Metabolic transcriptomics dictate responses of cone photoreceptors to retinitis pigmentosa.

Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow 13C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism.

Immune-Mediated Necrotizing Myopathy With Concurrent Statin Use After Routine COVID-19 Inoculation: A Case Report.

SARS-CoV-2 has been associated with multiple disease processes and chronic sequela. Much less understood are the neurological effects, ranging from headaches, pro-thrombotic state, encephalitis, and myopathic processes. Many case reports have documented post-SARS-CoV-2 virus effects; however, this case highlights the possibility of a less commonly described neurological manifestation possibly related to the BNT162b2 mRNA Pfizer vaccine. There is scant literature on immune-mediated necrotizing myopathy (IMNM) triggered after COVID-19 vaccination. The BNT162b2 mRNA COVID-19 vaccine (Pfizer, BioNTech) has proven to be safe and effective in reducing transmission of COVID-19, but post-vaccination neurological events, including venous sinus thrombosis, transverse myelitis, and immune-mediated diseases, such as Guillain-Barré syndrome, have been reported. We report a case of IMNM with HMG-CoA reductase antibody positivity in the setting of BNT162b2 vaccination. The patient presented with progressive muscle weakness with rhabdomyolysis and necrotizing autoimmune myopathy proven on muscle biopsy after the second dose of the BNT162b2 vaccine. Ultimately, this case report highlights the importance of clinical suspicion for early diagnosis and initiation of treatment after symptoms concerning necrotizing myopathy.

Systemic Risk Factors for Adult Spinal Deformity (ASD): A Retrospective Analysis of 48 Patients.

INTRODUCTION: Adult spinal deformity (ASD) results in significant patient morbidity and burden to quality of life. The degree to which systemic risk factors and comorbidities that contribute to ASD affect specific spinopelvic parameters is not well-documented. We determine the extent to which preoperative risk factors may contribute to spinopelvic parameters associated with ASD. METHODS: Retrospective single-center study of 48 patients with ASD. Analysis of variance (ANOVA) linear regression analysis was performed to evaluate correlation between systemic comorbidities (obesity, arterial hypertension (HTN), hyperlipidemia (HLD), cardiomyopathy, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), and asthma) and the following radiographic parameters: pelvic incidence (PI), lumbar lordosis (LL), C7 sagittal vertical axis (C7SVA), and the T10-L2 sagittal cobb angle. RESULTS: A total of 48 patients were included with mean C7SVA of 79.6 mm (SD: 63, range: 43-254), mean LL of 32.9° (SD: 15.9, range: -14 to 78), T10-L2 sagittal cobb angle of 3° (SD: 12.7, range: -24 to 30), and PI was 49° (SD: 10.7, range: 21 to 77). Only DM correlated with sagittal imbalance with high C7SVA and PI-LL mismatch. The beta coefficient for DM and preoperative C7SVA was 0.49, t=3.16, p=0.003, preoperative PI-LL mismatch standardized beta coefficient was -0.4, t=-2.38, p=0.022, and preoperative T10-L2 sagittal cobb standard beta coefficient was -0.07, t=-0.46, p=0.645. No significant correlations were found for asthma, COPD, HTN, HLD, or cardiomyopathy. CONCLUSIONS: Diagnosis of DM was found to correlate with pathologic C7SVA and significant PI-LL mismatch associated with ASD. HTN, HLD, cardiomyopathy, obesity, and pulmonary disease did not correlate with radiographic findings of sagittal imbalance.

Minimally Invasive Endoscopy for Acute Subdural Hematomas: A Report of 3 Cases.

BACKGROUND: Acute subdural hematomas (aSDHs) occur in approximately 10% to 20% of all closed head injury and represent a significant cause of morbidity and mortality in traumatic brain injury patients. Conventional craniotomy is an invasive intervention with the potential for excess blood loss and prolonged postoperative recovery time. OBJECTIVE: To evaluate the outcomes of minimally invasive endoscopy for evacuation of aSDHs in a pilot feasibility study. METHODS: We retrospectively reviewed the records of consecutive patients with aSDHs who underwent surgical treatment at our institution with minimally invasive endoscopy using the Apollo/Artemis Neuro Evacuation Device (Penumbra, Alameda, California) between April 2015 and July 2018. RESULTS: The study cohort comprised three patients. The Glasgow Coma Scale on admission was 15 for all 3 patients, median preoperative hematoma volume was 49.5 cm3 (range 44-67.8 cm3), median postoperative degree of hematoma evacuation was 88% (range 84%-89%), and median modified Rankin Scale at discharge was 1 (range 0-3). CONCLUSION: Endoscopic evacuation of aSDHs can be a safe and effective alternative to craniotomy in appropriately selected patients. Further studies are needed to refine the selection criteria for endoscopic aSDH evacuation and evaluate its long-term outcomes.

