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Abstract Asparaginase (ASP)-containing regimens for acute lymphoblastic leukemia (ALL) are associated with venous thromboembolism (VTE). We evaluated the prevalence, risk factors, role of prophylaxis and clinical impact of VTE among adolescents and young adult (AYA) patients (15–50 years) treated on Dana-Farber Cancer Institute (DFCI) ALL protocols. The 1- and 2-year cumulative incidence of VTE were 31.9% (95% CI: 27.0%, 36.9%) and 33.5% (95% CI: 28.5%, 38.5%) respectively, with most events occurring during ASP-based consolidation phase (68.6%). VTE was more frequent in patients with overweight/obese vs. normal BMI (39.2% vs. 29.0%, p = 0.048). In a 1-year landmark analysis, the 4-year overall survival was 91.5%, without difference between patients with vs. without VTE (93.8% vs. 90.0%, p = 0.93). Relapse and non-relapse mortality rates were also similar. Among patients treated at Dana-Farber/Harvard Cancer Center, cerebral sinus vein thrombosis occurred in 3.6% of patients (8.5% of VTE events) in comparison to pulmonary embolism (32.9%) and deep vein thromboses (58.6%, 24.4% line-associated). In a Cox regression model for VTE free-time, elevated BMI was associated with shorter VTE free-time (HR 1.94 [95% CI 1.13-3.35], p = 0.018), while low molecular weight heparin (LMWH) prophylaxis as time-varying covariate was not. In conclusion, we found that VTE was frequent in AYAs treated on DFCI ALL protocols but did not impact survival outcomes. Overweight/obese BMI increased risk for VTE.

Open surgical repair of abdominal aortic aneurysm (AAA) is often regarded as a near-permanent operation with little long-term complications. Reported herein is a case of delayed rupture of an enlarging AAA sac after open repair requiring re-exploration in a patient presenting with flank pain and ipsilateral hydronephrosis. The natural history of a large, excluded aneurysm sac after open AAA repair, hypothesized etiology for this rare occurrence, and proposed diagnostic and therapeutic algorithm are described.

Background High blood pressure (BP) increases recurrent stroke risk. Methods and Results We assessed hypertension prevalence, treatment, control, medication adherence, and predictors of uncontrolled BP 90 days after ischemic or hemorrhagic stroke among 561 Mexican American and non‐Hispanic White (NHW) survivors of stroke from the BASIC (Brain Attack Surveillance in Corpus Christi) cohort from 2011 to 2014. Uncontrolled BP was defined as average BP ≥140/90 mm Hg at 90 days poststroke. Hypertension was uncontrolled BP or antihypertensive medication prescribed or hypertension history. Treatment was antihypertensive use. Adherence was missing zero antihypertensive doses per week. We investigated predictors of uncontrolled BP using logistic regression adjusting for patient factors. Median (interquartile range) age was 68 (59–78) years, 64% were Mexican American, and 90% of strokes were ischemic. Overall, 94.3% of survivors of stroke had hypertension (95.6% Mexican American versus 92.0% non‐Hispanic White; P=0.09). Of these, 87.9% were treated (87.3% Mexican American versus 89.1% non‐Hispanic White; P=0.54). Among the total population, 38.3% (95% CI, 34.4%–42.4%) had uncontrolled BP. Among those with uncontrolled BP prescribed an antihypertensive, 84.5% reported treatment adherence (95% CI, 78.8%–89.3%). Uncontrolled BP 90 days poststroke was less likely in patients with stroke who had a primary care physician (adjusted odds ratio [aOR], 0.45 [95% CI, 0.24–0.83]; P=0.01), greater stroke severity (aOR per‐1‐point‐higher National Institutes of Health Stroke Scale score, 0.96 [95% CI, 0.93–0.99]; P=0.02), or more depressive symptoms (aOR per‐1‐point‐higher Personal Health Questionnaire Depression Scale‐8 score, 0.95 [95% CI, 0.92–0.99] among those with a history of hypertension at baseline; P=0.009). Conclusions Greater than one third of survivors of stroke have uncontrolled BP at 90 days poststroke in this population‐based study. Interventions are needed to improve BP control after stroke.

Background Stroke survivors believe neighborhood resources such as community centers are beneficial; however, little is known about the influence of these resources on stroke outcomes. We evaluated whether residing in neighborhoods with greater resource density is associated with favorable post‐stroke outcomes. Methods and Results We included Mexican American and non‐Hispanic White stroke survivors from the Brain Attack Surveillance in Corpus Christi project (2009–2019). The exposure was density of neighborhood resources (eg, community centers, restaurants, stores) within a residential census tract at stroke onset. Outcomes included time to death and recurrence, and at 3 months following stroke: disability (activities of daily living/instrumental activities of daily living), cognition (Modified Mini‐Mental State Exam), depression (Patient Health Questionnaire‐8), and quality of life (abbreviated Stroke‐Specific Quality of Life scale). We fit multivariable Cox regression and mixed linear models. We considered interactions with stroke severity, ethnicity, and sex. Among 1786 stroke survivors, median age was 64 years (interquartile range, 56–73), 55% men, and 62% Mexican American. Resource density was not associated with death, recurrence, or depression. Greater resource density (75th versus 25th percentile) was associated with more favorable cognition (Modified Mini‐Mental State Exam mean difference=0.838, 95% CI=0.092, 1.584) and among moderate–severe stroke survivors, with more favorable functioning (activities of daily living/instrumental activities of daily living=−0.156 [95% CI, −0.284 to 0.027]) and quality of life (abbreviated Stroke‐Specific Quality of Life scale=0.194 [95% CI, 0.029–0.359]). Conclusions We observed associations between greater resource density and cognition overall and with functioning and quality of life among moderate–severe stroke survivors. Further research is needed to confirm these findings and determine if neighborhood resources may be a tool for recovery.

