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1.
J Orthop Trauma ; 36(Suppl 1): S1-S7, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34924512

RESUMO

SUMMARY: Physical and psychological impairment resulting from traumatic injuries is often significant and affects employment and functional independence. Extremity trauma has been shown to negatively affect long-term self-reported physical function, the ability to work, and participation in recreational activities and contributes to increased rates of anxiety and/or depression. High pain levels early in the recovery process and psychosocial factors play a prominent role in recovery after traumatic lower extremity injury. Cognitive-behavioral therapy pain programs have been shown to mitigate these effects. However, patient access issues related to financial and transportation constraints and the competing demands of treatment focused on the physical sequelae of traumatic injury limit patient participation in this treatment modality. This article describes a telephone-delivered cognitive-behavioral-based physical therapy (CBPT-Trauma) program and design of a multicenter trial to determine its effectiveness after lower extremity trauma. Three hundred twenty-five patients from 7 Level 1 trauma centers were randomized to CBPT-Trauma or an education program after hospital discharge. The primary hypothesis is that compared with patients who receive an education program, patients who receive the CBPT-Trauma program will have improved physical function, pain, and physical and mental health at 12 months after hospital discharge.

2.
J Orthop Trauma ; 36(Suppl 1): S8-S13, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34924513

RESUMO

SUMMARY: In current clinical practice, weight-bearing is typically restricted for up to 12 weeks after definitive fixation of lower extremity periarticular fractures. However, muscle atrophy resulting from restricting weight-bearing has a deleterious effect on bone healing and overall limb function. Antigravity treadmill therapy may improve recovery by allowing patients to safely load the limb during therapy, thereby reducing the negative consequences of prolonged non-weight-bearing while avoiding complications associated with premature return to full weight-bearing. This article describes a multicenter randomized controlled trial comparing outcomes after a 10-week antigravity treadmill therapy program versus standard of care in adult patients with periarticular fractures of the knee and distal tibia. The primary hypothesis is that, compared with patients receiving standard of care, patients receiving antigravity treadmill therapy will report better function 6 months after definitive treatment.

3.
Front Neurol ; 12: 729831, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512537

RESUMO

Introduction: We investigated the effect of hematoma volume reduction with minimally invasive surgery (MIS) on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with large spontaneous intracerebral hemorrhage (ICH). Methods: Post-hoc analysis of the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE III) study, a clinical trial with blinded outcome assessments. The primary outcome was the proportion of ICP readings ≥20 and 30 mmHg, and CPP readings <70 and 60 mm Hg. Secondary outcomes included major disability (modified Rankin scale >3) and mortality at 30 and 365 days. We assessed the relationship between proportion of high ICP and low CPP events and MIS using binomial generalized linear models, and outcomes using multiple logistic regression. Results: Of 499 patients enrolled in MISTIE III, 72 patients had guideline based ICP monitors placed, 34 in the MIS group and 38 in control (no surgery) group. Threshold ICP and CPP events ≥20/ <70 mmHg occurred in 31 (43.1%) and 52 (72.2%) patients respectively. On adjusted analyses, proportion of ICP readings ≥20 and 30 mmHg were significantly lower in the MIS group vs. control group [Odds Ratio (OR) 0.27, 95% Confidence Interval [CI] 0.11-0.63 (p = 0.002); OR = 0.18, 0.04-0.75, p = 0.02], respectively. Proportion of CPP readings <70 and 60 mm Hg were also significantly lower in MIS patients [OR 0.31, 95% CI 0.15-0.63 (p = 0.001); OR 0.30, 95% CI 0.11-0.83 (p = 0.02)], respectively. Higher proportions of CPP readings <70 and 60 mm were significantly associated with short term mortality (p = 0.04), and (p = 0.006), respectively. Long term mortality was significantly associated with higher proportion of time with ICP ≥ 20 (p = 0.04), ICP ≥ 30 (p = 0.04), and CPP <70 mmHg (p = 0.01). Conclusion: Our results are consistent with the hypothesis that surgical reduction of ICH volume decreases proportion of high ICP and low CPP events and that these variables are associated with short- and long-term mortality.