Low-Dose Intravenous Heparin Infusion After Aneurysmal Subarachnoid Hemorrhage is Associated With Decreased Risk of Delayed Neurological Deficit and Cerebral Infarction.

BACKGROUND: Patients who survive aneurysmal subarachnoid hemorrhage (aSAH) are at risk for delayed neurological deficits (DND) and cerebral infarction. In this exploratory cohort comparison analysis, we compared in-hospital outcomes of aSAH patients administered a low-dose intravenous heparin (LDIVH) infusion (12 U/kg/h) vs those administered standard subcutaneous heparin (SQH) prophylaxis for deep vein thrombosis (DVT; 5000 U, 3 × daily). OBJECTIVE: To assess the safety and efficacy of LDIVH in aSAH patients. METHODS: We retrospectively analyzed 556 consecutive cases of aSAH patients whose aneurysm was secured by clipping or coiling at a single institution over a 10-yr period, including 233 administered the LDIVH protocol and 323 administered the SQH protocol. Radiological and outcome data were compared between the 2 cohorts using multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW). RESULTS: The unadjusted rate of cerebral infarction in the LDIVH cohort was half that in SQH cohort (9 vs 18%; P = .004). Multivariable logistic regression showed that patients in the LDIVH cohort were significantly less likely than those in the SQH cohort to have DND (odds ratio (OR) 0.53 [95% CI: 0.33, 0.85]) or cerebral infarction (OR 0.40 [95% CI: 0.23, 0.71]). Analysis following IPTW showed similar results. Rates of hemorrhagic complications, heparin-induced thrombocytopenia and DVT were not different between cohorts. CONCLUSION: This cohort comparison analysis suggests that LDIVH infusion may favorably influence the outcome of patients after aSAH. Prospective studies are required to further assess the benefit of LDIVH infusion in patients with aSAH.

Inverse National Trends in Decompressive Craniectomy versus Endovascular Thrombectomy for Stroke.

OBJECTIVE: Endovascular thrombectomy (ET) for acute large vessel occlusion reduces infarct size, and it should hypothetically decrease the incidence of major ischemic strokes requiring decompressive craniectomy (DC). The aim of this retrospective cohort study is to determine trends in the utilization of ET versus DC for stroke in the United States over a 10-year span. METHODS: We extracted data from the Nationwide Inpatient Sample using International Classification of Diseases-9/10 codes from 2006-2016. Patients with a primary diagnosis of stroke were included. Baseline demographics, outcomes, and hospital charges were analyzed. RESULTS: The study cohort comprised 14,578,654 patients diagnosed with stroke. During the study period, DC and ET were performed in 124,718 and 62,637 patients, respectively. The number of stroke patients who underwent either ET or DC increased by 266% from 2006 to 2016. During that time period, the ET utilization rate increased (0.19% in 2006 to 14.07% in 2016, P < 0.0004), whereas the DC utilization rate decreased (7.07% in 2006 to 6.43% in 2016, P < 0.0001). In 2015, the utilization rate of ET (9.73%) exceeded that of DC (9.67%). ET-treated patients had shorter hospitalization durations (mean 8.8 vs. 16.8 days, P < 0.0001), lower mortality (16.2% vs. 19.3%), higher likelihood of discharge home (27.1% vs. 24.1%, P < 0.0001), and reduced hospital charges (mean $189,724 vs. $261,314, P < 0.0001). CONCLUSIONS: We identified an inverse relationship between national trends in rising ET and diminishing DC utilization for stroke treatment over a recent decade. Although direct causation cannot be inferred, our findings suggest that ET curtails the necessity for DC.

Blood Pressure after Endovascular Therapy for Ischemic Stroke (BEST): A Multicenter Prospective Cohort Study.

