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Background: Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2. Methods: We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients Results: Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P P =0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P =0.14. Conclusions: The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism.

Tenecteplase is replacing alteplase as the fibrinolytic agent of choice for the acute management of ischemic stroke in many adult stroke centers due to practical and pharmacokinetic advantages in the setting of similar outcomes. Although thrombolytic use is increasing for acute childhood stroke, there is very limited experience with tenecteplase in children for any indication, and importantly, there are no data on safety, dosing, or efficacy of tenecteplase for childhood stroke. Changes in fibrinolytic capacity over childhood, pediatric pharmacological considerations such as age-specific differences in drug clearance and volume of distribution, and practical aspects of drug delivery such as availability in children’s hospitals may impact decisions about transitioning from alteplase to tenecteplase for acute pediatric stroke treatment. Pediatric and adult neurologists should prepare institution-specific guidelines and organize prospective data collection.

We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to evaluate a Stroke Prevention Team’s readiness to prevent strokes in children with sickle cell anemia living in northern Nigeria. The NIH sponsored Stroke Prevention Trial in Nigeria included a goal of a sustainable stroke prevention program. The program’s 1-year reach for transcranial Doppler screening was 14.7% (4710/32,000) of which 6.0% (281/4710) had abnormal velocities (≥200 cm/s). All participants with abnormal transcranial Doppler velocities were started on hydroxyurea (effectiveness). The leaders of all 5 hospitals agreed to adopt the program. After 1 year, program-implementation and maintenance rates were 100%, demonstrating the program’s feasibility and short-term sustainability.

OBJECTIVE: The primary objective of this study was to test perceived controllability of stressors as a moderator of the association between coping and depressive symptoms in children and adolescents with sickle cell anemia (SCA). METHOD: Twenty-eight children and adolescents (M(age) = 11.71, SD = 4.31; 60.7% female) with SCA were enrolled. Caregivers provided reports of child and adolescent coping using the Response to Stress Questionnaire (RSQ), perceived control of stressors on the RSQ, and depressive symptoms using the Child Behavior Checklist. Children and adolescents also completed Wechsler assessments of working memory and verbal comprehension. RESULTS: Secondary control coping (i.e., cognitive reappraisal, acceptance, distraction) was a significant predictor of depressive symptoms such that greater use of secondary control coping was related to fewer reported depressive symptoms when accounting for use of primary control (problem-solving, emotion expression and regulation) and disengagement coping and neurocognitive variables. Further, perceived control of peer-related stress was a significant moderator of the association between secondary control coping and depressive symptoms, such that there was a significant negative association of secondary control coping with depressive symptoms only for low perceived control. CONCLUSION: Secondary control coping may be particularly helpful for reducing depressive symptoms when adolescents’ peer-related stressors are perceived as uncontrollable. Interventions to reduce internalizing problems in this population should consider teaching children and adolescents secondary control coping skills in addition to skills in identifying uncontrollable sources of stress.

Background and ObjectivesTo describe the current landscape of gender and racial diversity among adult neurology residency and fellowship program directors (PDs). Diversity in medicine affects the quality of care provided to a diverse patient population. There are efforts in nearly every field of medicine to increase the diversity of the physician workforce. While there has been improvement in some of the known disparities in medicine such as gender disparities, these disparities have persisted in more senior academic positions in medicine.MethodsA data set was generated by the Association of American Medical Colleges for the purpose of this study using a variety of sources. The data included deidentified, person-level variables, including self-reported gender, race, or ethnicity, and the type of program for all PDs of Accreditation Council for Graduate Medical Education–accredited residencies and fellowships. This retrospective descriptive survey study sought to (1) describe the current gender and race climate of neurology PDs and (2) identify groups that may be disproportionally underrepresented in these positions compared with those in other specialties and levels of medical training. Descriptive statistics and tests of nonrandom association were performed to address the objectives.ResultsWe found that 56.7% of residency PDs and 58% of fellowship PDs are male. The male to female ratio of PDs was similar to current neurology residents who are 53.4% male. There were significantly more female medical students (51.5%) compared with all other categories of academic rank other than neurology residency PDs (41.1%). Only 4.3% of residency PDs were Black and only 3.7% were Hispanic. There were no Black fellowship PDs, and 5.1% were Hispanic. There were significantly more non-White medical students and trainees compared with each PD group. The breakdown of gender and ethnic diversity of neurology PDs was similar to that of PDs from all residencies and fellowships.DiscussionWhile there are many barriers to achieving diversity in medicine, program leadership in graduate medical education may be one of them. This report describes the current landscape of diversity among PDs of residency and fellowship programs in the United States. This study shows one snapshot in time, which can be used as a baseline during this era of change.