4.
Stroke ; 52(12): 3829-3838, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34525838

RESUMO

BACKGROUND AND PURPOSE: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH. METHODS: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion. RESULTS: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety (P=0.007), but better depression (P=0.002) and social satisfaction scores (P=0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites. CONCLUSIONS: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.

5.
J Stroke Cerebrovasc Dis ; 30(11): 106082, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34517296

RESUMO

OBJECTIVES: To determine factors associated with post-stroke depression (PSD) and relationship between PSD and functional outcomes in spontaneous intracerebral hemorrhage (ICH) using prospective data from a large clinical trial. MATERIALS AND METHODS: MISTIE III, a randomized, multicenter, placebo-controlled trial, was conducted to determine if minimally invasive surgery with thrombolysis improves outcome compared to standard medical care. Our primary outcome was post-stroke depression at 180 days. Secondary outcomes were change in blinded assessment of modified Rankin Scale (mRS) from 30 to 180 days, and from 180 to 365 days. Logistic regression models were used to assess the relationship between PSD and outcomes. RESULTS: Among 379 survivors at day 180, 308 completed Center for Epidemiologic Studies Depression Scale, of which 111 (36%) were depressed. In the multivariable analysis, female sex (Adjusted Odds Ratio [AOR], 95% Confidence Interval [CI]: 1.93 [1.07-3.48]), Hispanic ethnicity (3.05 [1.19-7.85]), intraventricular hemorrhage (1.88 [1.02-3.45]), right-sided lesions (3.00 [1.43-6.29]), impaired mini mental state examination at day 30 (2.50 [1.13-5.54]), and not being at home at day 30 (3.17 [1.05-9.57]) were significantly associated with higher odds of PSD. Patients with PSD were significantly more likely to have unchanged or worsening mRS from day 30 to 180 (42.3% vs. 25.9%; p=0.004), but not from day 180 to 365. CONCLUSIONS: We report high burden of PSD in patients with large volume ICH. Impaired cognition and not living at home may be more important than physical limitations in predicting PSD. Increased screening of high-risk post-stroke patients for depression, especially females and Hispanics may be warranted.

6.
Sci Immunol ; 6(56)2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33891558

RESUMO

Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14+ monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE2, which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.

7.
Neurosurgery ; 88(5): 961-970, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33475732

RESUMO

BACKGROUND: The extent of intracerebral hemorrhage (ICH) removal conferred survival and functional benefits in the minimally invasive surgery with thrombolysis in intracerebral hemorrhage evacuation (MISTIE) III trial. It is unclear whether this similarly impacts outcome with craniotomy (open surgery) or whether timing from ictus to intervention influences outcome with either procedure. OBJECTIVE: To compare volume evacuation and timing of surgery in relation to outcomes in the MISTIE III and STICH (Surgical Trial in Intracerebral Hemorrhage) trials. METHODS: Postoperative scans were performed in STICH II, but not in STICH I; therefore, surgical MISTIE III cases with lobar hemorrhages (n = 84) were compared to STICH II all lobar cases (n = 259) for volumetric analyses. All MISTIE III surgical patients (n = 240) were compared to both STICH I and II (n = 722) surgical patients for timing analyses. These were investigated using cubic spline modeling and multivariate risk adjustment. RESULTS: End-of-treatment ICH volume ≤28.8 mL in MISTIE III and ≤30.0 mL in STICH II had increased probability of modified Rankin Scale (mRS) 0 to 3 at 180 d (P = .01 and P = .003, respectively). The effect in the MISTIE cohort remained significant after multivariate risk adjustments. Earlier surgery within 62 h of ictus had a lower probability of achieving an mRS 0 to 3 at 180 d with STICH I and II (P = .0004), but not with MISTIE III. This remained significant with multivariate risk adjustments. There was no impact of timing until intervention on mortality up to 47 h with either procedure. CONCLUSION: Thresholds of ICH removal influenced outcome with both procedures to a similar extent. There was a similar likelihood of achieving a good outcome with both procedures within a broad therapeutic time window.