Background and Purpose- To identify the specific post-endovascular stroke therapy (EVT) peak systolic blood pressure (SBP) threshold that best discriminates good from bad functional outcomes (a priori hypothesized to be 160 mm Hg), we conducted a prospective, multicenter, cohort study with a prespecified analysis plan. Methods- Consecutive adult patients treated with EVT for an anterior ischemic stroke were enrolled from November 2017 to July 2018 at 12 comprehensive stroke centers accross the United States. All SBP values within 24 hours post-EVT were recorded. Using Youden index, the threshold of peak SBP that best discriminated primary outcome of dichotomized 90-day modified Rankin Scale score (0-2 versus 3-6) was identified. Association of this SBP threshold with the outcomes was quantified using multiple logistic regression. Results- Among 485 enrolled patients (median age, 69 [interquartile range, 57-79] years; 51% females), a peak SBP of 158 mm Hg was associated with the largest difference in the dichotomous modified Rankin Scale score (absolute risk reduction of 19%). Having a peak SBP >158 mm Hg resulted in an increased likelihood of modified Rankin Scale score 3 to 6 (odds ratio, 2.24 [1.52-3.29], P<0.01; adjusted odds ratio, 1.29 [0.81-2.06], P=0.28, after adjustment for prespecified variables). Conclusions- A peak post-EVT SBP of 158 mm Hg was prospectively identified to best discriminate good from bad functional outcome. Those with a peak SBP >158 had an increased likelihood of having a bad outcome in unadjusted, but not in adjusted analysis. The observed effect size was similar to prior studies. This finding should undergo further testing in a future randomized trial of goal-targeted post-EVT antihypertensive treatment.

Metabolic Deregulation of the Blood-Outer Retinal Barrier in Retinitis Pigmentosa.

Retinitis pigmentosa (RP) initiates with diminished rod photoreceptor function, causing peripheral and night-time vision loss. However, subsequent loss of cone function and high-resolution daylight and color vision is most debilitating. Visual pigment-rich photoreceptor outer segments (OS) undergo phagocytosis by the retinal pigment epithelium (RPE), and the RPE also acts as a blood-outer retinal barrier transporting nutrients, including glucose, to photoreceptors. We provide evidence that contact between externalized phosphatidylserine (PS) on OS tips and apical RPE receptors activates Akt, linking phagocytosis with glucose transport to photoreceptors for new OS synthesis. As abundant mutant rod OS tips shorten in RP, Akt activation is lost, and onset of glucose metabolism in the RPE and diminished glucose transport combine to cause photoreceptor starvation and accompanying retinal metabolome changes. Subretinal injection of OS tip mimetics displaying PS restores Akt activation, glucose transport, and cone function in end-stage RP after rods are lost.

Minimally Invasive Surgery for Spontaneous Cerebellar Hemorrhage: A Multicenter Study.

BACKGROUND: Spontaneous intracranial hemorrhage (ICH) of the cerebellum can be life threatening because of mass effect on the brainstem and fourth ventricle. Suboccipital craniectomy is currently the treatment of choice for cerebellar ICH evacuation. Minimally invasive surgery (MIS) is currently being investigated for the treatment of supratentorial ICH. However, its utility for cerebellar ICH is unknown. The aim of this multicenter, retrospective cohort study is to evaluate the outcomes of MIS for cerebellar ICH. METHODS: We retrospectively reviewed the records of all patients with cerebellar ICH who underwent MIS using either the Apollo or Artemis Neuro Evacuation Device (Penumbra Inc., Alameda, California, USA) at 3 institutions from May 2015 to July 2018. Data from each contributing center were deidentified and pooled for analysis. RESULTS: The study cohort comprised 6 patients with a median age of 62.5 years. The median pre- and postoperative Glasgow Coma Scale scores were 10.5 and 15, respectively. The median degree of hematoma evacuation was 97.5% (range, 79%-100%). There were no procedural complications, but 1 patient required subsequent craniectomy (retreatment rate 17%). The median discharge modified Rankin scale score was 4, including 3 patients who improved to functional independence at follow-up durations of 3 months. Two patients died from medical complications (mortality rate 33%). CONCLUSIONS: MIS could represent a reasonable alternative to conventional surgery for the treatment of appropriately selected patients with cerebellar ICH. However, further studies are needed to clarify the perioperative and long-term risk to benefit profiles of this technique.

National trends in cerebral bypass for unruptured intracranial aneurysms: a National (Nationwide) Inpatient Sample analysis of 1998-2015.