Background and Purpose: To assess whether initial imaging characteristics independently predict 1-year neurological outcomes in childhood arterial ischemic stroke patients. Methods: We used prospectively collected demographic and clinical data, imaging data, and 1-year outcomes from the VIPS study (Vascular Effects of Infection in Pediatric Stroke). In 288 patients with first-time stroke, we measured infarct volume and location on the acute magnetic resonance imaging studies and hemorrhagic transformation on brain imaging studies during the acute presentation. Neurological outcome was assessed with the Pediatric Stroke Outcome Measure. We used univariate and multivariable ordinal logistic regression models to test the association between imaging characteristics and outcome. Results: Univariate analysis demonstrated that infarcts involving uncinate fasciculus, angular gyrus, insular cortex, or that extended from cortex to the subcortical nuclei were significantly associated with poorer outcomes with odds ratios ranging from 1.95 to 3.95. All locations except the insular cortex remained significant predictors of poor outcome on multivariable analysis. When infarct volume was added to the model, the locations did not remain significant. Larger infarct volumes and younger age at stroke onset were significantly associated with poorer outcome, but the strength of the relationships was weak. Hemorrhagic transformation did not predict outcome. Conclusions: In the largest pediatric arterial ischemic stroke cohort collected to date, we showed that larger infarct volume and younger age at stroke were associated with poorer outcomes. We made the novel observation that the strength of these associations was modest and limits the ability to use these characteristics to predict outcome in children. Infarcts affecting specific locations were significantly associated with poorer outcomes in univariate and multivariable analyses but lost significance when adjusted for infarct volume. Our findings suggest that infarcts that disrupt critical networks have a disproportionate impact upon outcome after childhood arterial ischemic stroke.

BACKGROUND Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown. METHODS We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes. RESULTS After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates. CONCLUSIONS Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers.

Background and Purpose— The National Institutes of Health (NIH) StrokeNet provides a nationwide infrastructure to advance stroke research. Capitalizing on this unique opportunity, the NIH StrokeNet Training Core (NSTC) was established with the overarching goal of enhancing the professional development of a diverse spectrum of professionals who are embedded in the stroke clinical trials network of the NIH StrokeNet. Methods— This special report provides a descriptive account of the rationale, organization, and activities of the NSTC since its inception in 2013. Current processes and their evolution over time for facilitating training of NIH StrokeNet trainees have been highlighted. Data collected for monitoring training are summarized. Outcomes data (publications and grants) collected by NSTC was supplemented by publicly available resources. Results— The NSTC comprises of cross-network faculty, trainees, and education coordinators. It helps in the development and monitoring of training programs and organizes educational and career development activities. Trainees are provided directed guidance towards their mandated research projects, including opportunities to present at the International Stroke Conference. The committee has focused on developing sustainable models of peer-to-peer interaction and cross-institutional mentorships. A total of 124 professionals (43.7% female, 10.5% underrepresented minorities) have completed training between 2013 and 2018, of whom 55% were clinical vascular neurologists. Of the total, 85% transitioned to a formal academic position and 95% were involved in stroke research post-training. Altogether, 1659 indexed publications have been authored or co-authored by NIH StrokeNet Trainees, of which 58% were published during or after their training years. Based on data from 109 trainees, 33% had submitted 72 grant proposals as principal or co-principal investigators of which 22.2% proposals have been funded. Conclusions— NSTC has provided a foundation to foster nationwide training in stroke research. Our data demonstrate strong contribution of trainees towards academic scholarship. Continued innovation in educational methodologies is required to adapt to unique training opportunities such as the NIH StrokeNet.

Background and objectives Delayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial. Design, setting, participants, & measurements This is a post hoc analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (n=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model. Results Three deaths occurred among C1 esterase inhibitor–treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor–treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor–treated recipients compared with placebo (P=0.03). Although no difference in eGFR slopes was observed between groups (P for group-time interaction =0.12), eGFR declined in placebo-treated recipients (−4 ml/min per 1.73 m2 per year; 95% confidence interval, −8 to −0.1) but was stable in C1 esterase inhibitor–treated patients (eGFR slope: 0.5 ml/min per 1.73 m2 per year; 95% confidence interval, −4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m2 (95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m2 (95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m2 (95% confidence interval, 2 to 41 ml/min per 1.73 m2). Conclusions Treatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.

A healthy brain is critical for living a longer and fuller life. The projected aging of the population, however, raises new challenges in maintaining quality of life. As we age, there is increasing compromise of neuronal activity that affects functions such as cognition, also making the brain vulnerable to disease. Once pathology-induced decline begins, few therapeutic options are available. Prevention is therefore paramount, and primary care can play a critical role. The purpose of this American Heart Association scientific statement is to provide an up-to-date summary for primary care providers in the assessment and modification of risk factors at the individual level that maintain brain health and prevent cognitive impairment. Building on the 2017 American Heart Association/American Stroke Association presidential advisory on defining brain health that included “Life’s Simple 7,” we describe here modifiable risk factors for cognitive decline, including depression, hypertension, physical inactivity, diabetes, obesity, hyperlipidemia, poor diet, smoking, social isolation, excessive alcohol use, sleep disorders, and hearing loss. These risk factors include behaviors, conditions, and lifestyles that can emerge before adulthood and can be routinely identified and managed by primary care clinicians.

BACKGROUND Subcutaneous fixation of the anterior pelvic ring is an emerging surgical technique for trauma patients. The aim of this study was to biomechanically evaluate 2 internal fixation devices for stabilizing a disrupted pelvic ring and compare them with traditional external fixation. METHODS Thirty-six synthetic pelvises with a simulated unstable ring fracture (anteroposterior compression type III) were divided into 3 groups. Group A underwent fixation with a supra-acetabular external fixator; group B, with an internal fixator using the USS II polyaxial system; and group C, with an internal fixator using the Click'X polyaxial system. Biomechanical testing included measurement of peak-to-peak displacement at 300, 400, and 500 N; total displacement; plastic deformation; stiffness; and fracture-line displacement. RESULTS Statistical analysis of all measured parameters revealed no significant differences among the groups. However, vertical displacement of the preshaped connecting rod within the screw heads occurred as a result of inadequate stability of the internal fixation at the rod-screw interface. CONCLUSIONS Although internal fixator devices are placed close to the bone and should therefore maintain greater stiffness, our data did not support the hypothesis of superior stability. Special attention is required when using a curved connecting rod as the rod is easily displaced, placing relevant anatomical structures at risk. These devices require further refinement to avoid potential patient injury.

