UW Neurological Surgery Recent PubMed Publications

Mild, Redox-Neutral Formylation of Aryl Chlorides through the Photocatalytic Generation of Chlorine Radicals.

Angew Chem Int Ed Engl. 2017 06 12;56(25):7191-7194

Authors: Nielsen MK, Shields BJ, Liu J, Williams MJ, Zacuto MJ, Doyle AG

Abstract
We report a redox-neutral formylation of aryl chlorides that proceeds through selective 2-functionalization of 1,3-dioxolane through nickel and photoredox catalysis. This scalable benchtop approach provides a distinct advantage over traditional reductive carbonylation in that no carbon monoxide, pressurized gas, or stoichiometric reductant is employed. The mild conditions give unprecedented scope from abundant and complex aryl chloride starting materials.

PMID: 28471521 [PubMed - indexed for MEDLINE]

Matricidal cavernous aneurysms: a multicenter case series.

J Neurointerv Surg. 2019 Jun;11(6):584-590

Authors: Dacus MR, Nickele C, Welch BG, Ban VS, Ringer AJ, Kim LJ, Levitt MR, Lanzino G, Kan P, Arthur AS, Endovascular Neurosurgery Research Group (ENRG)

Abstract
BACKGROUND: Cavernous carotid artery aneurysms (CCAs) represent a unique subset of intracranial aneurysms due to their distinct natural history and the anatomy of the cavernous sinus. Enlarging CCAs can cause elastic compression of the parent internal carotid artery (ICA). We suggest defining aneurysms that cause luminal stenosis of their parent vessels as 'matricidal aneurysms.'Though many patients are asymptomatic, presenting symptoms of CCAs include ophthalmoplegia with resulting diplopia, vision changes, pain, ptosis, facial numbness, and cavernous-carotid fistula. Less commonly, patients with CCAs can present with epistaxis, subarachnoid hemorrhage, and-in cases of matricidal aneurysms-ischemia due to stenosis. The proper management of stenosis caused by a matricidal CCA is not well established and may not be intuitive.
METHODS: We present a multicenter retrospective case series of patients with matricidal CCAs.
RESULTS: Forty patients with matricidal aneurysms presented with both asymptomatic and symptomatic stenosis. These patients were either treated with conservative medical management, coiling, flow diversion, or endovascular sacrifice of the parent artery. Planned treatment modalities were not executed in 11 cases (28% treatment failure rate). Presenting symptoms, patient outcomes, and follow-up data are presented for all cases.
CONCLUSION: Matricidal aneurysms require careful consideration and planning. The restricted anatomy of the cavernous sinus can make successful execution of endovascular interventions more difficult. Direct elastic compression of the parent artery does not respond to angioplasty and stenting in the same way atherosclerotic stenosis does. Because of this, planning for the possibility of parent vessel sacrifice is important.

PMID: 30814330 [PubMed - indexed for MEDLINE]

siRNA rescues nonhuman primates from advanced Marburg and Ravn virus disease.

J Clin Invest. 2017 12 01;127(12):4437-4448

Authors: Thi EP, Mire CE, Lee AC, Geisbert JB, Ursic-Bedoya R, Agans KN, Robbins M, Deer DJ, Cross RW, Kondratowicz AS, Fenton KA, MacLachlan I, Geisbert TW

Abstract
Ebolaviruses and marburgviruses belong to the family Filoviridae and cause high lethality in infected patients. There are currently no licensed filovirus vaccines or antiviral therapies. The development of broad-spectrum therapies against members of the Marburgvirus genus, including Marburg virus (MARV) and Ravn virus (RAVV), is difficult because of substantial sequence variability. RNAi therapeutics offer a potential solution, as identification of conserved target nucleotide sequences may confer activity across marburgvirus variants. Here, we assessed the therapeutic efficacy of lipid nanoparticle (LNP) delivery of a single nucleoprotein-targeting (NP-targeting) siRNA in nonhuman primates at advanced stages of MARV or RAVV disease to mimic cases in which patients begin treatment for fulminant disease. Sixteen rhesus monkeys were lethally infected with MARV or RAVV and treated with NP siRNA-LNP, with MARV-infected animals beginning treatment four or five days after infection and RAVV-infected animals starting treatment three or six days after infection. While all untreated animals succumbed to disease, NP siRNA-LNP treatment conferred 100% survival of RAVV-infected macaques, even when treatment began just 1 day prior to the death of the control animals. In MARV-infected animals, day-4 treatment initiation resulted in 100% survival, and day-5 treatment resulted in 50% survival. These results identify a single siRNA therapeutic that provides broad-spectrum protection against both MARV and RAVV.

