Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.

Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular ß-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease-modifying treatment currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits. Here, we review recent advances in our understanding of AD pathobiology and discuss current treatment strategies, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies.

Superficial parasternal intercostal plane blocks in cardiac surgery: a systematic review and meta-analysis.

PURPOSE: Traditional multimodal analgesic strategies have several contraindications in cardiac surgery patients, forcing clinicians to use alternative options. Superficial parasternal intercostal plane blocks, anesthetizing the anterior cutaneous branches of the thoracic intercostal nerves, are being explored as a straightforward method to treat pain after sternotomy. We sought to evaluate the literature on the effects of superficial parasternal blocks on pain control after cardiac surgery. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We searched MEDLINE, Embase, CENTRAL, and Web of Science databases for RCTs evaluating superficial parasternal intercostal plane blocks in adult patients undergoing cardiac surgery via midline sternotomy published from inception to 11 March 2022. The prespecified primary outcome was opioid consumption at 12 hr. The risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool, and the quality of evidence was evaluated using the grading of recommendations, assessments, development, and evaluations. Outcomes were analyzed with a random-effects model. All subgroups were prespecified. RESULTS: We reviewed 1,275 citations. Eleven RCTs, comprising 756 patients, fulfilled the inclusion criteria. Only one study reported the prespecified primary outcome, precluding the possibility of meta-analysis. This study reported a reduction in opioid consumption (-11.2 mg iv morphine equivalents; 95% confidence interval [CI], -8.2 to -14.1) There was a reduction in opioid consumption at 24 hr (-7.2 mg iv morphine equivalents; 95% CI, -5.6 to -8.7; five trials; 436 participants; moderate certainty evidence). All five studies measuring complications reported that none were detected, which included a sample of 196 blocks. CONCLUSION: The literature suggests a potential benefit of using superficial parasternal blocks to improve acute postoperative pain control after cardiac surgery via midline sternotomy. Future studies specifying dosing regimens and adjuncts are required. STUDY REGISTRATION: PROSPERO (CRD42022306914); first submitted 22 March 2022.

RéSUMé: OBJECTIF: Il existe plusieurs contre-indications aux stratégies analgésiques multimodales traditionnelles chez la patientèle de chirurgie cardiaque, ce qui oblige les clinicien·nes à se tourner vers d'autres options. Les blocs des plans intercostaux parasternaux superficiels, anesthésiant les branches cutanées antérieures des nerfs intercostaux thoraciques, sont l'une des méthodes simples actuellement explorées pour traiter la douleur après une sternotomie. Nous avons cherché à évaluer la littérature sur les effets des blocs parasternaux superficiels sur le contrôle de la douleur après une chirurgie cardiaque. MéTHODE: Nous avons réalisé une revue systématique et une méta-analyse des études randomisées contrôlées (ERC). Nous avons fait des recherches dans les bases de données MEDLINE, Embase, CENTRAL et Web of Science pour en tirer les ERC évaluant les blocs des plans intercostaux parasternaux superficiels chez les patient·es adultes bénéficiant d'une chirurgie cardiaque par sternotomie médiane publiées depuis leur création jusqu'au 11 mars 2022. Le critère d'évaluation principal préspécifié était la consommation d'opioïdes à 12 heures. Le risque de biais a été évalué à l'aide de l'outil Cochrane Collaboration Risk of Bias, et la qualité des données probantes à l'aide de l'outil GRADE. Les résultats ont été analysés à l'aide d'un modèle à effets aléatoires. Tous les sous-groupes étaient préspécifiés. RéSULTATS: Nous avons examiné 1275 citations. Onze ERC, comprenant 756 patient·es, remplissaient les critères d'inclusion. Une seule étude a rapporté le critère d'évaluation principal préspécifié, ce qui a exclu la possibilité d'une méta-analyse. Cette étude a rapporté une réduction de la consommation d'opioïdes (−11,2 mg équivalents de morphine iv; intervalle de confiance [IC] à 95 %, −8,2 à −14,1). Il y a eu une réduction de la consommation d'opioïdes à 24 heures (−7,2 mg équivalents de morphine iv; IC 95 %, −5,6 à −8,7; cinq études; 436 participant·es; données probantes de certitude modérée). Les cinq études mesurant les complications ont rapporté qu'aucune complication n'avait été détectée, en incluant un échantillon de 196 blocs. CONCLUSION: La littérature suggère un avantage potentiel de l'utilisation de blocs parasternaux superficiels pour améliorer le contrôle de la douleur postopératoire aiguë après une chirurgie cardiaque par sternotomie médiane. Des études futures précisant les schémas posologiques et les adjuvants sont nécessaires. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42022306914); soumis pour la première fois le 22 mars 2022.

