Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants.

PURPOSE: Facilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically. METHODS: This phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. RESULTS: Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms. CONCLUSION: The favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Stroke-Related Visceral Alterations: A Voxel-Based Neuroanatomic Localization Study.

OBJECTIVE: Functional and morphologic changes in extracranial organs can occur after acute brain injury. The neuroanatomic correlates of such changes are not fully known. Herein, we tested the hypothesis that brain infarcts are associated with cardiac and systemic abnormalities (CSAs) in a regionally specific manner. METHODS: We generated voxelwise p value maps of brain infarcts for poststroke plasma cardiac troponin T (cTnT) elevation, QTc prolongation, in-hospital infection, and acute stress hyperglycemia (ASH) in 1,208 acute ischemic stroke patients prospectively recruited into the Heart-Brain Interactions Study. We examined the relationship between infarct location and CSAs using a permutation-based approach and identified clusters of contiguous voxels associated with p < 0.05. RESULTS: cTnT elevation not attributable to a known cardiac reason was detected in 5.5%, QTc prolongation in the absence of a known provoker in 21.2%, ASH in 33.9%, and poststroke infection in 13.6%. We identified significant, spatially segregated voxel clusters for each CSA. The clusters for troponin elevation and QTc prolongation mapped to the right hemisphere. There were 3 clusters for ASH, the largest of which was in the left hemisphere. We found 2 clusters for poststroke infection, one associated with pneumonia in the left and one with urinary tract infection in the right hemisphere. The relationship between infarct location and CSAs persisted after adjusting for infarct volume. INTERPRETATION: Our results show that there are discrete regions of brain infarcts associated with CSAs. This information could be used to bootstrap toward new markers for better differentiation between neurogenic and non-neurogenic mechanisms of poststroke CSAs. ANN NEUROL 2023;94:1155-1163.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Adverse effects of maternal retinyl palmitate, a vitamin A compound, on the fetal liver.

Background: Consuming high doses of vitamin A during pregnancy may lead to malformations in the offspring. Some reports state that low doses that do not cause macroscopic abnormalities may result in mental and behavioral disorders. However, there are few studies on the microscopic effects of these doses on the organism. Objective: The aim was to investigate the effects of early prenatal exposure to different doses of oral vitamin A on the fetal liver. Materials and methods: Twenty-five pregnant rats, divided into five groups, received oral vitamin A at doses of 10,000, 50,000, 100,000, and 200,000 IU/kg between days 10 and 12 of gestation. The fetuses were collected on day 19 of gestation, their livers were dissected, and histology, apoptosis, and proliferation were examined by hematoxylin-eosin, TUNEL assay, and Ki67 immunolabeling using stereological methods. Results: Vitamin A decreased fetal liver volume, the number of Ki67-positive cells per unit volume, and the total number of hepatocytes at all doses except 10,000 IU/kg (p<0.001). Consequently, apoptosis was significantly higher in the groups receiving 100,000 and 200,000 IU/kg vitamin A (p<0.001). Conclusion: Our study shows that vitamin A administered during gestation days 10-12 has a suppressive effect on the developing rat liver when the dose exceeds 10,000 IU/kg, probably due to increased apoptosis and suppressed cell division.

Stroke Care during the COVID-19 Pandemic: International Expert Panel Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.

White matter hyperintensity determines ischemic stroke severity in symptomatic carotid artery stenosis.

