Effectiveness of 1, 2, and 3 Doses of Human Papillomavirus Vaccine Against High-Grade Cervical Lesions Positive for Human Papillomavirus 16 or 18.

Before 2016, human papillomavirus (HPV) vaccination was recommended on a 3-dose schedule. However, many vaccine-eligible US females received fewer than 3 doses, which provided an opportunity to evaluate the real-world vaccine effectiveness (VE) of 1, 2, and 3 doses. We analyzed data on cervical intraepithelial neoplasia (CIN) grades 2-3 and adenocarcinoma in situ (designated CIN2+) from the HPV Vaccine Impact Monitoring Project (HPV-IMPACT; 2008-2014). Archived tissue from CIN2+ lesions was tested for 37 types of HPV. Women were classified by number of doses received ≥24 months before CIN2+ detection. Using a test-negative design, VE was estimated as 1 minus the adjusted odds ratio from a logistic regression model that compared vaccination history for women whose lesions tested positive for HPV-16/18 (vaccine-type cases) with that for women who had all other CIN2+ lesions (controls). Among 3,300 women with available data on CIN2+, typing results, and vaccine history, 1,561 (47%) were HPV-16/18-positive, 136 (4%) received 1 dose of HPV vaccine, 108 (3%) received 2 doses, and 325 (10%) received 3 doses. Adjusted odds ratios for vaccination with 1, 2, and 3 doses were 0.53 (95% confidence interval (CI): 0.37, 0.76; VE = 47%), 0.45 (95% CI: 0.30, 0.69; VE = 55%), and 0.26 (95% CI: 0.20, 0.35; VE = 74%), respectively. We found significant VE against vaccine-type CIN2+ after 3 doses of HPV vaccine and lower but significant VE with 1 or 2 doses.

Trends in High-grade Cervical Lesions and Cervical Cancer Screening in 5 States, 2008-2015.

BACKGROUND: We describe changes in rates of cervical intraepithelial neoplasia grades 2, 3 and adenocarcinoma in situ (CIN2+) during a period of human papillomavirus (HPV) vaccine uptake and changing cervical cancer screening recommendations. METHODS: We conducted population-based laboratory surveillance for CIN2+ in catchment areas in 5 states, 2008-2015. We calculated age-specific CIN2+ rates per 100000 women by age groups. We estimated incidence rate ratios (IRR) of CIN2+ for 2-year periods among all women and among screened women to evaluate changes over time. RESULTS: A total of 16572 CIN2+ cases were reported. Among women aged 18-20 and 21-24 years, CIN2+ rates declined in all sites, whereas in women aged 25-29, 30-34, and 35-39 years, trends differed across sites. The percent of women screened annually declined in all sites and age groups. Compared to 2008-2009, rates among screened women were significantly lower for all 3 periods in women aged 18-20 years (2010-2011: IRR 0.82, 95% confidence interval [CI] 0.67-0.99; 2012-2013: IRR 0.63, 95% CI 0.47-0.85; 2014-2015: IRR 0.44, 95% CI 0.28-0.68) and lower for the latter 2 time periods in women aged 21-24 years (2012-2013: IRR 0.86, 95% CI 0.79-0.94; 2014-2015: IRR 0.61, 95% CI 0.55-0.67). CONCLUSIONS: From 2008-2015, both CIN2+ rates and cervical cancer screening declined in women aged 18-24 years. The significant decreases in CIN2+ rates among screened women aged 18-24 years are consistent with a population-level impact of HPV vaccination.

Giardiasis in the United States - an epidemiologic and geospatial analysis of county-level drinking water and sanitation data, 1993-2010.

Giardiasis is the most commonly reported intestinal parasitic infection in the United States. Outbreak investigations have implicated poorly maintained private wells, and hypothesized a role for wastewater systems in giardiasis transmission. Surveillance data consistently show geographic variability in reported giardiasis incidence. We explored county-level associations between giardiasis cases, household water and sanitation (1990 census), and US Census division. Using 368,847 reported giardiasis cases (1993-2010), we mapped county-level giardiasis incidence rates, private well reliance, and septic system reliance, and assessed spatiotemporal clustering of giardiasis. We used negative binomial regression to evaluate county-level associations between giardiasis rates, region, and well and septic reliance, adjusted for demographics. Adjusted giardiasis incidence rate ratios (aIRRs) were highest (aIRR 1.3; 95% confidence interval 1.2-1.5) in counties with higher private well reliance. There was no significant association between giardiasis and septic system reliance in adjusted models. Consistent with visual geographic distributions, the aIRR of giardiasis was highest in New England (aIRR 3.3; 95% CI 2.9-3.9; reference West South Central region). Our results suggest that, in the USA, private wells are relevant to giardiasis transmission; giardiasis risk factors might vary regionally; and up-to-date, location-specific national data on water sources and sanitation methods are needed.