PMID: 29106386 [PubMed - indexed for MEDLINE]

Three-Dimensional Planning Tool for Breast Conserving Surgery: A Technological Review.

Crit Rev Biomed Eng. 2018;46(6):523-580

Authors: Oliveira SP, Morgado P, Gouveia PF, Teixeira JF, Bessa S, Monteiro JP, Zolfagharnasab H, Reis M, Silva NL, Veiga D, Cardoso MJ, Oliveira HP, Ferreira MJ

Abstract
Breast cancer is one of the most common malignancies affecting women worldwide. However, despite its incidence trends have increased, the mortality rate has significantly decreased. The primary concern in any cancer treatment is the oncological outcome but, in the case of breast cancer, the surgery aesthetic result has become an important quality indicator for breast cancer patients. In this sense, an adequate surgical planning and prediction tool would empower the patient regarding the treatment decision process, enabling a better communication between the surgeon and the patient and a better understanding of the impact of each surgical option. To develop such tool, it is necessary to create complete 3D model of the breast, integrating both inner and outer breast data. In this review, we thoroughly explore and review the major existing works that address, directly or not, the technical challenges involved in the development of a 3D software planning tool in the field of breast conserving surgery.

PMID: 30806213 [PubMed - indexed for MEDLINE]

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity.

Curr Protoc Pharmacol. 2019 03;84(1):e57

Authors: Mullane K, Williams M

Abstract
The only drugs currently approved for the treatment of Alzheimer's Disease (AD) are four acetylcholinesterase inhibitors and the NMDA antagonist memantine. Apart from these drugs, which have minimal to no clinical benefit, the 40-year search for effective therapeutics to treat AD has resulted in a clinical failure rate of 100% not only for compounds that prevent brain amyloid deposition or remove existing amyloid plaques but also those acting by a variety of other putative disease-associated mechanisms. This indicates that the preclinical data generated from current AD targets to support the selection, optimization, and translation of new chemical entities (NCEs) and biologics to clinical trials is seriously compromised. While many of these failures reflect flawed hypotheses or a lack of adequate characterization of the preclinical pharmacodynamic and pharmacokinetic (PD/PK) properties of lead NCEs-including their bioavailability and toxicity-the conceptualization, validation, and interrogation of the current animal models of AD represent key limitations. The overwhelming majority of these AD models are transgenic, based on aspects of the amyloid hypothesis and the genetics of the familial form of the disease. As a result, these generally lack construct and predictive validity for the sporadic form of the human disease. The 170 or so transgenic models, perhaps the largest number ever focused on a single disease, use rodents, mainly mice, and in addition to amyloid also address aspects of tau causality with more complex multigene models including other presumed causative factors together with amyloid. This overview discusses the current animal models of AD in the context of both the controversies surrounding the causative role of amyloid in the disease and the need to develop validated models of cognitive function/dysfunction that more appropriately reflect the phenotype(s) of human aged-related dementias. © 2019 by John Wiley & Sons, Inc.

PMID: 30802363 [PubMed - indexed for MEDLINE]

Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors.

J Immunother Cancer. 2019 02 22;7(1):53

Authors: Awadalla M, Golden DLA, Mahmood SS, Alvi RM, Mercaldo ND, Hassan MZO, Banerji D, Rokicki A, Mulligan C, Murphy SPT, Jones-O'Connor M, Cohen JV, Heinzerling LM, Armanious M, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Moslehi JJ, Shah SP, Ganatra S, Thavendiranathan P, Rizvi MA, Sahni G, Lyon AR, Tocchetti CG, Mercurio V, Thuny F, Ederhy S, Mahmoudi M, Lawrence DP, Groarke JD, Nohria A, Fradley MG, Reynolds KL, Neilan TG

Abstract
BACKGROUND: Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs.
METHODS: Patients on ICIs who developed myocarditis (n = 101) (cases) were compared to ICI-treated patients (n = 201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6 months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death.
RESULTS: The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p = 0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p = 0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p = 0.10) including lower rates of pneumonitis (12 vs. 36%, p = 0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p = 0.002).
CONCLUSION: The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.

