The Role of Neighborhoods in the Receipt of Transcranial Doppler Screening among Children with Sickle Cell Disease

Summary: Although transcranial Doppler (TCD) screening assesses the need for stroke prevention efforts among children with sickle cell disease (SCD), screening rates remain low across many parts of the United States. We sought to identify neighborhoods with low TCD screening rates and neighborhood-level factors related to screening to inform the utility of community-level interventions to improve TCD screening. Children ages 2 to 16 years with SCD (HbSS/HbS/b-thalassemia) living in Wayne County, MI, were identified in Michigan Medicaid (2007 to 2011) through newborn screening records. Children were enrolled for Z1 year and could contribute multiple years. We determined receipt of Z1 TCD screening and neighborhood (census tract) each year. The proportion of children receiving TCD in the tract was calculated and investigated for spatial patterns across tracts (Moran's I). Median household income, % unemployment, % black residents, and % less than high school education within each tract were ascertained from the American Community Survey. Logistic regression with generalized estimating equations was used to model associations between TCD screening and neighborhood-level factors. Overall, 329 children contributed 532 person-years and screening rates increased from 7% to 36% from 2007 to 2011. Median screening rate in tracts was 0% (interquartile range=29%) and there was no spatial pattern of TCD screening across tracts (Moran's I Z-score= 0.94, P-value=0.35). No associations were found between neighborhood characteristics and receipt of TCD screening in this disadvantaged Michigan county. Additional research is needed to inform interventions to increase TCD screening in this high stroke-risk population

Influence of stair descent strategies and step height on centre of mass and gait kinetics in the elderly

Age-associated alterations in balance mechanisms and deteriorations in muscle strength may necessitate alternate stair descent strategies to ensure safe negotiation. The aim of the study was to compare the influence of increased step height and stair negotiation strategies; step-over-step (SoS) and step-by-step (SbS) on gait patterns in the elderly. Eleven elderly participants descended a four step custom built instrumented staircase at a self-selected speed. Participants descended using a SoS or SbS strategy on two step configurations: a rise height of 170mm (STD) and a rise height of 255mm (INC). A 3D motion analysis system synchronised with force platforms embedded into the staircase, was used to capture whole body centre of mass (CoM) velocity, acceleration and kinetic data of the leading limb.Compared to STDSoS, STDSbS resulted in reduced CoM vertical (-0.48m/s vs -0.09m/s) and A/P velocity (0.50m/s vs 0.21m/s) during late stance and swing transition with similar reductions in vertical and A/P velocity in INCSoS vs INCSbS (-0.67m/s vs -0.11m/s and 0.49m/s vs 0.23m/s). INCSoS resulted in increased plantarflexor (1.10Nm/kg vs 1.45Nm/kg) and hip extensor moment (-0.08Nm/kg vs 0.43Nm/kg) compared to STDSoS with no differences seen in SbS strategy. An alternate stair descent strategy offers greater CoM control in the potentially dangerous transition between stance and swing. Concurrently, the tandem double stance period negates the need for increased muscle moments in late stance required to eccentrically control the falling body mass in the traditional SoS strategy. SbS could offer increased CoM control and stability during stair descent

Interprofessional communication with hospitalist and consultant physicians in general internal medicine : a qualitative study

This study helps to improve our understanding of the collaborative environment in GIM, comparing the communication styles and strategies of hospitalist and consultant physicians, as well as the experiences of providers working with them. The implications of this research are globally important for understanding how to create opportunities for physicians and their colleagues to meaningfully and consistently participate in interprofessional communication which has been shown to improve patient, provider, and organizational outcomes

Alternate stair descent strategies for reducing joint moment demands in older individuals.

Descending stairs requires elevated joint moment-generating capability in the lower limbs, making it a challenging daily activity, particularly for older individuals. The aim of the study was to investigate the influence of three different strategies for descending standard and increased height stairs: step-over-step (SoS), step-by-step (SbS) and side-step (SS) on lower limb kinetics in older people. Eleven participants (mean ± SD age: 74.8 ± 3.1 years, height: 1.63 ± 0.07 m, mass: 67.7 ± 9.5 kg) descended a four-step custom built instrumented staircase at a self-selected speed, adopting each of the three strategies, at two configurations: a step-rise height of 170 mm (standard; STD) and a step-rise height of 255 mm (increased; INC). 3D motion capture, synchronised with embedded force plates enabled the calculation of joint kinetics of lead and trail limbs. Data were analysed using a Linear Mixed Model with gait speed selected as a covariate during weight acceptance (WA) and controlled lowering (CL) phases. A large increase in hip extensor moment in both WA and CL in the lead limb was evident during both SoS and SbS at INC step height compared to STD (P < .015 for all), with no such increase in hip flexor moment evident in SS strategy (P = .519). Lead limb knee extensor moment decreased and plantarflexor moment increased in INC SoS compared to STD SoS during CL (P < .001 for both). In the trail limb, increased hip extensor and plantarflexor moments were seen in INC SS compared to STD SS (P < .001 for both). The alternate strategies result in the overall task demand being split between the lead limb (weight acceptance) and trail limb (controlled lowering). Differential demand distribution patterns exist between strategies that imply targeted interventions and/or advice could be provided to older individuals in order to promote safe descent of stairs, particularly for those with specific muscle weaknesses or at high risk of falls

New drugs on the horizon for cerebral edema: what’s in the clinical development pipeline?