INTRODUCTION: The aim of this study is to investigate the influence of white matter hyperintensity (WMH) on stroke severity and prognosis in patients with symptomatic carotid artery stenosis. METHODS: Patients with symptomatic carotid artery stenosis were retrieved from the Samsung Medical Center stroke registry from January 2011 to December 2016. Stroke severity was categorized into three levels according to National Institutes of Health Stroke Scale (NIHSS): transient ischemic attack (TIA) or transient symptoms with infarction (TSI), mild stroke, and moderate to severe stroke. WMH volume was measured with medical image processing and visualization. The clinical outcome was assessed using the modified Rankin scale on the 90th day from which the latest onset of the neurological symptom. Logistic regression was used to predict stroke severity, and ordinal regression was used to compare the clinical outcome. RESULTS: Among 158 patients, the numbers of patients with TIA or TSI, mild stroke, and moderate to severe stroke were 48 (30.4%), 59 (37.3%), and 51 (32.3%), respectively. The larger WMH volume was associated with moderate to severe strokes (TIA/TSI vs. moderate to severe strokes, odds ratio (OR) 2.318, 95% confidence interval (CI) 1.194-4.502, p = 0.007; mild vs. moderate to severe strokes, OR 1.972, 95% CI 1.118-3.479, p = 0.013). Patients with larger volume of WMH showed poorer clinical outcome (cutoff value: 9.71 cm3, OR 2.099, 95% CI 1.030-4.311, p = 0.042). CONCLUSION: Our study showed that larger WMH volume is associated with more severe stroke and poorer prognosis in patients with symptomatic carotid artery stenosis.

Cerebral Small Vessel Diseases and Sleep Related Strokes.

BACKGROUND AND PURPOSE: Sleep related Stroke (SRS) is common and has been associated with cerebral small vessel diseases (SVD) in ischemic strokes (ISs). We tested the hypothesis that SRS is associated with SVD in both ischemic and hemorrhagic stroke. METHODS: Prospectively collected data from patients consecutively enrolled after intracerebral hemorrhage (ICH) related to SVD or after IS were analyzed. Symptom onset was recorded as SRS versus awake. Each ICH was grouped according to lobar and deep locations. The IS cohort was etiologically characterized based on the Causative Classification of Stroke system. Frequencies of SRS within and between ICH and IS cohorts as well as its associations (etiology, risk factors) were analyzed. RESULTS: We analyzed 1812 IS (mean age 67.9 years ± 15.9 years, 46.4% female) and 1038 ICH patients (mean age 72.5 years ± 13.0 years, 45.4% female). SRS was significantly more common among SVD-related ICH patients (n = 276, 26.6%) when compared to all IS (n = 363, 20.0%, P < .001) and in both, small artery occlusion (SAO) related IS and lobar ICH within the respective IS and ICH cohorts (16.3% SRS versus 9.1% awake for SAO within all IS, P < .001; and 57.1% SRS versus 47.7% awake for lobar bleeds within all ICH, P = .008). These associations remained significant after controlling for age, sex and risk factors. CONCLUSIONS: SRS was associated with SVD. The SAO etiology and cerebral amyloid angiopathy related lobar ICH suggest that the presence of SVD can interact with sleep or arousal related hemodynamic changes to cause ischemic and hemorrhagic stroke.

Reduced Ischemic Lesion Growth with Heparin in Acute Ischemic Stroke.

OBJECTIVE: The role of heparin in acute ischemic stroke is controversial. We investigated the effect of heparin on ischemic lesion growth. METHODS: Data were analyzed on nonthrombolyzed ischemic stroke patients in whom diffusion-weighted imaging (DWI)/perfusion-weighted imaging (PWI) MRI was performed less than 12 hours of last known well and showed a PWI-DWI lesion mismatch, and who underwent follow-up neuroimaging at least 4 days after admission. Lesion growth was assessed by (1) absolute lesion growth and (2) percentage mismatch lost (PML). Univariate and multivariate regression analysis, and propensity score matching, were used to determine the effects of heparin on ischemic lesion growth. RESULTS: Of the 113 patients meeting study criteria, 59 received heparin within 24 hours. Heparin use was associated with ∼5-fold reductions in PML (3.5% versus 19.2%, P = .002) and absolute lesion growth (4.7 versus 20.5 mL, P = .009). In multivariate regression models, heparin independently predicted reduced PML (P = .04) and absolute lesion growth (P = .04) in the entire cohort, and in multiple subgroups (patients with and without proximal artery occlusion; DWI volume greater than 5 mL; cardio-embolic mechanism; DEFUSE-3 target mismatch). In propensity score matching analysis where patients were matched by admission NIHSS, DWI volume and proximal artery occlusion, heparin remained an independent predictor of PML (P = .048) and tended to predict absolute lesion growth (P = .06). Heparin treatment did not predict functional outcome at discharge or 90 days. CONCLUSION: Early heparin treatment in acute ischemic stroke patients with PWI-DWI mismatch attenuates ischemic lesion growth. Clinical trials with careful patient selection are warranted to investigate the potential ischemic protective effects of heparin.

New biomarker for acute ischaemic stroke: plasma glycogen phosphorylase isoenzyme BB.

BACKGROUND: Glycogen phosphorylase is the key enzyme that breaks down glycogen to yield glucose-1-phosphate in order to restore depleted energy stores during cerebral ischaemia. We sought to determine whether plasma levels of glycogen phosphorylase BB (GPBB) isoform increased in patients with acute ischaemic stroke (AIS). METHODS: We studied plasma GPBB levels within 12 hours and again at 48±24 hours of symptom onset in 172 patients with imaging-confirmed AIS and 133 stroke-free individuals. We determined the ability of plasma GPBB to discriminate between cases and controls and examined the predictive value of plasma GPBB for 90-day functional outcome, 90-day survival and acute lesion volumes on neuroimaging. RESULTS: The mean (SD) GPBB levels were higher in cases (46.3±38.6 ng/mL at first measurement and 38.6±36.5 ng/mL at second measurement) than in controls (4.1±7.6 ng/mL, p<0.01 for both). The area under the receiver operating characteristic (ROC) curve for case-control discrimination based on first GPBB measurement was 0.96 (95% CI 0.93 to 0.98). The sensitivity and specificity based on optimal operating point on the ROC curve (7.0 ng/mL) were both 93%. GPBB levels increased in 90% of patients with punctate infarcts (<1.5 mL) and in all patients admitted within the first 4.5 hours of onset. There was no correlation between GPBB concentration and either clinical outcome or acute infarct volume. CONCLUSION: GPBB demonstrates robust response to acute ischaemia and high sensitivity for small infarcts. If confirmed in more diverse populations that also include stroke mimics, GPBB could find utility as a stand-alone marker for acute brain ischaemia.

Baseline Predictors of Poor Outcome in Patients Too Good to Treat With Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: Several studies have reported poor outcomes in patients too good to treat with intravenous thrombolysis because of mild or rapidly improving symptoms. We sought to determine baseline clinical and imaging predictors of poor outcome in these patients. METHODS: Among 3950 consecutive stroke admissions (2009-2015) in our local Get With the Guidelines-Stroke database, 632 patients presented ≤4.5 hours and did not receive tissue-type plasminogen activator, with 380 of 632 (60.1%) being too good to treat. Univariate and multivariable analyses explored the clinical and imaging features associated with poor outcome (defined as not being discharged to home) in these 380 cases. RESULTS: Among these 380 cases, only 68% were discharged home; the other 25% to inpatient rehabilitation, 4% to a skilled nursing facility, and 3% expired or were discharged to hospice. Patients with poor outcome were older, were more often Hispanic, had more vascular risk factors, and had higher median National Institutes of Health Stroke Scale. Imaging characteristics associated with poor outcomes included large or multifocal infarction and poor collaterals. In multivariable analysis, only age, initial National Institutes of Health Stroke Scale, and infarct location were independently associated with poor outcome. CONCLUSIONS: Approximately one third of patients deemed too good for intravenous tissue-type plasminogen activator are unable to be discharged directly to home. Given the current safety profile of intravenous tissue-type plasminogen activator, our results suggest that the concept of being too good to treat should be re-examined with an emphasis on the features associated with poor outcome identified in our study. If replicated, these findings could be incorporated into tissue-type plasminogen activator decision-making algorithms.