PMID: 30795818 [PubMed - indexed for MEDLINE]

The de-Alzheimerization of age-related dementias: implications for drug targets and approaches to effective therapeutics.

Curr Opin Pharmacol. 2019 02;44:62-75

Authors: Mullane K, Williams M

Abstract
Alzheimer's disease (AD) was differentiated from senile dementia (SD) in 1910 due to its early onset and pathological severity. In 1976, this distinction was upended when SD was redesignated as AD to focus efforts and funding in dementia-related research. AD then became conflated with amyloid plaques and, to a lesser degree, neurofibrillary tangles complicating efforts in understanding dementia causality and its treatment. The resultant four-decade search for therapies-based almost exclusively on amyloid was an exercise in futility. While dementia is a complex, multifactorial syndrome, AD is viewed as a homogeneous, linear disease. An amyloid-agnostic approach is necessary to discover therapeutics for age-related dementias.

PMID: 30795894 [PubMed - indexed for MEDLINE]

Why Is It Easier to Get Mad Than It Is to Feel Sad? Pilot Study of Regulation-Focused Psychotherapy for Children.

Am J Psychother. 2019 Mar 01;72(1):2-8

Authors: Prout TA, Rice T, Murphy S, Gaines E, Aizin S, Sessler D, Ramchandani T, Racine E, Gorokhovsky Y, Hoffman L

Abstract
OBJECTIVE:: This article reports results of a pilot study of three participants receiving regulation-focused psychotherapy for children (RFP-C), a manualized, short-term, psychodynamic treatment for children with oppositional defiant disorder and other externalizing problems. RFP-C targets implicit emotion regulation while using an intensive, psychodynamic, play therapy approach to decrease the child's need for disruptive behaviors.
METHODS:: Three children with oppositional defiant disorder participated in a trial of RFP-C. Externalizing symptoms were assessed with the Oppositional Defiant Disorder Rating Scale, and emotion regulation was assessed with the Emotion Regulation Checklist.
RESULTS:: All three children improved in accordance with expectations. Participants exhibited clinically significant and reliable change, as assessed by the primary symptom measure, and demonstrated improved capacity for emotional regulation.
CONCLUSIONS:: Results suggest that RFP-C has the potential to produce significant improvements in emotion regulation capacity and in symptoms of oppositional defiant disorder. This pilot study provides initial support for RFP-C as an efficacious and cost-effective intervention, with high treatment compliance rates, and lays the groundwork for a randomized controlled trial of the intervention.

PMID: 30786738 [PubMed - indexed for MEDLINE]

Bacterial cGAS-like enzymes synthesize diverse nucleotide signals.

Nature. 2019 03;567(7747):194-199

Authors: Whiteley AT, Eaglesham JB, de Oliveira Mann CC, Morehouse BR, Lowey B, Nieminen EA, Danilchanka O, King DS, Lee ASY, Mekalanos JJ, Kranzusch PJ

Abstract
Cyclic dinucleotides (CDNs) have central roles in bacterial homeostasis and virulence by acting as nucleotide second messengers. Bacterial CDNs also elicit immune responses during infection when they are detected by pattern-recognition receptors in animal cells. Here we perform a systematic biochemical screen for bacterial signalling nucleotides and discover a large family of cGAS/DncV-like nucleotidyltransferases (CD-NTases) that use both purine and pyrimidine nucleotides to synthesize a diverse range of CDNs. A series of crystal structures establish CD-NTases as a structurally conserved family and reveal key contacts in the enzyme active-site lid that direct purine or pyrimidine selection. CD-NTase products are not restricted to CDNs and also include an unexpected class of cyclic trinucleotide compounds. Biochemical and cellular analyses of CD-NTase signalling nucleotides demonstrate that these cyclic di- and trinucleotides activate distinct host receptors and thus may modulate the interaction of both pathogens and commensal microbiota with their animal and plant hosts.

PMID: 30787435 [PubMed - indexed for MEDLINE]

Will converting naloxone to over-the-counter status increase pharmacy sales?