Assuntos
Hemorragia Cerebral , Procedimentos Cirúrgicos Minimamente Invasivos , Terapia Trombolítica , Tempo para o Tratamento , Hemorragia Cerebral/mortalidade , Hemorragia Cerebral/cirurgia , Craniotomia , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos/mortalidade , Procedimentos Cirúrgicos Minimamente Invasivos/estatística & dados numéricos , Terapia Trombolítica/mortalidade , Terapia Trombolítica/estatística & dados numéricos , Resultado do Tratamento
8.
Am Surg ; 87(4): 576-580, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33125276

RESUMO

Some forms of bariatric surgery make patients susceptible to calcium malabsorption, and the parathyroid hormone (PTH) axis is important for maintaining normocalcemia in these patients. Injury to the parathyroid glands due to anterior neck surgery commonly causes PTH axis disruption and can result in severe hypocalcemia in bariatric surgery patients. Herein, we present a case of a patient with a history of stomach intestinal pylorus-sparing bariatric surgery who developed refractory hypocalcemia requiring daily intravenous (IV) calcium 2 years after thyroidectomy. PTH levels were inappropriately normal during episodes of hypocalcemia, and urinary calcium level was <3.0 mg/dL following large oral doses of calcium, suggesting that both inadequate PTH response and malabsorption contributed to her severe hypocalcemia. In order to enhance calcium absorptive capacity while minimizing the risk of weight regain, she was surgically treated with a Roux-en-Y gastric bypass proximal to the prior operation. The surgery successfully improved blood calcium levels; the patient was successfully weaned from IV calcium and was able to maintain normocalcemia with oral supplements. We discuss the case in the context of available literature and provide our recommendations.


Assuntos
Cirurgia Bariátrica/efeitos adversos , Derivação Gástrica/métodos , Hipocalcemia/etiologia , Hipocalcemia/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Tireoidectomia/efeitos adversos , Adulto , Cirurgia Bariátrica/métodos , Feminino , Humanos , Tratamentos com Preservação do Órgão , Piloro , Indução de Remissão
9.
Arch Dis Child ; 106(4): 345-354, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33004310

RESUMO

BACKGROUND: The primary aim was to evaluate the efficacy of financial incentives for reducing paediatric tobacco smoke exposures (TSEs) through motivating cigarette usage reduction among low-income maternal caregivers and members of their social network. DESIGN: Randomised control pilot trial over a 6-month study follow-up time period. The study was undertaken from May 2017 to -May 2018. Once monthly follow-up visits occurred over the 6-month study period. SETTING: Baltimore City, Maryland, USA. PARTICIPANTS: We grouped 135 participants into 45 triads (asthmatic child (2-12 years of age), maternal caregiver and social network member). Triads were assigned in a 1:1 allocation ratio. The maternal caregiver and social network members were active smokers and contributed to paediatric TSE. INTERVENTIONS: Triads were randomised to receive either usual care (TSE education and quitline referrals) or usual care plus financial incentives. Cash incentives up to $1000 were earned by caregivers and designated social network participants. Incentives for either caregivers or social network participants were provided contingent on their individual reduction of tobacco usage measured by biomarkers of tobacco usage. Study visits occurred once a month during the 6-month trial. MAIN OUTCOME MEASURES: The main outcome measure was mean change in monthly paediatric cotinine levels over 6 months of follow-up interval and was analysed on an intention-to-treat basis. RESULTS: The mean change in monthly child cotinine values was not significantly different in the intervention cohort over the 6-month follow-up period, compared with the control group (p=0.098, CI -0.16 to 1.89). Trends in child cotinine could not be ascribed to caregivers or social network members. Despite decreasing mean monthly cotinine values, neither the intervention cohort's caregivers (difference in slope (control-intervention)=3.30 ng/mL/month, CI -7.72 to 1.13, p=0.144) or paired social network members (difference in slope (control-intervention)=-1.59 ng/mL/month, CI -3.57 to 6.74, p=0.546) had significantly different cotinine levels than counterparts in the control group. CONCLUSIONS: Financial incentives directed at adult contributors to paediatric TSE did not decrease child cotinine levels. TRIAL REGISTRATION NUMBER: NCT03099811.


