Nebulizer versus metered dose inhaler with space chamber (MDI spacer) for acute asthma and chronic obstructive pulmonary disease exacerbation: attitudes of patients and healthcare providers in the COVID-19 era.

OBJECTIVE: Short-acting bronchodilators for asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly delivered by nebulizers although administration using metered dose inhaler with space chamber (MDI spacer) has been shown to be equally efficacious. There are few studies examining patients' and healthcare providers' attitudes on the two administration methods in adults. This study explores patients' and healthcare providers' attitudes on the use of nebulizer versus MDI spacer for acute asthma and COPD exacerbations in adults. METHODS: Patients admitted for asthma or COPD exacerbations, doctors, and nurses in a university-affiliated hospital were surveyed from 1 April 2021 to 30 September 2021 regarding their views on the effectiveness, ease of use, preparation and administration, side effects, and infection risk of the two administration methods. RESULTS: Ninety-nine patients, 103 doctors, and 650 nurses completed the survey. 60.6% of patients perceived nebulizer to be more effective. Patients who found nebulizer more comfortable were more likely to prefer nebulizer (OR 43.97, p = 0.01), while those who associated it with a greater infection risk were less likely to prefer nebulizer (OR 0.15, p = 0.03). 49.5% of doctors and 49.1% of nurses perceived nebulizer to be more effective, compared to 10.7% and 34.5%, respectively, for MDI spacer. Effectiveness and patient comfort influenced doctors' and nurses' preference for nebulizer while ease of preparation and administration influenced nurses' preference only. CONCLUSIONS: Patients and healthcare providers perceived nebulizer to be more effective. Factors unique to each group influenced their preference for nebulizer.

Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain.

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

Timing of Revascularization in Ischemic Moyamoya Disease: Association of Early Versus Delayed Surgery with Perioperative and Long-Term Outcomes.

OBJECTIVE: Patients with nmoyamoya disease (MMD) who present primarily with ischemic stroke are known to have greater rates of perioperative strokes as compared with those who present with nonstroke symptoms. The optimal timing for revascularization for these patients remains unclear. METHODS: From 1994 to 2015, 91 patients with MMD presented with signs and symptoms of an acute ischemic stroke with diffusion restriction correlate on magnetic resonance imaging, and these patients were subdivided into those who underwent early revascularization (<90 days from last stroke), versus those who underwent delayed revascularization (≥90 days after last stroke), based on evidence that most neurological recovery after stroke occurs during the first three months. Perioperative and long-term outcomes were compared between the 2 surgical cohorts. RESULTS: In total, 27 patients underwent early revascularization, and 64 patients underwent delayed revascularization. Patients who underwent early revascularization had a statistically greater rate of perioperative stroke (P = 0.04) and perioperative mortality (P = 0.03), and overall complication rate (P = 0.049). At last follow-up of 5.2 ± 4.3 years, patients who underwent delayed revascularization had a lower mortality rate (P = 0.01) and a lower overall postoperative stroke incidence (P = 0.002). As a function of time, patients with MMD undergoing delayed revascularization had a statistically higher length of stroke-free survival (P = 0.005). CONCLUSIONS: Patients with MMD who present with ischemic stroke are more likely to have perioperative strokes, overall perioperative complications, worse long-term mortality rates, and lower rates of stroke-free survival if revascularization surgery occurred within 90 days of last stroke.

Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling.

