MicroRNA profiling reveals marker of motor neuron disease in ALS models

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining thein vivomiRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.</jats:p

A Cross-Sectional Study to Assess HPV Knowledge and HPV Vaccine Acceptability in Mali

Despite a high prevalence of oncogenic human papilloma virus (HPV) infection and cervical cancer mortality, HPV vaccination is not currently available in Mali. Knowledge of HPV and cervical cancer in Mali, and thereby vaccine readiness, may be limited. Research staff visited homes in a radial pattern from a central location to recruit adolescent females and males aged 12–17 years and men and women aged ≥18 years (N = 51) in a peri-urban village of Bamako, Mali. Participants took part in structured interviews assessing knowledge, attitudes, and practices related to HPV, cervical cancer, and HPV vaccination. We found low levels of HPV and cervical cancer knowledge. While only 2.0% of respondents knew that HPV is a sexually transmitted infection (STI), 100% said they would be willing to receive HPV vaccination and would like the HPV vaccine to be available in Mali. Moreover, 74.5% said they would vaccinate their child(ren) against HPV. Men were found to have significantly greater autonomy in the decision to vaccinate themselves than women and adolescents (p = 0.005), a potential barrier to be addressed by immunization campaigns. HPV vaccination would be highly acceptable if the vaccine became widely available in Bamako, Mali. This study demonstrates the need for a significant investment in health education if truly informed consent is to be obtained for HPV vaccination. Potential HPV vaccination campaigns should provide more information about HPV and the vaccine. Barriers to vaccination, including the significantly lower ability of the majority of the target population to autonomously decide to get vaccinated, must also be addressed in future HPV vaccine campaigns

Frailty and Risk of Falls, Fracture, and Mortality in Older Women: The Study of Osteoporotic Fractures

Background. A standard phenotype of frailty was associated with an increased risk of adverse outcomes including mortality in a recent study of older adults. However, the predictive validity of this phenotype for fracture outcomes and across risk subgroups is uncertain. Methods. To determine whether a standard frailty phenotype was independently associated with risk of adverse health outcomes in older women and to evaluate the consistency of associations across risk subgroups defined by age and body mass index (BMI), we ascertained frailty status in a cohort of 6724 women ≥ 69 years and followed them prospectively for incident falls, fractures, and mortality. Frailty was defined by the presence of three or more of the following criteria: unintentional weight loss, weakness, self-reported poor energy, slow walking speed, and low physical activity. Incident recurrent falls were defined as at least two falls during the subsequent year. Incident fractures (confirmed with x-ray reports), including hip fractures, and deaths were ascertained during an average of 9 years of follow-up. Results. After controlling for multiple confounders such as age, health status, medical conditions, functional status, depressive symptoms, cognitive function, and bone mineral density, frail women were subsequently at increased risk of recurrent falls (multivariate odds ratio = 1.38, 95% confidence interval [CI], 1.02-1.88), hip fracture (multivariate hazards ratio [MHR] = 1.40, 95% CI, 1.03-1.90), any nonspine fracture (MHR = 1.25, 95% CI, 1.05-1.49), and death (MHR = 1.82, 95% CI, 1.56-2.13). The associations between frailty and these outcomes persisted among women ≥ 80 years. In addition, associations between frailty and an increased risk of falls, fracture, and mortality were consistently observed across categories of BMI, including BMI ≥ 30 kg/m2. Conclusion. Frailty is an independent predictor of adverse health outcomes in older women, including very elderly women and older obese wome

High Prevalence of Hypertension and Placental Insufficiency, but No In Utero HIV Transmission, among Women on HAART with Stillbirths in Botswana

Background: Increased stillbirth rates occur among HIV-infected women, but no studies have evaluated the pathological basis for this increase, or whether highly active antiretroviral therapy (HAART) influences the etiology of stillbirths. It is also unknown whether HIV infection of the fetus is associated with stillbirth. Methods: HIV-infected women and a comparator group of HIV-uninfected women who delivered stillbirths were enrolled at the largest referral hospital in Botswana between January and November 2010. Obstetrical records, including antiretroviral use in pregnancy, were extracted at enrollment. Verbal autopsies; maternal HIV, CD4 and HIV RNA testing; stillbirth HIV PCR testing; and placental pathology (blinded to HIV and treatment status) were performed. Results: Ninety-nine stillbirths were evaluated, including 62 from HIV-infected women (34% on HAART from conception, 8% on HAART started in pregnancy, 23% on zidovudine started in pregnancy, and 35% on no antiretrovirals) and 37 from a comparator group of HIV-uninfected women. Only 2 (3.7%) of 53 tested stillbirths from HIV-infected women were HIV PCR positive, and both were born to women not receiving HAART. Placental insufficiency associated with hypertension accounted for most stillbirths. Placental findings consistent with chronic hypertension were common among HIV-infected women who received HAART and among HIV-uninfected women (65% vs. 54%, p = 0.37), but less common among HIV-infected women not receiving HAART (28%, p = 0.003 vs. women on HAART). Conclusions: In utero HIV infection was rarely associated with stillbirths, and did not occur among women receiving HAART. Hypertension and placental insufficiency were associated with most stillbirths in this tertiary care setting

Gender and Time to Arrival among Ischemic Stroke Patients in the Greater Cincinnati/Northern Kentucky Stroke Study