Stridulation is used by male katydids to produce sound via the rubbing together of their specialised forewings, either by sustained or interrupted sweeps of the file producing different tones and call structures. There are many species of Orthoptera that remain undescribed and their acoustic signals are unknown. This study aims to measure and quantify the mechanics of wing vibration, sound production and acoustic properties of the hearing system in a new genus of Pseudophyllinae with taxonomic descriptions of two new species. The calling behaviour and wing mechanics of males were measured using micro-scanning laser Doppler vibrometry, microscopy, and ultrasound sensitive equipment. The resonant properties of the acoustic pinnae of the ears were obtained via μ-CT scanning and 3D printed experimentation, and numerical modelling was used to validate the results. Analysis of sound recordings and wing vibrations revealed that the stridulatory areas of the right tegmen exhibit relatively narrow frequency responses and produce narrowband calls between 12 and 20 kHz. As in most Pseudophyllinae, only the right mirror is activated for sound production. The acoustic pinnae of all species were found to provide a broadband increased acoustic gain from ~40–120 kHz by up to 25 dB, peaking at almost 90 kHz which coincides with the echolocation frequency of sympatric bats. The new genus, named Satizabalus n. gen., is here derived as a new polytypic genus from the existing genus Gnathoclita, based on morphological and acoustic evidence from one described (S. sodalis n. comb.) and two new species (S. jorgevargasi n. sp. and S. hauca n. sp.). Unlike most Tettigoniidae, Satizabalus exhibits a particular form of sexual dimorphism whereby the heads and mandibles of the males are greatly enlarged compared to the females. We suggest that Satizabalus is related to the genus Trichotettix, also found in cloud forests in Colombia, and not to Gnathoclita.

Abstract Background The National Institutes of Health has advocated for improved minority participation in clinical research, including clinical trials and observational epidemiologic studies since 1993. An understanding of Mexican Americans (MAs) participation in clinical research is important for tailoring recruitment strategies and enrollment techniques for MAs. However, contemporary data on MA participation in observational clinical stroke studies are rare. We examined differences between Mexican Americans (MAs) and non-Hispanic whites (NHWs) participation in a population-based stroke study. Methods We included 3,594 first ever stroke patients (57.7% MAs, 48.7% women, median [IQR] age 68 [58–79]) from the Brain Attack Surveillance in Corpus Christi Project, 2009–2020 in Texas, USA, who were approached and invited to participate in a structured baseline interview. We defined participation as completing a baseline interview by patient or proxy. We used log-binomial models adjusting for prespecified potential confounders to estimate prevalence ratios (PR) of participation comparing MAs with NHWs. We tested interactions of ethnicity with age or sex to examine potential effect modification in the ethnic differences in participation. We also included an interaction between year and ethnicity to examine ethnic-specific temporal trends in participation. Results Baseline participation was 77.0% in MAs and 64.2% in NHWs (Prevalence Ratio [PR] 1.20; 95% CI, 1.14–1.25). The ethnic difference remained after multivariable adjustment (1.17; 1.12–1.23), with no evidence of significant effect modification by age or sex (P interaction by age = 0.68, P interaction by sex = 0.83). Participation increased over time for both ethnic groups (P trend

Unstructured abstract: Open surgical bypass with single-segment greater saphenous vein remains the most durable revascularization option in symptomatic peripheral arterial disease. Aneurysmal degeneration of autologous conduit is quite rare. Herein is reported a case of a 78-year-old man who presented with a pulsatile medial thigh mass twenty-six years after ipsilateral infrainguinal autologous vein bypass grafting for lifestyle-limiting intermittent claudication. This was found to represent aneurysmal degeneration of the proximal vein graft with mural thrombus. He underwent an uneventful percutaneous endovascular venous aneurysm repair with implantation of a covered self-expanding endoprosthesis and preservation of his patent bypass.

Retroperitoneal fibrosis (RPF) is an uncommon fibrotic disorder that can cause pain, ureteral obstruction, deep venous thrombosis, hydrocele, and, rarely, aortic occlusion. Herein is described a 65-year-old man with aortic occlusion from idiopathic RPF who was treated with axillobifemoral bypass grafting, which failed in the intermediate term. On representation with critical claudication, he underwent thoracobifemoral bypass grafting via a lateral retroperitoneal tunnel created through a midline, infraumbilical counterincision. He was discharged home on postoperative day 5. This illustrates the successful use of thoracic aortic inflow to treat the aortoiliac occlusive complication of RPF.

Understanding and recognizing anatomic anomalies of the aortic arch is important when planning extra-anatomic debranching before thoracic endovascular aortic repair. A rare anomaly is the left vertebral artery aberrantly arising from the aortic arch; found in ∼5% of adults. When present, the artery courses through the carotid sheath at a variable length before entering the third or fourth cervical transverse foramen. In the present report, we have described the case of a 49-year-old man with a symptomatic, enlarging type B aortic dissection with an aberrant left vertebral artery and the novel methods used to surgically correct his pathology.

