Double blind, nonrandomized crossover study of active recharge biphasic deep brain stimulation for primary dystonia.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is an effective therapy for select patients with primary dystonia. DBS programming for dystonia is often challenging due to variable time to symptomatic improvement or stimulation induced side effects (SISE) such as capsular or optic tract activation which can prolong device optimization. OBJECTIVE: To characterize the safety and tolerability of active recharge biphasic DBS (bDBS) in primary dystonia and to compare it to conventional clinical DBS (clinDBS). METHODS: Ten subjects with primary dystonia and GPi DBS underwent a single center, double blind, nonrandomized crossover study comparing clinDBS versus bDBS. The testing occurred over two-days. bDBS and clinDBS were administered on separate days and each was activated for 6 h. Rating scales were collected by video recording and scored by four blinded movement disorders trained neurologists. RESULTS: The bDBS paradigm was safe and well-tolerated in all ten subjects. There were no persistent SISE reported. The mean change in the Unified Dystonia Rating Scale after 4 h of stimulation was greater in bDBS when compared to clinDBS (-6.5 vs 0.3, p < 0.04). CONCLUSION: In this pilot study, we demonstrated that biphasic DBS is a novel stimulation paradigm which can be administered safely. The biphasic waveform revealed a greater immediate improvement. Further studies are needed to determine whether this immediate improvement persists with chronic stimulation or if clinDBS will eventually achieve similar levels of improvement to bDBS over time.

Harnessing natural killer cells to develop next-generation cellular immunotherapy.

Cellular immunotherapy harnesses the body's own immune system to fight cancer by using engineered T cells, macrophages, or natural killer (NK) cells. Compared to chimeric antigen receptor T (CAR-T) cells that are commonly used to treat hematological malignancies, CAR-NK cells have shown remarkable therapeutic effectiveness while exhibiting enhanced safety, reduced risk of graft-versus-host disease, fewer side effects, and amplified antitumor efficacy. Preclinical trials have unveiled the high potential of adoptive CAR-NK cell therapy to curtail or even eliminate both hematological malignancies and solid tumors in animal models. We brought forth herein the design principle of CAR-NK cells, highlighted the latest progress in the preclinical testing and clinical trials of CAR-NK cells, briefly delved into discussed major roadblocks in CAR-NK therapy, and discussed potential solutions to surmount these challenges. Given the accelerated progress in both basic and translational studies on immune cell engineering, CAR-NK cell therapy promises to become a serious contender and important addition to the next-generation cell-based immunotherapy.

Potential distributional shifts in North America of allelopathic invasive plant species under climate change models.

Predictive studies play a crucial role in the study of biological invasions of terrestrial plants under possible climate change scenarios. Invasive species are recognized for their ability to modify soil microbial communities and influence ecosystem dynamics. Here, we focused on six species of allelopathic flowering plants-Ailanthus altissima, Casuarina equisetifolia, Centaurea stoebe ssp. micranthos, Dioscorea bulbifera, Lantana camara, and Schinus terebinthifolia-that are invasive in North America and examined their potential to spread further during projected climate change. We used Species Distribution Models (SDMs) to predict future suitable areas for these species in North America under several proposed future climate models. ENMEval and Maxent were used to develop SDMs, estimate current distributions, and predict future areas of suitable climate for each species. Areas with the greatest predicted suitable climate in the future include the northeastern and the coastal northwestern regions of North America. Range size estimations demonstrate the possibility of extreme range loss for these invasives in the southeastern United States, while new areas may become suitable in the northeastern United States and southeastern Canada. These findings show an overall northward shift of suitable climate during the next few decades, given projected changes in temperature and precipitation. Our results can be utilized to analyze potential shifts in the distribution of these invasive species and may aid in the development of conservation and management plans to target and control dissemination in areas at higher risk for potential future invasion by these allelopathic species.

Blood Pressure Trajectory Groups and Outcome After Endovascular Thrombectomy: A Multicenter Study.