Background Some studies of stroke patients report longer pre-hospital delays in women, but others conflict; studies vary in their inclusion of factors including age and stroke severity. We aimed to investigate the relationship between gender and time to emergency department (ED) arrival and the influence of age and stroke severity on this relationship. Methods Ischemic stroke patients ≥ 20 years old who presented to 15 hospitals within a 5-county region of Greater Cincinnati/Northern Kentucky during 2010 were included. Time from symptom onset to ED arrival and covariates were abstracted by study nurses and reviewed by study physicians. Data were analyzed using logistic regression with time to arrival dichotomized at ≤ 3 hours, in the overall sample and then stratified by NIHSS and age. Results 1991 strokes (55% women) were included. Time to arrival was slightly longer in women (geometric mean 337 minutes [95%CI 307–369] vs. 297 [95%CI 268–329], p =0.05), and 24% of women vs. 27% of men arrived within 3 hours (p=0.15). After adjusting for age, race, NIHSS, living situation, and other covariates, gender was not associated with delayed time to arrival (OR=1.00, 95%CI 0.78–1.28). This did not change across age or NIHSS categories. Conclusions After adjusting for factors including age, NIHSS, and living alone, women and men with ischemic stroke had similar times to arrival. Arrival time is not likely a major contributor to differences in outcome between men and women

Sex-specific stroke incidence over time in the Greater Cincinnati/Northern Kentucky Stroke Study

OBJECTIVE: Recent data suggest stroke incidence is decreasing over time, but it is unknown whether incidence is decreasing in women and men to the same extent. METHODS: Within our population of 1.3 million, all incident strokes among residents ≥20 years old were ascertained at all hospitals during July 1993-June 1994 and calendar years 1999, 2005, and 2010. A sampling scheme was used to ascertain out-of-hospital cases. Sex-specific incidence rates per 100,000 among black and white participants, age- and race-adjusted, were standardized to the 2000 US Census population. Trends over time by sex were compared; a Bonferroni correction was applied for multiple comparisons. RESULTS: Over the 4 study periods, there were 7,710 incident strokes; 57.2% (n = 4,412) were women. Women were older than men (mean ± SE 72.4 ± 0.34 vs 68.2 ± 0.32, p < 0.001). Incidence of all strokes decreased over time in men (263 [confidence interval 246-281] to 192 [179-205], p < 0.001) but not in women (217 [205-230] to 198 [187-210], p = 0.15). Similar sex differences were seen for ischemic stroke (men, 238 [223-257] to 165 [153-177], p < 0.01; women, 193 [181-205] to 173 [162-184], p = 0.09). Incidence of all strokes and of ischemic strokes was similar between women and men in 2010. Incidence of intracerebral hemorrhage and subarachnoid hemorrhage were stable over time in both sexes. CONCLUSIONS: Decreases in stroke incidence over time are driven by a decrease in ischemic stroke in men. Contrary to previous study periods, stroke incidence rates were similar by sex in 2010. Future research is needed to understand why the decrease in ischemic stroke incidence is more pronounced in men

Sex differences in cardiovascular risk profiles of ischemic stroke patients with diabetes in the Greater Cincinnati/Northern Kentucky Stroke Study

Background The aim of the present study was to compare sex-specific associations between cardiovascular risk factors and diabetes mellitus (DM) among patients with acute ischemic stroke (AIS) in the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS). Methods The GCNKSS ascertained AIS cases in 2005 and 2010 among adult (age ≥ 20 years) residents of a biracial population of 1.3 million. Past and current stroke risk factors were compared between those with and without DM using Chi-squared tests and multiple logistic regression analysis to examine sex-specific profiles. Results There were 3515 patients with incident AIS; 1919 (55%) were female, 697 (20%) were Black, and 1146 (33%) had DM. Among both women and men with DM, significantly more were obese and had hypertension, high cholesterol, and coronary artery disease (CAD) compared with those without DM. For women with AIS, multivariable sex-specific adjusted analyses revealed that older age was associated with decreased odds of having DM (adjusted odds ratio [aOR] 0.88, 95% confidence interval [CI] 0.80–0.98). For women with CAD, the odds of DM were increased (aOR 1.76, 95% CI 1.33–2.32). Age and CAD were not significant factors in differentiating the profiles of men with and without DM. Conclusions Women with DM had strokes at a younger age, whereas no such age difference existed in men. Compared with men, women with DM were also more likely to have CAD than those without DM, suggesting a sex difference in the association between DM and vascular disease. These findings may suggest a need for more aggressive risk factor management in diabetic women

Moving beyond dosage and adherence: A protocol for capturing dimensions of active child engagement as a measure of fidelity for social-emotional learning interventions

Social-emotional competencies are important for school-readiness and can be supported through social-emotional learning (SEL) interventions in the preschool years. However, past research has demonstrated mixed efficacy of early SEL interventions across varied samples, highlighting a need to unpack the black box of which early interventions work, under what conditions, and for whom. In the present article we discuss the critical implementation component of active child engagement in an intervention as a potential point of disconnect between the intervention as designed and as implemented. Children who are physically present but unengaged during an intervention may lead to decreased average impacts of an intervention. Furthermore, measuring young children’s active engagement with an intervention may help to guide iterative intervention development. We propose a four-step protocol for capturing the multi-dimensional and varied construct of active child engagement in a SEL intervention. To illustrate the utility of the protocol, we apply it to data from a pilot study of a researcher-implemented, semi-structured block play intervention focused on supporting the development of SEL and math skills in preschoolers. We then present future directions for the integration of active participant engagement into the measurement of implementation of SEL interventions for young children