Symptomatic femoropopliteal occlusive disease has been increasingly treated using endovascular methods. However, restenosis, especially after implantation of permanent metallic stents, has remained common. To date, resorbable scaffolds have failed to achieve sufficient radial strength to enable the successful treatment of long, mobile, peripheral arteries. In the present nonsurvival, large animal experiment, a novel device consisting of multiple, short, serial, balloon-expandable, bioresorbable scaffolds was deployed in arteries subjected to supraphysiologic deformation. Compared with native vessels, the scaffolded arteries continued to bend (113° ± 19° vs 110° ± 20°; P = .10) and shorten (15% ± 15% vs 20% ± 14%; P = .16), unencumbered by the placement of the investigational device. The mean luminal diameter of the scaffolded arteries was preserved without kinks or occlusions in exaggerated flexion (4.7 ± 0.7 vs 4.7 ± 0.5 mm in extension vs flexion; P = .80). Arterial deformation was borne by shortening of the interscaffold spaces (2.2 ± 0.8 mm vs 1.9 ± 0.7 mm in extension vs flexion; P < .01) and the scaffolds themselves (10.7 ± 1.4 mm vs 9.9 ± 1.1 mm in extension vs flexion; P < .01). The results from the present study challenge the perceived limitations of balloon-expandable devices implanted in peripheral mobile arteries. We have presented a bioresorbable scaffold that combines sufficient radial strength to preserve the mean luminal diameter with movement and the flexibility to accommodate femoropopliteal deformation. : Clinical Relevance: In the present study, we have described a novel treatment paradigm for femoropopliteal arterial occlusive disease using bioresorbable scaffolds. The balloon-expandable nature and material properties of the polylactide-based scaffolds combined with the short and segmented configuration provided the radial force to resist the physiologic mechanical deformation of the lower extremity artery while accompanying its natural motion. In the present study an acute animal model was tested, and the experimental device is now undergoing a first-in-human clinical trial (ClinicalTrials.gov identifier, NCT04584632).

Objective: Recanalization with balloon angioplasty and/or self-expanding stents (SES) has become the endovascular treatment of choice for symptomatic femoropopliteal occlusive disease. These strategies generate suboptimal clinical results, however, because they fail to expand the artery fully and ineffectively prevent recoil, neointimal hyperplasia, and restenosis. Balloon-expandable stents, given their greater radial force and rigid structure, represent a more effective treatment strategy, but only short lengths can be implanted safely in arteries that deform and bend with skeletal motion. The purpose of this preclinical experiment was to test the hypothesis that simultaneous implantation of a series of short, resorbable, balloon-expandable, paclitaxel-eluting scaffolds would prevent neointimal hyperplasia and stenosis compared with SES in an animal model of percutaneous femoropopliteal intervention. Methods: We extruded 6 × 60 mm Efemoral Vascular Scaffold Systems (EVSS) from copolymers of poly-L-lactic acid, coated with paclitaxel 3 μg/mm2, crimped onto a single delivery balloon, and implanted percutaneously into the iliofemoral arteries of eight Yucatan mini-swine. We implanted 7- to 8-mm × 60 mm SES into the contralateral experimental arteries. The animals were serially imaged with contrast angiography and optical coherence tomography after 30, 90, 180, 365, and 730 days. The primary end point of this study was neointimal morphometry over time. Secondary end points included acute deformation and angiographic and optical coherence tomography-derived measurements of chronic vascular response. Results: Over the 2-year study period, one SES was found to be completely occluded at 90 days; all EVSS were widely patent at all time points. Arteries treated with SES exhibited profound neointimal hyperplasia with in-stent stenosis. In contrast, arteries treated with EVSS exhibited only modest vascular responses and minimal stenosis. After 2 years, the mean neointimal thickness (0.45 ± 0.12 vs 1.31 ± 0.91 mm; P < .05) and area (8.41 ± 3.35 vs 21.86 ± 7.37 mm2; P < .05) were significantly decreased after EVSS implantation. By 2 years, all scaffolds in all EVSS-treated arteries had resorbed fully. Conclusions: In this preclinical animal model of peripheral endovascular intervention, the EVSS decreased neointimal hyperplasia and stenosis significantly compared with SES, then dissolved completely between the first and second years after implantation. : Clinical Relevance: Although generally successful in restoring patency immediately patency and improving arterial blood flow, commercially available peripheral endovascular devices rarely restore the target lesion to its full, original diameter, and often create a pathological environment in a disease artery that is prone to inflammation, cellular activation, proliferation, migration, restenosis, and therapeutic failure. In this preclinical chronic animal study, a novel drug-eluting, bioresorbable, balloon-expandable scaffold system was tested in a validated model of the human femoropopliteal artery.

Background Women have been reported to have worse health‐related quality of life (HRQoL) following stroke than men, but uncertainty exists over the reasons for the sex difference. Methods and Results We included all ischemic strokes registered with the BASIC (Brain Attack Surveillance in Corpus Christi) project (May 2010–December 2016), a population‐based stroke study, who completed a 90‐day outcome interview. Information on baseline characteristics was obtained from medical records and in‐person interviews. HRQoL was measured by the 12‐item short‐form Stroke Specific Quality of Life Scale. Multivariable Tobit regression was used to estimate the mean difference in overall HRQoL scores (range, 1–5; higher indicating better HRQoL) between sexes and to identify contributing factors to the differences. We included 1061 cases with complete data on HRQoL and covariates (median age, 67 years; 51% women). In unadjusted analyses, women had poorer overall HRQoL than men (mean difference, −0.26 [95% CI, −0.40 to −0.13]). Contributors to this difference included sociodemographic/prestroke factors (eg, age, race and ethnicity, prestroke function), risk factors/comorbidities (eg, history of stroke, Alzheimer disease/dementia), and initial stroke severity. Sociodemographic/prestroke factors explained 62% of the sex difference (mean difference, −0.08 [95% CI, −0.21 to 0.04]). In a fully adjusted model that included adjustment for all confounding factors, the sex difference was eliminated and became nonsignificant (mean difference, −0.03 [95% CI, −0.16 to 0.09]). Conclusions Poorer HRQoL in women compared with men was observed and explained by the combination of sociodemographic and prestroke factors, including physical function before stroke and stroke severity. The findings suggest potential subgroups of women who might benefit from more targeted interventions before and after stroke to improve HRQoL.