Presenting symptoms and onset-to-arrival time in patients with acute stroke and transient ischemic attack.

Delayed arrival to the emergency department (ED) precludes most stroke patients from receiving thrombolytic treatment. Our objective in this study was to examine the association between presenting symptoms and onset-to-arrival time (ie, time between onset of symptoms to arrival at the ED) in a statewide stroke registry. Demographics, clinical data, and presenting symptoms were collected for patients with acute stroke or symptomatic transient ischemic attack (TIA) admitted to 15 Michigan hospitals (n = 1922). Polytomous logistic regression models were developed to test the association between presenting symptoms and onset-to-arrival time (classified as <2 hours, 2-6 hours, or >6 hours/unknown). Onset-to-arrival time was <2 hours in 19% of the patients, 2-6 hours in 22%, and >6 hours/unknown in 59%. Unilateral symptoms (reported by 40%) and speech difficulties (reported by 22%) were associated with increased likelihood of arriving within 2 hours (unilateral: adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 1.1-1.9; speech: aOR, 1.6; 95% CI, 1.2-2.2). Difficulty with walking, balance, or dizziness (12%), confusion (9%), loss of consciousness (6.7%) and falls (3.4%) were associated with lower likelihood of arriving within 2 hours (walking: aOR, 0.7; 95% CI, 0.4-1.0; confusion: aOR, 0.5; 95% CI, 0.3-0.8; consciousness: aOR, 0.5; 95% CI, 0.1-0.9; falls: aOR, 0.4; 95% CI, 0.3-0.9). Presenting symptoms were strongly associated with time of arrival; patients with unilateral symptoms and speech difficulties were more likely to seek care early. Future studies should consider including more specific patient-level data to identify psychosocial and behavioral aspects of recognition and action to stroke symptoms.

Do presenting symptoms explain sex differences in emergency department delays among patients with acute stroke?

BACKGROUND AND PURPOSE: Previous studies report that women with stroke may experience longer delays in diagnostic workup than men after arriving at the emergency department. We hypothesized that presenting symptom differences could explain these delays. METHODS: Data were collected on 1922 acute stroke cases who presented to 15 hospitals participating in a statewide stroke registry. We evaluated 2 in-hospital time intervals: emergency department arrival to physician examination ("door-to-doctor") and emergency department arrival to brain imaging ("door-to-image"). We used parametric survival models to estimate time ratios, which represent the ratio of average times comparing women to men, after adjusting for symptom presentation and other confounders. RESULTS: Women were significantly less likely than men to present with any stroke warning sign or suspected stroke (87.5% versus 91.4%) or to report trouble with walking, balance, or dizziness (9.5% versus 13.7%). Difficulty speaking and loss of consciousness were associated with shorter door-to-doctor times. Weakness, facial droop, difficulty speaking, and loss of consciousness were associated with shorter door-to-image times, whereas difficulty with walking/balance was associated with longer door-to-image times. In adjusted analyses, women had 11% longer door-to-doctor intervals (time ratio, 1.11; 95%, CI 1.02 to 1.22) and 15% longer door-to-image intervals (time ratio, 1.15; 95% CI, 1.08 to 1.25) after accounting for presenting symptoms, age, and other confounders. Furthermore, these sex differences remained evident after restricting to patients who arrived within 6 or within 2 hours of symptom onset. CONCLUSIONS: Women with acute stroke experienced greater emergency department delays than men, which were not attributable to differences in presenting symptoms, time of arrival, age, or other confounders.

Polymorphisms in thrombophilia and renin-angiotensin system pathways, preterm delivery, and evidence of placental hemorrhage.

OBJECTIVE: The purpose of this study was to analyze functional polymorphisms in candidate genes (methylenetetrahydrofolate reductase [MTHFR]677C>T, MTHFR1298A>C, factor 5 1691G>A [FVL], and angiotensinogen (AGT)-6G>A) in relation to a hypothesized placental hemorrhage pathway to preterm delivery (PTD). STUDY DESIGN: We assessed maternal genotypes, pregnancy outcomes, and placental pathologic evidence among 560 white and 399 black women who were recruited at mid trimester into a prospective cohort study (1998-2004). Odds of dominant genotypes were calculated for PTDs with (n = 56) or without (n = 177) evidence of placental hemorrhage (referent = term) with the use of race-stratified polytomous logistic regression models. RESULTS: Among white women, FVL GA/AA and AGT(-6) GA/AA were both associated with hemorrhage-related PTDs (odds ratio [OR], 4.8; 95% confidence interval [CI], 1.6-14.2 and OR, 3.8; 95% CI, 1.3-10.5, respectively), but not other PTDs (ORs, 1.2 and 0.9, respectively). FVL GA/AA was associated with placental abruption (OR, 5.8; 95% CI, 1.1-30) among white women. All results were null for MTHFR genotypes. CONCLUSION: FVL and AGT variant genotypes were associated specifically with hemorrhage-related PTDs.

Sex differences in acute stroke care in a statewide stroke registry.

BACKGROUND AND PURPOSE: Many studies have reported poorer stroke outcomes in women, and some studies have reported sex differences in care. We analyzed data from a hospital-based stroke registry to determine whether acute stroke care and discharge status differed by sex. METHODS: Detailed chart-level information was collected on 2566 subjects admitted for acute stroke or transient ischemic attack to 15 Michigan hospitals in 2002. Sex differences in stroke care and patient status at discharge (in-hospital mortality and modified Rankin Scale score) were assessed after adjusting for differences in demographics, clinical characteristics, and comorbidities by multivariable models. Modified Rankin Scale score data were analyzed by proportional-odds models. RESULTS: Women were older than men (70 vs 67 years) and were more likely to have congestive heart failure and hypertension. Men were more likely to smoke and have a history of heart disease and dyslipidemia. After multivariable adjustment, women were less likely to receive thrombolytic therapy (odds ratio [OR]=0.56; 95% CI, 0.37 to 0.86) or lipid testing (OR=0.76; 95% CI, 0.61 to 0.94) and were more likely to suffer urinary tract infections (OR=2.57; 95% CI, 1.87 to 3.54). In-hospital mortality was similar in women and men (9% vs 8%); however, women had poorer discharge modified Rankin Scale scores (OR=1.17; 95% CI, 1.01 to 1.35). CONCLUSIONS: Although considerable parity exists in many aspects of acute stroke care, women were less likely than men to receive thrombolytic treatment and lipid testing, even after adjustment. However, given the largely similar care observed, it is unlikely that differences in care explain the poorer functional outcomes in female stroke survivors.

Effect of pretreatment with statins on ischemic stroke outcomes.

BACKGROUND AND PURPOSE: Statins reduce the risk of stroke in at-risk populations and may improve outcomes in patients taking statins before an ischemic stroke (IS). Our objectives were to examine the effects of pretreatment with statins on poor outcome in IS patients. METHODS: Over a 6-month period all acute IS admissions were prospectively identified in 15 hospitals participating in a statewide acute stroke registry. Poor stroke outcome was defined as modified Rankin score >/=4 at discharge (ie, moderate-severe disability or death). Multivariable logistic regression models and matched propensity score analyses were used to quantify the effect of statin pretreatment on poor outcome. RESULTS: Of 1360 IS patients, 23% were using statins before their stroke event and 42% had a poor stroke outcome. After multivariable adjustment, pretreatment with statins was associated with lower odds of poor outcome (OR=0.74, 95% CI 0.52, 1.02). A significant interaction (P<0.01) was found between statin use and race. In whites, statins were associated with statistically significantly lower odds of poor outcome (OR=0.61, 95% CI 0.42, 0.86), but in blacks statins were associated with a nonstatistically significant increase in poor outcome (OR=1.82, 95% CI 0.98, 3.39). Matched propensity score analyses were consistent with the multivariable model results. CONCLUSIONS: Pretreatment with statins was associated with better stroke outcomes in whites, but we found no evidence of a beneficial effect of statins in blacks. These findings indicate the need for further studies, including randomized trials, to examine differential effects of statins on ischemic stroke outcomes among whites and blacks.

Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes.

Stroke has a greater effect on women than men because women have more events and are less likely to recover. Age-specific stroke rates are higher in men, but, because of their longer life expectancy and much higher incidence at older ages, women have more stroke events than men. With the exception of subarachnoid haemorrhage, there is little evidence of sex differences in stroke subtype or severity. Although several reports found that women are less likely to receive some in-hospital interventions, most differences disappear after age and comorbidities are accounted for. However, sex disparities persist in the use of thrombolytic treatment (with alteplase) and lipid testing. Functional outcomes and quality of life after stroke are consistently poorer in women, despite adjustment for baseline differences in age, prestroke function, and comorbidities. Here, we comprehensively review the epidemiology, clinical presentation, medical care, and outcomes of stroke in women.

Mid-pregnancy circulating cytokine levels, histologic chorioamnionitis and spontaneous preterm birth.

Some spontaneous preterm deliveries (PTD) are caused by occult infections of the fetal membranes (histologic chorioamnionitis [HCA]). High levels of infection-related markers, including some cytokines, sampled from maternal circulation in mid-pregnancy have been linked to PTD, but whether these specifically identify HCA has not been established. We have tested associations between 13 Th1, Th2 and Th17 cytokines and PTD with and without HCA in a prospective cohort study. The study sample included 926 Pregnancy Outcomes and Community Health Study subcohort women; women with medically indicated PTD or incomplete data excluded. A panel of cytokines was assessed using a multiplex assay in maternal plasma collected at 15-27 weeks of gestation. Severe HCA was scored by a placental pathologist blinded to clinical variables. Multivariable polytomous logistic regression was used to estimate adjusted odds ratios (OR) per 1 standard deviation (S.D.) increase in cytokine levels using a 5 level outcome variable: PTD <35 weeks with HCA, PTD <35 weeks without HCA, PTD 35-36 weeks with HCA, PTD 35-36 weeks without HCA, and term (referent). Interleukin (IL)-1beta, IL-2, IL-12, interferon-gamma, IL-4, IL-6 and transforming growth factor-beta were all significantly associated with PTD <35 weeks with HCA, with ORs of 1.6-2.3 per S.D. increase. None of these were associated with PTD <35 weeks without HCA or PTD 35-36 weeks with HCA. Although the tissues of origin of circulating cytokines are unclear, the observed elevations across many cytokines among women who later delivered <35 weeks with HCA may represent a robust immune response to infection within gestational tissues. These results suggest that women with HCA could be identified using relatively non-invasive means.

Sex differences in stroke recovery and stroke-specific quality of life: results from a statewide stroke registry.

BACKGROUND AND PURPOSE: Little is known about sex differences in stroke recovery. The few available studies have found that female stroke survivors are less likely to achieve independence in activities of daily living and have poorer quality of life than male survivors. METHODS: A total of 373 acute stroke survivors discharged from 9 hospitals participating in a statewide stroke registry were prospectively enrolled in an outcomes study. Follow-up data, including the Barthel Index and Stroke-Specific Quality of Life, were obtained from the survivor or a proxy by telephone interview 90 days postdischarge. The independent effects of sex on activities of daily living independence (Barthel Index > or =95) and Stroke-Specific Quality of Life scores, controlling for age, race, subtype, prestroke ambulatory status, and other patient characteristics, were determined using adjusted odds ratios and least-squares means, respectively. RESULTS: Twenty-five percent of the patients required a proxy respondent. In adjusted models, females were less likely to achieve activities of daily living independence (adjusted OR: 0.37, 95% CI: 0.19 to 0.87). Females had lower least-squares means Stroke-Specific Quality of Life scores in Physical Function (3.9 versus 4.2, P=0.02), Thinking (2.8 versus 3.4, P<0.001), Language (4.3 versus 4.5, P=0.03), and Energy (2.6 versus 3.0, P<0.01). Interactions between sex and prior stroke were found for Mood, Role Function, and Summary Score, resulting in lower least-squares means for females only among subjects without prior stroke. CONCLUSIONS: Compared with males, female stroke survivors had lower functional recovery and poorer quality of life 3 months postdischarge. These differences were not explained by females' greater age at stroke onset or other demographic or clinical characteristics.

A proposed set of descriptors for functional senescence data.

