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OBJECTIVE Children with medical complexity (CMC) have significant health care costs, but they also experience substantial unmet health care needs, hospitalizations, and medical errors. Their parents often report psychosocial stressors and poor care satisfaction. Complex care programs can improve the care for CMC. At our tertiary care institution, we developed a consultative complex care program to improve the quality and cost of care for CMC and to improve the experience of care for patients and families. METHODS To address the needs of CMC at our institution, we developed the Compass Care Program, a consultative complex care program across inpatient and outpatient settings. Utilization data [hospital admissions per patient month; length of stay per admission; hospital days per patient month; emergency department (ED) visits per patient month; and institutional charges per patient month] and caregiver satisfaction data (obtained via paper survey at outpatient visits) were tracked over the period of participation in the program and compared preenrollment and postenrollment for program participants. RESULTS Participants had significant decreases in hospital admissions per patient month, length of stay per admission, hospital days per patient month, and charges per patient month following enrollment (P

Key Points Question How has timing of antibiotics for sepsis changed over time in US Department of Veterans Affairs Hospitals? Findings In this cohort of 111 385 veterans hospitalized with sepsis from 2013 to 2018, median time to antibiotics declined by 9 minutes per year. However, there was significant variation in time to antibiotics across hospitals, even after adjustment for patient characteristics. Meaning These findings suggest that there is potential for performance improvement for sepsis hospitalizations, but efforts to further accelerate time-to-antibiotics must be weighed against the risks of overtreatment., This cohort study examines temporal trends and variations in time-to-antibiotics for sepsis in the US Department of Veterans Affairs health care system., Importance It is unclear whether antimicrobial timing for sepsis has changed outside of performance incentive initiatives. Objective To examine temporal trends and variation in time-to-antibiotics for sepsis in the US Department of Veterans Affairs (VA) health care system. Design, Setting, and Participants This observational cohort study included 130 VA hospitals from 2013 to 2018. Participants included all patients admitted to the hospital via the emergency department with sepsis from 2013 to 2018, using a definition adapted from the Centers for Disease Control and Prevention Adult Sepsis Event definition, which requires evidence of suspected infection, acute organ dysfunction, and systemic antimicrobial therapy within 12 hours of presentation. Data were analyzed from October 6, 2020, to July 1, 2021. Exposures Time from presentation to antibiotic administration. Main Outcomes and Measures The main outcome was differences in time-to-antibiotics across study periods, hospitals, and patient subgroups defined by presenting temperature and blood pressure. Temporal trends in time-to-antibiotics were measured overall and by subgroups. Hospital-level variation in time-to-antibiotics was quantified after adjusting for differences in patient characteristics using multilevel linear regression models. Results A total of 111 385 hospitalizations for sepsis were identified, including 107 547 men (96.6%) men and 3838 women (3.4%) with a median (interquartile range [IQR]) age of 68 (62-77) years. A total of 7574 patients (6.8%) died in the hospital, and 13 855 patients (12.4%) died within 30 days. Median (IQR) time-to-antibiotics was 3.9 (2.4-6.5) hours but differed by presenting characteristics. Unadjusted median (IQR) time-to-antibiotics decreased over time, from 4.5 (2.7-7.1) hours during 2013 to 2014 to 3.5 (2.2-5.9) hours during 2017 to 2018 (P

Electrical stimulation of the cervical spinal cord is gaining traction as a therapy following spinal cord injury; however, it is difficult to target the cervical motor region in a rodent using a non-penetrating stimulus compared with direct placement of intraspinal wire electrodes. Penetrating wire electrodes have been explored in rodent and pig models and, while they have proven beneficial in the injured spinal cord, the negative aspects of spinal parenchymal penetration (e.g., gliosis, neural tissue damage, and obdurate inflammation) are of concern when considering therapeutic potential. We therefore designed a novel approach for epidural stimulation of the rat spinal cord using a wireless stimulation system and ventral electrode array. Our approach allowed for preservation of mobility following surgery and was suitable for long term stimulation strategies in awake, freely functioning animals. Further, electrophysiology mapping of the ventral spinal cord revealed the ventral approach was suitable to target muscle groups of the rat forelimb and, at a single electrode lead position, different stimulation protocols could be applied to achieve unique activation patterns of the muscles of the forelimb.

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Rationale: In 2017, the U.S. Centers for Disease Control and Prevention (CDC) developed a new surveillance definition of sepsis, the adult sepsis event (ASE), to better track sepsis epidemiology. The ASE requires evidence of acute organ dysfunction and defines baseline organ function pragmatically as the best in-hospital value. This approach may undercount sepsis if new organ dysfunction does not resolve by discharge. Objectives: To understand how sepsis identification and outcomes differ when using the best laboratory values during hospitalization versus methods that use historical lookbacks to define baseline organ function. Methods: We identified all patients hospitalized at 138 Veterans Affairs hospitals (2013–2018) admitted via the emergency department with two or more systemic inflammatory response criteria, were treated with antibiotics within 48 hours (i.e., had potential infection), and completed 4+ days of antibiotics (i.e., had suspected infection). We considered the following three approaches to defining baseline renal, hematologic, and liver function: the best values during hospitalization (as in the Centers for Disease Control and Prevention’s ASE), the best values during hospitalization plus the prior 90 days (3-mo baseline), and the best values during hospitalization plus the prior 180 days (6-mo baseline). We determined how many patients met the criteria for sepsis by each approach, and then compared characteristics and outcomes of sepsis hospitalizations between the three approaches. Results: Among 608,128 hospitalizations with potential infection, 72.1%, 68.5%, and 58.4% had creatinine, platelet, and total bilirubin measured, respectively, in the prior 3 months. A total of 86.0%, 82.6%, and 74.8%, respectively, had these labs in the prior 6 months. Using the hospital baseline, 100,568 hospitalizations met criteria for community-acquired sepsis. By contrast, 111,983 and 117,435 met criteria for sepsis using the 3- and 6-month baselines, for a relative increase of 11% and 17%, respectively. Patient characteristics were similar across the three approaches. In-hospital mortality was 7.2%, 7.0%, and 6.8% for sepsis hospitalizations identified using the hospital, 3-month baseline, and 6-month baseline. The 30-day mortality was 12.5%, 12.7%, and 12.5%, respectively. Conclusions: Among veterans hospitalized with potential infection, the majority had laboratory values in the prior 6 months. Using 3- and 6-month lookbacks to define baseline organ function resulted in an 11% and 17% relative increase, respectively, in the number of sepsis hospitalizations identified.