This is the author accepted manuscript. the final version is available from Taylor & Francis via the DOI in this recordIntroduction: Research has advanced our understanding of the molecular and cellular mechanisms of cerebral edema and has propelled the development of novel antiedema therapeutics. Current evidence supports aberrant neuro-glial ion transport as a central mechanism that underlies pathological fluid accumulation after central nervous system injury. Areas covered: Novel agents in clinical development show potential in altering the natural history and treatment of cerebral edema. Using the PubMed and Google Scholar databases, we review recent advances in our understanding of cerebral edema and describe agents under active investigation, their mechanism, and their application in recent and ongoing clinical trials. Expert opinion: Pharmacotherapies that target molecular mechanisms underlying the compensatory post-injury response of ion channels and transporters that lead to pathological alteration of osmotic gradients are the most promising therapeutic strategies. Repurposing of drugs such as glyburide that inhibit the aberrant upregulation of ion channels such as SUR1-TRPM4, and novel agents, such as ZT-1a, which reestablish physiological regulation of ion channels such as NKCC1/KCC, could be useful adjuvants to prevent and even reverse fluid accumulation in the brain parenchyma

Control of the Centre of Mass during different stair descent strategies in the elderly

The elderly are at an increased risk of falls and trips during stair descent due to the increased musculoskeletal demand imposed by this task (Reeves et al. 2008). Reduced functional capacity, muscle recruitment, coordination or strength may limit the ability to adjust the limb to safely control the body in instances of unexpected instability (Buckley et al. 2013). The aim of this study was to determine how the elderly controlled their centre of mass (CoM) during different stair descent strategies. Eleven elderly participants descended a four step custom built instrumented staircase at a self-selected speed. Two step configurations were tested: 1) a standard rise height of 170mm using a step over step strategy (STD SoS) and 2) a rise height of 255mm using step over step, (INC SoS), step by step (INC SbS) and side step (INC SS) strategies. The going stayed constant at 280mm. Centre of pressure (CoP) and whole body model accelerations and A/P displacement were captured at 1080Hz and 120Hz respectively. Data were analysed using a repeated measures GLM. Significance was accepted at p<0.05.Significantly reduced CoP-CoM A/P separation during the landing phase was evident in STD SoS compared to INC SoS and INC SbS (6.1vs10.6 and 10.7cm, p<0.05). INC SS resulted in significantly greater separation during mid-stance compared to STD SoS, INC SbS, INC SS (10.4vs-4.3,-2.2,-2.5cm, p<0.01). During toe off, INC SbS resulted in a larger A/P acceleration compared to STD SoS and INC SoS (0.8vs-0.7 and -1.0m/s/s, p<0.01) with a reduced CoP-CoM separation compared to INC SoS and INC SS (2.5vs10.0 and 6.2cm, p<0.02).The capability of the elderly to control their CoM during stair descent can fluctuate. During the landing phase a greater posterior ‘lean’ towards the staircase occurs with increased step rise, which could reduce the eccentric muscle action necessary to control lowering of the CoM. This lean was maintained by the SS strategy during mid-stance suggesting that this approach provides a mechanism for a safer single limb support. However, this strategy resulted in a simultaneous rapid CoM acceleration (1m/s/s) and large CoP-CoM separation (10cm) prior to toe off, indicating an unstable and potentially dangerous transition into swing. Whilst the INC SbS strategy also resulted in a large peak acceleration, a smaller CoP-CoM separation (1.2cm) occurred at a slower rate (0.07m/s/s) during this transition. This INC SbS strategy could offer increased CoM control, stability and support during stair descent

Inter-rater reliability of data elements from a prototype of the Paul Coverdell National Acute Stroke Registry

<p>Abstract</p> <p>Background</p> <p>The Paul Coverdell National Acute Stroke Registry (PCNASR) is a U.S. based national registry designed to monitor and improve the quality of acute stroke care delivered by hospitals. The registry monitors care through specific performance measures, the accuracy of which depends in part on the reliability of the individual data elements used to construct them. This study describes the inter-rater reliability of data elements collected in Michigan's state-based prototype of the PCNASR.</p> <p>Methods</p> <p>Over a 6-month period, 15 hospitals participating in the Michigan PCNASR prototype submitted data on 2566 acute stroke admissions. Trained hospital staff prospectively identified acute stroke admissions, abstracted chart information, and submitted data to the registry. At each hospital 8 randomly selected cases were re-abstracted by an experienced research nurse. Inter-rater reliability was estimated by the kappa statistic for nominal variables, and intraclass correlation coefficient (ICC) for ordinal and continuous variables. Factors that can negatively impact the kappa statistic (i.e., trait prevalence and rater bias) were also evaluated.</p> <p>Results</p> <p>A total of 104 charts were available for re-abstraction. Excellent reliability (kappa or ICC > 0.75) was observed for many registry variables including age, gender, black race, hemorrhagic stroke, discharge medications, and modified Rankin Score. Agreement was at least moderate (i.e., 0.75 > kappa ≥; 0.40) for ischemic stroke, TIA, white race, non-ambulance arrival, hospital transfer and direct admit. However, several variables had poor reliability (kappa < 0.40) including stroke onset time, stroke team consultation, time of initial brain imaging, and discharge destination. There were marked systematic differences between hospital abstractors and the audit abstractor (i.e., rater bias) for many of the data elements recorded in the emergency department.</p> <p>Conclusion</p> <p>The excellent reliability of many of the data elements supports the use of the PCNASR to monitor and improve care. However, the poor reliability for several variables, particularly time-related events in the emergency department, indicates the need for concerted efforts to improve the quality of data collection. Specific recommendations include improvements to data definitions, abstractor training, and the development of ED-based real-time data collection systems.</p