Background: Most end-of-life decisions after stroke are made by a surrogate decision maker, yet there has been limited study of surrogate assessment of the quality of end-of-life stroke care. Objective: To assess surrogate perceptions of quality of end-of-life care (QEOLC) in stroke and explore factors associated with quality. Design: Cross-sectional analysis of interviewer-administered survey. Settings/subjects: Surrogate decision makers for deceased stroke patients in a population-based study. Measurements: The primary outcome was the validated 10-item family version of the QEOLC scale. The univariate association between prespecified patient and surrogate factors and dichotomized QEOLC score (high: 8?10, low: 0?7) was explored with logistic regression fit using generalized estimating equations. Results: Seventy-nine surrogates for 66 deceased stroke cases were enrolled (median patient age: 76, female patient: 53%, Mexican American patient: 59%, median time from stroke to death: seven days, median surrogate age: 59, and female surrogate: 72%). The overall QEOLC was generally high (median 8.3, quartiles 6.1, 9.6) although several individual items had a high proportion (?30%?50%) of surrogates who felt that the questions did not apply to the patient's situation. No hypothesized factors were associated with QEOLC score, including demographics, stroke type, location/timing of death, advance directives, health literacy, or understanding of patient wishes. Conclusions: Surrogates reported generally high QEOLC. Although this finding is encouraging, modifications to the QEOLC may be needed in stroke as some surrogates were unable to provide a valid response for certain items.

Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I trial of the mTOR inhibitor temsirolimus in combination with cyclophosphamide and etoposide was performed in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily on days 1-5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphoflow cytometry analysis of peripheral blood specimens from treated patients. Sixteen heavily-pretreated patients were enrolled with 15 evaluable for toxicity. One dose-limiting toxicity of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels with a 47% overall response rate and 27% complete response rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. Future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be warranted to increase response rates in children with relapsed/refractory ALL.

We used high-resolution [C ii ] 158 μ m mapping of two nebulae IC 59 and IC 63 from SOFIA/upGREAT in conjunction with ancillary data of the gas, dust, and polarization to probe the kinematics, structure, and magnetic properties of their photodissociation regions (PDRs). The nebulae are part of the Sh 2-185 H ii region that is illuminated by the B0 IVe star γ Cas. The velocity structure of each PDR changes with distance from γ Cas, which is consistent with driving by the radiation. Based on previous far-ultraviolet (FUV) flux measurements of, and the known distance to, γ Cas, along with the predictions of 3D distances to the clouds, we estimated the FUV radiation field strength ( G _0 ) at the clouds. Assuming negligible extinction between the star and clouds, we find their 3D distances from γ Cas. For IC 63, our results are consistent with earlier estimates of distance from Andersson et al., locating the cloud at ∼2 pc from γ Cas at an angle of 58° to the plane of the sky behind the star. For IC 59, we derive a distance of 4.5 pc at an angle of 70° in front of the star. We do not detect any significant correlation between the orientation of the magnetic field and the velocity gradients of [C ii ] gas, which indicates a moderate magnetic field strength. The kinetic energy in IC 63 is estimated to be an order of 10 higher than the magnetic energies. This suggests that kinetic pressure in this nebula is dominant.

Photodissociation regions (PDRs), where the (far-)ultraviolet light from hot young stars interact with the gas in surrounding molecular clouds, provide laboratories for understanding the nature and role of feedback by star formation on the interstellar medium. While the general nature of PDRs is well understood—at least under simplified conditions—the detailed dynamics and chemistry of these regions, including gas clumping, evolution over time, etc., can be very complex. We present interferometric observations of the 21 cm atomic hydrogen line, combined with [C ii ] 158 μ m observations, toward the nearby reflection nebula IC 63. We find a clumpy H i structure in the PDR, and a ring morphology for the H i emission at the tip of IC 63. We further unveil kinematic substructure, of the order of 1 km s ^−1 , in the PDR layers and several legs that will disperse IC 63 in

The thermo-mechanical properties of carbon black reinforced natural and styrene butadiene rubbers are investigated under rapid adiabatic conditions. Eleven carbon black grades with varying surface area and structure properties at 40 parts per hundred (phr) loading are studied and the unreinforced equivalents are included for reference. The results show a strong correlation of the modulus, mechanical hysteresis, temperature rise and calculated crystallinity of the rubbers measured in tensile extension with strain amplification factors. This highlights the influence of matrix overstraining on microstructural deformations of the rubber upon extension. The strain amplification factors are calculated via the Guth-Gold equation directly from carbon black type and loading, allowing a correlation of the fundamental morphological properties of carbon black with thermal and mechanical properties of rubbers upon extension. Analysis of the thermal measurements of the rubber compounds upon extension and retraction and contrasting between crystallizing and non-crystallizing rubbers reveals that a substantial irreversible heat generation is present upon extension of the rubber compounds. These irreversible effects most likely originate from microstructural damage mechanisms which have been proposed to account for the Mullins Effect in particle reinforced rubbers.

Background This study examined the prevalence and longitudinal course of depression during the first year after mild to moderate stroke. Methods and Results We identified patients with mild to moderate ischemic stroke or intracerebral hemorrhage (National Institutes of Health Stroke Scale score

Abstract Background Carotid endarterectomy (CEA) is routinely performed for asymptomatic carotid stenosis, yet its average net benefit is small. Risk stratification may identify high risk patients that would clearly benefit from treatment. Methods Retrospective cohort study using data from the Asymptomatic Carotid Atherosclerosis Study (ACAS). Risk factors for poor outcomes were included in backward and forward selection procedures to develop baseline risk models estimating the risk of non-perioperative ipsilateral stroke/TIA. Baseline risk was estimated for all ACAS participants and externally validated using data from the Atherosclerosis Risk in Communities (ARIC) study. Baseline risk was then included in a treatment risk model that explored the interaction of baseline risk and treatment status (CEA vs. medical management) on the patient-centered outcome of any stroke or death, including peri-operative events. Results Three baseline risk factors (BMI, creatinine and degree of contralateral stenosis) were selected into our baseline risk model (c-statistic 0.59 [95% CI 0.54–0.65]). The model stratified absolute risk between the lowest and highest risk quintiles (5.1% vs. 12.5%). External validation in ARIC found similar predictiveness (c-statistic 0.58 [0.49–0.67]), but poor calibration across the risk spectrum. In the treatment risk model, CEA was superior to medical management across the spectrum of baseline risk and the magnitude of the treatment effect varied widely between the lowest and highest absolute risk quintiles (3.2% vs. 10.7%). Conclusion Even modestly predictive risk stratification tools have the potential to meaningfully influence clinical decision making in asymptomatic carotid disease. However, our ACAS model requires target population recalibration prior to clinical application.

Abstract Background Post-stroke disability is common, costly, and projected to increase. Acute stroke treatments can substantially reduce post-stroke disability, but few patients take advantage of these cost-effective treatments. Practical, cost-efficient, and sustainable interventions to address underutilized acute stroke treatments are currently lacking. In this context, we present the Stroke Ready project, a stepped wedge design, multi-level intervention that combines implementation science and community-based participatory research approaches to increase acute stroke treatments in the predominately African American community of Flint, Michigan, USA. Methods Guided by the Tailored Implementation of Chronic Disease (TICD) framework, we begin with optimization of acute stroke care in emergency departments, with particular attention given to our safety-net hospital partners. Then, we move to a community-wide, multi-faceted, stroke preparedness intervention, with workshops led by peer educators, over 2 years. Measures of engagement of the safety-net hospital and the feasibility and sustainability of the implementation strategy as well as community intervention reach, dose delivered, and satisfaction will be collected. The primary outcome is acute stroke treatment rates, which includes both intravenous tissue plasminogen activator, and endovascular treatment. The co-secondary outcomes are intravenous tissue plasminogen activator treatment rates and the proportion of stroke patients who arrive by ambulance. Discussion If successful, Stroke Ready will increase acute stroke treatment rates through emergency department and community level interventions. The stepped wedge design and process evaluation will provide insight into how Stroke Ready works and where it might work best. By exploring the relative effectiveness of the emergency department optimization and the community intervention, we will inform hospitals and communities as they determine how best to use their resources to optimize acute stroke care. Trial registration ClinicalTrials.gov Trial Identifier NCT03645590.

Chaga, a sclerotia formed by the Inonotus obliquus fungus, has been widely recognized for a number of medicinal properties. Although numerous scientific investigations have been published describing various biological activities of chaga from different geographical locations, little work has focused on chaga harvested in the USA or extraction techniques to maximize anti-inflammatory properties. The aim of this study was to investigate the anti-inflammatory properties of chaga collected in Maine (USA) extracted using traditional aqueous (hot water steeping) methods against lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Chaga extracts obtained from both conventional (ethanol/water) extraction methods and an accelerated solvent extraction method (ASE) at optimized conditions were compared to aqueous extracts (tea) obtained from chaga in the powder form (P) and powder form in tea bags (B) based on their effect on both nitric oxide (NO) production and pro-inflammatory cytokine expression, in particular, the expression of TNF-α, interleukin-6 (IL-6), and interleukin-β (IL-1β). Phenolic acid extracts from chaga and individual phenolic acid standards were also investigated for their effect on the same parameters. Results indicated that various chaga extracts have significant anti-inflammatory activity on LPS-stimulated RAW 264.7 cells. The inhibitory effect was through a decrease in the production of NO and the downregulation of TNF-α, IL-6, and IL-1β in RAW 264.7 macrophages. ASE1 (novel, optimized ethanol/water extraction) and P6 (six-minute steeping of powder in 100 °C water) extracts showed the highest inhibitory activity on NO production and on the expression of the inflammatory cytokines, compared to extracts obtained by conventional extraction methods.