Health Serv Res. 2019 08;54(4):764-772

Authors: Murphy SM, Morgan JR, Jeng PJ, Schackman BR

Abstract
OBJECTIVE: To estimate the own-price elasticity of demand for naloxone, a prescription medication that can counter the effects of an opioid overdose, and predict the change in pharmacy sales following a conversion to over-the-counter status.
DATA SOURCES/STUDY SETTING: The primary data source was a nationwide prescription claims dataset for 2010-2017. The data cover 80 percent of US retail pharmacies and account for roughly 90 percent of prescriptions filled. Additional covariates were obtained from various secondary data sources.
STUDY DESIGN: We estimated a longitudinal, simultaneous equation model of naloxone supply and demand. Our primary variables of interest were the quantity of naloxone sold, measured as total milligrams sold at pharmacies, and the out-of-pocket price paid per milligram, both measured per ZIP Code and quarter-year.
DATA COLLECTION/EXTRACTION METHODS: Primary data came directly from payers and processors of prescription drug claims.
PRINCIPAL FINDINGS: We found that, on average, a 1 percent increase in the out-of-pocket price paid for naloxone would result in a 0.27 percent decrease in pharmacy sales. We predict that the total quantity of naloxone sold in pharmacies would increase 15 percent to 179 percent following conversion to over-the-counter status.
CONCLUSIONS: Naloxone is own-price inelastic, and conversion to over-the-counter status is likely to lead to a substantial increase in total pharmacy sales.

PMID: 30790269 [PubMed - indexed for MEDLINE]

Has Self-reported Marijuana Use Changed in Patients Undergoing Total Joint Arthroplasty After the Legalization of Marijuana?

Clin Orthop Relat Res. 2019 01;477(1):95-100

Authors: Jennings JM, Williams MA, Levy DL, Johnson RM, Eschen CL, Dennis DA

Abstract
BACKGROUND: Marijuana use has become more accessible since its recent legalization in several states. However, its use in a total joint arthroplasty population to our knowledge has not been reported, and the implications of its use in this setting remain unclear.
QUESTIONS/PURPOSES: We report (1) the self-reported use of marijuana in patients undergoing total joint arthroplasty both before and after its legalization; and (2) clinical and demographic factors associated with marijuana use in patients undergoing total joint arthroplasty.
METHODS: One thousand records of patients undergoing primary total joint arthroplasty (500 consecutive before and 500 consecutive after the legalization of the commercial sale of marijuana in Colorado) were included for analysis. Preoperative medical history and physicals were retrospectively reviewed for self-reported and reasons (medicinal versus recreational) for use. Additionally, patient records were used to determine insurance type, age, gender, smoking status, history of substance abuse, preoperative narcotic use, alcohol intake, and the type of arthroplasty performed.
RESULTS: Self-reported use after legalization dramatically increased from 1% (four of 500) to 11% (55 of 500) (odds ratio [OR], 15.3 [95% confidence interval, 5.5-42.6]; p < 0.001) after legalization. For those reporting use after legalization, 46% (25 of 55) of patients reported recreational use, 26% (14 of 55) medicinal use, 27% (15 of 55) did not report a reason for use, and 2% (one of 55) reported both recreational and medicinal use. Factors associated with use included younger age (with a 10-year mean difference between the groups [p < 0.001]), male gender (36 of 59 users [61%] versus 411 of 941 nonusers [44%]; OR, 2.02; p < 0.01), current smokers (22 of 59 users [37%] versus 54 of 941 [6%] nonusers; OR, 0.09; p < 0.01), a history of substance abuse (eight of 59 users [14%] versus 18 of 941 nonusers [2%]; OR, 8.04; p < 0.001), insurance type (Medicaid only, 28 of 59 [48%] users versus 56 of 941 [6%] nonusers; OR, 20.45; p < 0.01), and preoperative narcotic use (eight of 59 users [14%] versus 17 of 941 nonusers [2%]; OR, 2.4; p < 0.001). We did not find differences with regard to alcohol use, amount of alcohol consumption, or insurance types other than Medicaid.
CONCLUSIONS: These results suggest the legalization of marijuana has led to either more users or more patients who are willing to report its use given the lack of legal ramifications. Despite these findings, the evidence to date precludes the use of marijuana postoperatively in patients undergoing total joint arthroplasty. Further investigation, ideally in a prospective randomized manner, should focus on opioid consumption, nausea, sleep patterns, and outcomes in patients using marijuana who are undergoing total joint arthroplasty before recommendations can be made for its use.
LEVEL OF EVIDENCE: Level III, therapeutic study.