Synapses connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. Synaptic function and plasticity, the neuronal process of adapting to diverse and variable inputs, depend on the dynamic nature of synaptic molecular components, which is mediated in part by cell adhesion signaling pathways. Here, we found that the enzyme biliverdin reductase (BVR) physically links together key focal adhesion signaling molecules at the synapse. BVR-null (BVR-/-) mice exhibited substantial deficits in learning and memory on neurocognitive tests, and hippocampal slices in which BVR was postsynaptically depleted showed deficits in electrophysiological responses to stimuli. RNA sequencing, biochemistry, and pathway analyses suggested that these deficits were mediated through the loss of focal adhesion signaling at both the transcriptional and biochemical level in the hippocampus. Independently of its catalytic function, BVR acted as a bridge between the primary focal adhesion signaling kinases FAK and Pyk2 and the effector kinase Src. Without BVR, FAK and Pyk2 did not bind to and stimulate Src, which then did not phosphorylate the N-methyl-d-aspartate (NMDA) receptor, a critical posttranslational modification for synaptic plasticity. Src itself is a molecular hub on which many signaling pathways converge to stimulate NMDAR-mediated neurotransmission, thus positioning BVR at a prominent intersection of synaptic signaling.

Risk Factor-Guided Early Discharge and Potential Resource Allocation Benefits in Patients with Traumatic Subarachnoid Hemorrhage.

OBJECTIVE: We sought to develop screening criteria predicting the lack of poor neurologic outcomes in patients presenting with traumatic subarachnoid hemorrhage (tSAH) and to evaluate their potential to improve resource allocation in these cases. METHODS: We retrospectively reviewed patients presenting with tSAH to the emergency department (ED) of a tertiary-care institution from 2016 to 2018. We defined good neurologic outcomes as patients with stable/improving neurologic status, who did not require neurosurgical intervention, had no expanding bleed, and needed no hospital readmission. Univariate and multivariate models were generated to predict risk factors inversely associated with good neurologic outcome. RESULTS: A total of 167 patients presented with tSAH from 2016 to 2018. The presence of depressed skull fracture, concomitant spinal fracture, low Glasgow Coma Scale (GCS) score, cranial nerve palsies, disorientation, concomitant hemorrhages, midline shift, increased international normalized ratio (INR), and emergent medical intervention were inversely correlated with likelihood of good neurologic outcome on univariate analysis. Multivariate regression showed that midline shift (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.05-0.89; P = 0.04), GCS score <13 (OR, 0.22; 95% CI, 0.05-0.99; P = 0.05), increased INR (OR, 0.18; 95% CI, 0.03-0.85; P = 0.04), and emergent medical intervention (OR, 0.18; 95% CI, 0.04-0.63; P = 0.01) were independently associated with lower likelihood of good neurologic outcome. Forty-six patients without any factors had good outcomes but were held in the ED or admitted to the hospital. These patients (if instead discharged directly) meant a potential cost savings of $179,172. CONCLUSIONS: In our study, we found multiple risk factors inversely associated with good neurologic outcome, namely low GCS score, midline shift, emergent medical intervention, and INR ≥1.4. Our findings may aid clinicians in determining which tSAH patients are candidates for safe early discharge.

Revascularization of Hemorrhagic Moyamoya Disease in a North American Cohort: The Role of Timing in Perioperative and Long-Term Outcomes.

BACKGROUND: Several East Asian studies have examined the role of revascularization in the context of hemorrhagic moyamoya disease (MMD) and found a decrease in postoperative rehemorrhage rates. To date, no data exist comparing revascularization with conservative management in North American patients with hemorrhagic MMD. OBJECTIVE: To compare the clinical outcomes of conservative management vs surgical revascularization for North American patients with hemorrhagic MMD and investigate the effect of revascularization timing. METHODS: We retrospectively studied the mortality and stroke-free survival of patients with MMD presenting with hemorrhagic stroke between 1994 and 2015. RESULTS: The diagnosis of hemorrhagic MMD was established in 38 patients. Seventeen patients were managed conservatively, and 21 were surgically revascularized. Twelve patients underwent revascularization within 6 months of hemorrhage, and 9 underwent surgery in a delayed fashion. Six conservatively managed patients (35.3%) died within the follow-up period compared with 0 (0%) surgically revascularized patients, P = .004. Conservatively managed patients also experienced an increased number of postoperative strokes, P = .037, and shorter stroke-free survival compared with patients undergoing revascularization, P = .047. On multivariate analysis, increased age, worse baseline modified Rankin score, and conservative management were independently associated with worse neurological outcomes, P < .05. Early revascularization was associated with higher rates of postoperative seizures, P = .033, and wound complications, P = .031, compared with those who underwent delayed surgery. CONCLUSION: Conservative management in a North American patient cohort was associated with greater mortality and worsened neurological outcomes compared with those undergoing revascularization. Early revascularization was associated with higher rates of postoperative seizures and wound complications, although these risks must be balanced against the risk of rehemorrhage.