Abstract Background Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder, and accounts for 8% of individuals with moderate or severe dizziness. BPPV patients experience substantial inconveniences and disabilities during symptomatic periods. BPPV therapeutic processes – the Dix-Hallpike Test (DHT) and the Canalith Repositioning Maneuver (CRM) – have an evidence base that is at the clinical practice guideline level. The most commonly used CRM is the modified Epley maneuver. The DHT is the gold standard test for BPPV and the CRM is supported by numerous randomized controlled trials and systematic reviews. Despite this, BPPV care processes are underutilized. Methods/design This is a stepped-wedge, randomized clinical trial of a multi-faceted educational and care-process-based intervention designed to improve the guideline-concordant care of patients with BPPV presenting to the emergency department (ED) with dizziness. The unit of randomization and target of intervention is the hospital. After an initial observation period, the six hospitals will undergo the intervention in five waves (two closely integrated hospitals will be paired). The order will be randomized. The primary endpoint is measured at the individual patient level, and is the presence of documentation of either the Dix-Hallpike Test or CRM. The secondary endpoints are referral to a health care provider qualified to treat dizziness for CRM and 90-day stroke rates following an ED dizziness visit. Formative evaluations are also performed to monitor and identify potential and actual influences on the progress and effectiveness of the implementation efforts. Discussion If this study safely increases documentation of the DHT/CRM, this will be an important step in implementing the use of these evidenced-based processes of care. Positive results will support conducting larger-scale follow-up studies that assess patient outcomes. The data collection also enables evaluation of potential and actual influences on the progress and effectiveness of the implementation efforts. Trial registration ClinicalTrials.gov, ID: NCT02809599. The record was first available to the public on 22 June 2016 prior to the enrollment of the first patients in October 2016.

Background The study investigated sex differences in cognitive outcomes at 90 days after first‐ever stroke using data from a population‐based sample. Methods and Results The study sample consisted of 1227 participants from the 2009–2016 Brain Attack Surveillance in Corpus Christi project (south Texas, United States) who had first‐ever ischemic stroke or intracerebral hemorrhage and survived 90 days after stroke. Poststroke cognitive function was assessed by the Modified Mini‐Mental State Examination (3MSE) (range: 0–100; dementia:

Evidence suggests that older adults with mild cognitive impairment (MCI) might not receive evidence-based treatments. We explored the impact of patient MCI on physician decision-making and recommendations for acute ischemic stroke (AIS) and acute myocardial infarction (AMI) in a pilot concurrent mixed-methods study of physicians recruited from one academic center. The mailed survey included a clinical vignette of AIS or AMI where the patient cognitive status was randomized (normal cognition, MCI, or early-stage dementia). The primary outcome was a composite summary measure of the proportion of guideline-concordant treatments recommended. Linear regression compared the primary outcome across patient cognition groups adjusting for physician characteristics. Semi-structured interviews done with 18 physicians (4 cardiologists, 9 neurologists, 5 internists) using a standard guide. Survey response rate was 72% (82/114) (49/61 neurologists; 33/53 cardiologists). As patient cognition worsened, neurologists recommended less guideline-concordant treatments after AIS (Ptrend

As microbreweries have flourished and craft beer brewing has expanded into a multibillion-dollar industry, the ingredients and techniques used to brew beer have changed and diversified. New brewing ingredients and techniques have led to increased concern over biogenic amines in the final product. Biogenic amine composition and concentration in beer, as well as the changes to the protein and amino acid content when adjuncts are used, have received little attention. A complex biochemical mixture, the proteins, amino acids, and biogenic amines undergo a variety of enzymatic and non-enzymatic catabolic, proteolytic, and oxidative reactions during brewing. As biogenic amines in fermented food receive increased scrutiny, evaluating knowledge gaps in the evolution of these compounds in the beer brewing process is critical.

Abstract: Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001 tested a new risk stratification system in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). At study entry, B-ALL patients were classified as standard risk (SR) or high risk (HR) based on age, white blood cell (WBC) count, and central nervous system status. After achieving complete remission (CR), patients with high end-induction minimal residual disease (MRD) (≥10−3 by polymerase chain reaction analysis of patient-specific antigen receptor rearrangements) and/or adverse cytogenetics (KMT2A rearrangement or hypodiploidy) were reclassified as very high risk (VHR) and received intensified therapy. IKZF1 deletion status was retrospectively evaluated by multiplex ligation-dependent probe amplification. Between 2005 and 2011, 678 Philadelphia chromosome-negative B-ALL patients aged 1 to 18 years enrolled; 651 achieved CR and 648 received a final risk group. Among all 678 patients, 5-year event-free survival (EFS) was 87% (95% confidence interval [CI], 84-89) and overall survival 93% (95% CI, 90-94). Five-year disease-free survival of SR patients (N = 407) was 94% (95% CI, 91-96), HR (N = 176) was 84% (95% CI, 77-88), and VHR (N = 65) was 79% (95% CI, 67-87). IKZF1 deletion was present in 62 of 385 (16%) assessed patients and was associated with inferior 5-year EFS (63%; 95% CI, 49%-74% vs 88%; 95% CI, 84%-91%; P < .001), and higher 5-year cumulative incidence of relapse, including among those with low MRD (24% vs 8%, P = .001). In multivariable analysis, age ≥15 years, WBC ≥50 × 109/L, IKZF1 deletion, and MRD ≥10−4 was each associated with inferior outcome. In conclusion, risk-stratified therapy on DFCI 05-001 resulted in favorable outcomes for B-ALL patients, including those with VHR features. IKZF1 deletion was an independent predictor of inferior outcome. This trial was registered at www.clinicaltrials.gov as #NCT00400946.