OBJECTIVEThe development and recent widespread dissemination of flow diverters may have reduced the utilization of surgical bypass procedures to treat complex or giant unruptured intracranial aneurysms (UIAs). The aim of this retrospective cohort study was to observe trends in cerebral revascularization procedures for UIAs in the United States before and after the introduction of flow diverters by using the National (Nationwide) Inpatient Sample (NIS).METHODSThe authors extracted data from the NIS database for the years 1998-2015 using the ICD-9/10 diagnostic and procedure codes. Patients with a primary diagnosis of UIA with a concurrent bypass procedure were included in the study. Outcomes and hospital charges were analyzed.RESULTSA total of 216,212 patients had a primary diagnosis of UIA during the study period. The number of patients diagnosed with a UIA increased by 128% from 1998 (n = 7718) to 2015 (n = 17,600). Only 1328 of the UIA patients (0.6%) underwent cerebral bypass. The percentage of patients who underwent bypass in the flow diverter era (2010-2015) remained stable at 0.4%. Most patients who underwent bypass were white (51%), were female (62%), had a median household income in the 3rd or 4th quartiles (57%), and had private insurance (51%). The West (33%) and Midwest/North Central regions (30%) had the highest volume of bypasses, whereas the Northeast region had the lowest (15%). Compared to the period 1998-2011, bypass procedures for UIAs in 2012-2015 shifted entirely to urban teaching hospitals (100%) and to an elective basis (77%). The median hospital stay (9 vs 3 days, p < 0.0001), median hospital charges ($186,746 vs $66,361, p < 0.0001), and rate of any complication (51% vs 17%, p < 0.0001) were approximately threefold higher for the UIA patients with bypass than for those without bypass.CONCLUSIONSDespite a significant increase in the diagnosis of UIAs over the 17-year study period, the proportion of bypass procedures performed as part of their treatment has remained stable. Therefore, advances in endovascular aneurysm therapy do not appear to have affected the volume of bypass procedures performed in the UIA population. The authors' findings suggest a potentially ongoing niche for bypass procedures in the contemporary treatment of UIAs.

Wide-neck bifurcation aneurysms of the middle cerebral artery and basilar apex treated by endovascular techniques: a multicentre, core lab adjudicated study evaluating safety and durability of occlusion (BRANCH).

BACKGROUND AND PURPOSE: BRANCH (wide-neck bifurcation aneurysms of the middle cerebral artery and basilar apex treated by endovascular techniques) is a multicentre, retrospective study comparing core lab evaluation of angiographic outcomes with self-reported outcomes. MATERIALS AND METHODS: Consecutive patients were enrolled from 10 US centres, aged between 18 and 85 with unruptured wide-neck middle cerebral artery (MCA) or basilar apex aneurysms treated endovascularly. Patient demographics, aneurysm morphology, procedural information, mortality and morbidity data and core lab and self-reported modified Raymond Roy (RR) outcomes were obtained. RESULTS: 115 patients met inclusion criteria. Intervention-related mortality and significant morbidity rates were 1.7% (2/115) and 5.8% (6/103) respectively. Core lab adjudicated RR1 and 2 occlusion rates at follow-up were 30.6% and 32.4% respectively. The retreatment rate within the follow-up window was 10/115 (8.7%) and in stent stenosis at follow-up was 5/63 (7.9%). Self-reporting shows a statistically significant direction to angiographic RR one outcomes at follow-up compared with core lab evaluation, with OR 1.75 (95% CI 1.08 to 2.83). CONCLUSION: Endovascular treatment of wide-neck MCA and basilar apex aneurysms resulted in a core lab adjudicated RR1 occlusion rate of 30.6%. Self-reported results at follow-up favour better angiographic outcomes, with OR 1.75 (95% CI 1.08 to 2.83). These data demonstrate the need for novel endovascular devices specifically designed to treat complex intracranial aneurysms, as well as the importance of core lab adjudication in assessing outcomes in such a trial.

Management of Unruptured Traumatic Middle Meningeal Artery Pseudoaneurysms through Onyx Embolization.

Traumatic pseudoaneurysms of the middle meningeal artery (MMA) represent less than 1% of all intracranial aneurysms, and occur mostly in association with temporal bone fractures following head trauma. Given the unknown natural history, it is unclear whether they should be treated. We present two cases of MMA pseudoaneurysms discovered during trauma workups. The first patient is a 44-year-old male with severe traumatic brain injury (TBI) following a motor vehicle accident. The patient was found to have two right-sided middle meningeal artery pseudoaneurysms that were treated successfully with Onyx® (Medtronic, Minneapolis, MN) embolization. The second patient is a 56-year-old male that sustained a severe TBI and skull fracture following a motorcycle collision. Angiography demonstrated an unruptured right MMA aneurysm, which was also treated successfully with Onyx embolization. MMA pseudoaneurysms occur rarely in the setting of severe traumatic injuries. In select patients, treatment by an experienced neuro-interventionalist can prevent highly morbid future intracranial hemorrhages with minimal risk of complications.