Complement plays important roles in both ischemia-reperfusion injury (IRI) and antibody-mediated rejection (AMR) of solid organ allografts. One approach to possibly improve outcomes after transplantation is the use of C1 inhibitor (C1-INH), which blocks the first step in both the classical and lectin pathways of complement activation and also inhibits the contact, coagulation, and kinin systems. C1-INH can also directly block leukocyte-endothelial cell adhesion. C1-INH contrasts with eculizumab and other distal inhibitors, which do not affect C4b or C3b deposition or noncomplement pathways. Authors of reports on trials in kidney transplant recipients have suggested that C1-INH treatment may reduce IRI and delayed graft function, based on decreased requirements for dialysis in the first month after transplantation. This effect was particularly marked with grafts with Kidney Disease Profile Index ≥ 85. Other clinical studies and models suggest that C1-INH may decrease sensitization and donor-specific antibody production and might improve outcomes in AMR, including in patients who are refractory to other modalities. However, the studies have been small and often only single-center. This article reviews clinical data and ongoing trials with C1-INH in transplant recipients, compares the results with those of other complement inhibitors, and summarizes potentially productive directions for future research.

Background In the 8th edition of the American Joint Committee on Cancer melanoma staging system, the T1b category has been redefined based solely on thickness and ulceration. National Comprehensive Cancer Network guidelines recommend consideration of sentinel lymph node biopsy (SLNB) for all patients with T1b melanomas (0.8 to 1.0 mm thick). We hypothesized that the new staging system would lead to excessive use of SLNB in patients with non-ulcerated T1b melanomas with a low risk of positive sentinel lymph nodes. Study Design The National Cancer Database 2015 Melanoma Public Use File was used to select patients undergoing SLNB for thin T1 cutaneous melanoma from 2010 to 2015. Clinicopathologic risk factors for having a positive SLNB were evaluated. Univariable and multivariable logistic regression models and classification and regression tree analysis were performed to identify groups with high and low risk of positive SLNB. Results We selected patients undergoing SLNB without ulceration with thickness 0.75 to 1.04 mm, staged T1b in the new 8th edition American Joint Committee on Cancer by thickness criteria alone (6,894 patients). Independent risk factors for a positive sentinel lymph node were age 56 years or younger (odds ratio [OR] 1.74; 95% CI 1.38 to 2.17), thickness 1.0 vs 0.8 to 0.9 mm (OR 1.36; 95% CI 1.09 to 1.70), female sex (OR 1.36; 95% CI 1.09 to 1.69), and mitotic rate ≥1/mm2 (OR 2.01; 95% CI 1.54 to 2.64). Classification and regression tree analysis identified 2 groups based on age, mitotic rate, and thickness with a risk of positive SLNB Conclusions The new 8th edition American Joint Committee on Cancer melanoma staging system T1b category should not be used to determine use of SLNB in thin melanoma, as more than one half of T1b lesions without ulceration have a low risk of positive sentinel lymph nodes.

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Background: Despite a lack of empirical data, an unprecedented rise in electronic cigarettes (ECs) has been widely perceived as safe. Multiple studies support a causal link between tobacco cigarette (TC) use and a decline in cardiovascular (CV) health; however, there is a paucity of data with EC use. A study showed EC use decreased HRV in humans via increased sympathetic activation- a known mechanism predictive of CV disease from TC use. We aimed to develop a mouse model to determine if acute EC exposure modifies HRV in mice. Methods: Telemetry devices were implanted in the abdomen of 6 eight-week-old C57BL/6 mice to monitor ECG activity continuously. Mice underwent a 1-hr acclimation phase in exposure chambers followed by a 1-hour exposure to air (control). EC exposures consisted of two 15-min sessions (4-sec puff/26-sec air) to BluPlus® 2.4% nicotine (Classic Tobacco) with a 15-min period of aerosolized PBS added as a secondary control. For each exposure episode, a 45-min post-exposure event followed. Ponemah v6.20 software was used for HRV analysis of the time domain. A linear mixed-effects model with a robust estimator was used to determine the relationship between air vs. combined EC events and PBS (n = 1,109). R (Version R3.6.3) was utilized to test for statistical significance at α = 0.05. Results: EC exposures significantly decreased the standard deviation of NN intervals (SDNN) and root mean square of successive differences (RMSSD) by 5.00 and 9.34 units as compared to air exposures, suggesting reductions in total and short-term autonomic variability (Table 1). Both parameters increased in the post-EC periods as compared with the EC exposures. Conversely, PBS vs. air exposure showed a marked increase in SDNN and RMSSD. Conclusion: Short-term exposures to ECs decreased HRV in mice, consistent with similar results in human studies, suggesting that ECs could increase cardiovascular risk in an acute manner.