Intracerebral and subarachnoid hemorrhage in pregnancy.

Maternal stroke occurs in around 34 out of every 100,000 deliveries and is responsible for around 5%-12% of all maternal deaths. It is most commonly hemorrhagic, and women are at highest risk for developing pregnancy-related hemorrhage during the early postpartum period through 6 weeks following the delivery. The most common causes of hemorrhagic stroke in pregnant patients are arteriovenous malformations and cerebral aneurysms. Management is similar to that for acute hemorrhagic stroke in the nonpregnant population with standard use of computed tomography and judicious utilization of intracranial vessel imaging and contrast. The optimal delivery method is evaluated on a case-by-case basis, and cesarean delivery is not always required. As most current studies are limited by retrospective design, relatively small sample sizes, and heterogeneous study term definitions, strong and comprehensive evidence-based guidelines on the management of acute hemorrhagic stroke in pregnant patients are still lacking. In the future, multicenter registries and prospective studies with uniform definitions will help improve management strategies in this complex patient population.

Incidence of Spontaneous Obliteration in Untreated Brain Arteriovenous Malformations.

BACKGROUND: Spontaneous obliteration (SpO) of untreated arteriovenous malformations (AVMs) is rare with fewer than 100 cases reported. The incidence and predisposing factors of SpO remain unclear, impeding our understanding of lesion progression in untreated patients. OBJECTIVE: To determine the incidence rate and predisposing factors of SpO in a North American cohort. METHODS: AVMs were retrospectively evaluated at our institution for over 25 yr. Untreated AVMs were divided into 2 groups: SpO-AVMs and non-SpO-AVMs. All statistical results were based on univariate analyses. Incidence was generated from counts of SpO over the untreated interval in patient years from birth until obliteration, treatment, or last follow-up. RESULTS: One hundred fifty-four patients had untreated AVMs; SpO was observed in 4. Average ages were 49.0 ± 23.6 and 48.7 ± 20.4 yr in the SpO-AVM and non-SpO-AVM group, respectively (P = .98). Average AVM sizes were 2.0 ± 1.8 cm (SpO-AVMs) and 3.7 ± 2.6 cm (non-SpO-AVMs, P = .25). All SpO-AVMs and 40 (27.0%) non-SpO-AVMs had a ruptured presentation (P = .006). A single draining vein was observed in all SpO-AVMs and 39 (32.8%) non-SpO-AVMs (P = .01). Deep venous drainage was not observed in any SpO-AVMs, but in 81 (57.9%) non-SpO-AVMs (P = .04). Mean follow-up time was 37.0 ± 42.6 and 75.6 ± 161.7 mo in SpO-AVM and non-SpO-AVMs patients, respectively. Of the 2 SpO-AVM patients with postobliteration follow-up, 1 experienced recanalization. From a 672-patient cohort, the incidence of SpO over 28 961 patient years was 0.014%. CONCLUSION: SpO-AVMs have an annual incidence rate of approximately 0.014% and tend to present with rupture, a single draining vein, and superficial venous drainage. Expectation of SpO for untreated AVMs is not justified, and patients should anticipate life-long hemorrhagic risk for untreated AVMs.

Moyamoya disease versus moyamoya syndrome: comparison of presentation and outcome in 338 hemispheres.