PMID: 30794232 [PubMed - indexed for MEDLINE]

Gene gun DNA immunization of cattle induces humoral and CD4 T-cell-mediated immune responses against the Theileria parva polymorphic immunodominant molecule.

Vaccine. 2019 03 14;37(12):1546-1553

Authors: Fry LM, Bastos RG, Stone BC, Williams LB, Knowles DP, Murphy SC

Abstract
Theileria parva kills over one million cattle annually in sub-Saharan Africa. Parasite genetic complexity, cellular response immunodominance, and bovine MHC diversity have precluded traditional vaccine development. One potential solution is gene gun (GG) immunization, which enables simultaneous administration of one or more DNA-encoded antigens. Although promising in murine, porcine, and human vaccination trials, bovine GG immunization studies are limited. We utilized the model T. parva antigen, polymorphic immunodominant molecule (PIM) to test bovine GG immunization. GG immunization using a mammalian codon optimized PIM sequence elicited significant anti-PIM antibody and cell-mediated responses in 7/8 steers, but there was no difference between immunized and control animals following T. parva challenge. The results suggest immunization with PIM, as delivered here, is insufficient to protect cattle from T. parva. Nonetheless, the robust immune responses elicited against this model antigen suggest GG immunization is a promising vaccine platform for T. parva and other bovine pathogens.

PMID: 30782490 [PubMed - indexed for MEDLINE]

Gallium-68 Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer-Updated Diagnostic Utility, Sensitivity, Specificity, and Distribution of Prostate-specific Membrane Antigen-avid Lesions: A Systematic Review and Meta-analysis.

Eur Urol. 2019 Feb 14;:

Authors: Perera M, Papa N, Roberts M, Williams M, Udovicich C, Vela I, Christidis D, Bolton D, Hofman MS, Lawrentschuk N, Murphy DG

Abstract
CONTEXT: Accurate staging of high-risk localised, advanced, and metastatic prostate cancer is becoming increasingly more important in guiding local and systemic treatment. Gallium-68 prostate-specific membrane antigen (PSMA) positron emission tomography (PET) has increasingly been utilised globally to assess the local and metastatic burden of prostate cancer, typically in biochemically recurrent or advanced disease. Following our previous meta-analysis, a high-volume series has been reported highlighting the utility of 68Ga-PSMA PET in this setting.
OBJECTIVE: To perform a systematic review and meta-analysis to update reported predictors of positive 68Ga-PSMA PET according to prior therapy and proportion of positivity in various anatomical locations with sensitivity and specificity profiles.
EVIDENCE ACQUISITION: We performed critical reviews of MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science databases in July 2018 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Quality assessment was performed using Quality Assessment if Diagnostic Accuracy Studies-2 tool. Meta-analyses of proportions were performed using a random-effect model. Summary sensitivity and specificity values were obtained by fitting bivariate hierarchical regression models.
EVIDENCE SYNTHESIS: A total of 37 articles including 4790 patients were analysed. For patients with biochemical recurrence, positive 68Ga-PSMA PET scans increased with higher pre-PET prostate-specific antigen (PSA) levels. For PSA categories 0-0.19, 0.2-0.49, 0.5-0.99, 1-1.99, and ≥2ng/ml, the percentages of positive scans were 33%, 45%, 59%, 75%, and 95%, respectively. No significant differences in positivity were noted between Gleason sums ≤7 and ≥8. Significant differences in positivity after biochemical recurrence in the prostate bed were noted between radical prostatectomy (22%) and radiotherapy (52%) patients. On per-node analysis, high sensitivity (75%) and specificity (99%) were observed.
CONCLUSIONS: Ga-68-PSMA PET improves detection of metastases with biochemical recurrence, particularly at low pre-PET PSA levels of >0.2ng/ml (33%) and 0.2-0.5ng/ml (45%). Ga-68-PSMA-PET produces favourable sensitivity and specificity profiles on meta-analysis of pooled data. This analysis highlights different anatomic patterns of metastatic spread according to PSMA PET in the primary and biochemically recurrent settings.
PATIENT SUMMARY: Gallium-68 prostate-specific membrane antigen positron emission tomography is now an established imaging technique that has been developed in response to inadequacies in standard of care imaging modalities to improve the detection of metastatic disease in prostate cancer, particularly in the setting of disease recurrence. To date, this imaging modality in the setting of primary staging is controversial, given the paucity of data. In light of the growing body of evidence, we summarised the data to date to provide clinicians with an overview of this imaging modality.