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. There is an unmet need for antihypertensive drugs with novel mechanisms of action to better control hypertension and reduce cardiovascular morbidity and mortality. Here, we provide evidence that pharmacological inhibition of TMEM16A (transmembrane member 16A or anoctamin-1), a Ca 2+ -activated Cl - channel expressed in vascular smooth muscle cells, reduces in vitro vascular smooth muscle contraction and decreases blood pressure in spontaneously hypertensive rats (SHR). We recently identified by high-throughput screening and subsequent medicinal chemistry, small molecule TMEM16A inhibitor TM inh -23 (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide) that inhibits TMEM16A current fully, with IC 50 ~ 30 nM. TM inh -23 pretreatment blocked maximum in vitro vascular smooth muscle contractions induced by a thromboxane mimetic (U46619) in rat mesenteric arteries by 90%. Intraperitoneal (ip) administration of TM inh -23 to rodents at 10 mg/kg produced sustained serum concentrations of >10 μM for >4 hours. BP measurements by tail-cuff and telemetry showed a maximum ~45 mmHg reduction in SBP in spontaneously hypertensive rats (SHR) after a single dose (10 mg/kg, ip) TM inh -23 administration compared to vehicle treatment, with BP gradually returning to baseline values within 6-8 hours after TM inh -23 treatment. Minimal effect on BP (less than 10 mmHg decrease in SBP) was seen in wild-type rats and mice with TM inh -23 treatment (10 mg/kg, ip). Chronic 5-day treatment of SHR with TM inh -23 (10 mg/kg, ip, twice daily) caused sustained decreases (~20-25 mmHg) in daily average SBP, DBP and MAP during the treatment period. TM inh -23 action was reversible, with BP returning to baseline (~170/115 mmHg) by 3 days after discontinuation of treatment. These studies provide validation for TMEM16A as a target for antihypertensive therapy, and demonstrate the proof-of-concept for efficacy of TM inh -23 as an antihypertensive with a novel mechanism of action.

ObjectiveBecause of the high prevalence of silent cerebral infarcts (SCIs) in adults with sickle cell anemia (SCA) and lack of information to guide treatment strategies, we evaluated the risk of recurrent SCIs and overt stroke in adults with SCA with preexisting SCI.MethodsThis observational study included adults with SCA (HbSS or Sβ0 thalassemia) aged 18 to 40 years. Participants received 3-tesla brain MRI and a detailed neurologic examination. Time-to-event analysis assessed those with or without baseline SCI and with new or progressive infarcts. The incidence rate of new events was compared by log-rank test. Univariable Cox regression assessed the association of SCI with infarct progression.ResultsAmong adults with SCA with 2 MRIs and at least 6 months between MRIs (n = 54, mean interval = 2.5 years), 43% had SCI at baseline. Of participants with baseline SCI, 30% had new or progressive SCI over 2.5 years compared to 6% with no SCI at baseline; no participant had an overt stroke. New SCIs at follow-up were present in 12.9 per 100 patient-years with existing SCI compared with 2.4 per 100 patient-years without prior SCI (log-rank test, p = 0.021). No statistically significant differences were seen among those with or without baseline SCI in use of hydroxyurea therapy, hydroxyurea dose, or other stroke risk factors. The presence of SCI was associated with increased hazard of a new or progressive infarct (hazard ratio 5.27, 95% confidence interval 1.09–25.51, p = 0.039).ConclusionsSilent infarcts in adults with SCA are common and are a significant risk factor for future silent infarcts.

Background and Purpose— Intracerebral hemorrhage is a considerable source of morbidity and mortality. This 3-center study describes outcomes of pediatric intracerebral hemorrhage and identifies 2-year neurological outcome predictors. Methods— Children 29 days to 18 years of age presenting with intracerebral hemorrhage from March 2007 to May 2015 were enrolled prospectively. Exclusion criteria included trauma; intracranial tumor; hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis; isolated subdural, epidural, or subarachnoid hemorrhage; and abnormal baseline neurological function. Intracerebral hemorrhage and total brain volumes were measured on neuroimaging. The Pediatric Stroke Outcome Measure assessed outcomes. Results— Sixty-nine children were included (median age: 9.7 years; interquartile range: 2.2–14). Six children (9%) died during hospitalization. Outcomes in survivors were assessed at early follow-up in 98% (median 3.1 months; interquartile range: 3.1–3.8) and at later follow-up in 94% (median: 2.1 years; interquartile range: 1.3–2.8). Over a third had a significant disability at 2 years (Pediatric Stroke Outcome Measure >2). Total Pediatric Stroke Outcome Measure score improved over time ( P =0.0003), paralleling improvements in the sensorimotor subscore ( P =0.0004). Altered mental status (odds ratio, 13; 95% confidence interval, 3.9–46; P P =0.01), and intensive care unit length of stay (odds ratio, 1.1; 95% confidence interval, 1.0–1.2; P =0.002) were significantly associated with poor 2-year outcome. Conclusions— Over one third of children experienced significant disability at 2 years. Improvements in outcomes were driven by recovery of sensorimotor function. Altered mental status, hemorrhage volume ≥4% of total brain volume, and intensive care unit length of stay were independent predictors of significant disability at 2 years.

Purpose To compare fixed- or variable-angle locking screws in calcaneal fracture plates using a sawbones biomechanical model. Methods Intra-articular calcaneal fractures were created in synthetic bones. Reduction and stabilization was performed with 3 different plates. In group A, a fixed-angle locking plate was used with screws fastened perpendicularly to the plate (3.5 LCP, DePuySynthes). In groups B and C (2.7 VA-LCP, DePuySynthes and 3.5 Aptus, Medartis, respectively), fracture fixation was performed using variable-angle locking plates. Biomechanical testing was conducted. Displacement of the subtalar articular surface, stiffness, maximum displacement, change in the angle of Gissane, and mode of failure under cyclic loading at 200 N, 600 N, and 1000 N (500 cycles each) were determined. Results No statistically significant difference of articular surface dislocation under cyclic loading was detected. The stiffness and maximum displacement did not reveal any disparity as well. The change in the angle of Gissane showed only minor displacement of the articular surface. Conclusion In our study, the resistance of variable-angle locking plates against articular surface displacement was similar to fixed-angle locking screws.

Currently trials of immunosuppression in transplantation are in decline because their objectives remain focused on improving acute rejection rates and graft survival in the first 12 months. With 1 year renal graft survival rates of greater than 90% the best that can be hoped for is noninferiority trial outcomes compared with current standard of care. Current trial design is not leading to novel therapies improving long-term outcomes and safety, and hence important unmet clinical needs in transplantation remain unanswered. Issues that need to be addressed include but are not limited to: prevention of subclinical rejection in the first year, better 5- and 10-year graft outcomes, more effective treatment for high immunological risk and sensitized (including donor-specific antibody) patients, immunosuppressive combinations that are better tolerated by patients with fewer side effects and less morbidity and mortality. In September 2015, the Transplantation Society convened a group of transplant clinical trial experts to address these problems. The aims were to substantially realign the priorities of clinical trials for renal transplant immunosuppression with the current unmet needs and to propose new designs for clinical trials for transplant immunosuppression. Moving forward, the transplant community needs to provide trial data that will identify superior treatment options for patient subgroups and allow new agents to be evaluated for efficacy and safety and achieve timely regulatory approval. Trial designs for new transplant immunosuppression must be intelligently restructured to ensure that short- and long-term clinical outcomes continue to improve.

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P 1% indicate a probability of active rejection.

BACKGROUND Pediatric blunt cerebrovascular injury (BCVI) lacks accepted treatment algorithms, and postinjury outcomes are ill defined. OBJECTIVE To compare treatment practices among pediatric trauma centers and to describe outcomes for available treatment modalities. METHODS Clinical and radiographic data were collected from a patient cohort with BCVI between 2003 and 2013 at 4 academic pediatric trauma centers. RESULTS Among 645 pediatric patients evaluated with computed tomography angiography for BCVI, 57 vascular injuries (82% carotid artery, 18% vertebral artery) were diagnosed in 52 patients. Grade I (58%) and II (23%) injuries accounted for most lesions. Severe intracranial or intra-abdominal hemorrhage precluded antithrombotic therapy in 10 patients. Among the remaining patients, primary therapy was an antiplatelet agent in 14 (33%), anticoagulation in 8 (19%), endovascular intervention in 3 (7%), open surgery in 1 (2%), and no treatment in 16 (38%). Among 27 eligible grade I injuries, 16 (59%) were not treated, and the choice to not treat varied significantly among centers (P < .001). There were no complications from medical management. Glasgow Coma Scale (GCS) score

Posterior circulation strokes often strike fear in the hearts of neurologists. We think of them as high risk for poor outcome and death because the posterior circulation supplies blood flow to the brainstem and there is high risk for stroke recurrence. The literature on posterior circulation stroke in children is limited and highly variable because most studies have been single-center with small numbers of patients.1–3

In a recent Perspectives article in the Clinical Journal of the American Society of Nephrology , Formica and Kulkarni ([1][1]) contextualize the use of the IgG-degrading enzyme of Streptococcus pyogenes (IgG endopeptidase) for desensitization to the era of the new kidney allocation system (KAS).

INTRODUCTION AND OBJECTIVES:The role of androgen receptor (AR) signaling in bladder cancer (BCa) is not fully characterized. This study aimed to delineate the role of AR signaling in BCa and to det...

Each chapter listed in the Table of Contents (see next page) is a hyperlink to that chapter. The reader clicks the chapter name to access that chapter. Each chapter listed here is a hyperlink. Click on the chapter name to be taken to that chapter. Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA’s My Life Check - Life’s Simple 7 (Figure1), which include core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure [BP], and glucose control) that contribute to cardiovascular health. The Statistical Update represents …

Introduction: At our institution, the pediatric stroke alert activations started in April 2011 to allow for rapid evaluation and imaging of children presenting within 48 hours with acute stroke symptoms. In a previously published paper, stroke alerts initiated in the pediatric emergency department confirmed strokes in 25% of children. The purpose of this study was to characterize pediatric stroke alerts in hospitalized children. Methods: Demographic and clinical information was obtained from a quality improvement database and medical records for patients (28 days -20 years) at a single institution. Stroke alerts were activated after hospital admission from April 2011 through December 2016. A stroke alert activation means that a neurology resident sees the patient within 15 minutes and MRI is acutely made available. All values were assessed with descriptive statistics. Results: There were 56 in-hospital stroke alerts (mean age 7.5 y, SD 6.1y, 52% male) over 5.75 years. Stroke was the final diagnosis for 25 (45%) children, 72% ischemic, 28% hemorrhage (Figure 1). Other diagnoses included other neurological urgencies including seizure (21%), posterior reversible encephalopathy syndrome (9%), transient ischemic attack (5%) and acute demyelinating encephalomyelitis (4%). Of 25 actual strokes, 68% were stroke alerts initiated by the pediatric ICU or pediatric cardiac ICU. Rapid imaging was completed in 91% of stroke alerts; MRI brain was the 1 st image in 55%. Nine of 25 children with stroke died (36%); 4 secondary to the stroke and the remainder were critically ill prior to stroke diagnosis. Conclusions: Pediatric in-hospital stroke alerts were confirmed stroke in 45% of children, while 38% were other neurological conditions requiring urgent neurologic evaluation. The high frequency of stroke and other serious illnesses in already hospitalized children demonstrates the importance of rapid evaluation via a pediatric stroke alert protocol when stroke is suspected.