IMPORTANCE: Children with medical complexity (CMC) frequently experience fragmented care. We have demonstrated that outpatient comprehensive care (CC) reduces serious illnesses, hospitalizations, and costs for high-risk CMC. Yet continuity of care for CMC is often disrupted with emergency department (ED) visits and hospitalizations. OBJECTIVE: To evaluate a hospital consultation (HC) service for CMC from their outpatient CC clinicians. DESIGN, SETTING, AND PARTICIPANTS: Randomized quality improvement trial at the University of Texas Health Science Center at Houston with an outpatient CC clinic and tertiary pediatric hospital (Children’s Memorial Hermann Hospital). Participants included high-risk CMC (≥2 hospitalizations or ≥1 pediatric intensive care unit [PICU] admission in the year before enrolling in our clinic) receiving CC. Data were analyzed between January 11, 2018, and December 20, 2019. INTERVENTIONS: The HC included serial discussions between CC clinicians, ED physicians, and hospitalists addressing need for admission, inpatient treatment, and transition back to outpatient care. Usual hospital care (UHC) involved routine pediatric hospitalist care. MAIN OUTCOMES AND MEASURES: Total hospital days (primary outcome), PICU days, hospitalizations, and health system costs in skeptical bayesian analyses (using a prior probability assuming no benefit). RESULTS: From October 3, 2016, through October 2, 2017, 342 CMC were randomized to either HC (n = 167) or UHC (n = 175) before meeting the predefined bayesian stopping guideline (>80% probability of reduced hospital days). In intention-to-treat analyses, the probability that HC reduced total hospital days was 91% (2.72 vs 6.01 per child-year; bayesian rate ratio [RR], 0.61; 95% credible interval [CrI], 0.30-1.26). The probability of a reduction with HC vs UHC was 98% for hospitalizations (0.60 vs 0.93 per child-year; RR, 0.68; 95% CrI, 0.48-0.97), 89% for PICU days (0.77 vs 1.89 per child-year; RR, 0.59; 95% CrI, 0.26-1.38), and 94% for mean total health system costs ($24 928 vs $42 276 per child-year; cost ratio, 0.67; 95% CrI, 0.41-1.10). In secondary analysis using a bayesian prior centered at RR of 0.78, reflecting the opinion of 7 experts knowledgeable about CMC, the probability that HC reduced hospital days was 96%. CONCLUSIONS AND RELEVANCE: Among CMC receiving comprehensive outpatient care, an HC service from outpatient clinicians likely reduced total hospital days, hospitalizations, PICU days, other outcomes, and health system costs. Additional trials of an HC service from outpatient CC clinicians are needed for CMC in other centers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02870387

Made available in DSpace on 2021-06-25T10:13:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-01 Background: Neurodegeneration is a complex cellular process linked to prompt changes in myelin integrity and gradual neuron loss. Current imaging techniques offer estimations of myelin volumes in lesions/remyelinated areas but are limited to detect subtle injury. Purpose: To investigate whether measurements detected by a signal hierarchically isolated as a function of time-to-echo (SHIFT) MRI technique can determine changes in myelin integrity and fiber axolemma. Study Type: Prospective animal model. Animal Model: Surgically demyelinated spinal cord (SC) injury model in rodents (n = 6). Field Strength/Sequence: Gradient-echo spin-echo at 3T. Assessment: Multicompartment T2 relaxations were computed by SHIFT MRI in 75-microns-resolution images of the SC injury penumbra region 2 weeks post-trauma. G-ratio and axolemma delamination were assessed by transmission electron microscopy (TEM) in intact and injured samples. SC myelinated nerve fraction was computed by SHIFT MRI prospectively and assessed histologically. Statistical Tests: Relations between SHIFT-isolated T2-components and TEM measurements were studied using linear regression and t-tests. Pearson's correlation and significance were computed to determine the SHIFT's sensitivity to detect myelinated fibers ratio in gray matter. Regularized least-squares-based ranking analysis was employed to determine SHIFT MRI's ability to discern intact and injured myelinated nerves. Results: Biexponential signals isolated by SHIFT MRI for intact vs. lesion penumbra exhibited changes in T2, shifting from intermediate components (25 ± 2 msec) to long (43 ± 11 msec) in white matter, and similarly in gray matter regions-of-interest (31 ± 2 to 46 ± 16 msec). These changes correlated highly with TEM g-ratio and axon delamination measurements (P < 0.05). Changes in short T2 components were observed but not statistically significant (8.5 ± 0.5 to 7 ± 3 msec, P = 0.445, and 4.0 ± 0.9 to 7 ± 3 msec, P = 0.075, respectively). SHIFT MRI's ability to detect myelinated fibers within gray matter was confirmed (P < 0.001). Data Conclusion: Changes detected by SHIFT MRI are associated with abnormal intermembrane spaces formed upon mild injury, directly correlated with early neuro integrity loss. Level of Evidence 1. Technical Efficacy Stage 2. Center for Neuroregneration Department of Neurosurgery Houston Methodist Research Institute Houston Methodist Hospital Department of Biological Physics Universidade Estadual Paulista UNESP Division of Arts and Sciences NYU Shanghai NYU-ECNU Institute of Cognitive Neuroscience at NYU Shanghai Center for Neural Science and Department of Psychology New York University Department of Biological Physics Universidade Estadual Paulista UNESP

The planar cell polarity (PCP) pathway is essential for tissue morphogenesis. However, the roles of Wnt ligands in the mammalian PCP pathway remain poorly understood. This study identifies a Wnt/heterotrimeric G protein/PI3K pathway that regulates cell-intrinsic and tissue-level PCP in the mouse cochlea., In the mammalian cochlea, the planar cell polarity (PCP) pathway aligns hair cell orientation along the plane of the sensory epithelium. Concurrently, multiple cell intrinsic planar polarity (referred to as iPCP) modules mediate planar polarization of the hair cell apical cytoskeleton, including the kinocilium and the V-shaped hair bundle essential for mechanotransduction. How PCP and iPCP are coordinated during development and the roles of Wnt ligands in this process remain unresolved. Here we show that genetic blockade of Wnt secretion in the cochlear epithelium resulted in a shortened cochlear duct and misoriented and misshapen hair bundles. Mechanistically, Wnts stimulate Gi activity by regulating the localization of Daple, a guanine nucleotide exchange factor (GEF) for Gαi. In turn, the Gβγ complex signals through phosphoinositide 3-kinase (PI3K) to regulate kinocilium positioning and asymmetric localizations of a subset of core PCP proteins, thereby coordinating PCP and iPCP. Thus, our results identify a putative Wnt/heterotrimeric G protein/PI3K pathway for PCP regulation.

UBR7 supports nucleotide biosynthesis and NOTCH1-driven T cell acute lymphoblastic leukemia through regulation of PRPS enzymes., Ubiquitin protein ligase E3 component N-recognin 7 (UBR7) is the most divergent member of UBR box–containing E3 ubiquitin ligases/recognins that mediate the proteasomal degradation of its substrates through the N-end rule. Here, we used a proteomic approach and found phosphoribosyl pyrophosphate synthetases (PRPSs), the essential enzymes for nucleotide biosynthesis, as strong interacting partners of UBR7. UBR7 stabilizes PRPS catalytic subunits by mediating the polyubiquitination-directed degradation of PRPS-associated protein (PRPSAP), the negative regulator of PRPS. Loss of UBR7 leads to nucleotide biosynthesis defects. We define UBR7 as a transcriptional target of NOTCH1 and show that UBR7 is overexpressed in NOTCH1-driven T cell acute lymphoblastic leukemia (T-ALL). Impaired nucleotide biosynthesis caused by UBR7 depletion was concomitant with the attenuated cell proliferation and oncogenic potential of T-ALL. Collectively, these results establish UBR7 as a critical regulator of nucleotide metabolism through the regulation of the PRPS enzyme complex and uncover a metabolic vulnerability in NOTCH1-driven T-ALL.

The mammalian cochlea contains two types of mechanosensory hair cell that have different and critical functions in hearing. Inner hair cells (IHCs), which have an elaborate presynaptic apparatus, signal to cochlear neurons and communicate sound information to the brain. Outer hair cells (OHCs) mechanically amplify sound-induced vibrations, providing enhanced sensitivity to sound and sharp tuning. Cochlear hair cells are solely generated during development, and hair cell death—most often of OHCs—is the most common cause of deafness. OHCs and IHCs, together with supporting cells, originate in embryos from the prosensory region of the otocyst, but how hair cells differentiate into two different types is unknown1–3. Here we show that Insm1, which encodes a zinc finger protein that is transiently expressed in nascent OHCs, consolidates their fate by preventing trans-differentiation into IHCs. In the absence of INSM1, many hair cells that are born as OHCs switch fates to become mature IHCs. To identify the genetic mechanisms by which Insm1 operates, we compared the transcriptomes of immature IHCs and OHCs, and of OHCs with and without INSM1. In OHCs that lack INSM1, a set of genes is upregulated, most of which are normally preferentially expressed by IHCs. The homeotic cell transformation of OHCs without INSM1 into IHCs reveals a mechanism by which these neighbouring mechanosensory cells begin to differ: INSM1 represses a core set of early IHC-enriched genes in embryonic OHCs and makes them unresponsive to an IHC-inducing gradient, so that they proceed to mature as OHCs. Without INSM1, some of the OHCs in which these few IHC-enriched transcripts are upregulated trans-differentiate into IHCs, identifying candidate genes for IHC-specific differentiation. Conditional deletion of Insm1 in mice demonstrates that INSM1 is the key switch that causes the maturation of outer hair cells in the cochlea, with its absence resulting in an increase in inner hair cells instead.