Assuntos
Asma/etiologia , Asma/prevenção & controle , Exposição por Inalação/prevenção & controle , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto , Asma/epidemiologia , Cuidadores/educação , Estudos de Casos e Controles , Criança , Pré-Escolar , Cotinina/análise , Exposição Ambiental/análise , Feminino , Seguimentos , Humanos , Masculino , Maryland/epidemiologia , Motivação , Projetos Piloto , Pobreza/etnologia , Pobreza/estatística & dados numéricos , Abandono do Hábito de Fumar/métodos , Abandono do Hábito de Fumar/psicologia , Rede Social
10.
Artigo em Inglês | MEDLINE | ID: mdl-33212796

RESUMO

(1) Background: Monthly variability in smoking behaviors in caregivers of pediatric asthmatics yields questions of how much and when does smoking reduction result in improved environmental and clinical outcomes. (2) Methods: Post hoc analysis of data from a 6 month pilot randomized-control trial occurring from May 2017 to May 2018 in Baltimore City (MD, USA). The initial trial's primary intervention explored the utility of financial incentives in modifying caregiver smoking behaviors. Post hoc analyses examined all dyads independent of the initial trial's randomization status. All caregivers received pediatric tobacco smoke harm reduction education, in addition to monthly encouragement to access the state tobacco quitline for individual phone-based counseling and nicotine replacement therapy. Maternal caregivers who were active cigarette smokers and their linked asthmatic child (aged 2-12 years) were grouped into two classifications ("high" versus "low") based on the child and caregiver's cotinine levels. A "low" cotinine level was designated by at least a 25% reduction in cotinine levels during 3 months of the trial period; achieving ≤2 months of low cotinine levels defaulted to the "high" category. Twenty-seven dyads (caregivers and children) (total n = 54) were assigned to the "high" category, and eighteen dyads (caregivers and children) (total n = 36) were allocated to the "low" category. The primary outcome measure was the correlation of caregiver cotinine levels with pediatric cotinine values. Secondary outcomes included asthma control, in addition to caregiver anxiety and depression. (3) Results: Caregivers with 3 months of ≥25% decrease in cotinine levels had a significantly greater mean change in child cotinine levels (p = 0.018). "Low" caregiver cotinine levels did not significantly improve pediatric asthma control (OR 2.12 (95% CI: 0.62-7.25)). Caregiver anxiety and depression outcomes, measured by Patient Health Questionnaire (PHQ)-4 scores, was not significantly different based on cotinine categorization (p = 0.079); (4) Conclusion: Reduced pediatric cotinine levels were seen in caregivers who reduced their smoking for at least 3 months, but clinical outcome measures remained unchanged.