We aimed to characterize the timing of recovery and predictors of outcome following pediatric stroke, with the hypothesis that the recovery pattern after stroke is influenced by age. While the immature brain is often presumed to have an increased capacity for neuroplasticity, there is little direct data examining how recovery differs in children of different ages. We reviewed data for children with arterial ischemic stroke (AIS) who were enrolled in the International Pediatric Stroke Study, a prospective registry of children with stroke. Inclusion criteria included a diagnosis of AIS and the availability of outcome at two years after the index stroke event. A subset of these patients who had multiple assessments over time were used to study longitudinal patterns of recovery. We investigated demographic, clinical, and radiologic associations with both early outcome at discharge and long term outcome at two years using multinomial logistic regression. Categorical outcomes at each timepoint were defined by Pediatric Stroke Outcome Measure (PSOM). We studied longitudinal recovery using time-to-event (survival) analysis. 614 out of 4,294 patients met our inclusion criteria. 202 patients had perinatal AIS while 412 had childhood AIS. Perinatal AIS was associated with significant worsening between discharge and two years, as neurologic impairment became more apparent, but with better outcomes at both timepoints compared with childhood AIS (moderate/severe: 14% vs 49% at discharge, 47% vs 54% at 2 years). Predictors of severe deficits in univariate analyses included age at stroke (perinatal vs. childhood), hemiparesis or decreased consciousness at presentation, anterior circulation, and large vessel involvement. In longitudinal analysis, improvement in PSOM occurred for a longer time after stroke onset in younger children compared to older children. Although age has a strong influence on recovery after pediatric stroke, all children had the capacity to demonstrate recovery over extended periods of time. Understanding the timing and predictors of recovery will allow us to better target therapies to the appropriate windows of opportunity, thereby improving outcomes after pediatric stroke.

Background and Purpose— Although arteriopathies are the most common cause of childhood arterial ischemic stroke, and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with arterial ischemic stroke. Methods— Vascular effects of infection in pediatric stroke, an international prospective study, enrolled 355 cases of arterial ischemic stroke (age, 29 days to 18 years) at 39 centers. A neuroradiologist and stroke neurologist independently reviewed vascular imaging of the brain (mandatory for inclusion) and neck to establish a diagnosis of arteriopathy (definite, possible, or absent) in 3 steps: (1) baseline imaging alone; (2) plus clinical data; (3) plus follow-up imaging. A 4-person committee, including a second neuroradiologist and stroke neurologist, adjudicated disagreements. Using the final diagnosis as the gold standard, we calculated the sensitivity and specificity of each step. Results— Cases were aged median 7.6 years (interquartile range, 2.8–14 years); 56% boys. The majority (52%) was previously healthy; 41% had follow-up vascular imaging. Only 56 (16%) required adjudication. The gold standard diagnosis was definite arteriopathy in 127 (36%), possible in 34 (9.6%), and absent in 194 (55%). Sensitivity was 79% at step 1, 90% at step 2, and 94% at step 3; specificity was high throughout (99%, 100%, and 100%), as was agreement between reviewers (κ=0.77, 0.81, and 0.78). Conclusions— Clinical data and follow-up imaging help, yet uncertainty in the diagnosis of childhood arteriopathy remains. This presents a challenge to better understanding the mechanisms underlying these arteriopathies and designing strategies for prevention of childhood arterial ischemic stroke.

Donor-specific anti–histocompatibility leukocyte antigen antibodies (DSAs) have a strong and frequently considered universally deleterious effect on allografts. Preformed or de novo DSAs activate complement, induce endothelial cell proliferation, and mediate antibody-dependent cellular

Introduction: Lower socioeconomic status (SES) is associated with poorer outcome after adult stroke. In a large cohort of children with arterial ischemic stroke (AIS), we determined 12-month neurological outcome and tested the hypothesis that SES is a determinant of outcome in children. Methods: From 2009-2014, the Vascular Effects of Infection in Pediatric Stroke (VIPS) study enrolled 355 children with AIS (29 days-18 years) at 37 international centers, including 3 in lower and middle income (LAMI) countries. Outcome was assessed at 12 months via the recurrence and recovery questionnaire (RRQ) parental report of the pediatric stroke outcome measure (PSOM). Poor outcome was defined as a PSOM of ≥1. Results: Of 355 children, outcome was available for 310 (87%) at a median of 12 months (IQR 11-13). Ten children died prior to hospital discharge and 4 by 12 months. Outcomes improved from discharge to 12 months (Figure). Of 23 cases in LAMI countries, 88% had an income $100,000). Other markers of SES (maternal education level and rural/suburban/urban residence) also did not predict outcome. Independent predictors of poor outcome included moderate (OR 4.6, 95% CI 2.0, 11) or severe (OR 21, 95% CI 7.1, 60) neurological deficits at discharge (compared to no deficits) and recurrent stroke (OR 3.5, 95% CI 1.5, 8.3). Conclusion: Outcomes after childhood stroke may be worse in LAMI countries, although we were underpowered to study this subgroup. Within non-LAMI countries, SES does not appear to impact outcome in children, unlike reports in adults, perhaps reflecting better access to rehabilitation services in the pediatric population.