Abstract: Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes. Among the 105 patients screened, 16 (15%) harbored an ABL-class fusion (ETV6-ABL1: n = 1; FOXP1-ABL1: n = 1; SFPQ-ABL1: n = 1; ZC3HAV1-ABL2: n = 1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n = 8; PAX5-JAK2: n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant IKZF1 deletion (n = 11). In univariate analysis, fusion-positivity and IKZF1 deletion were each associated with inferior event-free survival; IKZF1 deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; P = .019). Our findings support therapy intensification for IKZF1-altered patients, irrespective of the presence of a kinase-activating fusion.

Background Prestroke depression status and post–acute rehabilitation care (PARC) are determinants of poststroke depression and function. However, little is known on how prestroke depression status affects PARC placement, a possible pathway for upstream intervention. We examined how prestroke depression status affects PARC in a population‐based study. Methods and Results Incident ischemic stroke cases were from the BASIC (Brain Attack Surveillance in Corpus Christi) Project from 2008 to 2012. Prestroke depression status was self‐reported and categorized as (1) never depressed, (2) history of depression without antidepressant use before stroke onset, or (3) antidepressant use before stroke onset. PARC included home, a skilled nursing facility, or an inpatient rehabilitation facility. Confounder‐adjusted multinomial regression models were used to examine the association between prestroke depression status and PARC. Adjustment for stroke severity was deferred in the main analyses because it may lie on the causal pathway. There were 548 stroke survivors (mean age 65.3 years, 48.3% female, 62.6% Mexican‐American). The adjusted odds ratios comparing home discharge to a skilled nursing facility were 1.88 (95% CI: 0.86‐4.11) for those with a history of depression and 2.55 (95% CI: 1.11‐5.83) for those using an antidepressant at stroke onset, relative to those never depressed. The adjusted odds ratios comparing an inpatient rehabilitation facility to a skilled nursing facility were 1.17 (95% CI 0.40‐3.42) and 3.28 (95% CI 1.24‐8.67) for those with a history of depression and those using an antidepressant at stroke onset, respectively, relative to those never depressed. Conclusions Antidepressant use before stroke onset may increase odds of home and inpatient rehabilitation facility discharge compared with skilled nursing facility discharge.

Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0−17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 × upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2×10−8). Moreover, rs13228878 (OR=0.61; P=7.1×10−6) and rs10273639 (OR=0.62; P=1.1×10−5) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children’s Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (P=0.77), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination.

To control the population of an invasive species of green crab, we investigated the feasibility of producing a fermented crab condiment. Commercial fermented fish condiments were tested to assess variability in the marketplace and to identify targets for lab-fermented sauces. Finely chopped crab was combined with 100 mg g−1, 200 mg g−1, or 300 mg g−1 NaCl, and spontaneously fermented for up to 120 days. Chromatographic analysis revealed that histamine content was not a safety concern as all treatments were below the current U.S. legal threshold (50 mg 100 mL−1). The majority of microbial and physicochemical properties measured within salt level (proteolytic bacterial population, total volatile basic nitrogen (TVBN), amine nitrogen, water activity, moisture, and biogenic amines) were statistically unchanged between days 60 and 120 of fermentation, suggesting that most of the biochemical changes happened early in the fermentation. While the production of a fermented condiment was successful and could represent an opportunity for the valorization of this invasive species, additional work is needed to accelerate the process and further understand the dynamics of the early fermentation stages.

Summary: Background: Global rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana. Methods: In this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofovir-emtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes were the combined endpoints of any adverse outcome (stillbirth, preterm birth [

Due to disparities in stroke risk among U.S. Hispanics, the need for culturally tailored, theory based effective health behavior change interventions persists. The purpose of this study was to examine self-determination theory (SDT) constructs related to cardiovascular disease (CVD) risk factors in a predominantly Mexican American population. The Stroke Health and Risk Education (SHARE) project was a cluster-randomized, faith-based behavioral intervention trial that enrolled Mexican Americans (MAs) and non-Hispanic whites (NHWs) from Catholic Churches in Nueces County, Texas. Data regarding SDT constructs and dietary and physical activity behaviors were collected via computer-assisted interviews using standardized instruments at the baseline assessment. Of the 801 subjects who consented, 760 completed baseline interviews. After eliminating cases with missing data, 733 participants (617 MA and 116 NHW) were included in the analyses. Participants were predominantly Mexican American (84%) and female (64%), and had a median age of 53 years. There were no significant ethnic differences in any of the baseline SDT scale scores with the exception of higher autonomous motivation scores for exercise among MAs (7.00 vs. 6.67, p= 0.01). Demographic differences in mean SDT scale scores were identified for sex, age, and income. Perceived competence and autonomous motivation were both significant predictors of diet and physical activity behaviors. This study increases our understanding of SDT constructs relative to diet and physical activity in a large, predominantly Mexican American sample. The results indicate that SDT is an appropriate framework to address CVD behavioral risk factors in a predominantly Hispanic population.