Assuntos
Asma , Cuidadores , Abandono do Hábito de Fumar , Adulto , Asma/prevenção & controle , Cuidadores/estatística & dados numéricos , Criança , Pré-Escolar , Cotinina/sangue , Feminino , Humanos , Masculino , Motivação , Fumar/sangue , Abandono do Hábito de Fumar/estatística & dados numéricos , Poluição por Fumaça de Tabaco/prevenção & controle , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Dispositivos para o Abandono do Uso de Tabaco
11.
Neurocrit Care ; 33(2): 516-524, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32026447

RESUMO

BACKGROUND/OBJECTIVE: Intracerebral hemorrhage (ICH) patients commonly have concomitant white matter lesions (WML) which may be associated with poor outcome. We studied if WML affects hematoma expansion (HE) and post-stroke functional outcome in a post hoc analysis of patients from randomized controlled trials. METHODS: In ICH patients from the clinical trials MISTIE II and CLEAR III, WML grade on diagnostic computed tomography (dCT) scan (dCT, < 24 h after ictus) was assessed using the van Swieten scale (vSS, range 0-4). The primary outcome for HE was > 33% or > 6 mL ICH volume increase from dCT to the last pre-randomization CT (< 72 h of dCT). Secondary HE outcomes were: absolute ICH expansion, > 10.4 mL total clot volume increase, and a subgroup analysis including patients with dCT < 6 h after ictus using the primary HE definition of > 33% or > 6 mL ICH volume increase. Poor functional outcome was assessed at 180 days and defined as modified Rankin Scale (mRS) ≥ 4, with ordinal mRS as a secondary endpoint. RESULTS: Of 635 patients, 55% had WML grade 1-4 at dCT (median 2.2 h from ictus) and 13% had subsequent HE. WML at dCT did not increase the odds for primary or secondary HE endpoints (P ≥ 0.05) after adjustment for ICH volume, intraventricular hemorrhage volume, warfarin/INR > 1.5, ictus to dCT time in hours, age, diabetes mellitus, and thalamic ICH location. WML increased the odds for having poor functional outcome (mRS ≥ 4) in univariate analyses (vSS 4; OR 4.16; 95% CI 2.54-6.83; P < 0.001) which persisted in multivariable analyses after adjustment for HE and other outcome risk factors. CONCLUSIONS: Concomitant WML does not increase the odds for HE in patients with ICH but increases the odds for poor functional outcome. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov trial-identifiers: NCT00224770 and NCT00784134.


Assuntos
Substância Branca , Hemorragia Cerebral/diagnóstico por imagem , Hematoma , Humanos , Fatores de Risco , Varfarina , Substância Branca/diagnóstico por imagem
12.
Int J Stroke ; 15(8): 872-880, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32075571

RESUMO

BACKGROUND: Intraventricular hemorrhage occurs due to intracerebral hemorrhage with intraventricular extension or without apparent parenchymal involvement, known as primary intraventricular hemorrhage. AIMS: We evaluated the prognosis of primary intraventricular hemorrhage patients in the CLEAR III trial (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage). METHODS: In patients with primary intraventricular hemorrhage versus those with secondary intraventricular hemorrhage, we compared intraventricular alteplase response and outcomes including modified Rankin Scale, Barthel Index, National Institutes of Health Stroke Scale (NIHSS), and extended Glasgow Outcome Scale (eGOS) at 30, 180, and 365 days. Outcomes were also compared in primary intraventricular hemorrhage patients who received intraventricular alteplase versus placebo (normal saline) and in matched primary and secondary intraventricular hemorrhage patients using inverse-probability-weighted regression adjustment. RESULTS: Of 500 patients enrolled in CLEAR III, 46 (9.2%) had primary intraventricular hemorrhage. Combining both treatment groups, primary intraventricular hemorrhage patients had larger intraventricular hemorrhage volumes (median: 34.2 mL vs. 20.8 mL, p < 0.01) but similar intraventricular hemorrhage removal (51.0% vs. 59.0%, p = 0.24) compared to secondary intraventricular hemorrhage patients, respectively. Confirming previous studies, primary intraventricular hemorrhage patients achieved better NIHSS, modified Rankin Scale, Barthel Index, and eGOS scores at days 30, 180, and 365, respectively (all p < 0.01), although mortality was similar to secondary intraventricular hemorrhage patients; matching analysis yielded similar results. Primary intraventricular hemorrhage patients who received intraventricular alteplase (n = 19) and saline (n = 27) achieved similar outcomes. CONCLUSIONS: In CLEAR III, primary intraventricular hemorrhage patients who survived achieved better long-term outcomes than surviving secondary intraventricular hemorrhage patients with similar mortality. Outcomes and safety were similar between primary intraventricular hemorrhage patients receiving alteplase and those receiving saline.


Assuntos
Fibrinolíticos , Acidente Vascular Cerebral , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Humanos , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento
13.
Eur J Nucl Med Mol Imaging ; 47(4): 816-827, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31741021

RESUMO

PURPOSE: In Y90 radioembolization, the number of microspheres infused varies by more than a factor of 20 over the shelf-life of the glass radioembolization device. We investigated the effect of the number of Y90 microspheres on normal liver tissue. METHOD: Healthy pigs received lobar radioembolization with glass Y90 microspheres at 4, 8, 12, and 16 days post-calibration, representing a > 20× range in the number of microspheres deposited per milliliter in tissue. Animals were survived for 1-month post-treatment and the livers were explanted and scanned on a micro CT system to fully characterize the microscopic distribution of individual microspheres. A complete 3D microdosimetric evaluation of each liver was performed with a spatially correlated analysis of histopathologic effect. RESULTS: Through whole-lobe microscopic identification of each microsphere, a consistent number of microspheres per sphere cluster was found at 4, 8, and 12 days postcalibration, despite an 8-fold increase in total microspheres infused from days 4 to 12. The additional microspheres instead resulted in more clusters formed and, therefore, a more homogeneous microscopic absorbed dose. The increased absorbed-dose homogeneity resulted in a greater volume fraction of the liver receiving a potentially toxic absorbed dose based on radiobiologic models. Histopathologic findings in the animals support a possible increase in normal liver toxicity in later treatments with more spheres (i.e., ≥ day 12) compared to early treatments with less spheres (i.e., ≤ day 8). CONCLUSION: The microdosimetric evidence presented supports a recommendation of caution when treating large volumes (e.g., right lobe) using glass 90Y microspheres at more than 8 days post-calibration, i.e., after "2nd week" Monday. The favorable normal tissue microscopic distribution and associated low toxicity of first week therapies may encourage opportunities for dose escalation with glass microspheres and could also be considered for patients with decreased hepatic reserve.


Assuntos
Braquiterapia , Embolização Terapêutica , Neoplasias Hepáticas , Exposição à Radiação , Animais , Embolização Terapêutica/efeitos adversos , Neoplasias Hepáticas/radioterapia , Microesferas , Suínos , Radioisótopos de Ítrio/efeitos adversos
14.
Stroke ; 50(7): 1688-1695, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31177984

RESUMO

Background and Purpose- We investigated the prognostic significance of spontaneous intracerebral hemorrhage location in presence of severe intraventricular hemorrhage. Methods- We analyzed diagnostic computed tomography scans from 467/500 (excluding primary intraventricular hemorrhage) subjects from the CLEAR (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) III trial. We measured intracerebral hemorrhage engagement with specific anatomic regions, and estimated association of each region with blinded assessment of dichotomized poor stroke outcomes: mortality, modified Rankin Scale score of 4 to 6, National Institutes of Health Stroke Scale score of >4, stroke impact scale score of <60, Barthel Index <86, and EuroQol visual analogue scale score of <50 and <70 at days 30 and 180, respectively, using logistic regression models. Results- Frequency of anatomic region involvement consisted of thalamus (332 lesions, 71.1% of subjects), caudate (219, 46.9%), posterior limb internal capsule (188, 40.3%), globus pallidus/putamen (127, 27.2%), anterior limb internal capsule (108, 23.1%), and lobar (29, 6.2%). Thalamic location was independently associated with mortality (days 30 and 180) and with poor outcomes on most stroke scales at day 180 on adjusted analysis. Posterior limb internal capsule and globus pallidus/putamen involvement was associated with increased odds of worse disability at days 30 and 180. Anterior limb internal capsule and caudate locations were associated with decreased mortality on days 30 and 180. Anterior limb internal capsule lesions were associated with decreased long-term morbidity. Conclusions- Acute intracerebral hemorrhage lesion topography provides important insights into anatomic correlates of mortality and functional outcomes even in severe intraventricular hemorrhage causing obstructive hydrocephalus. Models accounting for intracerebral hemorrhage location in addition to volumes may improve outcome prediction and permit stratification of benefit from aggressive acute interventions. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00784134.