Introduction: High blood velocity can cause rapid erythrocyte transit through capillaries, reducing efficiency of oxygen delivery to tissue (capillary arteriovenous shunting). Arterial spin labeling (ASL) is an MRI technique that utilizes magnetic labeling of arterial blood water for CBF quantitation. Labeled water that traverses capillaries without exchanging with tissue leads to hyperintense venous signal indicative of arteriovenous shunting. We hypothesized that venous hyperintensity is present in sickle cell anemia (SCA) adults, correlates with flow velocity, and corresponds with clinical impairment and oxygen extraction fraction (OEF). Methods: ASL for shunting determination, TRUST for OEF measurement, phase contrast angiography for velocity assessment, and FLAIR / MRA for infarct / vasculopathy evaluation were performed at 3T in adults with SCA (n=36) and age- and race-matched controls (n=11). Three reviewers assessed for hyperintensity in the superior sagittal sinus on ASL images (Fig) and assigned scores of 0 (none), 1 (mild, focal), 2 (significant, focal), or 3 (significant, diffuse). Shunting scores were compared with the presence of clinical impairment (prior infarcts, stenosis>50%, or severe disease requiring transfusions) and OEF. Results: Interobserver agreement was excellent (Fleiss’ κ=0.91). Consensus shunting score in SCA adults (1.2±1.1) was higher (p Conclusion: Venous hyperintensity in ASL images may indicate capillary arteriovenous shunting and may reflect higher clinical impairment and elevated OEF.

Introduction: Spontaneous intracerebral hemorrhage (ICH) accounts for 40% of stroke in children. Few studies report cognitive outcomes and none have conducted serial testing over time. We hypothesized that children with ICH would continue to make cognitive improvements over a two-year period. Methods: Children with spontaneous ICH, including those with primary intraparenchymal hemorrhage (IPH) and/or intraventricular hemorrhage (IVH), were prospectively enrolled from 2011-2015 at a single institution. Two raters measured total brain volume, IPH, and IVH volumes. Outcome was assessed with the Pediatric Stroke Outcome Measure and a cognitive testing battery (Wechsler IQ) at 3 (T1), 12 (T2) and 24 months (T3) after ICH. Results: Sample included 7 children, 6-16 years (median=12.9); 2 had pure ICH, 1 had pure IVH, and 4 had both. Brain AVM was the cause of ICH in 6 of 7; 1 was idiopathic. Initial Glasgow coma scale ranged from 3-14 (median=9). Median hemorrhage volume as a percentage of brain volume was 1.96, interquartile range (IQR) 1.17-3.74. Total PSOMs improved over time from median of 3 (IQR=1.5-4.5) at T1 to 2 (IQR =0.5-3.0) at T3. PSOM worsened in 2 children, 1 with recurrent ICH (pt #2) and 1 with worsening expressive language and increased depression despite full surgical resection of AVM (pt #3). However, serial cognitive testing indicated greater heterogeneity over time, including general improvements in Verbal IQ and sustained low performance in working memory and processing speed in a subgroup (Figure). Conclusion: Children with spontaneous ICH may continue to improve cognitively over two years. However, cognitive performance is heterogeneous across participants and across domains of cognitive functioning with some worsening as cognitive demands increase developmentally with age. Clinical implications include the need for early and serial cognitive testing to assess for cognitive difficulties as children age.

BACKGROUND: Desensitization with intravenous immune globulin (IVIG) and rituximab improves transplantation rates. It is unclear if desensitization increases the risk of polyomavirus BK (BKV) viremia. Here, BKV viremia in HLA-sensitized patients after desensitization with IVIG and rituximab was analyzed. METHODS: Baseline characteristics and outcomes were compared in the desensitized group (N=187) and the non-desensitized group (N=284). Surveillance for BKV viremia was done at 1, 2, 3, 6, 9, and 12 months posttransplant. Univariable and multivariable analyses were performed. RESULTS: BKV viremia was observed in 20% of the desensitized and 10% of the non-desensitized (P

BACKGROUND It was demonstrated that human natural killer (NK) cells, via antibody-dependent cellular cytotoxicity (ADCC)-like mechanism, increase IFNγ production after exposure to alloantigens. This finding was associated with an increased risk for antibody-mediated rejection (ABMR). Although the effects of various immunosuppressive drugs on T cells and B cells have been extensively studied, their effects on NK cells are less clear. This study reports the effect of immunosuppressive agents on antibody-mediated NK cell activation in vitro. METHODS Whole blood from normal individuals was incubated with irradiated peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody+ sera (in vitro ADCC), with or without immunosuppressive agents. The %IFNγ+ and CD107a+ (degranulation marker) in CD56+ NK cells were enumerated by flow cytometry. RESULTS Cyclosporine A and tacrolimus significantly reduced IFNγ production in a dose-dependent manner (53%-83%), but showed minimal effect on degranulation (20%). Prednisone significantly reduced both IFNγ production and degranulation (50%-66% reduction at maximum therapeutic levels). Calcineurin inhibitors (CNIs) in combination with prednisone additively suppressed IFNγ production and degranulation. The effect of sirolimus or mycophenolate mofetil on NK cells was minimal. CONCLUSIONS These results suggest that potent suppressive effects of CNIs and prednisone on antibody-mediated NK cell activation may contribute to the reduction of ADCC in sensitized patients and possibly reduce the risk for ADCC-mediated ABMR. These further underscore the importance of medication compliance in prevention of ABMR and possibly chronic rejection, and suggest that ADCC-mediated injury may increase in strategies aimed at CNI or steroid minimization or avoidance.