BACKGROUND: Elevated blood pressure after endovascular thrombectomy (EVT) has been associated with an increased risk of hemorrhagic transformation and poor functional outcomes. However, the optimal hemodynamic management after EVT remains unknown, and the blood pressure course in the acute phase of ischemic stroke has not been well characterized. This study aimed to identify patient subgroups with distinct blood pressure trajectories after EVT and study their association with radiographic and functional outcomes. METHODS: This multicenter retrospective cohort study included consecutive patients with anterior circulation large-vessel occlusion ischemic stroke who underwent EVT. Repeated time-stamped blood pressure data were recorded for the first 72 hours after thrombectomy. Latent variable mixture modeling was used to separate subjects into five groups with distinct postprocedural systolic blood pressure (SBP) trajectories. The primary outcome was functional status, measured on the modified Rankin Scale 90 days after stroke. Secondary outcomes included hemorrhagic transformation, symptomatic intracranial hemorrhage, and death. RESULTS: Two thousand two hundred sixty-eight patients (mean age [±SD] 69±15, mean National Institutes of Health Stroke Scale 15±7) were included in the analysis. Five distinct SBP trajectories were observed: low (18%), moderate (37%), moderate-to-high (20%), high-to-moderate (18%), and high (6%). SBP trajectory group was independently associated with functional outcome at 90 days (P<0.0001) after adjusting for potential confounders. Patients with high and high-to-moderate SBP trajectories had significantly greater odds of an unfavorable outcome (adjusted odds ratio, 3.5 [95% CI, 1.8-6.7], P=0.0003 and adjusted odds ratio, 2.2 [95% CI, 1.5-3.2], P<0.0001, respectively). Subjects in the high-to-moderate group had an increased risk of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.82 [95% CI, 1-3.2]; P=0.04). No significant association was found between trajectory group and hemorrhagic transformation. CONCLUSIONS: Patients with acute ischemic stroke demonstrate distinct SBP trajectories during the first 72 hours after EVT that have differing associations with functional outcome. These findings may help identify potential candidates for future blood pressure modulation trials.

Safety and Tolerability of Burst-Cycling Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease.

Background: Freezing of gait (FOG) is a common symptom in Parkinson's disease (PD) and can be difficult to treat with dopaminergic medications or with deep brain stimulation (DBS). Novel stimulation paradigms have been proposed to address suboptimal responses to conventional DBS programming methods. Burst-cycling deep brain stimulation (BCDBS) delivers current in various frequencies of bursts (e.g., 4, 10, or 15 Hz), while maintaining an intra-burst frequency identical to conventional DBS. Objective: To evaluate the safety and tolerability of BCDBS in PD patients with FOG. Methods: Ten PD subjects with STN or GPi DBS and complaints of FOG were recruited for this single center, single blinded within-subject crossover study. For each subject, we compared 4, 10, and 15 Hz BCDBS to conventional DBS during the PD medication-OFF state. Results: There were no serious adverse events with BCDBS. It was feasible and straightforward to program BCDBS in the clinic setting. The benefit was comparable to conventional DBS in measures of FOG, functional mobility and in PD motor symptoms. BCDBS had lower battery consumption when compared to conventional DBS. Conclusions: BCDBS was feasible, safe and well tolerated and it has potential to be a viable future DBS programming strategy.

The adverse health effects of punitive immigrant policies in the United States: A systematic review.

BACKGROUND: Immigrants in the United States (US) today are facing a dynamic policy landscape. The Trump administration has threatened or curtailed access to basic services for 10.5 million undocumented immigrants currently in the US. We sought to examine the historical effects that punitive laws have had on health outcomes in US immigrant communities. METHODS: In this systematic review, we searched the following databases from inception-May 2020 for original research articles with no language restrictions: Ovid MEDLINE, Ovid EMBASE, Cochrane Library (Wiley), Web of Science Core Collection (Clarivate), CINAHL (EBSCO), and Social Work Abstracts (Ovid). This study is registered with PROSPERO, CRD42019138817. Articles with cohort sizes >10 that directly evaluated the health-related effects of a punitive immigrant law or policy within the US were included. FINDINGS: 6,357 studies were screened for eligibility. Of these, 32 studies were selected for inclusion and qualitatively synthesized based upon four themes that appeared throughout our analysis: (1) impact on healthcare utilization, (2) impact on women's and children's health, (3) impact on mental health services, and (4) impact on public health. The impact of each law, policy, mandate, and directive since 1990 is briefly discussed, as are the limitations and risk of bias of each study. INTERPRETATION: Many punitive immigrant policies have decreased immigrant access to and utilization of basic healthcare services, while instilling fear, confusion, and anxiety in these communities. The federal government should preserve and expand access for undocumented individuals without threat of deportation to improve health outcomes for US citizens and noncitizens.

