Far lateral approach to anterior foramen magnum meningiomas - When should condyle be drilled?
Neurol India. 2019 Jan-Feb;67(1):59-60
Authors: Sekhar L, Zeeshan Q
Abstract
PMID: 30860093 [PubMed - indexed for MEDLINE]
Deltamethrin Exposure Daily From Postnatal Day 3-20 in Sprague-Dawley Rats Causes Long-term Cognitive and Behavioral Deficits.
Toxicol Sci. 2019 06 01;169(2):511-523
Authors: Pitzer EM, Sugimoto C, Gudelsky GA, Huff Adams CL, Williams MT, Vorhees CV
Abstract
Pyrethroids are synthetic insecticides that act acutely on voltage gated sodium channels to prolong channel opening and depolarization. Epidemiological studies find that exposure to pyrethroids are associated with neurological and developmental abnormalities in children. The long-term effects of type II pyrethroids, such as deltamethrin (DLM), on development have received little attention. We exposed Sprague-Dawley rats to DLM by gavage at doses of 0, 0.25, 0.5, and 1.0 mg/kg/day from postnatal day (P) 3-20 in a split-litter design. Following behavioral testing as adults, monoamine levels, release, and mRNA were assessed via high performance liquid chromatography, microdialysis, and qPCR, respectively. Long-term potentiation (LTP) was assessed at P25-35. Developmental DLM exposure resulted in deficits in allocentric and egocentric learning and memory, increased startle reactivity, reduced conditioned contextual freezing, and attenuated MK-801 induced hyperactivity compared with controls. Startle and egocentric learning were preferentially affected in males. Deltamethrin-treated rats exhibited increased CA1 hippocampal LTP, decreased extracellular dopamine release by microdialysis, reduced dopamine D1 receptor mRNA expression in neostriatum, and decreased norepinephrine levels in the hippocampus. The data indicate that neonatal DLM exposure has adverse long-term effects on learning, memory, startle, glutamatergic function, LTP, and norepinephrine.
PMID: 30850843 [PubMed - indexed for MEDLINE]
Left Ventricular Thrombus: Contemporary Etiologies, Treatment Strategies, and Outcomes.
J Am Coll Cardiol. 2019 04 23;73(15):2007-2009
Authors: McCarthy CP, Murphy S, Venkateswaran RV, Singh A, Chang LL, Joice MG, Rivero JM, Vaduganathan M, Januzzi JL, Bhatt DL
PMID: 30846340 [PubMed - indexed for MEDLINE]
Underutilization of Cardiac Rehabilitation for Type 2 Myocardial Infarction.
J Am Coll Cardiol. 2019 04 23;73(15):2005-2007
Authors: McCarthy CP, Murphy S, Cohen JA, Rehman S, Jones-O'Connor M, Olshan DS, Singh A, Vaduganathan M, Januzzi JL, Wasfy JH
PMID: 30846342 [PubMed - indexed for MEDLINE]
Immunotherapy for brain tumors: understanding early successes and limitations.
Expert Rev Neurother. 2018 03;18(3):251-259
Authors: Lieberman NAP, Vitanza NA, Crane CA
Abstract
INTRODUCTION: Adverse effects and toxicities related to standard treatments for brain tumors significantly reduce patients' quality of life. Although most immunotherapy approaches for solid tumors have not been successful, several early-phase clinical trials are beginning to reveal a potential role for immunotherapy in the treatment of brain tumors. In particular, methods that activate the innate immune system and induce a polyclonal anti-cancer response have demonstrated that brain tumors are susceptible to immune-mediated tumor destruction. Compared with conventional therapies, modulation of the immune system may improve both survivorship and quality of life during and following treatment. Areas covered: An overview of mechanisms of immunotherapy in the context of current treatments for adult and pediatric brain tumors is provided. Results from recent clinical trials will be discussed, focusing on the favorable safety and efficacy profiles of immunotherapeutics. Expert commentary: Although it is too early to judge the long-term safety of immunotherapy for the treatment of patients with brain tumors, early results suggest that these drugs are well-tolerated and may improve survival and quality of life. Importantly, approaches that activate an anti-tumor immune response lay the framework for iterative development of immunotherapies that can reliably treat patients with brain tumors.
PMID: 29322843 [PubMed - indexed for MEDLINE]
Endovascular thrombectomy in pediatric patients with large vessel occlusion.
J Neurointerv Surg. 2019 Jul;11(7):729-732
Authors: Shoirah H, Shallwani H, Siddiqui AH, Levy EI, Kenmuir CL, Jovin TG, Levitt MR, Kim LJ, Griauzde J, Pandey AS, Gemmete JJ, Abruzzo T, Arthur AS, Elijovich L, Hoit D, Cheema A, Aghaebrahim A, Sauvageau E, Hanel R, Ringer AJ, Nascimento FA, Kan P, Mocco J
Abstract
BACKGROUND: Pediatric acute ischemic stroke with underlying large vessel occlusion is a rare disease with significant morbidity and mortality. There is a paucity of data about the safety and outcomes of endovascular thrombectomy in these cases, especially with modern devices.
METHODS: We conducted a retrospective review of all pediatric stroke patients who underwent endovascular thrombectomy in nine US tertiary centers between 2008 and 2017.
RESULTS: Nineteen patients (63.2% male) with a mean (SD) age of 10.9(6) years and weight 44.6 (30.8) kg were included. Mean (SD) NIH Stroke Scale (NIHSS) score at presentation was 13.9 (5.7). CT-based assessment was obtained in 88.2% of the patients and 58.8% of the patients had perfusion-based assessment. All procedures were performed via the transfemoral approach. The first-pass device was stentriever in 52.6% of cases and aspiration in 36.8%. Successful revascularization was achieved in 89.5% of the patients after a mean (SD) of 2.2 (1.5) passes, with a mean (SD) groin puncture to recanalization time of 48.7 (37.3) min (median 41.5). The mean (SD) reduction in NIHSS from admission to discharge was 10.2 (6.2). A good neurological outcome was achieved in 89.5% of the patients. One patient had post-revascularization seizure, but no other procedural complications or mortality occurred.
CONCLUSIONS: Endovascular thrombectomy is safe and feasible in selected pediatric patients. Technical and neurological outcomes were comparable to adult literature with no safety concerns with the use of standard adult devices in patients as young as 18 months. This large series adds to the growing literature but further studies are warranted.
PMID: 30842301 [PubMed - indexed for MEDLINE]
Nanoparticle Biokinetics in Mice and Nonhuman Primates.
ACS Nano. 2017 09 26;11(9):9514-9524
Authors: Chiarelli PA, Revia RA, Stephen ZR, Wang K, Jeon M, Nelson V, Kievit FM, Sham J, Ellenbogen RG, Kiem HP, Zhang M
Abstract
Despite the preponderance of iron oxide nanoparticles (NPs) designed for theranostic applications, widespread clinical translation of these NPs lags behind. A better understanding of how NP pharmacokinetics vary between small and large animal models is needed to rapidly customize NPs for optimal performance in humans. Here we use noninvasive magnetic resonance imaging (MRI) to track iron oxide NPs through a large number of organ systems in vivo to investigate NP biokinetics in both mice and nonhuman primates. We demonstrate that pharmacokinetics are similar between mice and macaques in the blood, liver, spleen, and muscle, but differ in the kidneys, brain, and bone marrow. Our study also demonstrates that full-body MRI is practical, rapid, and cost-effective for tracking NPs noninvasively with high spatiotemporal resolution. Our techniques using a nonhuman primate model may provide a platform for testing a range of NP formulations.
PMID: 28885825 [PubMed - indexed for MEDLINE]
Functional Status Examination versus Glasgow Outcome Scale Extended as Outcome Measures in Traumatic Brain Injuries: How Do They Compare?