Stroke is a feared complication of major trauma.1 Multiple guidelines exist regarding screening for blunt cerebrovascular injury (BCVI)2–5 though reliable estimates of the incidence of stroke after trauma are limited. In this issue of Neurology® , Fox et al.6 utilize a retrospective cohort within the Kaiser Permanente of Northern California (KPNC) system to assess incidence, timing, and risk factors for stroke after trauma in children and adults

Background Transplantation rates are very low for the broadly sensitized patient (panel reactive antibody [PRA]>80%; HS). Here, we examine the efficacy, outcomes, and cost-effectiveness of desensitization using high-dose intravenous immunoglobulin (IVIG) and rituximab to improve transplantation rates in HS patients. Methods From July 2006 to December 2011, 207 HS (56 living donors/151 deceased donors) patients (donor-specific antibody positive, PRA>80%) were desensitized using IVIG and rituximab. After desensitization, responsive patients proceeded to transplantation with an acceptable crossmatch. Cost and outcomes of desensitization were compared with dialysis. Results Of the 207 treated patients, 146 (71%) were transplanted. At 48 months, patient and graft survival by Kaplan-Meier were 95% and 87.5%, respectively. The total 3-year cost for patients treated in the desensitization arm was $219,914 per patient compared with $238,667 per patient treated in the dialysis arm. Thus, each patient treated with desensitization is estimated to save the U.S. healthcare system $18,753 in 2011 USD. Overall, estimated patient survival at the end of 3 years was 96.6% for patients in the desensitization arm of the model (based on Cedars-Sinai survival rate) compared with 79.0% for an age, end-stage renal disease etiology, and PRA matched group of patients remaining on dialysis during the study period. Conclusions We conclude that desensitization with IVIG+rituximab is clinically and cost-effective, with both financial savings and an estimated 17.6% greater probability of 3-year survival associated with desensitization versus dialysis alone. However, the benefits of desensitization and transplantation are limited by organ availability and allocation policies.

Background. Global immunosuppression can be measured by assessing adenosine triphospate (ATP) levels in mitogen-stimulated CD4+ T cells.Methods. We investigated the effect of storage time on ATP levels in 234 blood samples from 18 healthy individualsand 152 transplant patients. The difference between day 0 (G13 hours post-blood draw) and day 1 (24Y37 hours) mea-surements was analyzed and compared with various factors; a subset of samples was also analyzed in 6-hour intervals.Results. The ATP levels were significantly lower on day 1 compared with that on day 0 in healthy individuals(279T159 vs 414T159 ng/mL, PG0.001) and patients (356T209 vs 455T221 ng/mL, PG0.0001). Of the 18 healthyindividuals, 17 showed ATP reduction, whereas 192 (89%) of 216 patients did so on day 1 (24.8T24.1%). In the timecourse analysis, ATP levels decreased with the blood storage time in healthy and patient samples, and the reductionbegan as early as 7 hours post-blood draw. The reduction rate was significantly higher in patient samples with low day0 ATP levels compared with samples with moderate or high levels (44.7T31.3% vs 23.2T23.6% or 18.7T15.7%;PG0.001). The reduction rate in patients treated with alemtuzumab induction was slightly higher than that indaclizumab-treated patients (28.8T24.6% vs 21.3T21.3%, P=0.09). CD4+ cell number did not change within 24 hourspost-blood draw, but CD4 expression decreased 2.0T2.8% (PG0.05).Conclusions. The ATP levels are significantly lower in 1-day-old blood compared with fresh blood, suggesting thatfresh blood should be used for assessing the T cell immune function to obtain the most accurate results.Keywords: T cell immune function assay, Blood storage, ATP levels, Monitoring of transplant patients.(Transplantation 2012;94: 00Y00)

Sarcospan (SSPN) has an important role in stabilizing sarcolemmal dystrophin- and utrophin-glycoprotein adhesion complexes at the cell membrane. Loss of cell adhesion leads to contraction-induced muscle damage, causing muscle dysfunction and cell death. Recently we have shown a specific role for SSPN in modulating cardiac cell adhesion and physiological function. After transthoracic aortic constriction (TAC), SSPN-null mice transitioned toward failure faster than wild-type (WT) mice. Muscle histology revealed large focal areas of collagen deposition in SSPN-null hearts after TAC compared to WT hearts, suggesting that increased membrane fragility affected cardiomyocyte survival. Our laboratory has shown that SSPN loss reduces sarcolemmal dystrophin levels and associated adhesion complexes in the heart. Whereas, the complete loss of dystrophin leads to development of Duchenne muscular dystrophy (DMD), causing cardiac dysfunction and early mortality. Overexpression of SSPN in DMD mice increased cell adhesion and laminin binding in hearts, leading to improvements in tissue histopathology and increased expression of utrophin, a functional homologue of dystrophin. Examining the restorative potential of SSPN in dystrophic cardiac tissue, led us to query whether compensatory upregulation of SSPN occurs in failing hearts of TAC-treated WT mice. In failing non-DMD hearts, we found that SSPN expression is increased. We have evidence of a chaperone role for SSPN, and its increased expression in the failing heart may contribute to the increased localization of dystrophin and associated glycoprotein complexes at the sarcolemma, which we observed in failing WT hearts compared to untreated controls. The upregulation of cell-stabilizing cell adhesion complexes may compensate for increased wall stress and counter pathological processes that culminate in cardiomyocyte demise, and we are exploring whether naturally increased expression or transgenic overexpression of SSPN in the heart may protect against damage. In summary, we have found that SSPN promotes cardiac function by maintaining cell adhesion and promoting cell survival during disease conditions.