Impact of a Multidisciplinary Service Line and Program for Transcatheter Device Closure of the Neonatal Ductus Arteriosus.

Outline a quality initiative establishing an institutional service line for neonatal transcatheter device closure of the patent ductus arteriosus (TDC-PDA). A retrospective descriptive observational study surrounds programmatic approach to TDC-PDA in premature neonates with process measure spanning education, implementation, referral, and post-procedural care. Metrics tracked pre- and post-program creation with statistical analyses performed. Neonatal TDC-PDA referrals increased exponentially since program inception (n = 13 in year prior; n = 42 year 1; n = 74 year 2), especially in patients weighing less than 1.3 kg (12.5%; 55%; 50%), and were associated with an increased procedural success rate (81%; 95%; 99%). Procedural checklist creation decreased procedural "out of isolette" time (median 93 min; 59; 52), and procedural-related complication or clinical sequelae (19%; 12%; 4%). A multidisciplinary service line and program dedicated to neonatal TDC-PDA can result in a significant increase in referrals as well as procedural efficacy and safety for this medically fragile population.

Team dynamics after implementation of guidelines for anaesthesia for children with CHD.

Guidelines were created at our single centrer institution for which anesthesiology team should care for pediatric cardiac patients for noncardiac surgery. The goal of the survey was to assess inter-team dynamics after the implementation of guidelines and revealed that practice behaviour can quickly change but a sustained change in team dynamics and workplace culture takes time.

Regulation of astrocyte lipid metabolism and ApoE secretionby the microglial oxysterol, 25-hydroxycholesterol.

Neuroinflammation, a major hallmark of Alzheimer's disease and several other neurological and psychiatric disorders, is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC). 25HC is an oxysterol with interesting immune roles stemming from its ability to regulate cholesterol metabolism. Since astrocytes synthesize cholesterol in the brain and transport it to other cells via ApoE-containing lipoproteins, we hypothesized that secreted 25HC from microglia may influence lipid metabolism as well as extracellular ApoE derived from astrocytes. Here, we show that astrocytes take up externally added 25HC and respond with altered lipid metabolism. Extracellular levels of ApoE lipoprotein particles increased after treatment of astrocytes with 25HC without an increase in Apoe mRNA expression. In mouse astrocytes-expressing human ApoE3 or ApoE4, 25HC promoted extracellular ApoE3 better than ApoE4. Increased extracellular ApoE was due to elevated efflux from increased Abca1 expression via LXRs as well as decreased lipoprotein reuptake from suppressed Ldlr expression via inhibition of SREBP. 25HC also suppressed expression of Srebf2, but not Srebf1, leading to reduced cholesterol synthesis in astrocytes without affecting fatty acid levels. We further show that 25HC promoted the activity of sterol-o-acyl transferase that led to a doubling of the amount of cholesteryl esters and their concomitant storage in lipid droplets. Our results demonstrate an important role for 25HC in regulating astrocyte lipid metabolism.

Preclinical Alzheimer's disease biomarkers accurately predict cognitive and neuropathological outcomes.

Alzheimer's disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer's disease biomarkers predict Alzheimer's neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer's disease neuropathological findings. This study included 720 participants, 42-91 years of age, who were enrolled in longitudinal studies of memory and aging in the Washington University Knight Alzheimer Disease Research Center and were cognitively normal at baseline, underwent amyloid PET imaging and/or CSF collection within 1 year of baseline clinical assessment, and had subsequent clinical follow-up. Cognitive status was assessed longitudinally by Clinical Dementia Rating®. Biomarker status was assessed using predefined cut-offs for amyloid PET imaging or CSF p-tau181/amyloid-ß42. Subsequently, 57 participants died and underwent neuropathologic examination. Alzheimer's disease neuropathological changes were assessed using standard criteria. We assessed the predictive value of Alzheimer's disease biomarker status on progression to cognitive impairment and for presence of Alzheimer's disease neuropathological changes. Among cognitively normal participants with positive biomarkers, 34.4% developed cognitive impairment (Clinical Dementia Rating > 0) as compared to 8.4% of those with negative biomarkers. Cox proportional hazards modelling indicated that preclinical Alzheimer's disease biomarker status, APOE ɛ4 carrier status, polygenic risk score and centred age influenced risk of developing cognitive impairment. Among autopsied participants, 90.9% of biomarker-positive participants and 8.6% of biomarker-negative participants had Alzheimer's disease neuropathological changes. Sensitivity was 87.0%, specificity 94.1%, positive predictive value 90.9% and negative predictive value 91.4% for detection of Alzheimer's disease neuropathological changes by preclinical biomarkers. Single CSF and amyloid PET baseline biomarkers were also predictive of Alzheimer's disease neuropathological changes, as well as Thal phase and Braak stage of pathology at autopsy. Biomarker-negative participants who developed cognitive impairment were more likely to exhibit non-Alzheimer's disease pathology at autopsy. The detection of preclinical Alzheimer's disease biomarkers is strongly predictive of future cognitive impairment and accurately predicts presence of Alzheimer's disease neuropathology at autopsy.

Postoperative Hematocrit and Adverse Outcomes in Pediatric Cardiac Surgery Patients: A Cross-Sectional Study From the Society of Thoracic Surgeons and Congenital Cardiac Anesthesia Society Database Collaboration.

BACKGROUND: We sought to examine potential associations between pediatric postcardiac surgical hematocrit values and postoperative complications or mortality. METHODS: A retrospective, cross-sectional study from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) and Congenital Cardiac Anesthesia Society Database Module (2014-2019) was completed. Multivariable logistic regression models, adjusting for covariates in the STS-CHSD mortality risk model, were used to assess the relationship between postoperative hematocrit and the primary outcomes of operative mortality or any major complication. Hematocrit was assessed as a continuous variable using linear splines to account for nonlinear relationships with outcomes. Operations after which the oxygen saturation is typically observed to be <92% were classified as cyanotic and ≥92% as acyanotic. RESULTS: In total, 27,462 index operations were included, with 4909 (17.9%) being cyanotic and 22,553 (82.1%) acyanotic. For cyanotic patients, each 5% incremental increase in hematocrit over 42% was associated with a 1.31-fold (95% confidence interval [CI], 1.10-1.55; P = .003) increase in the odds of operative mortality and a 1.22-fold (95% CI, 1.10-1.36; P < .001) increase in the odds of a major complication. For acyanotic patients, each 5% incremental increase in hematocrit >38% was associated with a 1.45-fold (95% CI, 1.28-1.65; P < .001) increase in the odds of operative mortality and a 1.21-fold (95% CI, 1.14-1.29; P < .001) increase in the odds of a major complication. CONCLUSIONS: High hematocrit on arrival to the intensive care unit (ICU) is associated with increased operative mortality and major complications in pediatric patients following cardiac surgery.

Novel upregulation of amyloid-ß precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease.

In addition to the devastating symptoms of dementia, Alzheimer's disease (AD) is characterized by accumulation of the processing products of the amyloid-ß (Aß) peptide precursor protein (APP). APP's non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3'-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5'-UTR to upregulate APP translation and Aß production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a "FeAR" (Fe, APP, RNA) nexus in the APP 5'-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a "healthy FeAR" exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production.

Neonatal intensive care unit patients recovering in the post anesthesia care unit: An observational analysis of postextubation complications.