J Neurotrauma. 2019 08 15;36(16):2423-2429
Authors: Dikmen S, Machamer J, Manley GT, Yuh EL, Nelson LD, Temkin NR, TRACK-TBI Investigators
Abstract
Outcome measures are essential components of natural history studies of recovery and treatment effects after traumatic brain injury (TBI). The Glasgow Outcome Scale (GOS) and its revised version, the Glasgow Outcome Scale Extended (GOSE), are well accepted and widely used for both observational and intervention studies, but there are concerns about their psychometric properties and aptness as outcome measures for TBI. The present study compares the Functional Status Examination (FSE) with the GOSE to assess outcome after TBI in a sample of 533 participants with TBI from the Magnesium Sulfate study and the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study by evaluating the sensitivity of each measure to severity of brain injury and recovery of function over time. The results indicate that both measures are strongly correlated with TBI severity. At three months, the correlation strengths between injury severity and each outcome measure do not differ (p = 0.88 for Glasgow Coma Scale [GCS], p = 0.13 for computed tomography [CT] abnormalities) but at six months, the FSE is more strongly related to TBI severity indices than is the GOSE (p = 0.045 for GCS, p = 0.014 for CT abnormalities). In addition, the FSE generally shows significantly more improvement over time than the GOSE (p < 0.001). Detailed, structured administration rules and a wider score range of the FSE likely yields more sensitive and precise assessment of functional level than the GOSE. The FSE may be a valuable alternative to the GOSE for assessing functional outcome after TBI.
PMID: 30827167 [PubMed - indexed for MEDLINE]
Investigating racial disparities in bariatric surgery referrals.
Surg Obes Relat Dis. 2019 Apr;15(4):615-620
Authors: Johnson-Mann C, Martin AN, Williams MD, Hallowell PT, Schirmer B
Abstract
BACKGROUND: Prior studies investigating racial, socioeconomic, and/or insurance disparities with regard to access to care and outcomes in bariatric surgery have been performed with varying results.
OBJECTIVES: Our aim was to determine if racial or ethnic disparities exist in referral patterns for bariatric surgery at a single center.
METHODS: An institutional, retrospective chart review from January 2012 through June 2017 was performed for patients meeting referral criteria to bariatric surgery. Data collection was limited to patients referred to the bariatric surgery clinic from on-site primary care clinics.
RESULTS: In total, 4736 patients were eligible for bariatric surgery during the study period. Patients were 63.8% female (n = 3022), and 36.2% male (n = 1714); 53.9% white (n = 2553), 37.8% black (n = 1790), and 8.3% Hispanic (n = 393). Female patients were more likely to be referred than male patients (5.5% versus 4.1%, χ2 4.59, P = .032). On univariate comparison, Hispanic patients were less likely to be referred compared with black or white patients (2.0% versus 5.3% and 5.2%, χ2 7.88, P = .019).
CONCLUSION: Hispanic patients were less likely to be referred at our institution for bariatric surgery compared with white or black patients. A barrier to referral may be explained by the disproportionate number of Hispanic patients that were designated as "self-pay" rather than private insurance or Medicaid/Medicare coverage that is required for bariatric surgery referral. This finding underscores the need for further research surrounding barriers to access to care for Hispanic patients.
PMID: 30824334 [PubMed - indexed for MEDLINE]
Direct stimulation of somatosensory cortex results in slower reaction times compared to peripheral touch in humans.
Sci Rep. 2019 03 01;9(1):3292
Authors: Caldwell DJ, Cronin JA, Wu J, Weaver KE, Ko AL, Rao RPN, Ojemann JG
Abstract
Direct cortical stimulation (DCS) of primary somatosensory cortex (S1) could help restore sensation and provide task-relevant feedback in a neuroprosthesis. However, the psychophysics of S1 DCS is poorly studied, including any comparison to cutaneous haptic stimulation. We compare the response times to DCS of human hand somatosensory cortex through electrocorticographic grids with response times to haptic stimuli delivered to the hand in four subjects. We found that subjects respond significantly slower to S1 DCS than to natural, haptic stimuli for a range of DCS train durations. Median response times for haptic stimulation varied from 198 ms to 313 ms, while median responses to reliably perceived DCS ranged from 254 ms for one subject, all the way to 528 ms for another. We discern no significant impact of learning or habituation through the analysis of blocked trials, and find no significant impact of cortical stimulation train duration on response times. Our results provide a realistic set of expectations for latencies with somatosensory DCS feedback for future neuroprosthetic applications and motivate the study of neural mechanisms underlying human perception of somatosensation via DCS.
PMID: 30824821 [PubMed - indexed for MEDLINE]
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]