PMID: 30773328 [PubMed - as supplied by publisher]

An Economic Evaluation of Coordinated Specialty Care (CSC) Services for First-Episode Psychosis in the U.S. Public Sector.

J Ment Health Policy Econ. 2018 Sep 01;21(3):123-130

Authors: Murphy SM, Kucukgoncu S, Bao Y, Li F, Tek C, Breitborde NJK, Guloksuz S, Phutane VH, Ozkan B, Pollard JM, Cahill JD, Woods SW, Cole RA, Schoenbaum M, Srihari VH

Abstract
BACKGROUND: Schizophrenia spectrum disorders exert a large and disproportionate economic impact. Early intervention services may be able to alleviate the burden of schizophrenia spectrum disorders on diagnosed individuals, caregivers, and society at large. Economic analyses of observational studies have supported investments in specialized team-based care for early psychosis; however, questions remain regarding the economic viability of first-episode services in the fragmented U.S. healthcare system. The clinic for Specialized Treatment Early in Psychosis (STEP) was established in 2006, to explicitly model a nationally-relevant U.S. public-sector early intervention service. The purpose of this study was to conduct an economic evaluation of STEP, a Coordinated Specialty Care service (CSC) based in a U.S. State-funded community mental health center, relative to usual treatment (UT).
METHODS: Eligible patients were within 5 years of psychosis onset and had no more than 12 weeks of lifetime antipsychotic exposure. Participants were randomized to STEP or UT. The annual per-patient cost of the STEP intervention per se was estimated assuming a steady-state caseload of 30 patients. A cost-offset analysis was conducted to estimate the net value of STEP from a third-party payer perspective. Participant healthcare service utilization was evaluated at 6 months and over the entire 12 months post randomization. Generalized linear model multivariable regressions were used to estimate the effect of STEP on healthcare costs over time, and generate predicted mean costs, which were combined with the per-patient cost of STEP.
RESULTS: The annual per-patient cost of STEP was $1,984. STEP participants were significantly less likely to have any inpatient or ED visits; among individuals who did use such services in a given period, the associated costs were significantly lower for STEP participants at month 12. We did not observe a similar effect with regard to other healthcare services. The predicted average total costs were lower for STEP than UT, indicating a net benefit for STEP of $1,029 at month 6 and $2,991 at month 12; however, the differences were not statistically significant.
CONCLUSIONS: Our findings are promising with regard to the value of STEP to third-party payers.

PMID: 30530872 [PubMed - indexed for MEDLINE]

Ahnak scaffolds p11/Anxa2 complex and L-type voltage-gated calcium channel and modulates depressive behavior.

Mol Psychiatry. 2019 Feb 13;:

Authors: Jin J, Bhatti DL, Lee KW, Medrihan L, Cheng J, Wei J, Zhong P, Yan Z, Kooiker C, Song C, Ahn JH, Obermair GJ, Lee A, Gresack J, Greengard P, Kim Y

