Julia Warner Gargano

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.

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.

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 ≥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.

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.

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.

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.

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.

Patient-Level and Hospital-Level Determinants of the Quality of Acute Stroke Care A Multilevel Modeling Approach

Background and Purpose— Quality of care may be influenced by patient and hospital factors. Our goal was to use multilevel modeling to identify patient-level and hospital-level determinants of the quality of acute stroke care in a stroke registry. Methods— During 2001 to 2002, data were collected for 4897 ischemic stroke and TIA admissions at 96 hospitals from 4 prototypes of the Paul Coverdell National Acute Stroke Registry. Duration of data collection varied between prototypes (range, 2-6 months). Compliance with 8 performance measures (recombinant tissue plasminogen activator treatment, antithrombotics <24 hours, deep venous thrombosis prophylaxis, lipid testing, dysphagia screening, discharge antithrombotics, discharge anticoagulants, smoking cessation) was summarized in a composite opportunity score defined as the proportion of all needed care given. Multilevel linear regression analyses with hospital specified as a random effect were conducted. Results— The average hospital composite score was 0.627. Hospitals accounted for a significant amount of variability (intraclass correlation=0.18). Bed size was the only significant hospital-level variable; the mean composite score was 11% lower in small hospitals (≤145 beds) compared with large hospitals (≥500 beds). Significant patient-level variables included age, race, ambulatory status documentation, and neurologist involvement. However, these factors explained <2.0% of the variability in care at the patient level. Conclusions— Multilevel modeling of registry data can help identify the relative importance of hospital-level and patient-level factors. Hospital-level factors accounted for 18% of total variation in the quality of care. Although the majority of variability in care occurred at the patient level, the model was able to explain only a small proportion.

In-hospital stroke in a statewide stroke registry.

Background:In-hospital stroke (IHS) represents 5–15% of all hospitalized acute stroke cases, and is associated with poor outcomes. IHS represents an important area for prevention since many cases occur in high-risk patients undergoing cardiovascular procedures. Our objectives were to compare the quality of care, treatments, and outcomes of IHS with out-of-hospital stroke (OHS) cases. Methods: A 6-month prospective cohort of IHS and OHS stroke cases from a statewide acute stroke registry of 15 representative hospitals was assembled. Data were abstracted on demographic, clinical characteristics, in-hospital care (including tPA treatment), discharge instructions, and in-hospital outcomes (mortality and modified Rankin Scale [mRS] at discharge). Results:177 (6.5%) of the 2,743 cases in the registry were IHS cases. 40% of IHS cases were admitted with a cardiovascular or neurologically related problem, and 68% underwent an invasive diagnostic or surgical procedure prior to their stroke. IHS cases were less likely to have the cerebral vasculature examined or to have a lipid panel drawn. Compared to OHS, IHS had higher case fatality (14.6 vs. 6.9%; p = 0.04), greater functional impairment (mRS ≧4) (61 vs. 36%; p < 0.001), and were less likely to be discharged home (23 vs. 52%, p < 0.01). Conclusions:In this prospective registry, 1 in 15 acute stroke cases occurred in the hospital, and almost 70% had an invasive procedure undertaken prior to their stroke event. In-hospital cases received similar quality of care as OHS cases, but had significantly worse outcomes.

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.