INTRODUCTION:A large and increasing number of HIV-infected women are conceiving on antiretroviral treatment (ART). While most antiretrovirals are considered safe in pregnancy, monitoring for rare pregnancy and infant adverse outcomes is warranted. METHODS:We conducted a retrospective secondary analysis nested within a clinical trial of infant cotrimoxazole vs. placebo prophylaxis in Botswana (the Mpepu Study). Infants were examined at birth, and at least every 3 months through 18 months of age. Abnormal physical findings and diagnostic testing revealing malformations were documented. Post hoc, a geneticist classified all reported malformations based on available documentation. Structural malformations with surgical, medical or cosmetic importance were classified as major malformations. We present a descriptive analysis of identified malformations. RESULTS:Between 2011 and 2014, 2,933 HIV-infected women who enrolled in the Mpepu study delivered 2,971 live-born infants. Study staff conducted 2,944 (99%) newborn exams. One thousand eighty-eight (38%) women were taking ART at conception; 1,147 (40%) started ART during pregnancy; 442 (15%) received zidovudine monotherapy; and 223 (7%) received no antiretroviral during pregnancy. Of 33 reported anomalies, 25 (76%) met congenital malformations criteria, 10 (30%) were classified as major malformations, 4 (40%) of which were identified after the birth exam. DISCUSSION:Our results highlight the importance of staff training on identification of congenital malformations, programmatic monitoring beyond the birth examination and the value of geneticist involvement in the malformations classification process in resource-limited settings. These elements will be important to fully define antiretroviral drug safety in pregnancy. SIGNIFICANCE:Surveillance systems for monitoring the safety of antiretroviral use during pregnancy among HIV-infected women in resource-limited setting are lacking. The World Health Organization's published programmatic recommendations for such surveillance systems represents the gold standard. We employed data from a clinical trial in Botswana, a country with a generalized HIV epidemic and high antiretroviral uptake by HIV-infected women, to highlight practical opportunities to strengthen congenital malformation surveillance systems in these settings where over 1 million HIV infected pregnant women reside. TRIAL REGISTRATION:Clinical Trials.gov NCT01229761.

Background: Ticagrelor is an orally available, direct acting and reversible P2Y12 receptor antagonist approved for treatment of acute coronary syndrome. The objectives of these studies were to (1) evaluate the Ticagrelor 2-year rat carcinogenicity bioassay data; (2) investigate potential mode of action (MOA) and (3) interpret human relevance. Methods: The following studies were done (1) rat two-year carcinogenicity study in male and female rats, (2) in vitro and in vivo genotoxicity assays, (3) quantitative whole body autoradiography (QWBA; male and female rats), (4) in vitro pharmacological profiling for more than 300 assays, and (5) in vivo ovariectomized rat assay. Results: The carcinogenicity study indicated Ticagrelor increased uterine tumor incidence while decreasing mammary and pituitary tumors/hyperplasia incidences in only high dose female rats. However, this altered tumor incidences were not P2Y12 target related since marketed non-reversible P2Y12 receptor antagonists were not associated with alter tumor incidences. MOA studies determined Ticagrelor exposure in the anterior pituitary and Ticagrelor was (1) non-genotoxic, (2) peripherally-restricted, (3) a dopamine transport (DAT) inhibitor with an IC50 lower than systemic free exposure in the rat carcinogenic study and more than a log higher than the free systemic exposure seen in clinical trials and (4) an inhibitor of estradiol-induced prolactin secretion. Discussion: Similar to Ticagrelor, centrally active dopamine agonists induce the same altered tumor incidence patterns that according to literature do not translate into the clinical setting, with a MOA involving decreased prolactin secretion. The Ticagrelor MOA data and literature suggest that altered dopamine levels in the hypophyseal part of the hypothalamus–hypophyseal axis (by Ticagrelor) will result in similar altered tumor incidences in rat that do not translate into the clinical setting, based on qualitative species differences. In conclusion Ticagrelor increased uterine tumors in the rat carcinogenesis study by a MOA consistent with reduced dopamine inhibition of prolactin, which is not a patient safety risk.

BackgroundTime‐limited acute stroke treatments are underused, primarily due to prehospital delay. One approach to decreasing prehospital delay is to increase stroke preparedness, the ability to recognize stroke, and the intention to immediately call emergency medical services, through community engagement with high‐risk communities. Methods and ResultsOur community–academic partnership developed and tested “Stroke Ready,” a peer‐led, workshop‐based, health behavior intervention to increase stroke preparedness among African American youth and adults in Flint, Michigan. Outcomes were measured with a series of 9 stroke and nonstroke 1‐minute video vignettes; after each video, participants selected their intended response (primary outcome) and symptom recognition (secondary outcome), receiving 1 point for each appropriate stroke response and recognition. We assessed differences between baseline and posttest appropriate stroke response, which was defined as intent to call 911 for stroke vignettes and not calling 911 for nonstroke, nonemergent vignettes and recognition of stroke. Outcomes assessments were performed before workshop 1 (baseline), at the conclusion of workshop 2 (immediate post‐test), and 1 month later (delayed post‐test). A total of 101 participants completed the baseline assessment (73 adults and 28 youths), 64 completed the immediate post‐test, and 68 the delayed post‐test. All participants were African American. The median age of adults was 56 (interquartile range 35–65) and of youth was 14 (interquartile range 11–16), 65% of adults were women, and 50% of youths were women. Compared to baseline, appropriate stroke response was improved in the immediate post‐test (4.4 versus 5.2, P

L-asparaginase is an integral component of therapy for acute lymphoblastic leukemia. However, asparaginase-related complications, including the development of hypersensitivity reactions, can limit its use in individual patients. Of considerable concern in the setting of clinical allergy is the development of neutralizing antibodies and associated asparaginase inactivity. Also problematic in the use of asparaginase is the potential for the development of silent inactivation, with the formation of neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident allergic reaction. Here we present guidelines for the identification and management of clinical hypersensitivity and silent inactivation with Escherichia coli- and Erwinia chrysanthemi- derived asparaginase preparations. These guidelines were developed by a consensus panel of experts following a review of the available published data. We provide a consensus of expert opinions on the role of serum asparaginase level assessment, indications for switching asparaginase preparation, and monitoring after change in asparaginase preparation.