Assuntos
Hemorragia Cerebral/diagnóstico por imagem , Ventrículos Cerebrais/diagnóstico por imagem , Idoso , Gânglios da Base/diagnóstico por imagem , Hemorragia Cerebral/mortalidade , Hemorragia Cerebral/terapia , Estudos de Coortes , Feminino , Escala de Coma de Glasgow , Globo Pálido/diagnóstico por imagem , Humanos , Hidrocefalia/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Tálamo/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
15.
Int J Stroke ; 14(5): 548-554, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30943878

RESUMO

RATIONALE AND HYPOTHESIS: Surgical removal of spontaneous intracerebral hemorrhage may reduce secondary destruction of brain tissue. However, large surgical trials of craniotomy have not demonstrated definitive improvement in clinical outcomes. Minimally invasive surgery may limit surgical tissue injury, and recent evidence supports testing these approaches in large clinical trials. METHODS AND DESIGN: MISTIE III is an investigator-initiated multicenter, randomized, open-label phase 3 study investigating whether minimally invasive clot evacuation with thrombolysis improves functional outcomes at 365 days compared to conservative management. Patients with supratentorial intracerebral hemorrhage clot volume ≥ 30 mL, confirmed by imaging within 24 h ofknown symptom onset,and intact brainstem reflexes were screened with a stability computed tomography scan at least 6 h after diagnostic scan. Patients who met clinical and imaging criteria (no ongoing coagulopathy; no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly; and stable hematoma size on consecutive scans) were randomized to either minimally invasive surgery plus thrombolysis or medical therapy. The sample size of 500 was based on findings of a phase 2 study. STUDY OUTCOMES: The primary outcome measure is dichotomized modified Rankin Scale 0-3 vs. 4-6 at 365 days adjusting for severity variables. Clinical secondary outcomes include dichotomized extended Glasgow Outcome Scale and all-cause mortality at 365 days; rate and extent of parenchymal blood clot removal; patient disposition at 365 days; efficacy at 180 days; type and intensity of ICU management; and quality of life measures. Safety was assessed at 30 days and throughout the study.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Adolescente , Adulto , Hemorragia Cerebral/diagnóstico por imagem , Terapia Combinada/métodos , Angiografia por Tomografia Computadorizada , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Método Simples-Cego , Resultado do Tratamento , Adulto Jovem
16.
Radiology ; 291(3): 792-800, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30938624