Association between atrial fibrillation and silent cerebral infarctions: a systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is a common cause of stroke. Silent cerebral infarctions (SCIs) are known to occur in the presence and absence of AF, but the association between these disorders has not been well-defined. PURPOSE: To estimate the association between AF and SCIs and the prevalence of SCIs in stroke-free patients with AF. DATA SOURCES: Searches of MEDLINE, PsycINFO, Cochrane Library, CINAHL, and EMBASE from inception to 8 May 2014 without language restrictions and manual screening of article references. STUDY SELECTION: Observational studies involving adults with AF and no clinical history of stroke or prosthetic valves who reported SCIs. DATA EXTRACTION: Study characteristics and study quality were assessed in duplicate. DATA SYNTHESIS: Eleven studies including 5317 patients with mean ages from 50.0 to 83.6 years reported on the association between AF and SCIs. Autopsy studies were heterogeneous and low-quality; therefore, they were excluded from the meta-analysis of the risk estimates. When computed tomography (CT) and magnetic resonance imaging (MRI) studies were combined, AF was associated with SCIs in patients with no history of symptomatic stroke (odds ratio, 2.62 [95% CI, 1.81 to 3.80]; I(2) = 32.12%; P for heterogeneity = 0.118). This association was independent of AF type (paroxysmal vs. persistent). The results were not altered significantly when the analysis was restricted to studies that met at least 70% of the maximum possible quality score (odds ratio, 3.06 [CI, 2.24 to 4.19]). Seventeen studies reported the prevalence of SCIs. The overall prevalence of SCI lesions on MRI and CT among patients with AF was 40% and 22%, respectively. LIMITATION: Most studies were cross-sectional, and autopsy studies were heterogeneous and not sufficiently sensitive to detect small lesions. CONCLUSION: Atrial fibrillation is associated with more than a 2-fold increase in the odds for SCI. PRIMARY FUNDING SOURCE: Deane Institute for Integrative Research in Atrial Fibrillation and Stroke, Massachusetts General Hospital.

Efficiency of hyperbaric oxygen and steroid therapy in treatment of hearing loss following acoustic trauma.

INTRODUCTION: Most commonly used treatment modalities for acute acoustic trauma (AAT) include steroid and hyperbaric oxygen (HBO2) therapy. The aim of this study is to investigate the effectiveness of combined steroid and HBO2 therapy in patients who develop AAT during firearms training and the effect of delay to treatment on treatment success. MATERIALS AND METHODS: Patients admitted with the complaint of hearing loss after firearms training between January 2011 and April 2013 were evaluated retrospectively. Patients were grouped according to date of admission; patients admitted within the first 10 days were included in Group A and those admitted between Days 11 and 30 in Group B. RESULTS: A total of 48 patients (73 ears) with AAT were included. There were 37 ears in Group A and 36 ears in Group B. The number of ears with complete treatment response, partial treatment response and treatment failure (unchanged) were one (2.7%), 7 (18.9%) and 29 (78.4%) in Group A and 0 (0%), 3 (8.3%) and 33 (91.7%) in Group B, respectively. There was no statistically significant difference between the groups (p = 0.095). Late-term results (at Week 6) demonstrated Group A showed higher hearing gain on high frequencies than Group B (p < 0.05), but this result was not consistent with clinical outcome results. CONCLUSION: The success rate of combined HBO2 and steroid therapy was very low in our study. However, early initiation of treatment results in better outcomes. Protective measures have great importance in preventing AAT.

Extensive leukoaraiosis is associated with high early risk of recurrence after ischemic stroke.

BACKGROUND AND PURPOSE: The integrity of white matter tracts connecting different parts of the brain is important for rapid compensation for the lost function from ischemic stroke. Impaired white matter reserve capacity secondary to leukoaraiosis may facilitate detection of new symptomatic ischemic events that would otherwise remain inconspicuous after an initial ischemic stroke. We sought to identify whether the extent of leukoaraiosis was a predictor of risk of early stroke recurrence. METHODS: We used Cox regression analysis in consecutive patients with ischemic stroke to determine the relationship between leukoaraiosis burden and symptomatic stroke recurrence within 90 days. We graded total leukoaraiosis, periventricular leukoaraiosis, and subcortical leukoaraiosis using the Fazekas scale as mild (<2) and extensive (≥2) on fluid-attenuated inversion recovery images obtained within 72 hours of stroke onset in the hemisphere contralateral to acute stroke. RESULTS: There were 106 recurrent events in 2378 patients. The cumulative incidence of recurrence was 5.9% at 90 days. Kaplan-Meier estimate of recurrence-free survival rate was lower in patients with extensive leukoaraiosis (P=0.04) and extensive periventricular leukoaraiosis (P=0.02) but not in extensive subcortical leukoaraiosis (P=0.09). Multivariable Cox regression analysis revealed a hazard ratio of 1.50 (95% confidence interval, 1.00-2.25) for extensive leukoaraiosis, 1.67 (95% confidence interval, 1.11-2.51) for extensive periventricular leukoaraiosis, and 1.42 (95% confidence interval, 0.94-2.12) for extensive subcortical leukoaraiosis. CONCLUSIONS: The extent of leukoaraiosis independently predicts 90-day recurrent stroke risk after ischemic stroke. This suggests that leukoaraiosis may be used for risk stratification in ischemic stroke.

Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

BACKGROUND AND PURPOSE: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. METHODS: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. RESULTS: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). CONCLUSIONS: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.

The effect of hyperbaric conditions on olfactory functions.

OBJECTIVE: The aim of this study was to investigate the effect of increased atmospheric pressure (AP) on olfactory function. SUBJECTS AND METHODS: The present study included 40 healthy volunteers with no history of chronic rhinosinusitis and nasal polyposis. The experimental procedure consisted of two episodes: (a) baseline episode, with normal AP; 1 absolute atmosphere (atm abs) in a test room at sea level; (b) experimental episode, increased level of AP; 2.4 atm abs in the hyperbaric chamber. Sino-nasal outcome test-20, Trail Making Test A and olfactory testing were performed in each episodes. RESULTS: The study group consisted of 23 men (57.5%) and 17 women (42.5%); the mean age of the study population was 38.7 +/- 9 years (range 23-58 years). The current investigation produced two major findings: (1) the mean of odor threshold scores was significantly increased in the hyperbaric condition when compared to the normobaric condition; (2) rather, there was no significant change in odor discrimination and identification scores in the hyperbaric condition. CONCLUSION: Based on two measurements taken at two different barometric pressures and the same temperature and relative humidity, this study suggests that odor threshold scores increase under hyperbaric conditions.

Antibiotherapy with and without bone debridement in diabetic foot osteomyelitis: A retrospective cohort study.

BACKGROUND AND OBJECTIVE: The treatment of diabetic foot osteomyelitis (DFO) is a controversial issue, with disagreement regarding whether the best treatment is surgical or conservative. The purpose of this study was to compare the outcome of patients with DFO who were treated with antibiotherapy alone and those who underwent concurrent minor amputation. METHODS: Hospital records of patients who were diagnosed as having DFO within a 2-year study period were retrospectively reviewed. Patients were divided into two groups: those who received antibiotherapy alone and those who underwent concurrent minor amputation. Groups were compared in terms of duration in hospitalization, antibiotherapy, and wound healing. RESULTS: Thirty seven patients were included in the study. These comprised patients who received antibiotherapy alone (ABG, n=15) and patients who underwent concurrent minor amputation (AB-MAG, n=22). Hospitalization duration was 37.2 (± 16.2) days in ABG and 52.8 (± 40.2) days in AB-MAG (p = 0.166). Mean duration of antibiotherapy was 45.0 (± 21.7) days in ABG and 47.7 (± 19) days in AB-MAG (p = 0.689). Wound healing duration was 265.2 (± 132.7) days in ABG and 222.6 (± 85.9) days in AB-MAG (p = 0.243). None of the outcome measures were significantly different between ABG and AB-MAG. CONCLUSIONS: Our results have shown similar outcomes for both patient groups who received antibiotherapy alone and who underwent concurrent minor amputations. Considering the small sample sizes in this study, it is important to confirm these results on a larger scale.

Autistic-like behaviour and changes in thalamic cell numbers a rat model of valproic acid-induced autism; A behavioural and stereological study.

The contribution of the thalamus to the development and behavioural changes in autism spectrum disorders (ASD), a neurodevelopmental syndrome, remains unclear. The aim of this study was to determine the changes in thalamic volume and cell number in the valproic acid (VPA)-induced ASD model using stereological methods and to clarify the relationship between thalamus and ASD-like behaviour. Ten pregnant rats were administered a single dose (600 mg/kg) of VPA intraperitoneally on G12.5 (VPA group), while five pregnant rats were injected with 5 ml saline (control group). Behavioural tests were performed to determine appropriate subjects and ASD-like behaviours. At P55, the brains of the subjects were removed. The sagittal sections were stained with cresyl violet and toluidine blue. The thalamic and hemispheric volumes with their ratios, the total number of thalamic cells, neurons and non-neuronal cells were calculated using stereological methods. Data were compared using a t-test and a Pearson correlation analysis was performed to examine the relationship between behaviour and stereological outcomes. VPA-treated rats had lower sociability and sociability indexes. There was no difference in social novelty preference and anxiety. The VPA group had larger hemispheric volume, lower thalamic volume, and fewer neurons. The highest percentage decrease was in non-neuronal cells. There was a moderate positive correlation between the number of non-neuronal cells and sociability, thalamic volume and the number of neurons as well as the time spent in the light box. The correlation between behaviour and stereological data suggests that the thalamus is associated with ASD-like behaviour.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Reduction in early stroke risk in carotid stenosis with transient ischemic attack associated with statin treatment.

BACKGROUND AND PURPOSE: Statins reduce stroke risk when initiated months after transient ischemic attack (TIA)/stroke and reduce early vascular events in acute coronary syndromes, possibly via pleiotropic plaque stabilization. Few data exist on acute statin use in TIA. We aimed to determine whether statin pretreatment at TIA onset modified early stroke risk in carotid stenosis. METHODS: We analyzed data from 2770 patients with TIA from 11 centers, 387 with ipsilateral carotid stenosis. ABCD2 score, abnormal diffusion weighted imaging, medication pretreatment, and early stroke were recorded. RESULTS: In patients with carotid stenosis, 7-day stroke risk was 8.3% (95% confidence interval [CI], 5.7-11.1) compared with 2.7% (CI, 2.0%-3.4%) without stenosis (P<0.0001; 90-day risks 17.8% and 5.7% [P<0.0001]). Among carotid stenosis patients, nonprocedural 7-day stroke risk was 3.8% (CI, 1.2%-9.7%) with statin treatment at TIA onset, compared with 13.2% (CI, 8.5%-19.8%) in those not statin pretreated (P=0.01; 90-day risks 8.9% versus 20.8% [P=0.01]). Statin pretreatment was associated with reduced stroke risk in patients with carotid stenosis (odds ratio for 90-day stroke, 0.37; CI, 0.17-0.82) but not nonstenosis patients (odds ratio, 1.3; CI, 0.8-2.24; P for interaction, 0.008). On multivariable logistic regression, the association remained after adjustment for ABCD2 score, smoking, antiplatelet treatment, recent TIA, and diffusion weighted imaging hyperintensity (adjusted P for interaction, 0.054). CONCLUSIONS: In acute symptomatic carotid stenosis, statin pretreatment was associated with reduced stroke risk, consistent with findings from randomized trials in acute coronary syndromes. These data support the hypothesis that statins started acutely after TIA symptom onset may also be beneficial to prevent early stroke. Randomized trials addressing this question are required.