Dissociative Tremor Response with Pallidal Deep Brain Stimulation in Parkinson's Disease.

Background: Pallidal and subthalamic targets are commonly used for deep brain stimulation in Parkinson's disease (PD), with similar efficacy for resting tremor control. However, neuromodulatory effects on kinetic and postural tremor in PD is less clear. Case Report: We present a 67-year-old PD patient with marked dissociative tremor response following pallidal neuromodulation. We observed excellent resting tremor suppression, but postural and kinetic tremors remained severe, requiring additional thalamic VIM stimulation for management. Discussion: Our findings illustrate the phenotypical differences in PD and differential response to diverse tremor characteristics with distinctive stimulation targets. Additional studies are necessary to understand these differences.

Direct carotid puncture for mechanical thrombectomy in acute ischemic stroke patients with prohibitive vascular access.

OBJECTIVE: While the benefit of mechanical thrombectomy (MT) for patients with anterior circulation acute ischemic stroke with large-vessel occlusion (AIS-LVO) has been clearly established, difficult vascular access may make the intervention impossible or unduly prolonged. In this study, the authors evaluated safety as well as radiographic and functional outcomes in stroke patients treated with MT via direct carotid puncture (DCP) for prohibitive vascular access. METHODS: The authors retrospectively studied patients from their prospective AIS-LVO database who underwent attempted MT between 2015 and 2018. Patients with prohibitive vascular access were divided into two groups: 1) aborted MT (abMT) after failed transfemoral access and 2) attempted MT via DCP. Functional outcome was assessed using the modified Rankin Scale at 3 months. Associations with outcome were analyzed using ordinal logistic regression. RESULTS: Of 352 consecutive patients with anterior circulation AIS-LVO who underwent attempted MT, 37 patients (10.5%) were deemed to have prohibitive vascular access (mean age [± SD] 82 ± 11 years, mean National Institutes of Health Stroke Scale [NIHSS] score 17 ± 5, with females accounting for 75% of the patients). There were 20 patients in the DCP group and 17 in the abMT group. The two groups were well matched for the known predictors of clinical outcome: age, sex, and admission NIHSS score. Direct carotid access was successfully obtained in 19 of 20 patients. Successful reperfusion (thrombolysis in cerebral infarction score 2b or 3) was achieved in 16 (84%) of 19 patients in the DCP group. Carotid access complications included an inability to catheterize the carotid artery in 1 patient, neck hematomas in 4 patients, non-flow-limiting common carotid artery (CCA) dissections in 2 patients, and a delayed, fatal carotid blowout in 1 patient. The neck hematomas and non-flow-limiting CCA dissections did not require any subsequent interventions and remained clinically silent. Compared with the abMT group, patients in the DCP group had smaller infarct volumes (11 vs 48 ml, p = 0.04), a greater reduction in NIHSS score (-4 vs +2.9, p = 0.03), and better functional outcome (shift analysis for 3-month modified Rankin Scale score: adjusted OR 5.2, 95% CI 1.02-24.5; p = 0.048). CONCLUSIONS: DCP for emergency MT in patients with anterior circulation AIS-LVO and prohibitive vascular access is safe and effective and is associated with higher recanalization rates, smaller infarct volumes, and improved functional outcome compared with patients with abMT after failed transfemoral access. DCP should be considered in this patient population.