Background This study assessed the associations between nine differentially methylated regions (DMRs) of imprinted genes in DNA derived from umbilical cord blood leukocytes in males and females and (1) birth weight for gestational age z score, (2) weight-for-length (WFL) z score at 1 year, and (3) body mass index (BMI) z score at 3 years. Methods We conducted multiple linear regression in n = 567 infants at birth, n = 288 children at 1 year, and n = 294 children at 3 years from the Newborn Epigenetics Study (NEST). We stratified by sex and adjusted for race/ethnicity, maternal education, maternal pre-pregnancy BMI, prenatal smoking, maternal age, gestational age, and paternal race. We also conducted analysis restricting to infants not born small for gestational age. Results We found an association between higher methylation of the sequences regulating paternally expressed gene 10 (PEG10) and anthropometric z scores at 1 year (β = 0.84; 95% CI = 0.34, 1.33; p = 0.001) and 3 years (β = 1.03; 95% CI = 0.37, 1.69; p value = 0.003) in males only. Higher methylation of the DMR regulating mesoderm-specific transcript (MEST) was associated with lower anthropometric z scores in females at 1 year (β = − 1.03; 95% CI − 1.60, − 0.45; p value = 0.001) and 3 years (β = − 1.11; 95% CI − 1.98, − 0.24; p value = 0.01). These associations persisted when we restricted to infants not born small for gestational age. Conclusion Our data support a sex-specific association between altered methylation and weight status in early life. These methylation marks can contribute to the compendium of epigenetically regulated regions detectable at birth, influencing obesity in childhood. Larger studies are required to confirm these findings. Electronic supplementary material The online version of this article (10.1186/s13148-018-0521-0) contains supplementary material, which is available to authorized users.

Heart disease is the leading cause of death in the United States. African Americans and people of low socioeconomic status suffer disproportionately from heart disease–related morbidity and mortality. In Detroit, Michigan, a primarily African American and low-income urban area, heart disease mortality is at twice the national rate. Despite evidence for the effectiveness of self-management support interventions in reducing chronic disease burden for older adults, few are adapted for communities most in need. This article describes the process of adapting Take PRIDE, an evidence-based heart disease self-management intervention, for older adults in Detroit via the Replicating Effective Programs (REP) framework. Working within a community–academic partnership, we found REP useful in facilitating the identification of diverse stakeholders, core versus adaptable elements of the intervention and barriers to implementation. We also made several modifications to the REP framework in order to better fit our project needs. Overall, we found REP to be an effective, flexible tool that allowed us to successfully adapt a disease-management intervention for this setting. Processes, lessons learned, and recommendations offered in this article may help researchers and practitioners working to expand access to self-management support for populations most affected by chronic disease.

Children with special healthcare needs have been identified nationally as a population whose health care is associated with unmet needs; increased morbidity; fragmentation of care and medical errors; caregiver dissatisfaction; and disproportionately high costs. A subset of these children are medically fragile, with medical complexity that requires a reliance on tertiary care-based services-including subspecialty appointments, surgical procedures, and care coordination resources. For medically complex patients affected by upper and lower respiratory tract and gastrointestinal disorders, multidisciplinary aerodigestive centers have emerged at tertiary care centers across the United States to facilitate coordinated, high-quality, and high value care. We propose that the aerodigestive center is an effective vehicle for a tertiary care-based medical home. Within this model, the integration of a general pediatrician will help promote holistic, patient-centered care, and the general pediatrician can serve to both support and provide continuity with the primary care medical home.

Equity in breastfeeding could reduce excess morbidity and mortality among children and mothers of color. Few programs that support breastfeeding have been evaluated for their capacity to create equity. The aim of this study was to assess the extent to which a diverse set of national breastfeeding programs actively promoted equity.Qualitative data collection was conducted between December 2012 and July 2013 by visits to 29 of 58 breastfeeding programs selected by the funder. Programs underwent a site visit with open-ended interviews of staff. Investigators used Atlas.ti software to code data and content analysis of qualitative evaluation data. Key categories and themes were identified to answer the questions: how do the programs conceptualize equity? and how do the organizations operationalize an approach to equity?Programs had widely divergent and often limited conceptualizations of equity. Nine categories describe the equity approaches' programs used. The social, political, and environmental contexts in which programs operated varied in the degree of challenge they pose for implementing equity-focused breastfeeding methods. We found only a few programs that matched the social, cultural, and economic realities and context of women of color.Breastfeeding equity programs need to explicitly define and envision outcomes, and need to identify equity inhibiting policies and practices. Equity attainment is more likely to emerge from institutional transformational processes that collaborate with the populations at risk. These findings have implications for other programs addressing equity in health.

BackgroundFew published studies report lessons learned for recruiting older adults from racial/ethnic minority, low SES communities for behavioral interventions. In this article, we describe recruitment processes and results for Take Heart, a randomized controlled trial testing the effectiveness of an adapted heart disease self-management program for primarily African American, urban, low SES adults 50 years or older living in Detroit.MethodsOlder adults were recruited via community-based (CB), electronic medical record (EMR), and in-person hospital clinic (HC) methods. Recruitment processes, demographic characteristics of enrolled participants, yield and cost, lessons learned, and best practices for each method are described.ResultsWithin 22 months, 1,478 potential participants were identified, 1,223 were contacted and 453 enrolled, resulting in an overall recruitment yield of 37%. The CB method had the highest yield at 49%, followed by HC at 36% and EMR at 16%. Of six CB approaches, information sessions and flyers had the highest yields at 60% and 59%, respectively. The average cost of recruiting and enrolling one participant was $142.ConclusionsCB, EMR, and HC methods each made important contributions to reaching our recruitment goal. The CB method resulted in the highest recruitment yield, while EMR had the lowest. Face-to-face interaction with community members and hiring a community health worker were particularly useful in engaging this population. Further research is needed to confirm these findings in urban, minority, low SES populations of older adults.

Context:Talocrural joint mobilizations are commonly used to address deficits associated with chronic ankle instability (CAI).Objective:Examine the immediate effects of talocrural joint traction in those with CAI.Design:Blinded, crossover.Setting:Laboratory.Participants:Twenty adults (14 females; age = 23.80 ± 4.02 y; height = 169.55 ± 12.38 cm; weight = 78.34 ± 16.32 kg) with self-reported CAI participated. Inclusion criteria consisted of a history of ≥1 ankle sprain, ≥2 episodes of giving way in the previous 3 mo, answering “yes” to ≥4 questions on the Ankle Instability Instrument, and ≤24 on the Cumberland Ankle Instability Tool.Intervention:Subjects participated in 3 sessions in which they received a single treatment session of sustained traction (ST), oscillatory traction (OT), or a sham condition in a randomized order. Interventions consisted of four 30-s sets of traction with 1 min of rest between sets. During ST and OT, the talus was distracted distally from the ankle mortise to the end-range of accessory motion. ST consisted of continuous distraction and OT involved 1-s oscillations between the mid and end-range of accessory motion. The sham condition consisted of physical contact without force application. Preintervention and postintervention measurements of weight-bearing dorsiflexion, dynamic balance, and static single-limb balance were collected.Main Outcome Measures:The independent variable was treatment (ST, OT, sham). The dependent variables included pre-to-posttreatment change scores for the WBLT (cm), normalized SEBTAR (%), and time-to-boundary (TTB) variables(s). Separate 1-way ANOVAs examined differences between treatments for each dependent variable. Alpha was set a priori at P < .05.Results:No significant treatment effects were identified for any variables.Conclusion:A single intervention of ST or OT did not produce significant changes in weight-bearing dorsiflexion range of motion or postural control in individuals with CAI. Future research should investigate the effects of repeated talocrural traction treatments and the effects of this technique when combined with other manual therapies.