Declines in function are common manifestations of aging in many phyla. Because functional senescence is thought to drive the increasing risk of death with age, understanding functional senescence is important for understanding aging. Experimental investigation of functional senescence requires one to quantitative and compare age-dependent declines in function between cohorts. Such quantitation and comparison is often difficult due to complexities in functional senescence data sets. Here, we discuss issues related to describing and contrasting age-related declines in function. We parameterized functional senescence data in simple ways to generate descriptors for (1) rate of functional decline, (2) time to onset of functional decline, and (3) total function. To illustrate how these descriptors can be used, we analyzed a hypothetical data set and one of our previously published data sets. We conclude that no one descriptor sufficiently characterizes functional senescence. Useful distinctions between functional senescence in different cohorts can be made, however, when multiple descriptors are used in an integrated fashion [corrected]

Rapid iterative negative geotaxis (RING): a new method for assessing age-related locomotor decline in Drosophila.

Age-related behavioral declines are common manifestations of aging in animals. Negative geotaxis, an innate escape response during which flies ascend the wall of a cylinder after being tapped to its bottom, is one of the behaviors that senesces in Drosophila. Many laboratories, including ours, have used a variety of negative geotaxis assays based on the performance of single flies. To circumvent limitations of single-fly assays, we developed a new method for assessing negative geotaxis called rapid iterative negative geotaxis (RING). In RING assays, digital photography is used to document negative geotaxis in multiple groups of animals simultaneously. We show that performance in RING assays is not influenced by the density of flies being tested, the time of day, or repeated testing. We used the RING assay to demonstrate that negative geotaxis declines with the age of animals as previously shown in single fly studies and that senescence of negative geotaxis is sensitive to genetic background. Finally, we used RING assays to show that long-lived Indy and chico mutants exhibit delayed senescence of negative geotaxis. Our results demonstrate that RING is a powerful method for assessing negative geotaxis that should facilitate the search for manipulations that influence behavioral aging in Drosophila.

A forward genetic screen in Drosophila implicates insulin signaling in age-related locomotor impairment.

Age-related locomotor impairment (ARLI) is one of the most detrimental changes that occurs during aging. Elderly individuals with ARLI are at increased risks for falls, depression and a number of other co-morbidities. Despite its clinical significance, little is known about the genes that influence ARLI. We consequently performed a forward genetic screen to identify Drosophila strains with delayed ARLI using negative geotaxis as an index of locomotor function. One of the delayed ARLI strains recovered from the screen had a P-element insertion that decreased expression of the insulin signaling gene phosphoinositide-dependent kinase 1 (PDK1) Precise excision of the P-element insertion reverted PDK1 expression and ARLI to the same as control flies, indicating that disruption of PDK1 leads to delayed ARLI. Follow-up studies showed that additional loss of function mutations in PDK1 as well as loss of function alleles of two other insulin signaling genes, Dp110 and Akt (the genes for the catalytic subunit of phosphoinositide 3-kinase and AKT), also forestalled ARLI. Interestingly, only some of the strains with delayed ARLI had elevated resistance to paraquat, indicating that enhanced resistance to this oxidative stressor is not required for preservation of locomotor function across age. Our studies implicate insulin signaling as a key regulator of ARLI in Drosophila.

Behavioral responses to odorants in drosophila require nervous system expression of the beta integrin gene myospheroid.

Integrins are cell adhesion molecules that mediate numerous developmental processes in addition to a variety of acute physiological events. Two reports implicate a Drosophila beta integrin, betaPS, in olfactory behavior. To further investigate the role of integrins in Drosophila olfaction, we used Gal4-driven expression of RNA interference (RNAi) transgenes to knock down expression of myospheroid (mys), the gene that encodes betaPS. Expression of mys-RNAi transgenes in the wing reduced betaPS immunostaining and produced morphological defects associated with loss-of-function mutations in mys, demonstrating that this strategy knocked down mys function. Expression of mys-RNAi transgenes in the antennae, antennal lobes, and mushroom bodies via two Gal4 lines, H24 and MT14, disrupted olfactory behavior but did not alter locomotor abilities or central nervous system structure. Olfactory behavior was normal in flies that expressed mys-RNAi transgenes via other Gal4 lines that specifically targeted the antennae, the projection neurons, the mushroom bodies, bitter and sweet gustatory neurons, or Pox neuro neurons. Our studies confirm that mys is important for the development or function of the Drosophila olfactory system. Additionally, our studies demonstrate that mys is required for normal behavioral responses to both aversive and attractive odorants. Our results are consistent with a model in which betaPS mediates events within the antennal lobes that influence odorant sensitivity.