OBJECTIVE: Phenotypic differences between moyamoya disease (MMD) and moyamoya syndrome (MMS) remain unclear. The purpose of this study was to evaluate whether such differences exist when presentation, procedure-related, and outcome variables are compared quantitatively. METHODS: The study cohort included 185 patients with moyamoya presenting to the Johns Hopkins Medical Institutions between 1994 and 2015. Baseline demographic, angiographic, and clinical characteristics were compared between patients with MMS and MMD, in addition to procedure-related complications and length of stay (LOS) after surgery. Stroke-free survival was compared between both disease variants after diagnosis. Kaplan-Meier analysis and Cox proportional hazards regression were used to compare stroke-free survival between surgically treated and conservatively managed hemispheres in both types of disease, while evaluating interaction between disease variant and management. RESULTS: The cohort consisted of 137 patients with MMD (74%) with a bimodal age distribution and 48 patients with MMS (26%) who were mostly under 18 years of age (75%). Underlying diseases included sickle cell disease (48%), trisomy 21 (12%), neurofibromatosis (23%), and other disorders (17%). Patients with MMS were younger (p < 0.001) and less likely to be female (p = 0.034). Otherwise, baseline characteristics were statistically comparable. The rate of surgical complications was 33% in patients with MMD and 16% in patients with MMS (p = 0.097). Both groups of patients had a similar LOS after surgery (p = 0.823). Survival analysis (n = 330 hemispheres) showed similar stroke-free survival after diagnosis (p = 0.856) and lower stroke hazard in surgically managed patients in both MMD (hazard ratio [HR] 0.29, p = 0.028) and MMS (HR 0.62, p = 0.586). The disease variant (MMD vs MMS) did not affect the relationship between management approach (surgery vs conservative) and stroke hazard (p = 0.787). CONCLUSIONS: MMD and MMS have largely comparable clinical and angiographic phenotypes with analogously favorable responses to surgical revascularization.

Racial phenotypes in moyamoya disease: a comparative analysis of clinical presentation and natural history in a single multiethnic cohort of 250 hemispheres.

OBJECTIVE: The authors aimed to determine whether differences exist in presentation and natural history when comparing Asian patients with moyamoya disease (MMD) to those of other ethnicities in North America. METHODS: A database of 137 patients with MMD presenting to their institution between 1994 and 2015 was reviewed. Baseline characteristics and outcome variables, including stroke and functional outcome, were compared between Asian and non-Asian patients. Unadjusted Kaplan-Meier survival analysis and adjusted Cox regression models were used to compare stroke-free survival and stroke hazard after diagnosis among hemispheres of both racial groups. The analysis was stratified by age group, and censoring was performed until last follow-up or at the time of surgery. Because the relative rate of stroke changed between Asian and non-Asian adults after 1.5 years of follow-up, a time-segmented analysis focusing on the period 1.5 years after diagnosis was performed. RESULTS: The cohort comprised 23% (31/137) Asian and 77% (106/137) non-Asian patients with MMD with a bimodal age distribution. Non-Asian patients had a higher prevalence of increased BMI (p = 0.02) and smoking (p = 0.04). Among patients who presented with stroke (n = 90), hemorrhage was significantly more common among Asians (p = 0.02). The natural history analysis included 250 hemispheres: 67 pediatric and 183 adult hemispheres. The overall mean follow-up duration since diagnosis was 3.3 years. Among adults, Asian patients had a higher incidence of stroke (8.0 per 100 person-years vs 3.0 per 100 person-years) over a mean follow-up of 3.3 years, but results were not statistically significant (p = 0.45). In the period beginning 1.5 years after diagnosis, Asian adults had a significantly higher hazard of stroke over a mean follow-up of 7.7 years, while controlling for sex, hypertension, and stroke before diagnosis (hazard ratio 8.8, p = 0.02). Among pediatric patients, Asians also had a higher stroke incidence (10.0 per 100 person-years vs 3.5 per 100 person-years) over a mean follow-up of 3.2 years; however, results did not reach statistical significance (p = 0.40). Functional outcome was similar between both ethnic groups at last follow-up (p = 0.57). CONCLUSIONS: This study suggests a comparatively more progressive course of MMD in Asians. Further studies are required to fully characterize the phenotypic distinctions between different races and underlying pathophysiological mechanisms.