Key Points Question Is a targeted population health management intervention developed for children enrolled in Medicaid and cared for in a large pediatric health system associated with changes in hospital admissions or bed-days? Findings In this quality improvement study using difference-in-differences analysis of Medicaid-enrolled children, children exposed to an integrated population health management program experienced a reduction of 0.39 monthly admissions and 2.20 monthly bed-days per 1000 children compared with similar children in the community who were not exposed to the program. Annualized, these differences could translate to a reduction of 3600 bed-days for a population of 93 000 children eligible for Medicaid. Meaning Mobilizing interdisciplinary care teams for targeted children with high risk and spreading registry-based information technology tools across a Medicaid population may provide a scalable strategy for other health systems that aim to improve the value of services provided to this population., This quality improvement study estimates the association of a targeted population health management intervention for children eligible for Medicaid with changes in monthly hospital admissions and bed-days., Importance As the proportion of children with Medicaid coverage increases, many pediatric health systems are searching for effective strategies to improve management of this high-risk population and reduce the need for inpatient resources. Objective To estimate the association of a targeted population health management intervention for children eligible for Medicaid with changes in monthly hospital admissions and bed-days. Design, Setting, and Participants This quality improvement study, using difference-in-differences analysis, deployed integrated team interventions in an academic pediatric health system with 31 in-network primary care practices among children enrolled in Medicaid who received care at the health system’s hospital and primary care practices. Data were collected from January 2014 to June 2017. Data analysis took place from January 2018 to June 2019. Exposures Targeted deployment of integrated team interventions, each including electronic medical record registry development and reporting alongside a common longitudinal quality improvement framework to distribute workflow among interdisciplinary clinicians and community health workers. Main Outcomes and Measures Trends in monthly inpatient admissions and bed-days (per 1000 beneficiaries) during the preimplementation period (ie, January 1, 2014, to June 30, 2015) compared with the postimplementation period (ie, July 1, 2015, to June 30, 2017). Results Of 25 460 children admitted to the hospital’s health system during the study period, 8418 (33.1%) (3869 [46.0%] girls; 3308 [39.3%] aged ≤1 year; 5694 [67.6%] black) were from in-network practices, and 17 042 (67.9%) (7779 [45.7%] girls; 6031 [35.4%] aged ≤1 year; 7167 [41.2%] black) were from out-of-network practices. Compared with out-of-network patients, in-network patients experienced a decrease of 0.39 (95% CI, 0.10-0.68) monthly admissions per 1000 beneficiaries (P = .009) and 2.20 (95% CI, 0.90-3.49) monthly bed-days per 1000 beneficiaries (P = .001). Accounting for disproportionate growth in the number of children with medical complexity who were in-network to the health system, this group experienced a monthly decrease in admissions of 0.54 (95% CI, 0.13-0.95) per 1000 beneficiaries (P = .01) and in bed-days of 3.25 (95% CI, 1.46-5.04) per 1000 beneficiaries (P = .001) compared with out-of-network patients. Annualized, these differences could translate to a reduction of 3600 bed-days for a population of 93 000 children eligible for Medicaid. Conclusions and Relevance In this quality improvement study, a population health management approach providing targeted integrated care team interventions for children with medical and social complexity being cared for in a primary care network was associated with a reduction in service utilization compared with an out-of-network comparison group. Standardizing the work of care teams with quality improvement methods and integrated information technology tools may provide a scalable strategy for health systems to mitigate risk from a growing population of children who are eligible for Medicaid.

Made available in DSpace on 2019-10-06T15:24:22Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-03-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Several applications of nanoparticles rely on the internalization and accumulation of nanocarriers in specific cell compartments and tissues. However, the methods currently employed for characterizing such processes, although well described, are time consuming and do not provide in vivo information, which is a crucial barrier towards translational applications. Here, we hypothesize that the AC Biosusceptometry technique can be employed to assess cell internalization of magnetic nanoparticles, with possible applications in screening assays to track specific biomarkers and cell types. We tested a simpler and easier alternative to study cell internalization and tissue accumulation after perfusion. We utilized citrate coated, manganese ferrite nanoparticles and evaluated the internalization process in mouse macrophages cells (J774.A1) and in an embryonic neural stem cell culture (E14.5) after differentiation in astrocytes and neurons, to assess internalization specificity. Respecting the particles toxicity limits, we tested different concentration of particles, in different incubation times. Sequentially, we imaged the cell cultures to confirm internalization and nanoparticles localization, labeling nucleus and cell body to assure that the particles were inside the cells. Our results showed a linear behavior on internalization for different doses and an optimum incubation time of 2 h. Departamento de Física e Biofísica Institute of Biosciences Sao Paulo State University (Unesp) Center for Neuroregeneration Houston Methodist Research Institute Departamento de Física Faculdade de Física Ciências e Letras de Ribeirão Preto University of Sao Paulo (USP) Instituto de Física Federal University of Goiás Departamento de Física e Biofísica Institute of Biosciences Sao Paulo State University (Unesp) FAPESP: 2015/14914-0 FAPESP: 2017/00842-2

To investigate the effect of foot posture on postural control and dorsiflexion range of motion in individuals with chronic ankle instability.The study employed a cross-sectional, single-blinded design. Twenty-one individuals with self-reported chronic ankle instability (male=5; age=23.76(4.18)years; height=169.27(11.46)cm; weight=73.65(13.37)kg; number of past ankle sprains=4.71(4.10); episode of giving way=17.00(18.20); Cumberland Ankle Instability Score=18.24(4.52); Ankle Instability Index=5.86(1.39)) participated. The foot posture index was used to categorize subjects into pronated (n=8; Foot Posture Index=7.50(0.93)) and neutral (n=13; Foot Posture Index=3.08(1.93)) groups. The dependent variables of dorsiflexion ROM and dynamic and static postural control were collected for both groups at a single session.There were no significant differences in dorsiflexion range of motion between groups (p=0.22) or any of the eyes open time-to-boundary variables (p0.13). The pronated group had significantly less dynamic postural control than the neutral group as assessed by the anterior direction of the Star Excursion Balance Test (p0.04). However, the pronated group had significantly higher time-to-boundary values than the neutral group for all eyes closed time-to-boundary variables (p≤0.05), which indicates better eyes closed static postural control.Foot posture had a significant effect on dynamic postural control and eyes closed static postural control in individuals with chronic ankle instability. These findings suggest that foot posture may influence postural control in those with chronic ankle instability.

In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cell-nonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3-GEF-Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.

Stroke thrombolysis with alteplase is currently recommended 0-4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036.We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15-2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23-76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81-2·96, p=0·66).Patients with ischaemic stroke 4·5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.None.