Systolic Blood Pressure Within 24 Hours After Thrombectomy for Acute Ischemic Stroke Correlates With Outcome.

BACKGROUND: Current guidelines suggest treating blood pressure above 180/105 mm Hg during the first 24 hours in patients with acute ischemic stroke undergoing any form of recanalization therapy. Currently, no studies exist to guide blood pressure management in patients with stroke treated specifically with mechanical thrombectomy. We aimed to determine the association between blood pressure parameters within the first 24 hours after mechanical thrombectomy and patient outcomes. METHODS AND RESULTS: We retrospectively studied a consecutive sample of adult patients who underwent mechanical thrombectomy for acute ischemic stroke of the anterior cerebral circulation at 3 institutions from March 2015 to October 2016. We collected the values of maximum, minimum, and average values of systolic blood pressure, diastolic blood pressure, and mean arterial pressures in the first 24 hours after mechanical thrombectomy. Primary and secondary outcomes were patients' functional status at 90 days measured on the modified Rankin scale and the incidence and severity of intracranial hemorrhages within 48 hours. Associations were explored using an ordered multivariable logistic regression analyses. A total of 228 patients were included (mean age 65.8±14.3; 104 males, 45.6%). Maximum systolic blood pressure independently correlated with a worse 90-day modified Rankin scale and hemorrhagic complications within 48 hours (adjusted odds ratio=1.02 [1.01-1.03], P=0.004; 1.02 [1.01-1.04], P=0.002; respectively) in multivariable analyses, after adjusting for several possible confounders. CONCLUSIONS: Higher peak values of systolic blood pressure independently correlated with worse 90-day modified Rankin scale and a higher rate of hemorrhagic complications. Further prospective studies are warranted to identify whether systolic blood pressure is a therapeutic target to improve outcomes.

Biomarkers and mortality in severe Chagas cardiomyopathy.

BACKGROUND: Chagas cardiomyopathy is a chronic sequela of infection by the parasite, Trypanosoma cruzi. Advanced cardiomyopathy is associated with a high mortality rate, and clinical characteristics have been used to predict mortality risk. Though multiple biomarkers have been associated with Chagas cardiomyopathy, it is unknown how these are related to survival. OBJECTIVES: This study aimed to identify biomarkers associated with mortality in individuals with severe Chagas cardiomyopathy in an urban Bolivian hospital. METHODS: The population included individuals with and without T. cruzi infection recruited in an urban hospital in Santa Cruz, Bolivia. Baseline characteristics, electrocardiogram findings, medications, and serum cardiac biomarker levels (B-type natriuretic peptide [BNP], N-terminal pro-B-type natriuretic peptide [NT-proBNP], creatine kinase-myocardial band [CK-MB], troponin I, matrix metalloproteinase [MMP]-2, MMP-9, tissue inhibitor of metalloproteinases [TIMP] 1 and 2, transforming growth factor [TGF] beta 1 and 2) were ascertained. Echocardiograms were performed on those with cardiac symptoms or electrocardiogram abnormalities at baseline. Participants were contacted approximately 1 year after initial evaluation; deaths were reported by family members. Receiver-operating characteristic curves (ROC) were used to optimize cutoff values for each marker. For markers with area under the curve (AUC) >0.55, Cox proportional hazards models were performed to determine the hazards ratio (HR) and 95% confidence interval (CI) for the association of each marker with mortality. RESULTS: The median follow-up time was 14.1 months (interquartile range 12.5, 16.7). Of 254 individuals with complete cardiac data, 220 (87%) had follow-up data. Of 50 patients with severe Chagas cardiomyopathy at baseline, 20 (40%) had died. Higher baseline levels of BNP (HR: 3.1, 95% CI: 1.2 to 8.4), NT-proBNP (HR: 4.4, 95% CI: 1.8 to 11.0), CK-MB (HR: 3.3, 95% CI: 1.3 to 8.0), and MMP-2 (HR: 4.2, 95% CI: 1.5 to 11.8) were significantly associated with subsequent mortality. CONCLUSIONS: Severe Chagas cardiomyopathy is associated with high short-term mortality. BNP, NT-proBNP, CK-MB, and MMP-2 have added predictive value for mortality, even in the presence of decreased ejection fraction and other clinical signs of congestive heart failure.