Abstract
Genetic polymorphisms of the L-type voltage-gated calcium channel (VGCC) are associated with psychiatric disorders including major depressive disorder. Alterations of S100A10 (p11) level are also implicated in the etiology of major depressive disorder. However, the existence of an endogenous regulator in the brain regulating p11, L-type VGCC, and depressive behavior has not been known. Here we report that Ahnak, whose function in the brain has been obscure, stabilizes p11 and Anxa2 proteins in the hippocampus and prefrontal cortex in the rodent brain. Protein levels of Ahnak, p11, and Anxa2 are highly and positively correlated in the brain. Together these data suggest the existence of an Ahnak/p11/Anxa2 protein complex. Ahnak is expressed in p11-positive as well as p11-negative neurons. Ahnak, through its N-terminal region, scaffolds the L-type pore-forming α1 subunit and, through its C-terminal region, scaffolds the β subunit of VGCC and the p11/Anxa2 complex. Cell surface expression of the α1 subunits and L-type calcium current are significantly reduced in primary cultures of Ahnak knockout (KO) neurons compared to wild-type controls. A decrease in the L-type calcium influx is observed in both glutamatergic neurons and parvalbumin (PV) GABAergic interneurons of Ahnak KO mice. Constitutive Ahnak KO mice or forebrain glutamatergic neuron-selective Ahnak KO mice display a depression-like behavioral phenotype similar to that of constitutive p11 KO mice. In contrast, PV interneuron-selective Ahnak KO mice display an antidepressant-like behavioral phenotype. Our results demonstrate L-type VGCC as an effector of the Ahnak/p11/Anxa2 complex, revealing a novel molecular connection involved in the control of depressive behavior.

PMID: 30760886 [PubMed - as supplied by publisher]

In Situ Bioprinting of Autologous Skin Cells Accelerates Wound Healing of Extensive Excisional Full-Thickness Wounds.

Sci Rep. 2019 02 12;9(1):1856

Authors: Albanna M, Binder KW, Murphy SV, Kim J, Qasem SA, Zhao W, Tan J, El-Amin IB, Dice DD, Marco J, Green J, Xu T, Skardal A, Holmes JH, Jackson JD, Atala A, Yoo JJ

Abstract
The early treatment and rapid closure of acute or chronic wounds is essential for normal healing and prevention of hypertrophic scarring. The use of split thickness autografts is often limited by the availability of a suitable area of healthy donor skin to harvest. Cellular and non-cellular biological skin-equivalents are commonly used as an alternative treatment option for these patients, however these treatments usually involve multiple surgical procedures and associated with high costs of production and repeated wound treatment. Here we describe a novel design and a proof-of-concept validation of a mobile skin bioprinting system that provides rapid on-site management of extensive wounds. Integrated imaging technology facilitated the precise delivery of either autologous or allogeneic dermal fibroblasts and epidermal keratinocytes directly into an injured area, replicating the layered skin structure. Excisional wounds bioprinted with layered autologous dermal fibroblasts and epidermal keratinocytes in a hydrogel carrier showed rapid wound closure, reduced contraction and accelerated re-epithelialization. These regenerated tissues had a dermal structure and composition similar to healthy skin, with extensive collagen deposition arranged in large, organized fibers, extensive mature vascular formation and proliferating keratinocytes.

PMID: 30755653 [PubMed - indexed for MEDLINE]

Multipoint Background Analysis: Gaining Precision and Accuracy in Microprobe Trace Element Analysis.

Microsc Microanal. 2019 Feb 12;:1-17

Authors: Allaz JM, Williams ML, Jercinovic MJ, Goemann K, Donovan J

Abstract
Electron microprobe trace element analysis is a significant challenge. Due to the low net intensity of peak measurements, the accuracy and precision of such analyses relies critically on background measurements, and on the accuracy of any pertinent peak interference corrections. A linear regression between two points selected at appropriate background positions is a classical approach for electron probe microanalysis (EPMA). However, this approach neglects the accurate assessment of background curvature (exponential or polynomial), and the presence of background interferences, a hole in the background, or an absorption edge can dramatically affect the results if underestimated or ignored. The acquisition of a quantitative wavelength-dispersive spectrometry (WDS) scan over the spectral region of interest remains a reasonable option to determine the background intensity and curvature from a fitted regression of background portions of the scan, but this technique can be time consuming and retains an element of subjectivity, as the analyst has to select areas in the scan which appear to represent background. This paper presents a new multi-point background (MPB) method whereby the background intensity is determined from up to 24 background measurements from wavelength positions on either side of analytical lines. This method improves the accuracy and precision of trace element analysis in a complex matrix through careful regression of the background shape, and can be used to characterize the background over a large spectral region covering several elements to be analyzed. The overall efficiency improves as systematic WDS scanning is not required to assess background interferences. The method is less subjective compared to methods that rely on WDS scanning, including selection of two interpolation points based on WDS scans, because "true" backgrounds are selected through an exclusion method of possible erroneous backgrounds. The first validation of the MPB method involves blank testing to ensure the method can accurately measure the absence of an element. The second validation involves the analysis of U-Th-Pb in several monazite reference materials of known isotopic age. The impetus for the MPB method came from efforts to refine EPMA monazite U-Th-Pb dating, where it was recognized that background errors resulting from interference or strong background curvature could result in errors of several tens of millions of years on the calculated date. Results obtained on monazite reference materials using two different microprobes, a Cameca SX-100 Ultrachron and a JEOL JXA-8230, yield excellent agreement with ages obtained by isotopic methods (Thermal Ionization Mass Spectrometry [TIMS], Sensitive High-Resolution Ion MicroProbe [SHRIMP], or Secondary Ion Mass Spectrometry [SIMS]). Finally, the MPB method can be used to model the background over a large spectrometer range to improve the accuracy of background measurement of minor and trace elements acquired on a same spectrometer, a method called the shared background measurement. This latter significantly improves the accuracy of minor and trace element analysis in complex matrices, as demonstrated by the analysis of Rare Earth Elements (REE) in REE-silicates and phosphates and of trace elements in scheelite.