Clinical Scenario:Chronic low back pain is one of the most common causes of pain and disability. Currently, there is a need for more effective interventions to treat low back pain.Clinical Question:Does the use of custom foot orthotics improve self-reported measures of pain and function in adults with chronic low back pain?Summary of Key Findings:A comprehensive and systematic search was conducted for studies of level 2 evidence or higher that pertained to the clinical question. The search yielded 11 studies, of which one randomized control trial and two prospective cohorts fit the inclusion and exclusion criteria. The articles examined the effectiveness of custom foot orthotics in isolation compared with no treatment as well as custom foot orthotics in combination with usual care compared with usual care alone. The included studies all demonstrated that the use of custom foot orthotics reduce chronic low back pain after seven weeks of use. One included study was considered high-quality evidence while two were deemed low-quality evidence using the PEDro.Clinical Bottom Line:There is moderate evidence to support the use of custom foot orthotics to improve self-reported measures in adults with chronic low back pain after seven weeks of use.Strength of Recommendation:The Strength of Recommendation Taxonomy recommends a grade of B for consistent limited-quality patient-oriented evidence.

Air and light pollution contribute to fetal abnormalities, increase prevalence of cancer, metabolic and cardiorespiratory diseases, and central nervous system (CNS) disorders. A component of air pollution, particulate matter, and the phenomenon of dim light at night (dLAN) both result in neuroinflammation, which has been implicated in several CNS disorders. The combinatorial role of these pollutants on health outcomes has not been assessed. Male C3H/HeNHsd mice, with intact melatonin production, were used to model humans exposed to circadian disruption by dLAN and contaminated environmental air. We hypothesized exposure to 2.5μm of particulate matter (PM2.5) and dLAN (5 lux) combines to upregulate neuroinflammatory cytokine expression and alter hippocampal morphology compared to mice exposed to filtered air (FA) and housed under dark nights (LD). We also hypothesized that exposure to PM2.5 and dLAN provokes anxiety-like and depressive-like responses. For four weeks, four groups of mice were simultaneously exposed to ambient concentrated PM2.5 or FA and/or dLAN or LD. Following exposure, mice underwent several behavioral assays and hippocampi were collected for qPCR and morphological analyses. Our results are generally comparable to previous PM2.5 and dLAN reports conducted on mice and implicate PM2.5 and dLAN as potential factors contributing to depression and anxiety. Short-term exposure to PM2.5 and dLAN upregulated neuroinflammatory cytokines and altered CA1 hippocampal structural changes, as well as provoked depressive-like responses (anhedonia). However, combined, PM2.5 and dLAN exposure did not have additive effects, as hypothesized, suggesting a ceiling effect of neuroinflammation may exist in response to multiple pollutants.

Introduction Existing health disparities frameworks do not adequately incorporate unique interacting contributing factors leading to health inequities among African Americans, resulting in public health stakeholders’ inability to translate these frameworks into practice. Methods We developed dimensionality and R4P to integrate multiple theoretical perspectives into a framework of action to eliminate health inequities experienced by African Americans. Results The dimensional framework incorporates Critical Race Theory and intersectionality, and includes dimensions of time—past, present and future. Dimensionality captures the complex linear and non-linear array of influences that cause health inequities, but these pathways do not lend themselves to approaches to developing empirically derived programs, policies and interventions to promote health equity. R4P provides a framework for addressing the scope of actions needed. The five components of R4P are (1) Remove, (2) Repair, (3) Remediate, (4) Restructure and (5) Provide. Conclusion R4P is designed to translate complex causality into a public health equity planning, assessment, evaluation and research tool.

TOPIC This case report details the treatment of an early adolescent already receiving treatment for attention-deficit hyperactivity disorder who presents with recurrent obsessive-compulsive disorder. Potential atomoxetine (Strattera) and fluoxetine (Prozac) interactions via Cytochrome P450 (CYP450) pathways are examined and alternate therapies are recommended. PURPOSE Provide a discussion of psychopharmacogenomics, especially in the case of combining medications, CYP450 enzymes, and clinical implications in the context of the burgeoning field of precision medicine. The following questions are addressed: 1) What are the recommendations for pharmacogenetics testing? 2) How should pharmacogenetics inform medication selection? 3) What impact should CYP450 knowledge have on medication dosing? SOURCES Peer-reviewed journals, U.S. Health and Human Services, National Institutes of Health, National Medical Library, and the Clinical Pharmacology database. CONCLUSIONS Genetic testing as a prescriptive tool is not indicated for all medications; however, potential drug-drug interactions, narrow therapeutic drug index, and side effect toxicity contribute to the need for testing. An understanding of CYP450 metabolism and drug interaction as well as metabolism phenotypes should inform prescribing and dosing psychotropic medications.

Diet is dictated by the surrounding environment, as food access and availability may change depending on where one lives. Maternal diet during pregnancy is an important part of the in utero environment, and may affect the epigenome. Studies looking at overall diet pattern in relation to DNA methylation have been lacking. The Mediterranean diet is known for its health benefits, including decreased inflammation, weight loss, and management of chronic diseases. This study assesses the association between maternal adherence to a Mediterranean diet pattern during pregnancy and infant DNA methylation at birth. Mediterranean diet adherence in early pregnancy was measured in 390 women enrolled in the Newborn Epigenetic Study, and DNA methylation was assessed in their infants at birth. Multinomial logistic regression was used to assess the association between adherence to a Mediterranean diet and infant methylation at the MEG3, MEG3-IG, pleiomorphic adenoma gene-like 1, insulin-like growth factor 2 gene, H19, mesoderm-specific transcript, neuronatin, paternally expressed gene 3, sarcoglycan and paternally expressed gene 10 regions, measured by pyrosequencing. Infants of mothers with a low adherence to a Mediterranean diet had a greater odds of hypo-methylation at the MEG3-IG differentially methylated region (DMR). Sex-stratified models showed that this association was present in girls only. This study provides early evidence on the association between overall diet pattern and methylation at the 9 DMRs included in this study, and suggests that maternal diet can have a sex-specific impact on infant DNA methylation at specific imprinted DMRs.

Many older adults with heart disease, especially those from vulnerable populations, live with chronic pain. Self-management strategies for reducing cardiovascular risk (e.g., physical activity, stress reduction) are also recommended for management of chronic pain. It is not known, however, whether self-management education focused on heart health has a beneficial “side effect” on pain-related outcomes. We explored this possibility using data from a randomized controlled trial (n=405) of Take Heart, a group intervention adapted for low-income, African American adults 50 and over with heart disease or significant risk factors. We first assessed the sample prevalence of high-impact chronic pain; i.e., substantial pain-related disability in one or more life domains (National Pain Strategy, 2016). Next, we assessed whether participation in Take Heart resulted in decreased pain interference (PROMIS-29). One-third of participants (n=131) met criteria for high impact chronic pain. Mean pain interference T-score in the entire sample at baseline was 58.1 (SD=9.9), indicating a score one standard deviation greater than population average. Compared to controls, intervention participants had a greater, but non-significant, improvement in pain interference (0.7 vs. -0.8; p=.11). Overall, findings demonstrate that African American adults with cardiovascular conditions have a high burden of comorbid pain. This pain was not greatly improved by an intervention that taught key chronic disease self-management skills but did not address pain specifically. Future research can test whether incorporating pain-management content into heart disease education has a stronger impact on improving pain outcomes -- which may, in turn, promote adherence to behaviors to reduce cardiovascular risk.

Racial/ethnic disparities in the risk of preterm birth may be explained by various factors, and previous studies are limited in examining the role of institutional racism. This study focused on the following questions: what is the association between preterm birth and institutional racism as measured by residential racial segregation (geographic separation by race) and redlining (black-white disparity in mortgage loan denial); and what is the association between preterm birth and reported stress, discrimination, and neighborhood quality.We used data from a clinic-based sample of pregnant women (n = 3462) participating in a stress and pregnancy study conducted from 1999 to 2004 in Philadelphia, PA (USA). We linked data from the 2000 US Census and Home Mortgage Disclosure Act (HMDA) data from 1999 to 2004 and developed measures of residential redlining and segregation.Among the entire population, there was an increased risk for preterm birth among women who were older, unmarried, tobacco users, higher number of previous births, high levels of experiences of everyday discrimination, owned their homes, lived in nonredlined areas, and areas with high levels of segregation measured by the isolation index. Among black women, living in a redlined area (where blacks were more likely to be denied mortgage loans compared to whites) was moderately associated with a decreased risk of preterm birth (aRR = 0.8, 95% CI: 0.6, 0.99).Residential redlining as a form institutional racism and neighborhood characteristic may be important for understanding racial/ethnic disparities in pregnancy and preterm birth.

Quality care for infant mortality disparity elimination requires services that improve health status at both the individual and the population level. We examine disparity reduction due to effective care and ask the following question: Has clinical care ameliorated factors that make some populations more likely to have higher rates of infant mortality compared with other populations? Disparities in postneonatal mortality due to birth defects have emerged for non-Hispanic black and Hispanic infants. Surfactant and antenatal steroid therapy have been accompanied by growing disparities in respiratory distress syndrome mortality for black infants. Progesterone therapy has not reduced early preterm birth, the major contributor to mortality disparities among non-Hispanic black and Puerto Rican infants. The Back to Sleep campaign has minimally reduced SIDS disparities among American Indian/Alaska Native infants, but it has not reduced disparities among non-Hispanic black infants. In general, clinical care is not equitable and contributes to increasing disparities.

Objectives. We used Home Mortgage Disclosure Act (HMDA) data to demonstrate a method for constructing a residential redlining index to measure institutional racism at the community level. We examined the application of the index to understand the social context of health inequities by applying the residential redlining index among a cohort of pregnant women in Philadelphia. Methods. We used HMDA data from 1999–2004 to create residential redlining indices for each census tract in Philadelphia County, Pennsylvania. We linked the redlining indices to data from a pregnancy cohort study and the 2000 Census. We spatially mapped the levels of redlining for each census tract for this pregnancy cohort and tested the association between residential redlining and other community-level measures of segregation and individual health. Results. From 1999–2004, loan applicants in Philadelphia County, Pennsylvania, of black race/ethnicity were almost two times as likely to be denied a mortgage loan compared with applicants who were white (e.g., 1999 odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.63, 2.28; and 2004 OR=2.26, 95% CI 1.98, 2.58). The majority (77.5%) of the pregnancy cohort resided in redlined neighborhoods, and there were significant differences in residence in redlined areas by race/ethnicity ( pConclusions. The evidence of institutional racism may contribute to our understanding of health disparities. Residential redlining and mortgage discrimination against communities may be a major factor influencing neighborhood structure, composition, development, and wealth attainment. This residential redlining index as a measure for institutional racism can be applied in health research to understand the unique social and neighborhood contexts that contribute to health inequities.

Despite the best efforts by the public health community, the existence of disparity in African American infant mortality appears to be insurmountable. Eliminating this disparity is the public health challenge of the next decade. The public health community has engaged in copious activity regarding the identification and analysis of the etiology of health disparities. The resulting literature is substantial, yet, despite well-meaning interventions that have had varying degrees of success, the problem is so daunting that there has been very little progress in developing a comprehensive national plan to eradicate health disparities, in general, and, African American infant-mortality disparities, in particular. The process of identifying the causal pathways and risks of adverse African American birth outcomes could potentially impact the elimination of other health disparities since infant outcomes are the foundation for adult health. Unfortunately, as a nation, we have never deliberately invested the time and resources into developing an evidence base specific to the achievement of health equity. This endeavor will require dedicated resources, creativity, and a breadth of vision to work within, and exceed, the limits of traditional epidemiological and social science theory and methods. The literature cites various causes of overall disparities, including adverse health behaviors like smoking or drug use, poor nutrition, inadequate health care, and stress, to name a few [1]. The World Health Organization (WHO) Commission on Social Determinants of Health considers the major contributors to health disparities to be the conditions in which people are born, grow, live, work, and age [2]. In the United States, ethnic minorities, particularly African Americans, are more likely to be in socially and economically vulnerable positions. A number of studies have demonstrated that even while controlling for SES, racial and ethnic disparities are still found in health outcomes [3]. For example, African American women in Illinois at the highest education level have higher, i.e., worse low-birthweight rates than women of any other ethnicity at lower strata. The process that determines social stratification leading to poorer health outcomes is rooted in history, and while it is not about ‘‘race’’ as a risk factor, scientific investigation has resulted in a corpus of knowledge that places racism, perceived acts of racism, poverty, socialenvironment degradation, and violence into the etiological pathway [4–10]. These manifestations of ‘‘social ecology’’ are the type that WHO describes as resulting in unfair and avoidable differences in health status [2]. Some think that because racism is a causal factor, any quest for solutions may be doomed to failure, because, as one funding institution’s peer reviewer stated, ‘‘It is not a good investment of [our] dollars to study racism [as a cause of health disparities], because even if we fund something, there is nothing we can do about it’’ [11]. However, pre-term birth (PTB) and low birth weight (LBW) are the causes of firstyear mortality for African American infants. Therefore, understanding and eliminating the factors that cause high rates of PTB and LBW should remain at the forefront. V. K. Hogan (&) ! D. Rowley ! T. Bennett Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 425 Rosenau Hall, 421 Pittsboro Street, 135 Dauer Drive, Campus Box 7445, Chapel Hill, NC 27599, USA e-mail: vhogan@email.unc.edu

Segregation studies suggest that the health of blacks in the United States is poorer in majority-black compared with mixed-race neighborhoods. However, segregation studies have not examined black immigrants, who may benefit from social support and country-of-origin foods in black immigrant areas. The authors used 1995–2003 New York City birth records and a spatial measure of ethnic density to conduct a cross-sectional investigation of the risks of preterm birth for African-, Caribbean-, and US-born non-Hispanic black women associated with neighborhood-level African-, Caribbean-, and US-born non-Hispanic black density, respectively. Preterm birth risk differences were computed from logistic model coefficients, comparing neighborhoods in the 90th percentile of ethnic density with those in the 10th percentile. African black preterm birth risks increased with African density, especially in more deprived neighborhoods, where the risk difference was 6.1 per 1,000 (95% confidence interval: 1.9, 10.2). There was little evidence of an ethnic density effect among non-Hispanic black Caribbeans. Among US-born non-Hispanic blacks, an increase in preterm birth risk associated with US-born black density was observed in more deprived neighborhoods only (risk difference = 12.5, 95% confidence interval: 6.6, 18.4). Ethnic density seems to be more strongly associated with preterm birth for US-born non-Hispanic blacks than for non-Hispanic black immigrants.

This study examined what innovative strategies, including the use of health information technology (health IT), have been or can be used to reduce disparities in prenatal care quality in underresourced settings. Based on literature review and key informant interviews, the authors identified 17 strategies that have been or can be used to (a) increase access to timely prenatal care, (b) improve the content of prenatal care, and (c) enhance the organization and delivery of prenatal care. Health IT can be used to (a) increase consumer awareness about the importance of preconception and early prenatal care, facilitate spatial mapping of access gaps, and improve continuity of patient records; (b) support collaborative quality improvement, facilitate performance measurement, enhance health promotion, assist with care coordination, reduce clinical errors, improve delivery of preventive health services, provide decision support, and encourage completeness of documentation; and (c) support data integration and engineer collaborative innovation.

Women with low socioeconomic status are at greater risk of depressive symptomatology and health-compromising behaviors in pregnancy than women from less vulnerable populations (1-4). These characteristics are all associated with poor maternal-child outcomes, including low birthweight, developmental delay, and chronic illness in infancy (5-9). Smoking in pregnancy is associated with placental insufficiency, low birthweight, and preterm birth (5). Fetal exposure to alcohol is related to poor neurodevelopmental outcomes (7). Depressive symptoms, smoking, and alcohol use are all targets of major public health interventions for pregnant women, and the identification of social factors that contribute to their disproportional prevalence among vulnerable populations is critical to the development of effective risk reduction strategies. Perceived discrimination, or unfair treatment based on personal characteristics identifying membership in a group perceived as inferior (e.g., racism, classism, sexism), is associated, in nonpregnant samples, with poor mental and physical health as well as health compromising behaviors among adults in low-income populations (10-13). Framed as a psychosocial stressor linking the social environment with physiologic state, perceived discrimination has been proposed to have negative consequences for mental and physical health (11). Adults who report discrimination are more likely to report greater depressive symptoms and major depression, poor cardiovascular health, and health compromising behaviors including smoking and alcohol use (13-15). Interestingly, the type of discrimination has also been suggested to influence the strength of the association with outcomes; chronic low level “everyday” discrimination has been theorized to have a stronger association with health outcomes than more severe but infrequent discrimination (13). This suggestion has important implications for the design of potential mitigating strategies. Despite the evidence of links between depressive symptoms, health compromising behaviors, and perceived discrimination, little research has been conducted on this topic among pregnant women. In the few studies that have explored consequences of perceived discrimination in pregnancy, this exposure has been associated with higher levels of self-rated stress and adverse birth outcomes, including low birthweight and preterm birth for women with high depressive symptoms compared with women who have lower levels of symptoms (12, 16-20). In the only published study to date that assessed discrimination and depressive symptomatology in pregnancy, a positive and significant association was found (16). However, no analysis of links to health behaviors has been undertaken. In the present study we investigated whether perceived discrimination was associated with depressive symptoms and two health-compromising behaviors -- smoking during pregnancy and recent alcohol use -- in a sample of pregnant low- income inner-city women. We also assessed the relative contribution of chronic, low level “everyday” discrimination versus reported experiences of major discrimination.

Propôs-se discutir o uso da variável raça/cor como fator determinante de desigualdades sociais e de exposição social ao risco de adoecimento e morte. Trata-se de uma reflexão sobre a produção atual da literatura nacional e internacional da área de Saúde Pública/Epidemiologia. Foram incluídos no estudo 47 artigos originais e de revisão no período de 1990 a 2005. Observou-se que os estudos internacionais procuram debater e fundamentar o uso da variável raça/cor no campo da saúde. No Brasil, a utilização dessa variável em estudos de desigualdade em saúde é ainda incipiente, mas, entre as poucas investigações realizadas, têm sido evidenciados diferenciais que instigam maior produção de pesquisas nessa direção. Investigações sobre o papel da raça/cor na produção de diferenciais em saúde poderão produzir informações capazes de contribuir para a elaboração de políticas destinadas a reduzir desigualdades em saúde. This study aimed to discuss the use of the variable of race/color as a determining factor for social inequalities and social exposure to the risk of illness and death. This was a reflection on the present production of national and international literature within the field of Public Health and Epidemiology. Forty-seven original articles and reviews produced between 1990 and 2005 were included in this study. It was observed that international studies have sought to debate and find a basis for using the variable of race/color within the healthcare field. In Brazil, the use of this variable is still at an initial stage, but among the few investigations undertaken, differentials have been shown and further production of research along these lines has been encouraged. Investigations on the role of race/color in producing health differentials may produce information capable of contributing towards drawing up policies aimed at reducing healthcare inequalities. Se propone discutir el uso de la variable raza/color como factor determinante de desigualdades sociales y de exposición social al riesgo de adolecer y de muerte. Se trata de una reflexión sobre la producción actual de la literatura brasileña e internacional del área de Salud Pública/Epidemiología. Se incluyen en el estudio 47 artículos originales y de revisión en el periodo de 1990 a 2005. Se observa que los estudios internacionales tratan de debater y fundamentar el uso de la variable raza/color en el campo de la salud. En Brasil la utilización de esta variable en estudios de desigualdad en salud es todavía incipiente, pero entre las pocas investigaciones realizadas se han evidenciado diferenciales que instigan mayor producción de investigaciones en esta dirección. Investigaciones sobre el papel de la raza/color en la producción de diferenciales en salud podrán producir informaciones capaces de contribuir a la elaboración de políticas destinadas a reducir desigualdades en salud.

A number of infectious diseases should be considered for inclusion as part of clinical preconception care. Those infections strongly recommended for health promotion messages and risk assessment or for the initiation of interventions include Chlamydia infection, syphilis, and HIV. For selected populations, the inclusion of interventions for tuberculosis, gonorrheal infection, and herpes simplex virus are recommended. No clear evidence exists for the specific inclusion in preconception care of hepatitis C, toxoplasmosis, cytomegalovirus, listeriosis, malaria, periodontal disease, and bacterial vaginosis (in those with a previous preterm birth). Some infections that have important consequences during pregnancy, such as bacterial vaginosis (in those with no history of preterm birth), asymptomatic bacteriuria, parvovirus, and group B streptococcus infection, most likely would not be improved through intervention in the preconception time frame.

This study examines African American faith based leaders' attitudes and beliefs about providing HIV prevention education and services to adolescents. Using a convenience sample, we identified priority adolescent health issues, attitudes about abstinence messages, and willingness to provide and participate in HIV prevention. Leaders identified drugs, gangs, alcohol, sex, and pregnancy as priority health issues affecting youth in their institutions. Leaders' strongly preferred to emphasize abstinence messages. Although leaders were willing to provide youth with health education, they were not willing to discuss specific behaviors associated with HIV transmission. African American churches provide a venue to reach African American youth; however, there are limitations to relying on faith-based HIV prevention services. HIV prevention education should continue to be supplemented via parents, schools, and public health agencies.

Objective To assess the pharmacokinetics of hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. Study design Randomized experimental trial. Animals Seven healthy male neutered Beagles aged 12.13 ± 1.2 months and weighing 11.72 ± 1.10 kg. Methods The study was a randomized Latin square block design. Dogs were randomly assigned to receive hydromorphone hydrochloride 0.1 mg kg−1 or 0.5 mg kg−1 IV (n = 4 dogs) or 0.1 mg kg−1 (n = 6) or 0.5 mg kg−1 (n = 5) SC on separate occasions with a minimum 14-day washout between experiments. Blood was sampled via a vascular access port at serial intervals after drug administration. Serum was analyzed by mass spectrometry. Pharmacokinetic parameters were determined with computer software. Results Serum concentrations of hydromorphone decreased quickly after both routes of administration of either dose. The serum half-life, clearance, and volume of distribution after IV hydromorphone at 0.1 mg kg−1 were 0.57 hours (geometric mean), 106.28 mL minute−1 kg−1, and 5.35 L kg−1, and at 0.5 mg kg−1 were 1.00 hour, 60.30 mL minute−1 kg−1, and 5.23 L kg−1, respectively. The serum half-life after SC hydromorphone at 0.1 mg kg−1 and 0.5 mg kg−1 was 0.66 hours and 1.11 hours, respectively. Conclusions and clinical relevance Hydromorphone has a short half-life, suggesting that frequent dosing intervals are needed. Based on pharmacokinetic parameters calculated in this study, 0.1 mg kg−1 IV or SC q 2 hours or a constant rate infusion of hydromorphone at 0.03 mg kg−1 hour−1 are suggested for future studies to assess the analgesic effect of hydromorphone.

Neonatal marmosets express an adrenal fetal zone comparable to humans. While adult males fail to express a functional ZR, with barely detectable blood DHEA levels, females produce higher levels of DHEA than males in adulthood. We investigated the presence of a putative functional ZR in adult female marmosets. In contrast to males, immunohistochemical analysis showed the ZR marker cytochrome b5 was elevated in the innermost zone in cycling females (compared to testis-intact males), further elevated in the adrenals from anovulatory females, and substantially elevated and continuous in ovariectomized females. As a functional test in vivo, following overnight dexamethasone treatment, cycling and anovulatory females showed higher levels of DHEA relative to males, but DHEA failed to increase in response to ACTH. In direct contrast, while ovariectomized females exhibited lower initial DHEA levels, clear increases were detectable after ACTH administration (p < 0.05), suggesting an adrenal origin. The apparent differences in cytochrome b5 expression between groups were also further verified by Western blotting of adrenal microsomes, and compared to 17,20-lyase activity; the two parameters were positively correlated (p < 0.01) across multiple treatment groups. We conclude that the cycling female marmoset expresses a rudimentary ZR with at least a capacity for DHEA production that becomes significantly ACTH-responsive after anovulation. Expression of cytochrome b5 in this region may be directly or indirectly controlled by gonadal function, and is, at least in part, a critical determinant in the development of an adrenal ZR that is more defined and significantly ACTH-responsive. © 2006 Elsevier Ireland Ltd. All rights reserved.

While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.

Cytokines, growth factors, and other chemical messengers rely on a class of intracellular nonreceptor tyrosine kinases known as Janus kinases (JAKs) to rapidly transduce intracellular signals. A number of these cytokines are critical for lymphocyte development and mediating immune responses. JAK3 is of particular interest due to its importance in immune function and its expression, which is largely confined to lymphocytes, thus limiting the potential impact of JAK3 inhibition on nonimmune physiology. The aim of this study was to evaluate the potency and selectivity of the investigational JAK3 inhibitor VX-509 (decernotinib) [(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide] against JAK3 kinase activity and inhibition of JAK3-mediated signaling in vitro and JAK3-dependent physiologic processes in vivo. These results demonstrate that VX-509 potently inhibits JAK3 in enzyme assays (Ki = 2.5 nM + 0.7 nM) and cellular assays dependent on JAK3 activity (IC50 range, 50-170 nM), with limited or no measurable potency against other JAK isotypes or non-JAK kinases. VX-509 also showed activity in two animal models of aberrant immune function. VX-509 treatment resulted in dose-dependent reduction in ankle swelling and paw weight and improved paw histopathology scores in the rat collagen-induced arthritis model. In a mouse model of oxazolone-induced delayed-type hypersensitivity, VX-509 reduced the T cell-mediated inflammatory response in skin. These findings demonstrate that VX-509 is a selective and potent inhibitor of JAK3 in vitro and modulates proinflammatory response in models of immune-mediated diseases, such as collagen-induced arthritis and delayed-type hypersensitivity. The data support evaluation of VX-509 for treatment of patients with autoimmune and inflammatory diseases such as rheumatoid arthritis.

Behaviorally subordinate female marmosets undergo social suppression of ovulation and hypoestrogenism, as well as chronic reductions in circulating basal cortisol concentrations. Because estrogen elevates hypothalamic-pituitary-adrenal axis activity and circulating glucocorticoid levels in other species, we tested the hypothesis that socially induced hypoestrogenism contributes to cortisol reductions in subordinate female marmosets. We characterized morning basal plasma cortisol levels, as well as cortisol responses to exogenous adrenocorticotropic hormone (ACTH; 0, 1, or 10 microg/kg), in seven anovulatory subordinate females and six ovariectomized, non-subordinate females under two conditions: during long-term treatment with estradiol (E2) and control. Circulating E2 and cortisol levels were compared to those of six dominant females undergoing ovulatory cycles. Basal cortisol concentrations in the control condition were significantly lower in subordinates than in both dominant and ovariectomized females. E2 treatment elevated circulating E2 levels of subordinate and ovariectomized females into the range seen in dominant females but did not increase either mean basal or ACTH-stimulated cortisol levels. To the contrary, E2 treatment caused a decline in basal cortisol levels over time, especially in ovariectomized animals. These results indicate that treatment with exogenous estrogen does not elevate circulating cortisol levels in previously hypoestrogenemic female marmosets and, correspondingly that socially induced hypoestrogenism does not diminish cortisol levels in subordinate females.

To examine associations of vaginal Ureaplasma urealyticum (UU) and bacterial vaginosis (BV) with preterm delivery (PTD), small for gestational age (SGA), and low birth weight (LBW).A population-based, prospective cohort study of 2,927 pregnancies. After exclusion of multiples and antibiotic use sample size was 2,662. BV (Amsel's criteria) and UU (culture) were assessed in week 17. Gestational age was determined by last menstrual period, confirmed by ultrasound measurement in 97.5%. SGA infants were calculated from intrauterine fetal growth measurements.There was no increased risk for spontaneous PTD among women with BV only (crude odds ratio 1.0, 95% CI 0.4-2.7), among women with UU only (1.3, 0.8-2.0), nor among women with UU + BV (0.9, 0.4-2.3) compared to women without UU and BV. However, there was a threefold increased risk of a LBW birth in women with UU + BV (3.1, 1.8-5.4), a twofold risk of a LBW birth among women with UU only (1.9, 1.3-2.9), but no increased risk among women with BV only (0.8, 0.3-2.2). Similarly, women with UU + BV had over a twofold increased risk of an SGA birth (2.3, 1.3-4.0), women with UU only had a 70% increase (1.7, 1.1-2.5), whereas a nonsignificant increase was found in women with BV only (1.3, 0.6-2.9). Adjustment by established confounders (smoking, previous PTD, previous LBW, and Escherichia coli) did not affect risk estimates.This analysis suggests that UU is independently associated with fetal growth and LBW and that BV with UU may enhance the risk of these outcomes.

Objective: The purpose of this study was to assess the contribution of chronic social stressors to race/ethnic differences in the rate of bacterial vaginosis among pregnant women in the inner-city area. Study Design: We conducted a cross-sectional clinical prevalence study in a sample of 2304 women at the first prenatal visit (14.8 ± 0.2 weeks of gestation). Bacterial vaginosis was diagnosed by Nugent's method. Stress was measured at the individual and community levels with the use of interviews and administrative records. Logistic regression was used to assess the effects of stress on the odds of bacterial vaginosis occurrence, after adjustment for demographic and behavioral risk. Results: Black women had significantly higher rates of bacterial vaginosis (64%) compared with white women (35%). Exposure to chronic stressors at the individual level differed by race (eg, 32% of the black women reported threats to personal safety compared with 13% of white women). There were significant racial differences in exposure to stress at the community level (eg, 63% of the black women lived in neighborhoods with aggravated assault rates that were above the citywide mean compared with 25% of the white women). After the adjustment for sociodemographic, behavioral risk, and perceived stress, the odds of the occurrence of bacterial vaginosis that was associated with the community level stressor of "homelessness" was significant (odds ratio, 6.7; 95% CI, 1.6-27.8). Inclusion of both individual and community level stressors reduced the black/white bacterial vaginosis odds ratio by 27%. Conclusion: Stressful exposures are associated positively with bacterial vaginosis in pregnancy in a sample of women of low income in the inner city. The measurement of stressors at multiple levels explained a significant proportion of the racial disparity in the rates of occurrence of bacterial vaginosis. (Am J Obstet Gynecol 2002;187:1272-6.)