The protease associated (PA) domain in ScpA from Streptococcus pyogenes plays a role in substrate recruitment

Annually, over 18 million disease cases and half a million deaths worldwide are estimated to be caused by Group A Streptococcus. ScpA (or C5a peptidase) is a well characterised member of the cell enveleope protease family, which possess a S8 subtilisin-like catalytic domain and a shared multi-domain architecture. ScpA cleaves complement factors C5a and C3a, impairing the function of these critical anaphylatoxins and disrupts complement-mediated innate immunity. Although the high resolution structure of ScpA is known, the details of how it recognises its substrate are only just emerging. Previous studies have identified a distant exosite on the 2nd fibronectin domain that plays an important role in recruitment via an interaction with the substrate core. Here, using a combination of solution NMR spectroscopy, mutagenesis with functional assays and computational approaches we identify a second exosite within the protease-associated (PA) domain. We propose a model in which the PA domain assists optimal delivery of the substrate's C terminus to the active site for cleavage

Early Steps of HIV-1 Fusion Define the Sensitivity to Inhibitory Peptides That Block 6-Helix Bundle Formation

The HIV envelope (Env) glycoprotein mediates membrane fusion through sequential interactions with CD4 and coreceptors, followed by the refolding of the transmembrane gp41 subunit into the stable 6-helix bundle (6HB) conformation. Synthetic peptides derived from the gp41 C-terminal heptad repeat domain (C-peptides) potently inhibit fusion by binding to the gp41 pre-bundle intermediates and blocking their conversion into the 6HB. Our recent work revealed that HIV-1 enters cells by fusing with endosomes, but not with the plasma membrane. These studies also showed that, for the large part, gp41 pre-bundles progress toward 6HBs in endosomal compartments and are thus protected from external fusion inhibitors. Here, we examined the consequences of endocytic entry on the gp41 pre-bundle exposure and on the virus' sensitivity to C-peptides. The rates of CD4 and coreceptor binding, as well as the rate of productive receptor-mediated endocytosis, were measured by adding specific inhibitors of these steps at varied times of virus-cell incubation. Following the CD4 binding, CCR5-tropic viruses recruited a requisite number of coreceptors much faster than CXCR4-tropic viruses. The rate of subsequent uptake of ternary Env-CD4-coreceptor complexes did not correlate with the kinetics of coreceptor engagement. These measurements combined with kinetic analyses enabled the determination of the lifetime of pre-bundle intermediates on the cell surface. Overall, these lifetimes correlated with the inhibitory potency of C-peptides. On the other hand, the basal sensitivity to peptides varied considerably among diverse HIV-1 isolates and ranked similarly with their susceptibility to inactivation by soluble CD4. We conclude that both the longevity of gp41 intermediates and the extent of irreversible conformational changes in Env upon CD4 binding determine the antiviral potency of C-peptides

Modelling Conditions and Health Care Processes in Electronic Health Records : An Application to Severe Mental Illness with the Clinical Practice Research Datalink

BACKGROUND: The use of Electronic Health Records databases for medical research has become mainstream. In the UK, increasing use of Primary Care Databases is largely driven by almost complete computerisation and uniform standards within the National Health Service. Electronic Health Records research often begins with the development of a list of clinical codes with which to identify cases with a specific condition. We present a methodology and accompanying Stata and R commands (pcdsearch/Rpcdsearch) to help researchers in this task. We present severe mental illness as an example. METHODS: We used the Clinical Practice Research Datalink, a UK Primary Care Database in which clinical information is largely organised using Read codes, a hierarchical clinical coding system. Pcdsearch is used to identify potentially relevant clinical codes and/or product codes from word-stubs and code-stubs suggested by clinicians. The returned code-lists are reviewed and codes relevant to the condition of interest are selected. The final code-list is then used to identify patients. RESULTS: We identified 270 Read codes linked to SMI and used them to identify cases in the database. We observed that our approach identified cases that would have been missed with a simpler approach using SMI registers defined within the UK Quality and Outcomes Framework. CONCLUSION: We described a framework for researchers of Electronic Health Records databases, for identifying patients with a particular condition or matching certain clinical criteria. The method is invariant to coding system or database and can be used with SNOMED CT, ICD or other medical classification code-lists