromycin and tetracycline increased after 13-valent PCV use (14% [n= 30] versus 29% [n= 14]; P= 0.010) and (4% [n= 9] versus 22% [n= 11]; P< 0.001), respectively. The genetic diversity also increased after 13-valent PCV use (Simpson's diversity index =0.95 versus 0.91; P= 0.022).

OBJECTIVE: To measure the trends in traditional marine food intake and serum vitamin D levels in Alaska Native women of childbearing age (20-29 years old) from the 1960s to the present. DESIGN: We measured a biomarker of traditional food intake, the delta15N value, and vitamin D level, as 25-hydroxycholecalciferol (25(OH)D3) concentration, in 100 serum samples from 20-29-year-old women archived in the Alaska Area Specimen Bank, selecting twenty-five per decade from the 1960s to the 1990s. We compared these with measurements of red-blood-cell delta15N values and serum 25(OH)D3 concentrations from 20-29-year-old women from the same region collected during the 2000s and 2010s in a Center for Alaska Native Health Research study. SETTING: The Yukon Kuskokwim Delta region of south-west Alaska. SUBJECTS: Alaska Native women (n 319) aged 20-29 years at the time of specimen collection. RESULTS: Intake of traditional marine foods, as measured by serum delta15N values, decreased significantly each decade from the 1960s through the 1990s, then remained constant from the 1990s through the present (F 5,306=77.4, P<0.0001). Serum vitamin D concentrations also decreased from the 1960s to the present (F 4,162=26.1, P<0.0001). CONCLUSIONS: Consumption of traditional marine foods by young Alaska Native women dropped significantly between the 1960s and the 1990s and was associated with a significant decline in serum vitamin D concentrations. Studies are needed to evaluate the promotion of traditional marine foods and routine vitamin D supplementation during pregnancy for this population.

Alaska Native children experience high rates of respiratory infections and conditions. Household crowding, indoor smoke, lack of piped water, and poverty have been associated with respiratory infections. We describe the baseline household characteristics of children with severe or chronic lung disease participating in a 2012-2015 indoor air study. We monitored indoor PM2.5, CO2 , relative humidity %, temperature and VOCs, and interviewed caregivers about children's respiratory symptoms. We evaluated the association between reported children's respiratory symptoms and indoor air quality indicators using multiple logistic regression analysis. Compared with general U.S. households, study households were more likely overcrowded 73% (62%-82%) vs. 3.2% (3.1%-3.3%); had higher woodstove use as primary heat source 16% (9%-25%) vs. 2.1% (2.0%-2.2%); and higher proportion of children in a household with a smoker 49% (38%-60%) vs. 26.2% (25.5%-26.8%). Median PM2.5 was 33 mug/m3 . Median CO2 was 1401ppm. VOCs were detectable in all homes. VOCs, smoker, primary wood heat and PM2.5 >25 mug/m3 were associated with higher risk for cough between colds; VOCs were associated with higher risk for wheeze between colds and asthma diagnosis. High indoor air pollutants levels were associated with respiratory symptoms in household children, likely related to overcrowding, poor ventilation, woodstove use, and tobacco smoke.

BACKGROUND: Since 2006, the US Centers for Disease Control and Prevention has recommended hepatitis A (HepA) vaccination routinely for children aged 12-23months to prevent hepatitis A virus (HAV) infection. However, a substantial proportion of US children are unvaccinated and susceptible to infection. We present results of economic modeling to assess whether a one-time catch-up HepA vaccination recommendation would be cost-effective. METHODS: We developed a Markov model of HAV infection that followed a single cohort from birth through death (birth to age 95years). The model compared the health and economic outcomes from catch-up vaccination interventions for children at target ages from two through 17years vs. outcomes resulting from maintaining the current recommendation of routine vaccination at age one year with no catch-up intervention. RESULTS: Over the lifetime of the cohort, catch-up vaccination would reduce the total number of infections relative to the baseline by 741 while increasing doses of vaccine by 556,989. Catch-up vaccination would increase net costs by $10.2million, or $2.38 per person. The incremental cost of HepA vaccine catch-up intervention at age 10years, the midpoint of the ages modeled, was $452,239 per QALY gained. Across age-cohorts, the cost-effectiveness of catch-up vaccination is most favorable at age 12years, resulting in an Incremental Cost-Effectiveness Ratio of $189,000 per QALY gained. CONCLUSIONS: Given the low baseline of HAV disease incidence achieved by current vaccination recommendations, our economic model suggests that a catch-up vaccination recommendation would be less cost-effective than many other vaccine interventions, and that HepA catch-up vaccination would become cost effective at a threshold of $50,000 per QALY only when incidence of HAV rises about 5.0 cases per 100,000 population.

BACKGROUND: The American Association for the Study of Liver Diseases (AASLD) recommends semi-annual hepatocellular carcinoma (HCC) screening using ultrasound (US) in persons with chronic hepatitis B (CHB) virus infection at high risk for HCC such as Asian males aged ≥40 years and Asian females aged ≥50 years. OBJECTIVE: To analyse the cost-effectiveness of 2 HCC screening methods in the Alaska Native (AN) health system: US-alone, or screening by alpha-fetoprotein (AFP) initially and switching to US for subsequent screenings if AFP >10 ng/mL (AFP-->US). DESIGN: A spreadsheet-based model was developed for accounting the costs of 2 hypothetical HCC screening methods. We used epidemiologic data from a cohort of 839 AN persons with CHB who were offered HCC screening by AFP/US semi-annually during 1983-2012. We assumed that compared with AFP-->US, US-alone identifies 33% more tumours at an early stage (defined as a single tumour ≤5 cm or ≤3 tumours ≤3 cm in diameter). Years of life gained (YLG) attributed to screening was estimated by comparing additional years of survival among persons with early- compared with late-stage tumours. Screening costs were calculated using Medicare reimbursement rates in 2012. Future screening costs and YLG were projected over a 30-year time horizon using a 3% discount rate. RESULTS: The total cost of screening for the cohort by AFP-->US would have been approximately $357,000 ($36,000/early-stage tumour detected) compared to $814,000 ($59,000/early-stage tumour detected) by US-alone. The AFP-->US method would have yielded an additional 27.8 YLG ($13,000/YLG) compared with 38.9 YLG ($21,000/YLG) for US-alone. Screening by US-alone would incur an additional $114,000 per extra early-tumour detected compared with AFP-->US and $41,000 per extra YLG. CONCLUSIONS: Although US-alone HCC screening might have yielded more YLG than AFP-->US, the reduced costs of the AFP-->US method could expand access to HCC screening in resource constrained settings.

BACKGROUND AND AIMS: Alaska Native peoples have an increased rate of hepatocellular carcinoma compared to the United States population. Viral hepatitis is a risk factor for malignancy and the leading cause of hepatocellular carcinoma in Alaska. With the introduction of hepatitis B immunization in 1982, as well as the emergence of hepatitis C virus in this population, the epidemiology and etiology of hepatocellular carcinoma in Alaska have changed. METHODS: Using the Alaska Native Tumor Registry, all cases of viral and non-viral hepatocellular carcinoma occurring from 1969 through 2013 were identified and reviewed. Incidence rates per 100,000 population were calculated for hepatocellular carcinoma overall and by etiologic category. RESULTS: 152 cases of hepatocellular carcinoma were identified in 148 Alaska Native persons. Overall tumor rate was 3.82 per 100,000 and did not change significantly over the study period. Hepatitis B associated cases decreased significantly over the study period (p=0.048) and were eliminated in persons under the age of 20. Hepatitis C associated cases increased significantly (P<0.001). Undetermined hepatocellular carcinoma rates also decreased. (p=0.034) CONCLUSIONS: Overall hepatocellular carcinoma rates in Alaska Native peoples remained stable over the study period, but the epidemiology and etiology are changing. Two decades after routine hepatitis B immunization, the hepatocellular carcinoma age distribution has shifted to cases presenting later in life. This is consistent with an aging hepatitis B infected population with no new infected young persons coming into the population, as well as the emergence of hepatitis C in adults. This article is protected by copyright. All rights reserved.

BACKGROUND: Hepatocellular carcinoma (HCC) risk after resolving chronic hepatitis B virus (HBV) infection is unclear. AIM: To compare HCC risk between Alaska Native (AN) patients with and without hepatitis B surface antigen (HBsAg) seroclearance. METHODS: We selected persons with (case-patients) and without (control-patients) HBsAg seroclearance from a cohort of 1346 chronically HBV-infected AN patients followed during 1982-2013. We attempted to match two control-patients/case-patient on sex, HBV genotype, and age. Person-years of follow-up for case-patients began on the date of HBsAg resolution and for control-patients began on the date equivalent to the cohort entry date plus the years of HBsAg duration for their corresponding case-patient. We compared HCC risk using a Cox proportional hazards model. RESULTS: The 238 case-patients (4 with HCC) and 435 control-patients (9 with HCC) were similar in age [P-value (P) = 0.30], sex (P = 0.53) and HBV genotype (P = 0.99). Case-patients had longer person-years of follow-up than control-patients (11.7 vs. 10.1 years; P = 0.04). The HCC rate/100 000 persons was similar between case- (132) and control-patients (178; P = 0.65). The adjusted hazard ratio comparing case- and control-patients was similar for HCC [0.7; 95% confidence interval (CI): 0.2-2.4], increased for each 1-year increment for age (1.1; CI: 1.0-1.1; P < 0.01), and was greater if the initial HBeAg was positive (3.5; CI: 1.1-11.0; P = 0.03). CONCLUSIONS: Hepatitis B surface antigen seroclearance was not associated with reduced HCC risk; the HCC risk estimates are limited by wide 95% confidence intervals. Persons meeting HCC surveillance indications prior to HBsAg seroclearance could benefit from continued surveillance after seroclearance.