Fixed Compared With Autoregulation-Oriented Blood Pressure Thresholds After Mechanical Thrombectomy for Ischemic Stroke.

Background and Purpose- Loss of cerebral autoregulation in the acute phase of ischemic stroke leaves patients vulnerable to blood pressure (BP) changes. Effective BP management after endovascular thrombectomy may protect the brain from hypoperfusion or hyperperfusion. In this observational study, we compared personalized, autoregulation-based BP targets to static systolic BP thresholds. Methods- We prospectively enrolled 90 patients undergoing endovascular thrombectomy for stroke. Autoregulatory function was continuously measured by interrogating changes in near-infrared spectroscopy-derived tissue oxygenation (a cerebral blood flow surrogate) in response to changes in mean arterial pressure. The resulting autoregulatory index was used to trend the BP range at which autoregulation was most preserved. Percent time that mean arterial pressure exceeded the upper limit of autoregulation or decreased below the lower limit of autoregulation was calculated for each patient. Time above fixed systolic BP thresholds was computed in a similar fashion. Functional outcome was measured with the modified Rankin Scale at 90 days. Results- Personalized limits of autoregulation were successfully computed in all 90 patients (age 71.6±16.2, 47% female, mean National Institutes of Health Stroke Scale 13.9±5.7, monitoring time 28.0±18.4 hours). Percent time with mean arterial pressure above the upper limit of autoregulation associated with worse 90-day outcomes (odds ratio per 10% 1.84 [95% CI, 1.3-2.7] P=0.002), and patients with hemorrhagic transformation spent more time above the upper limit of autoregulation (10.9% versus 16.0%, P=0.042). Although there appeared to be a nonsignificant trend towards worse outcome with increasing time above systolic BP thresholds of 140 mm Hg and 160 mm Hg, the effect sizes were smaller compared with the personalized approach. Conclusions- Noninvasive determination of personalized BP thresholds for stroke patients is feasible. Deviation from these limits may increase risk of further brain injury and poor functional outcome. This approach may present a better strategy compared with the classical approach of maintaining systolic BP below a predetermined value, though a randomized trial is needed to determine the optimal approach for hemodynamic management.

Deviation From Personalized Blood Pressure Targets Is Associated With Worse Outcome After Subarachnoid Hemorrhage.

Background and Purpose- Optimal blood pressure (BP) management during the early stages of aneurysmal subarachnoid hemorrhage remains uncertain. Observational studies have found worse outcomes in patients with increased hemodynamic variability, suggesting BP optimization as a potential neuroprotective strategy. In this study, we calculated personalized BP targets at which cerebral autoregulation was best preserved. We analyzed how deviation from these limits correlates with functional outcome. Methods- We prospectively enrolled 31 patients with aneurysmal subarachnoid hemorrhage. Autoregulatory function was continuously measured by interrogating changes in near-infrared spectroscopy (NIRS)-derived tissue oxygenation-a surrogate for cerebral blood flow-as well as intracranial pressure (ICP) in response to changes in mean arterial pressure using time-correlation analysis. The resulting autoregulatory indices were used to identify the upper and lower limit of autoregulation. Percent time that mean arterial pressure exceeded limits of autoregulation was calculated for each patient. Functional outcome was assessed using the modified Rankin Scale at discharge and 90 days. Associations with outcome were analyzed using ordinal multivariate logistic regression. Results- Personalized limits of autoregulation were computed in all patients (age 57.5±13.4, 23F, mean World Federation of Neurological Surgeons 2±1, monitoring time 67.8±50.8 hours). Optimal BP and limits of autoregulation were calculated on average for 89.5±6.7% of the total monitoring period. ICP- and NIRS-derived optimal pressures strongly correlated with one another (P<0.0001). Percent time that mean arterial pressure deviated from limits of autoregulation significantly associated with worse functional outcome at discharge (NIRS, P=0.001; ICP, P=0.004) and 90 days (NIRS, P=0.002; ICP, P=0.003), adjusting separately for age, World Federation of Neurological Surgeons, vasospasm, and delayed cerebral ischemia. Conclusions- Both invasive (ICP) and noninvasive (NIRS) determination of personalized BP targets after aneurysmal subarachnoid hemorrhage is feasible, and these 2 approaches revealed significant collinearity. Furthermore, exceeding individualized limits of autoregulation was associated with poor functional outcomes.