PMID: 30744721 [PubMed - as supplied by publisher]

Matching early arterial oxygenation to long-term outcome in severe traumatic brain injury: target values.

J Neurosurg. 2019 02 08;132(2):537-544

Authors: Alali AS, Temkin N, Vavilala MS, Lele AV, Barber J, Dikmen S, Chesnut RM

Abstract
OBJECTIVE: The aim of this study was to examine the relationship between early arterial oxygenation thresholds and long-term outcome after severe traumatic brain injury (TBI).
METHODS: In a post hoc analysis of a randomized trial, adults with severe TBI were classified based on exposure to different levels of arterial oxygenation as measured using the average of arterial partial pressure of oxygen (PaO2) values obtained within 24 hours of admission. Potentially important PaO2 thresholds were defined a priori. The primary outcome was Glasgow Outcome Scale-Extended (GOSE) score at 6 months. Secondary outcomes were cognitive outcomes measured using a battery of 9 neuropsychological tests administered at 6 months, and 6-month mortality.
RESULTS: In adjusted analyses, oxygenation thresholds of 150 and 200 mm Hg were associated with better functional outcome at 6 months (adjusted OR for better functional outcome on GOSE 1.82 [95% CI 1.12-2.94] and 1.59 [95% CI 1.06-2.37], respectively) and improved cognitive outcome at 6 months (adjusted beta coefficients for better cognitive percentile across 9 neuropsychological tests: 6.9 [95% CI 1.3-12.5] and 6.8 [95% CI 2.4-11.3], respectively). There was no significant association between oxygenation level and 6-month mortality except at a PaO2 threshold of 200 mm Hg (OR for death 0.36, 95% CI 0.18-0.71). Higher or lower oxygenation thresholds were not associated with functional or cognitive outcome.
CONCLUSIONS: In this observational study, the relationship between early arterial oxygenation and long-term functional and cognitive TBI outcomes appears to be U-shaped. Mild levels of hyperoxemia within the first 24 hours after injury were associated with better long-term functional and cognitive outcomes. These findings highlight the importance of examining balanced oxygen supplementation as a potential strategy to improve TBI outcomes in future research.

PMID: 30738409 [PubMed - indexed for MEDLINE]

Challenges to curing primary brain tumours.

Nat Rev Clin Oncol. 2019 08;16(8):509-520

Authors: Aldape K, Brindle KM, Chesler L, Chopra R, Gajjar A, Gilbert MR, Gottardo N, Gutmann DH, Hargrave D, Holland EC, Jones DTW, Joyce JA, Kearns P, Kieran MW, Mellinghoff IK, Merchant M, Pfister SM, Pollard SM, Ramaswamy V, Rich JN, Robinson GW, Rowitch DH, Sampson JH, Taylor MD, Workman P, Gilbertson RJ

Abstract
Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment.

PMID: 30733593 [PubMed - indexed for MEDLINE]

Mild Traumatic Brain Injury and Mental Health-Reply.

JAMA Neurol. 2017 11 01;74(11):1378

Authors: Mac Donald CL, Fann JR, Temkin NR

PMID: 29049812 [PubMed - indexed for MEDLINE]