BACKGROUND & AIMS: Most regions of the world have <3 co-circulating hepatitis B virus (HBV) genotypes, which limits direct comparisons of hepatocellular carcinoma (HCC) risk among HBV-infected persons by genotype. We evaluated HCC incidence by HBV genotype in a cohort of Alaska Native (AN) persons where 5 HBV genotypes (A, B, C, D, F) have been identified. METHODS: Our cohort comprised AN persons with chronic HBV infection identified during 1983-2012 who consented to participate in the study. Cohort persons were offered annual hepatitis B e antigen (HBeAg) testing and semiannual HCC screening. We developed a logistic regression model to compare HCC risk by genotype, adjusting for age, sex, region, and HBeAg status. RESULTS: Among the 1,235 consenting study participants, 711 (57.6%) were male, 510 (41.3%) were HBeAg positive at cohort entry, and 43 (3.5%) developed HCC. The HBV genotype was known for 1,142 (92.5%) persons (13.5% A, 3.9% B, 6.7% C, 56.9% D, 19.0% F). The HCC incidence/1,000 person-years of follow-up for genotypes A, B, C, D, and F was 1.3, 0, 5.5, 0.4, and 4.2, respectively. Compared with persons with HBV genotype B/D infection, the HCC risk was higher for persons with genotypes A (adjusted odds ratio [aOR]: 3.9, 95% CI: 1.14-13.74), C (aOR: 16.3, 95% CI: 5.20-51.11), and F (aOR: 13.9, 95% CI: 5.30-36.69). CONCLUSION: HBV genotype is independently associated with HCC risk. AN persons with genotypes A, C, and F are at higher risk compared with genotypes B or D.

BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus infections are common to south-western Alaska and have been associated with traditional steambaths. More than a decade ago, recommendations were made to affected communities that included preventive skin care, cleaning methods for steambath surfaces, and the use of protective barriers while in steambaths to reduce the risk of S. aureus infection. OBJECTIVE: A review of community medical data suggested that the number of skin infection clinical encounters has increased steadily over the last 3 years and we designed a public health investigation to seek root causes. STUDY DESIGN: Using a mixed methods approach with in-person surveys, a convenience sample (n=492) from 3 rural communities assessed the range of knowledge, attitudes and practices concerning skin infections, skin infection education messaging, prevention activities and home self-care of skin infections. RESULTS: We described barriers to implementing previous recommendations and evaluated the acceptability of potential interventions. Prior public health messages appear to have been effective in reaching community members and appear to have been understood and accepted. We found no major misconceptions regarding what a boil was or how someone got one. Overall, respondents seemed concerned about boils as a health problem and reported that they were motivated to prevent boils. We identified current practices used to avoid skin infections, such as the disinfection of steambaths. We also identified barriers to engaging in protective behaviours, such as lack of access to laundry facilities. CONCLUSIONS: These findings can be used to help guide public health strategic planning and identify appropriate evidence-based interventions tailored to the specific needs of the region.