RESUMO

Background Bariatric embolization is a new endovascular procedure to treat patients with obesity. However, the safety and efficacy of bariatric embolization are unknown. Purpose To evaluate the safety and efficacy of bariatric embolization in severely obese adults at up to 12 months after the procedure. Materials and Methods For this prospective study (NCT0216512 on ClinicalTrials.gov ), 20 participants (16 women) aged 27-68 years (mean ± standard deviation, 44 years ± 11) with mean body mass index of 45 ± 4.1 were enrolled at two institutions from June 2014 to February 2018. Transarterial embolization of the gastric fundus was performed using 300- to 500-µm embolic microspheres. Primary end points were 30-day adverse events and weight loss at up to 12 months. Secondary end points at up to 12 months included technical feasibility, health-related quality of life (Short Form-36 Health Survey ([SF-36]), impact of weight on quality of life (IWQOL-Lite), and hunger or appetite using a visual assessment scale. Analysis of outcomes was performed by using one-sample t tests and other exploratory statistics. Results Bariatric embolization was performed successfully for all participants with no major adverse events. Eight participants had a total of 11 minor adverse events. Mean excess weight loss was 8.2% (95% confidence interval [CI]: 6.3%, 10%; P < .001) at 1 month, 11.5% (95% CI: 8.7%, 14%; P < .001) at 3 months, 12.8% (95% CI: 8.3%, 17%; P < .001) at 6 months, and 11.5% (95% CI: 6.8%, 16%; P < .001) at 12 months. From baseline to 12 months, mean SF-36 scores increased (mental component summary, from 46 ± 11 to 50 ± 10, P = .44; physical component summary, from 46 ± 8.0 to 50 ± 9.3, P = .15) and mean IWQOL-Lite scores increased from 57 ± 18 to 77 ± 18 (P < .001). Hunger or appetite decreased for 4 weeks after embolization and increased thereafter, without reaching pre-embolization levels. Conclusion Bariatric embolization is well tolerated in severely obese adults, inducing appetite suppression and weight loss for up to 12 months. Published under a CC BY-NC-ND 4.0 license. Online supplemental material is available for this article.


Assuntos
Cirurgia Bariátrica , Embolização Terapêutica , Obesidade/cirurgia , Adulto , Idoso , Cirurgia Bariátrica/efeitos adversos , Cirurgia Bariátrica/métodos , Cirurgia Bariátrica/estatística & dados numéricos , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/métodos , Embolização Terapêutica/estatística & dados numéricos , Endoscopia Gastrointestinal , Feminino , Fundo Gástrico/irrigação sanguínea , Fundo Gástrico/diagnóstico por imagem , Fundo Gástrico/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Perda de Peso/fisiologia
17.
Neurosurgery ; 84(6): 1157-1168, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30891610

RESUMO

BACKGROUND: Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). OBJECTIVE: To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. METHODS: Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. RESULTS: Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. CONCLUSION: This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.


Assuntos
Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas/terapia , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Terapia Combinada , Feminino , Hematoma/complicações , Hematoma/diagnóstico por imagem , Hematoma/cirurgia , Humanos , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Recuperação de Função Fisiológica , Resultado do Tratamento
18.
Lancet ; 393(10175): 1021-1032, 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30739747

RESUMO

BACKGROUND: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING: National Institute of Neurological Disorders and Stroke and Genentech.


Assuntos
Hemorragia Cerebral/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Idoso , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
19.
Neurosurgery ; 84(4): 954-964, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29660039

RESUMO

BACKGROUND: Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites. OBJECTIVE: To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health. METHODS: This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up. EXPECTED OUTCOMES: We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials. DISCUSSION: The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.


Assuntos
Neoplasias do Sistema Nervoso Central , Hemangioma Cavernoso do Sistema Nervoso Central , Biomarcadores , Estudos de Coortes , Estudos de Viabilidade , Hemorragia/etiologia , Humanos
20.
Neurosurgery ; 85(6): 843-853, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476251

RESUMO

BACKGROUND: More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. OBJECTIVE: To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. METHODS: The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. EXPECTED OUTCOMES: The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. DISCUSSION: With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.


Assuntos
Atorvastatina/uso terapêutico , Hemorragia Cerebral/tratamento farmacológico , Hemangioma Cavernoso do Sistema Nervoso Central/tratamento farmacológico , Hemangioma Cavernoso/tratamento farmacológico , Estudo de Prova de Conceito , Inibidores de Proteínas Quinases/uso terapêutico , Atorvastatina/farmacologia , Hemorragia Cerebral/diagnóstico por imagem , Método Duplo-Cego , Feminino , Seguimentos , Hemangioma Cavernoso/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Estudos Prospectivos , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/metabolismo
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