BACKGROUND: Neonatal patients are at higher risk in the perioperative period than older infants and children. Extubation as an early goal for noenatal intensive care unit patients presenting for surgery is undergoing a renaissance period, and an exploration of adverse events following selection for extubation immediately after general anesthesia has not specifically been undertaken in this population. AIMS: The objective of this study is to determine the adverse events most commonly encountered in neonatal intensive care unit patients recovering from anesthesia in the post anesthesia care unit, quantify the risk of event occurrence, and identify risk factors that may increase the risk of postoperative adverse events. METHODS: All neonatal intensive care unit patients presenting to the operating room 6/1/2014-5/31/2018 who recovered in the  post anesthesia care unit were included for analysis. Univariate analyses were conducted utilizing the Wilcoxon rank-sum test or Fisher exact test. Due to the low event rate, a small-sample generalized estimating equation model was created with a major event composite as the outcome and explanatory variables with P values < .1 on univariate analysis. Statistically significant continuous variables were then dichotomized based on Youden index. RESULTS: There were 707 operative cases in 607 patients. There were 81 total events recorded, and 64/81 were considered to be major events; all of which were respiratory. The risk of any postoperative event was 11.5%, major respiratory event requiring intervention by a nurse or provider was 9.1%, and reintubation was 0.8%. Birth weight < 1.58 kg (OR 3.71; 95% CI 2.11-6.53; P < .001) and postmenstrual age at surgery <41 weeks (OR 3.20; 95% CI 1.54-6.63; P < .001) were strongly associated with an increased risk of a major postoperative respiratory event. CONCLUSION: The most important factors associated with major events in the post anesthesia care unit following extubation of neonatal intensive care unit patients were birth weight < 1.58 kg and postmenstrual age at surgery < 41 weeks. A patient with both features has a 7-fold increase in the odds of a major respiratory event in the post anesthesia care unit. Careful consideration of the postoperative ventilation and monitoring strategy must be given to patients with low birth weight (<1.58 kg) or who are <41 weeks postmenstrual age at the time of surgery.

Complications in Pediatric Regional Anesthesia: An Analysis of More than 100,000 Blocks from the Pediatric Regional Anesthesia Network.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Complications in pediatric regional anesthesia are rare, so a large sample size is necessary to quantify risk. The Pediatric Regional Anesthesia Network contains data on more than 100,000 blocks administered at more than 20 children's hospitals. This study analyzed the risk of major complications associated with regional anesthesia in children. METHODS: This is a prospective, observational study of routine clinical practice. Data were collected on every regional block placed by an anesthesiologist at participating institutions and were uploaded to a secure database. The data were audited at multiple points for accuracy. RESULTS: There were no permanent neurologic deficits reported (95% CI, 0 to 0.4:10,000). The risk of transient neurologic deficit was 2.4:10,000 (95% CI, 1.6 to 3.6:10,000) and was not different between peripheral and neuraxial blocks. The risk of severe local anesthetic systemic toxicity was 0.76:10,000 (95% CI, 0.3 to 1.6:10,000); the majority of cases occurred in infants. There was one epidural abscess reported (0.76:10,000, 95% CI, 0 to 4.8:10,000). The incidence of cutaneous infections was 0.5% (53:10,000, 95% CI, 43 to 64:10,000). There were no hematomas associated with neuraxial catheters (95% CI, 0 to 3.5:10,000), but one epidural hematoma occurred with a paravertebral catheter. No additional risk was observed with placing blocks under general anesthesia. The most common adverse events were benign catheter-related failures (4%). CONCLUSIONS: The data from this study demonstrate a level of safety in pediatric regional anesthesia that is comparable to adult practice and confirms the safety of placing blocks under general anesthesia in children.

Autoimmune Dementia.

Dementia refers to an acquired syndrome of intraindividual cognitive decline that ultimately interferes with an individual's ability to manage their usual duties at work or home. As experience with the diagnosis and management of patients with autoimmune and paraneoplastic encephalitis (AE) has expanded, it has become increasingly apparent that dementia may arise as a subacute or chronic complication of immune-mediated injury to the central nervous system. Progressive memory and thinking problems may represent the first (or only) sign of an underlying autoimmune or paraneoplastic disease. Accordingly, there is a need to routinely consider the diagnosis of AE in patients with dementia, and to evaluate patients recovering from AE for clinically meaningful cognitive impairment. We review and summarize the available evidence concerning the diagnosis and care of AE patients with associated cognitive impairment, herein referred to as autoimmune dementia (AiD). Relevant information is used to propose a novel diagnostic framework that may be applied to improve recognition, and facilitate the expedited evaluation and treatment of patients with AiD.

Spatiotemporal changes in diffusion, T2 and susceptibility of white matter following mild traumatic brain injury.

Impaired white matter integrity in traumatic brain injury (TBI) can lead to deficits in various neurological functions. The differentiation of the underlying pathological processes, e.g. edema, demyelination, axonal damage, to name a few, is of key clinical interest for the assessment of white matter injury. In this study, a combination of T2 , diffusion and susceptibility MRI was used to study the spatiotemporal changes in white matter at 1 h, 3 h, and 1, 2, 7 and 14 days following TBI, using a rat controlled cortical impact (CCI) model. Based on radial diffusivity (RD), the rats were divided into two groups: group 1 showed widespread increases in RD along the corpus callosum of the ipsilesional hemisphere at day 2, and group 2 showed normal RD. Based on this group separation, group 1 also showed similar widespread changes in fractional anisotropy (FA) and T2 at day 2, and group 2 showed normal FA and T2 . The widespread changes in RD and T2 in group 1 on day 2 were apparently dominated by edema, which obscured possible myelin and axonal damage. In contrast, the susceptibility of group 1 showed more localized increases near the impact site on day 2, and otherwise similar contrast to the contralesional hemisphere. The localized susceptibility increase is probably a result of demyelination and axonal injury. The extent of brain damage between the two groups revealed by MRI was consistent with behavioral results, with the first group showing significantly increased forelimb asymmetry and increased forelimb foot fault deficits. Our results suggest that the combination of T2 , diffusion and susceptibility MRI may provide an opportunity for the differential assessment of edema and axonal damage in TBI. Copyright © 2016 John Wiley & Sons, Ltd.

The Use of Neuraxial Catheters for Postoperative Analgesia in Neonates: A Multicenter Safety Analysis from the Pediatric Regional Anesthesia Network.

BACKGROUND: Currently, there is limited evidence to support the safety of neuraxial catheters in neonates. Safety concerns have been cited as a major barrier to performing large randomized trials in this population. The main objective of this study is to examine the safety of neuraxial catheters in neonates across multiple institutions. Specifically, we sought to determine the incidence of overall and individual complications encountered when neuraxial catheters were used for postoperative analgesia in neonates. METHODS: This was an observational study that used the Pediatric Regional Anesthesia Network database. Complications and adverse events were defined by the presence of at least 1 of the following intraoperative and/or postoperative factors: catheter malfunction (dislodgment/occlusion), infection, block abandoned (unable to place), block failure (no evidence of block), vascular (blood aspiration/hematoma), local anesthetic systemic toxicity, excessive motor block, paresthesia, persistent neurologic deficit, and other (e.g., intra-abdominal misplacement, tremors). Additional analyses were performed to identify the use of potentially toxic doses of local anesthetics. RESULTS: The study cohort included 307 neonates with a neuraxial catheter. There were 41 adverse events and complications recorded, resulting in an overall incidence of complications of 13.3% (95% confidence interval, 9.8%-17.4%). Among the complications, catheter malfunction, catheter contamination, and vascular puncture were common. None of the complications resulted in long-term complications and/or sequelae, resulting in an estimated incidence of any serious complications of 0.3% (95% confidence interval, 0.08%-1.8%). There were 120 of 307 patients who received intraoperative and/or postoperative infusions consistent with a potentially toxic local anesthetic dose in neonates. The incidence of potentially toxic local anesthetic infusion rates increased over time (P = 0.008). CONCLUSIONS: Neuraxial catheter techniques for intraoperative and postoperative analgesia appear to be safe in neonates. Further studies to confirm our results and to establish the efficacy of these techniques across different surgical procedures are required. We suggest that each center that uses neuraxial anesthesia techniques in neonates closely evaluate the dose limits for local anesthetic agents and develop rigorous quality assurance methods to ensure potentially toxic doses are not used.

MicroRNA-339-5p down-regulates protein expression of ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects.

Alzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-ß (Aß) peptide as neuritic plaques in the brain. The short Aß peptide is derived from the large transmembrane Aß precursor protein (APP). The rate-limiting step in the production of Aß from APP is mediated by the ß-site APP-cleaving enzyme 1 (BACE1). Dysregulation of BACE1 levels leading to excess Aß deposition is implicated in sporadic AD. Thus, elucidating the full complement of regulatory pathways that control BACE1 expression is key to identifying novel drug targets central to the Aß-generating process. MicroRNAs (miRNAs) are expected to participate in this molecular network. Here, we identified a known miRNA, miR-339-5p, as a key contributor to this regulatory network. Two distinct miR-339-5p target sites were predicted in the BACE1 3'-UTR by in silico analyses. Co-transfection of miR-339-5p with a BACE1 3'-UTR reporter construct resulted in significant reduction in reporter expression. Mutation of both target sites eliminated this effect. Delivery of the miR-339-5p mimic also significantly inhibited expression of BACE1 protein in human glioblastoma cells and human primary brain cultures. Delivery of target protectors designed against the miR-339-5p BACE1 3'-UTR target sites in primary human brain cultures significantly elevated BACE1 expression. Finally, miR-339-5p levels were found to be significantly reduced in brain specimens isolated from AD patients as compared with age-matched controls. Therefore, miR-339-5p regulates BACE1 expression in human brain cells and is most likely dysregulated in at least a subset of AD patients making this miRNA a novel drug target.

Cerebral angiography, blood flow and vascular reactivity in progressive hypertension.

Chronic hypertension alters cerebral vascular morphology, cerebral blood flow (CBF), cerebrovascular reactivity, and increses susceptibility to neurological disorders. This study evaluated: i) the lumen diameters of major cerebral and downstream arteries using magnetic resonance angiography, ii) basal CBF, and iii) cerebrovascular reactivity to hypercapnia of multiple brain regions using arterial-spin-labeling technique in spontaneously hypertensive rats (SHR) at different stages. Comparisons were made with age-matched normotensive Wistar Kyoto (WKY) rats. In 10-week SHR, lumen diameter started to reduce, basal CBF, and hypercapnic CBF response were higher from elevated arterial blood pressure, but there was no evidence of stenosis, compared to age-matched WKY. In 20-week SHR, lumen diameter remained reduced, CBF returned toward normal from vasoconstriction, hypercapnic CBF response reversed and became smaller, but without apparent stenosis. In 40-week SHR, lumen diameter remained reduced and basal CBF further decreased, resulting in larger differences compared to WKY. There was significant stenosis in main supplying cerebral vessels. Hypercapnic CBF response further decreased, with some animals showing negative hypercapnic CBF responses in some brain regions, indicative of compromised cerebrovascular reserve. The territory with negative hypercapnia CBF responses corresponded with the severity of stenosis in arteries that supplied those territories. We also found enlargement of downstream vessels and formation of collateral vessels as compensatory responses to stenosis of upstream vessels. The middle cerebral and azygos arteries were amongst the most susceptible to hypertension-induced changes. Multimodal MRI provides clinically relevant data that might be useful to characterize disease pathogenesis, stage disease progression, and monitor treatment effects in hypertension.

Overutilization and Cost of Advanced Imaging for Long-Bone Cartilaginous Lesions.

BACKGROUND: The prevalence and cost of unnecessary advanced imaging studies (AIS) in the evaluation of long bone cartilaginous lesions have not been studied previously. METHODS: A total of 105 enchondromas and 19 chondrosarcomas arising in long bones from July 2008 until April 2012 in 121 patients were reviewed. Advanced imaging was defined as MRI, CT, bone scan, skeletal survey, or CT biopsy. Two blinded radiologists independently reviewed the initial imaging study and determined if further imaging was indicated based on that imaging study alone. The cost of imaging was taken from our institution's global charge list. Imaging was deemed unnecessary if it was not recommended by our radiologists after review of the initial imaging study. The difference in cost was calculated by subtracting the cost of imaging recommended by each radiologist from the cost of unnecessary imaging. The sensitivity and specificity for distinguishing enchondromas from chondrosarcomas was calculated. A minimum of 2 years from diagnosis of an enchondroma was required to monitor for malignant transformation. RESULTS: Of patients diagnosed with an enchondroma, 85 % presented with AIS. The average enchondroma patient presented with one unnecessary AIS. The radiologists' interpretations agreed 85 % of the time for enchondromas and 100 % for chondrosarcomas. The sensitivity and specificity for distinguishing enchondromas from chondrosarcomas was 95 % for one radiologist and 87 and 95 % for the other. The average unnecessary cost per enchondroma patient was $1,346.18. CONCLUSIONS: Unnecessary AIS are frequently performed and are a significant source of expense. The imaging algorithms outlined in this study may reduce unnecessary AIS.

Are caudal blocks for pain control safe in children? an analysis of 18,650 caudal blocks from the Pediatric Regional Anesthesia Network (PRAN) database.

BACKGROUND: The caudal block is the most commonly performed regional anesthesia technique in pediatric patients undergoing surgical procedures, but safety concerns raised by previous reports remain to be addressed. Our main objective in current investigation was to estimate the overall and specific incidence of complications associated with the performance of caudal block in children. METHODS: This was an observational study using the Pediatric Regional Anesthesia Network database. A complication after a caudal block was defined by the presence of at least 1 of the following: block failure, vascular puncture, intravascular test dose, dural puncture, seizure, cardiac arrest, sacral pain, or neurologic symptoms. In addition, if a complication was also coded, the presence of temporary or permanent sequelae was evaluated. Additional exploratory analyses were performed to identify patterns of local anesthetic dosage. RESULTS: Eighteen thousand six hundred-fifty children who received a caudal block were included in the study. The overall estimated incidence (95% confidence interval [CI]) of complications after caudal blocks was 1.9% (1.7%-2.1%). Patients who developed complications were younger, median (interquartile range) of 11 (5-24) months, compared to those who did not develop any complications, 14 (7-29) months, P = 0.001. The most common complications were block failure, blood aspiration, and intravascular injection. No cases of temporary or permanent sequelae were identified leading to an estimated incidence (95% CI) of 0.005% (- % to 0.03%). Four thousand four hundred-six of 17,867 (24.6%; 95% CI, 24%-25.2%) subjects received doses (>2 mg of bupivacaine equivalents/kg) that could be potentially unsafe. CONCLUSIONS: Safety concerns should not be a barrier to the use of caudal blocks in children assuming an appropriate selection of local anesthetic dosage.

Transversus abdominis plane block in children: a multicenter safety analysis of 1994 cases from the PRAN (Pediatric Regional Anesthesia Network) database.

BACKGROUND: Currently, there is not enough evidence to support the safety of the transversus abdominis plane (TAP) block when used to ameliorate postoperative pain in children. Safety concerns have been repeatedly mentioned as a major barrier to performing large randomized trials in children. The main objective of the current investigation was to determine the incidence of overall and specific complications resulting from the performance of the TAP block in children. In addition, we evaluated patterns of local anesthetic dosage selection in the same population. METHODS: This was an observational study using the Pediatric Regional Anesthesia Network database. A complication from the TAP block was defined by the presence of at least one of the following intraoperative and/or postoperative factors: puncture of the peritoneum or organs, vascular puncture, cardiovascular, pulmonary and/or neurological symptoms/signs, hematoma, and infection. Additional analyses were performed to identify patterns of local anesthetic dosage. RESULTS: One thousand nine hundred ninety-four children receiving a TAP block were included in the analysis. Only 2 complications were reported: a vascular aspiration of blood before local anesthetic injection and a peritoneal puncture resulting in an overall incidence of complications (95% CI) of 0.1% (0.02%-0.3%) and a specific incidence of complications (vascular aspiration or peritoneal puncture) of 0.05% (0.0054%-0.2000%). Neither of these complications resulted in additional interventions or sequelae. The median (95% range) for the local anesthetic dose per weight for bilateral TAP blocks was 1.0 (0.47-2.29) mg of bupivacaine equivalents per kilogram; however, subjects' weights were not sufficient to explain much of the variability in dose. One hundred thirty-five of 1944 (6.9%; 95% CI, 5.8%-8.1%) subjects received doses that could be potentially toxic. Subjects who received potentially toxic doses were younger than subjects who did not receive potentially toxic doses, 64 (19-100) months and 108 (45-158) months, respectively (P < 0.001). CONCLUSIONS: The upper incidence of overall complications associated with the TAP block in children was 0.3%. More important, complications were very minor and did not require any additional interventions. In contrast, the large variability of local anesthetic dosage used can not only minimize potential analgesic benefits of the TAP block but also result in local anesthetic toxicity. Safety concerns should not be a major barrier to performing randomized trials to test the efficacy of the TAP block in children as long as appropriate local anesthetic dose regimens are selected.

Lessons from a BACE1 inhibitor trial: off-site but not off base.

Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-ß peptide (Aß). The rate-limiting step in the production of Aß is the processing of Aß precursor protein (APP) by ß-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aß within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of ß-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future.