BACKGROUND: The duration of protection in children and adults resulting from hepatitis B vaccination is unknown. In 1981, we immunized a cohort of 1578 Alaska Native adults and children from 15 Alaska communities aged ≥6 months using 3 doses of plasma-derived hepatitis B vaccine. METHODS: Persons were tested for antibody to hepatitis B surface antigen (anti-HBs) levels 30 years after receiving the primary series. Those with levels <10 mIU/mL received 1 booster dose of recombinant hepatitis B vaccine 2-4 weeks later and were then evaluated on the basis of anti-HBs measurements 30 days after the booster. RESULTS: Among 243 persons (56%) who responded to the original primary series but received no subsequent doses during the 30-year period, 125 (51%) had an anti-HBs level ≥10 mIU/mL. Among participants with anti-HBs levels <10 mIU/mL who were available for follow-up, 75 of 85 (88%) responded to a booster dose with an anti-HBs level ≥10 mIU/mL at 30 days. Initial anti-HBs level after the primary series was correlated with higher anti-HBs levels at 30 years. CONCLUSIONS: Based on anti-HBs level ≥10 mIU/mL at 30 years and an 88% booster dose response, we estimate that ≥90% of participants had evidence of protection 30 years later. Booster doses are not needed.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common pathogen identified in young children with acute lower respiratory infection (ALRI) as well as an important cause of hospital admission. The high incidence of RSV infection and its potential severe outcome make it important to identify and prioritise children who are at higher risk of developing RSV-associated ALRI. We aimed to identify risk factors for RSV-associated ALRI in young children. METHODS: We carried out a systematic literature review across 4 databases and obtained unpublished studies from RSV Global Epidemiology Network (RSV GEN) collaborators. Quality of all eligible studies was assessed according to modified GRADE criteria. We conducted meta-analyses to estimate odds ratios with 95% confidence intervals (CI) for individual risk factors. RESULTS: We identified 20 studies (3 were unpublished data) with "good quality" that investigated 18 risk factors for RSV-associated ALRI in children younger than five years old. Among them, 8 risk factors were significantly associated with RSV-associated ALRI. The meta-estimates of their odds ratio (ORs) with corresponding 95% confidence intervals (CI) are prematurity 1.96 (95% CI 1.44-2.67), low birth weight 1.91 (95% CI 1.45-2.53), being male 1.23 (95% CI 1.13-1.33), having siblings 1.60 (95% CI 1.32-1.95), maternal smoking 1.36 (95% CI 1.24-1.50), history of atopy 1.47 (95% CI 1.16-1.87), no breastfeeding 2.24 (95% CI 1.56-3.20) and crowding 1.94 (95% CI 1.29-2.93). Although there were insufficient studies available to generate a meta-estimate for HIV, all articles (irrespective of quality scores) reported significant associations between HIV and RSV-associated ALRI. CONCLUSIONS: This study presents a comprehensive report of the strength of association between various socio-demographic risk factors and RSV-associated ALRI in young children. Some of these amenable risk factors are similar to those that have been identified for (all cause) ALRI and thus, in addition to the future impact of novel RSV vaccines, national action against ALRI risk factors as part of national control programmes can be expected to reduce burden of disease from RSV. Further research which identifies, accesses and analyses additional unpublished RSV data sets could further improve the precision of these estimates.

The effect of passively transferred maternal antibody to hepatitis A virus (anti-HAV) on the duration of seropositivity after hepatitis A vaccination during infancy and early childhood is unclear. We obtained levels of anti-HAV at intervals through ages 15-16 years among three groups of Alaskan Native children who initiated a two-dose inactivated hepatitis A vaccination series at ages 6 (Group 1), 12 (Group 2), and 15 months (Group 3), each group randomized according to maternal anti-HAV status. Seropositivity (anti-HAV ≥20 mIU/mL) 30 years after the second vaccine dose among the three groups was predicted using a random effects model. One hundred eighty-three children participated in the study; follow-up did not differ significantly by vaccine group or maternal anti-HAV status. Although the frequency of seropositivity among all participants through age 10 years was high (100% among Groups 2/3 and >90% among Group 1 children), there was a decrease thereafter through ages 15-16 years among Group 1 children, who initiated vaccination at age 6 months (50%-75%), and among maternal anti-HAV-positive children in Groups 2 and 3 (67%-87%), who initiated vaccination at ages 12 and 15 months, respectively. Nonetheless, the model indicated that anti-HAV seropositivity should persist for ≥30 years after vaccination in 64% of all participants; among those seropositive at ages 15-16 years, 84% were predicted to remain so for ≥30 years. CONCLUSIONS: Most children vaccinated during early childhood available for sampling maintained seropositivity through ages 15-16 years; however, seropositivity was less frequent among those starting vaccination at age 6 months and among maternal antibody-positive participants who started vaccination at age 12 or 15 months. Overall, our findings support current vaccine recommendations and continued follow-up of this cohort.

BACKGROUND: Rickets and vitamin D deficiency appeared to increase in Alaskan children starting in the 1990s. We evaluated the epidemiology of rickets and vitamin D deficiency in Alaska native (AN) children in 2001-2010. METHODS: We analyzed 2001-2010 visits with rickets or vitamin D deficiency diagnosis for AN and American Indian children and the general US population aged <10 years. We conducted a case-control study of AN rickets/vitamin D deficient cases and age- and region-matched controls. RESULTS: In AN children, annual rickets-associated hospitalization rate (2.23/100,000 children/year) was higher than the general US rate (1.23; 95% CI 1.08-1.39). Rickets incidence increased with latitude. Rickets/vitamin D deficiency cases were more likely to have malnutrition (OR 38.1; 95% CI 4.9-294), had similar breast-feeding prevalence, and were less likely to have received vitamin D supplementation (OR 0.23; 95% CI 0.1-0.87) than controls. CONCLUSIONS: Our findings highlight the importance of latitude, malnutrition, and lack of vitamin D supplementation as risk factors for rickets.