Decreases in Blood Pressure During Thrombectomy Are Associated With Larger Infarct Volumes and Worse Functional Outcome.

Background and Purpose- After large-vessel intracranial occlusion, the fate of the ischemic penumbra, and ultimately final infarct volume, largely depends on tissue perfusion. In this study, we evaluated whether blood pressure reduction and sustained relative hypotension during endovascular thrombectomy are associated with infarct progression and functional outcome. Methods- We identified consecutive patients with large-vessel intracranial occlusion ischemic stroke who underwent mechanical thrombectomy at 2 comprehensive stroke centers. Intraprocedural mean arterial pressure (MAP) was monitored throughout the procedure. ΔMAP was calculated as the difference between admission MAP and lowest MAP during endovascular thrombectomy until recanalization. Sustained hypotension was measured as the area between admission MAP and continuous measurements of intraprocedural MAP (aMAP). Final infarct volume was measured using magnetic resonance imaging at 24 hours, and functional outcome was assessed using the modified Rankin Scale at discharge and 90 days. Associations with outcome were analyzed using linear and ordinal multivariable logistic regression. Results- Three hundred ninety patients (mean age 71±14 years, mean National Institutes of Health Stroke Scale score of 17) were included in the study; of these, 280 (72%) achieved Thrombolysis in Cerebral Infarction 2B/3 reperfusion. Eighty-seven percent of patients experienced MAP reductions during endovascular thrombectomy (mean 31±20 mm Hg). ΔMAP was associated with greater infarct growth ( P=0.036) and final infarct volume ( P=0.035). Mean ΔMAP among patients with favorable outcomes (modified Rankin Scale score, 0-2) was 20±21 mm Hg compared with 30±24 mm Hg among patients with poor outcome ( P=0.002). In the multivariable analysis, ΔMAP was independently associated with higher (worse) modified Rankin Scale scores at discharge (adjusted odds ratio per 10 mm Hg, 1.17; 95% CI, 1.04-1.32; P=0.009) and at 90 days (adjusted odds ratio per 10 mm Hg, 1.22; 95% CI, 1.07-1.38; P=0.003). The association between aMAP and outcome was also significant at discharge ( P=0.002) and 90 days ( P=0.001). Conclusions- Blood pressure reduction before recanalization is associated with larger infarct volumes and worse functional outcomes for patients affected by large-vessel intracranial occlusion stroke. These results underscore the importance of BP management during endovascular thrombectomy and highlight the need for further investigation of blood pressure management after large-vessel intracranial occlusion stroke.

Autoregulation in the Neuro ICU.

PURPOSE OF REVIEW: The purpose of this review is to briefly describe the concept of cerebral autoregulation, to detail several bedside techniques for measuring and assessing autoregulation, and to outline the impact of impaired autoregulation on clinical and functional outcomes in acute brain injury. Furthermore, we will review several autoregulation studies in select forms of acute brain injuries, discuss the potential for its use in patient management in the ICU, and suggest further avenues for research. RECENT FINDINGS: Cerebral autoregulation plays a critical role in regulating cerebral blood flow, and impaired autoregulation has been associated with worse functional and clinical outcomes in various acute brain injuries. There exists a multitude of methods to assess the autoregulatory state in patients using both invasive and non-invasive modalities. Continuous monitoring of patients in the ICU has yielded autoregulatory-derived optimal perfusion pressures that may prevent secondary injury and improve outcomes. Measuring autoregulation continuously at the bedside is now a feasible option for clinicians working in the ICU, although there exists a great need to standardize autoregulatory measurement. While the clinical benefits await prospective and randomized trials, autoregulation-derived parameters show enormous potential for creating an optimal physiological environment for the injured brain.