R2eD AVM Score.

Background and Purpose- The management of unruptured brain arteriovenous malformations remains unclear. Using a large cohort to determine risk factors predictive of hemorrhagic presentation of arteriovenous malformations, this study aims to develop a predictive tool that could guide hemorrhage risk stratification. Methods- A database of 789 arteriovenous malformation patients presenting to our institution between 1990 and 2017 was used. A hold-out method of model validation was used, whereby the data was randomly split in half into training and validation data sets. Factors significant at the univariable level in the training data set were used to construct a model based on multivariable logistic regression. Model performance was assessed using receiver operating curves on the training, validation, and complete data sets. The predictors and the complete data set were then used to derive a risk prediction formula and a practical scoring system, where every risk factor was worth 1 point except race, which was worth 2 points (total score varies from 0 to 6). The factors are summarized by R2eD arteriovenous malformation (acronym: R2eD AVM). Results- In 755 patients with complete data, 272 (36%) presented with hemorrhage. From the training data set, a model was derived containing the following risk factors: nonwhite race (odds ratio [OR]=1.8; P=0.02), small nidus size (OR=1.47; P=0.14), deep location (OR=2.3; P<0.01), single arterial feeder (OR=2.24; P<0.01), and exclusive deep venous drainage (OR=2.07; P=0.02). Area under the curve from receiver operating curve analysis was 0.702, 0.698, and 0.685 for the training, validation, and complete data sets, respectively. In the entire study population, the predicted probability of hemorrhagic presentation increased in a stepwise manner from 16% for patients with no risk factors (score of 0) to 78% for patients having all the risk factors (score of 6). Conclusions- The final model derived from this study can be used as a predictive tool that supplements clinical judgment and aids in patient counseling.

Differing Surgical Outcomes in a Multiethnic Cohort Suggest Racial Phenotypes in Moyamoya Disease.

BACKGROUND: Variable Moyamoya disease (MMD) genotypes and phenotypes between different races have been suggested previously. This study investigates differences in surgical complications and response to revascularization among Asian patients with MMD compared with other ethnicities in North America. METHODS: From a database of 185 patients with moyamoya presenting to our institution between 1994 and 2015, 85 patients with MMD underwent surgery and constituted the study cohort. Baseline characteristics before surgery, procedure-related complications, length of hospital stay, and outcome variables including stroke and functional outcome were compared between Asian and non-Asian patients. Kaplan-Meier survival analyses were used to compare time to ipsilateral stroke and any cerebrovascular event after bypass. RESULTS: Our surgical cohort consisted of 27% (23/85) Asian and 73% (62/85) non-Asian patients with MMD with a bimodal age distribution. Among the subset of patients who presented with stroke (n = 55), hemorrhage was significantly more common among Asian patients (P = 0.007). In 120 revascularization procedures, per-operative complication rates were greater among Asian patients while controlling for age, type of surgery, and stroke history (odds ratio 2.94; 95% confidence interval 1.16-7.48; P = 0.02). The mean follow-up time after surgery was 4.57 years. Ipsilateral cerebrovascular event rates were 4.77 per 100 person-years in non-Asian patients and 6.51 per 100 person-years in Asians (P = 0.66). Unfavorable modified Rankin Scale scores (>2) were found in 22% of Asian patients and 8% of non-Asian patients on last follow-up (P = 0.13). CONCLUSIONS: Asian patients with MMD may be more susceptible to surgical complications and may differ from other races in their response to revascularization. Further long-term prospective studies are needed to investigate these findings.

Impairment of paravascular clearance pathways in the aging brain.

OBJECTIVE: In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain. METHODS: CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. RESULTS: Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-ß was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. INTERPRETATION: We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates.