UW Neurological Surgery Recent PubMed Publications

Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation.

NPJ Regen Med. 2020 Nov 23;5(1):22

Authors: Norat P, Soldozy S, Sokolowski JD, Gorick CM, Kumar JS, Chae Y, Yağmurlu K, Prada F, Walker M, Levitt MR, Price RJ, Tvrdik P, Kalani MYS

Abstract
Mitochondria are fundamental for metabolic homeostasis in all multicellular eukaryotes. In the nervous system, mitochondria-generated adenosine triphosphate (ATP) is required to establish appropriate electrochemical gradients and reliable synaptic transmission. Notably, several mitochondrial defects have been identified in central nervous system disorders. Membrane leakage and electrolyte imbalances, pro-apoptotic pathway activation, and mitophagy are among the mechanisms implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, as well as ischemic stroke. In this review, we summarize mitochondrial pathways that contribute to disease progression. Further, we discuss pathological states that damaged mitochondria impose on normal nervous system processes and explore new therapeutic approaches to mitochondrial diseases.

PMID: 33298971 [PubMed]

Whole brain proton irradiation in adult Sprague Dawley rats produces dose dependent and non-dependent cognitive, behavioral, and dopaminergic effects.

Sci Rep. 2020 Dec 09;10(1):21584

Authors: Williams MT, Sugimoto C, Regan SL, Pitzer EM, Fritz AL, Mascia AE, Sertorio M, Vatner RE, Perentesis JP, Vorhees CV

Abstract
Proton radiotherapy causes less off-target effects than X-rays but is not without effect. To reduce adverse effects of proton radiotherapy, a model of cognitive deficits from conventional proton exposure is needed. We developed a model emphasizing multiple cognitive outcomes. Adult male rats (10/group) received a single dose of 0, 11, 14, 17, or 20 Gy irradiation (the 20 Gy group was not used because 50% died). Rats were tested once/week for 5 weeks post-irradiation for activity, coordination, and startle. Cognitive assessment began 6-weeks post-irradiation with novel object recognition (NOR), egocentric learning, allocentric learning, reference memory, and proximal cue learning. Proton exposure had the largest effect on activity and prepulse inhibition of startle 1-week post-irradiation that dissipated each week. 6-weeks post-irradiation, there were no effects on NOR, however proton exposure impaired egocentric (Cincinnati water maze) and allocentric learning and caused reference memory deficits (Morris water maze), but did not affect proximal cue learning or swimming performance. Proton groups also had reduced striatal levels of the dopamine transporter, tyrosine hydroxylase, and the dopamine receptor D1, effects consistent with egocentric learning deficits. This new model will facilitate investigations of different proton dose rates and drugs to ameliorate the cognitive sequelae of proton radiotherapy.

PMID: 33299021 [PubMed - in process]

Quantifying neurologic disease using biosensor measurements in-clinic and in free-living settings in multiple sclerosis.

NPJ Digit Med. 2019 Dec 11;2(1):123

Authors: Chitnis T, Glanz BI, Gonzalez C, Healy BC, Saraceno TJ, Sattarnezhad N, Diaz-Cruz C, Polgar-Turcsanyi M, Tummala S, Bakshi R, Bajaj VS, Ben-Shimol D, Bikhchandani N, Blocker AW, Burkart J, Cendrillon R, Cusack MP, Demiralp E, Jooste SK, Kharbouch A, Lee AA, Lehár J, Liu M, Mahadevan S, Murphy M, Norton LC, Parlikar TA, Pathak A, Shoeb A, Soderberg E, Stephens P, Stoertz AH, Thng F, Tumkur K, Wang H, Rhodes J, Rudick RA, Ransohoff RM, Phillips GA, Bruzik E, Marks WJ, Weiner HL, Snyder TM

Abstract
Technological advances in passive digital phenotyping present the opportunity to quantify neurological diseases using new approaches that may complement clinical assessments. Here, we studied multiple sclerosis (MS) as a model neurological disease for investigating physiometric and environmental signals. The objective of this study was to assess the feasibility and correlation of wearable biosensors with traditional clinical measures of disability both in clinic and in free-living in MS patients. This is a single site observational cohort study conducted at an academic neurological center specializing in MS. A cohort of 25 MS patients with varying disability scores were recruited. Patients were monitored in clinic while wearing biosensors at nine body locations at three separate visits. Biosensor-derived features including aspects of gait (stance time, turn angle, mean turn velocity) and balance were collected, along with standardized disability scores assessed by a neurologist. Participants also wore up to three sensors on the wrist, ankle, and sternum for 8 weeks as they went about their daily lives. The primary outcomes were feasibility, adherence, as well as correlation of biosensor-derived metrics with traditional neurologist-assessed clinical measures of disability. We used machine-learning algorithms to extract multiple features of motion and dexterity and correlated these measures with more traditional measures of neurological disability, including the expanded disability status scale (EDSS) and the MS functional composite-4 (MSFC-4). In free-living, sleep measures were additionally collected. Twenty-three subjects completed the first two of three in-clinic study visits and the 8-week free-living biosensor period. Several biosensor-derived features significantly correlated with EDSS and MSFC-4 scores derived at visit two, including mobility stance time with MSFC-4 z-score (Spearman correlation -0.546; p = 0.0070), several aspects of turning including turn angle (0.437; p = 0.0372), and maximum angular velocity (0.653; p = 0.0007). Similar correlations were observed at subsequent clinic visits, and in the free-living setting. We also found other passively collected signals, including measures of sleep, that correlated with disease severity. These findings demonstrate the feasibility of applying passive biosensor measurement techniques to monitor disability in MS patients both in clinic and in the free-living setting.

PMID: 33299125 [PubMed]

Impact of New Motor Deficit on HRQOL after Adult Spinal Deformity Surgery: Subanalysis from Scoli Risk 1 Prospective Study.

Spine (Phila Pa 1976). 2020 Dec 07;:

Authors: Saigal R, Lau D, Berven SH, Carreon L, Dekutoski MB, Kebaish KM, Qiu Y, Matsuyama Y, Kelly M, Dahl BT, Mehdian H, Pellisé F, Lewis SJ, Cheung KM, Shaffrey CI, Fehlings MG, Lenke LG, Ames CP, AOSpine Knowledge Forum Deformity

Abstract
STUDY DESIGN: International, multi-center, prospective, longitudinal observational cohort.
OBJECTIVE: To assess how new motor deficits affect patient reported quality of life scores after adult deformity surgery.
SUMMARY OF BACKGROUND DATA: Adult spinal deformity surgery is associated with high morbidity, including risk of new post-operative motor deficit. It is unclear what effect new motor deficit has on HRQOL scores.
METHODS: Adult spinal deformity patients were enrolled prospectively at 15 sites worldwide. Other inclusion criteria included major Cobb >80 degrees, C7-L2 curve apex, and any patient undergoing 3 column osteotomy. ASIA scores and standard HRQOL scores were recorded pre-op, 6 weeks, 6 months, and 2 years.
RESULTS: 272 complex adult spinal deformity (ASD) patients enrolled. HRQOL scores were worse for patients with lower LEMS scores. Mean HRQOL changes at 6 weeks and 2 years compared to pre-op for patients with motor worsening were: ODI (+12.4 at 6 weeks and -4.7 at 2 years), SF-36v2 physical (-4.5 at 6 weeks and +2.3 at 2 years), SRS-22r (0.0 at 6 weeks and +0.4 at 2 years). Mean HRQOL changes for motor-neutral patients were: ODI (+0.6 at 6 weeks and -12.1 at 2 years), SF-36v2 physical (-1.6 at 6 weeks and +5.9 at 2 years), and SRS-22r (+0.4 at 6 weeks and +0.7 at 2 years). For patients with LEMS improvement, mean HRQOL changes were: ODI (-0.6 at 6 weeks and -16.3 at 2 years), SF-36v2 physical (+1.0 at 6 weeks and +7.0 at 2 years), and SRS-22r (+0.5 at 6 weeks and +0.9 at 2 years).
CONCLUSION: In the subgroup of deformity patients who developed a new motor deficit, total HRQOLs and HRQOL changes were negatively impacted. Patients with more than 2 points of LEMS worsening had the worst changes, but still showed overall HRQOL improvement at 6 months and 2 years compared to pre-op baseline.
LEVEL OF EVIDENCE: 3.

PMID: 33290376 [PubMed - as supplied by publisher]

Short chain fatty acids produced by Cutibacterium acnes inhibit biofilm formation by Staphylococcus epidermidis.

Sci Rep. 2020 Dec 04;10(1):21237

Authors: Nakamura K, O'Neill AM, Williams MR, Cau L, Nakatsuji T, Horswill AR, Gallo RL

Abstract
Biofilm formation by bacterial pathogens is associated with numerous human diseases and can confer resistance to both antibiotics and host defenses. Many strains of Staphylococcus epidermidis are capable of forming biofilms and are important human pathogens. Since S. epidermidis coexists with abundant Cutibacteria acnes on healthy human skin and does not typically form a biofilm in this environment, we hypothesized that C. acnes may influence biofilm formation of S. epidermidis. Culture supernatants from C. acnes and other species of Cutibacteria inhibited S. epidermidis but did not inhibit biofilms by Pseudomonas aeruginosa or Bacillus subtilis, and inhibited biofilms by S. aureus to a lesser extent. Biofilm inhibitory activity exhibited chemical properties of short chain fatty acids known to be produced from C. acnes. The addition of the pure short chain fatty acids propionic, isobutyric or isovaleric acid to S. epidermidis inhibited biofilm formation and, similarly to C. acnes supernatant, reduced polysaccharide synthesis by S. epidermidis. Both short chain fatty acids and C. acnes culture supernatant also increased sensitivity of S. epidermidis to antibiotic killing under biofilm-forming conditions. These observations suggest the presence of C. acnes in a diverse microbial community with S. epidermidis can be beneficial to the host and demonstrates that short chain fatty acids may be useful to limit formation of a biofilm by S. epidermidis.

PMID: 33277548 [PubMed - as supplied by publisher]

Economic modeling of reSET-O, a prescription digital therapeutic for patients with opioid use disorder.

J Med Econ. 2020 Dec 03;:1

Authors: Wang W, Gellings Lowe N, Jalali A, Murphy SM

Abstract
AIMS: reSET-O is a Food and Drug Administration-cleared prescription digital therapeutic indicated to improve outpatient-treatment retention of patients with opioid use disorder (OUD). This study examined the cost-effectiveness and budget impact of reSET-O in conjunction with treatment as usual (reSET-O + TAU) relative to TAU.
MATERIALS AND METHODS: Adult patients with ≥1 OUD diagnosis, treated with buprenorphine from January 1, 2015 to March 30, 2018, were identified from Truven Health MarketScan® Commercial and Medicare Supplemental Research Databases. Twelve-week healthcare resource utilization (HCRU) costs for patients categorized as adherent and nonadherent to buprenorphine treatment were estimated. Total 12-week costs included OUD treatment and other HCRU costs. The cost-effectiveness of reSET-O + TAU was modeled in accordance with prior clinical trial outcomes. The 12-week budget impact of reSET-O was modeled for a 1 million-member healthcare plan.
RESULTS: Higher buprenorphine adherence was associated with lower HCRU costs in claims data. Twelve-week per-patient total costs were $305 more for those receiving reSET-O + TAU than those receiving TAU. The incremental cost-effectiveness ratio was $18.70 per 1 percentage-point increase in the treatment retention rate. The probability that reSET-O + TAU would be considered cost-effective was over 92% for willingness-to-pay thresholds of $6,000 or more. The 12-week budget impact of reSET-O was $8,908, translating to $0.003 per member per month.
LIMITATIONS: The findings of the cost-effectiveness and budget impact modeling are limited by the assumptions of the models due to uncertainty around some inputs. While no model is free of bias, the inputs for this model were carefully selected to reflect contemporary treatment patterns.
CONCLUSIONS: Depending on the payer's willingness to pay, reSET-O may be cost-effective in increasing buprenorphine treatment retention rates. reSET-O results in an approximate budget impact of $0.003 per member per month, depending on market share and the prevalence of the population receiving treatment for OUD.

PMID: 33267633 [PubMed - as supplied by publisher]

Reducing Intracranial Pressure by Reducing Central Venous Pressure: Assessment of potential countermeasures to spaceflight associated neuro-ocular syndrome.

J Appl Physiol (1985). 2020 Dec 03;:

Authors: Hansen AB, Lawley JS, Rickards CA, Howden EJ, Sarma S, Cornwell WK, Amin SB, Mugele H, Marume K, Possnig C, Whitworth LA, Williams MA, Levine BD

Abstract
Spaceflight-associated neuro-ocular syndrome (SANS) involves unilateral or bilateral optic disc edema, widening of the optic nerve sheath, and posterior globe flattening. Due to posterior globe flattening, it is hypothesized that microgravity causes a disproportionate change in intracranial pressure (ICP) relative to intraocular pressure. Countermeasures capable of reducing ICP include thigh cuffs and breathing against inspiratory resistance. Due to the coupling of central venous (CVP) and intracranial pressure, we hypothesized that both ICP and CVP will be reduced during both countermeasures. In four male participants (32±13 yrs) who were previously implanted with Ommaya reservoirs for treatment of unrelated clinical conditions, ICP was measured invasively through these ports. Subjects were healthy at the time of testing. CVP was measured invasively by a peripherally inserted central catheter. Participants breathed through an Impedance Threshold Device (ITD, -7 cm.H2O) to generate negative intrathoracic pressure for five-mins, and subsequently, wore bilateral thigh cuffs at 30-mmHg for two-mins. Breathing through an ITD reduced both CVP (6±2 vs 3±1 mmHg; P=0.02) and ICP (16±3 vs 12±1 mmHg; P=0.04) compared to the supine posture, which was not observed during the free breathing condition (CVP, 6±2 vs 6±2 mmHg; P=0.87 and ICP, 15±3 vs 15±4 mmHg; P=0.68). Inflation of the thigh cuffs to 30-mmHg caused no meaningful reduction in CVP in all four individuals (5±4 vs 5±4 mmHg; P=0.1), coincident with a minimal reduction in ICP (15±3 vs 14±4 mmHg; P=0.13). The application of inspiratory resistance breathing resulted in reductions in both ICP and CVP, likely due to intrathoracic unloading.

PMID: 33270516 [PubMed - as supplied by publisher]

Insights on cross-species transmission of SARS-CoV-2 from structural modeling.

PLoS Comput Biol. 2020 12;16(12):e1008449

Authors: Rodrigues JPGLM, Barrera-Vilarmau S, M C Teixeira J, Sorokina M, Seckel E, Kastritis PL, Levitt M

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 31 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic and confirmed cases of cross-species transmission, the question of the extent to which this transmission is possible emerges, as well as what molecular features distinguish susceptible from non-susceptible animal species. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also allow us to predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.

PMID: 33270653 [PubMed - indexed for MEDLINE]

The authors reply.

Crit Care Med. 2020 Dec;48(12):e1366-e1367

Authors: Chesnut RM, Videtta W

PMID: 33255133 [PubMed - in process]

Effect of bodyweight on VerifyNow Aspirin platelet function test: a retrospective review.

J Neurointerv Surg. 2020 Nov 30;:

Authors: Sandler M, Hoang C, Mak HY, Levitt MR

Abstract
BACKGROUND: Antiplatelet therapy is used to prevent stent thrombosis in intracranial stents, but the optimal dose of aspirin is unknown. This study sought to determine whether the degree of platelet inhibition with aspirin is affected by bodyweight as observed through a platelet reactivity assay.
METHODS: This is a retrospective review of patients who underwent neurovascular stent placement and had a VerifyNow Aspirin assay result. The primary outcome was the correlation between the VerifyNow Aspirin result, bodyweight, and the initial dose of aspirin. Secondary outcomes included the impact of the VerifyNow P2Y12 result and of weight on the incidence of bleeding or a thrombotic event.
RESULTS: Of the 142 included patients, 62.7% weighed ≥70 kg and 88.7% were initiated on aspirin 300-325 mg daily. 83.8% achieved a therapeutic VerifyNow Aspirin result. There was minimal correlation between the VerifyNow Aspirin result, bodyweight, and aspirin dose (R2=0.02). Between patients who weighed <70 kg versus ≥70 kg, there was no difference in the mean aspirin reaction units (ARU) (449 vs 435, p=0.32) or in the incidence of bleeding (28% vs 17.1%, p=0.14) or a thrombotic event (4% vs 5.3%, p=0.59). No patient experienced stent thrombosis and eight patients experienced in-stent stenosis. In a multivariate analysis, only the VerifyNow P2Y12 result predicted the development of either bleeding or a thrombotic event (p<0.01).
CONCLUSIONS: Bodyweight did not influence the likelihood of obtaining a therapeutic VerifyNow Aspirin result. The clinical utility of obtaining VerifyNow Aspirin assays for this patient population is unknown.

PMID: 33257413 [PubMed - as supplied by publisher]

Costs of using evidence-based implementation strategies for behavioral health integration in a large primary care system.

Health Serv Res. 2020 Dec;55(6):913-923

Authors: Yeung K, Richards J, Goemer E, Lozano P, Lapham G, Williams E, Glass J, Lee A, Achtmeyer C, Caldeiro R, Parrish R, Bradley K

Abstract
OBJECTIVE: To describe the cost of using evidence-based implementation strategies for sustained behavioral health integration (BHI) involving population-based screening, assessment, and identification at 25 primary care sites of Kaiser Permanente Washington (2015-2018).
DATA SOURCES/STUDY SETTING: Project records, surveys, Bureau of Labor Statistics compensation data.
STUDY DESIGN: Labor and nonlabor costs incurred by three implementation strategies: practice coaching, electronic health records clinical decision support, and performance feedback.
DATA COLLECTION/EXTRACTION METHODS: Personnel time spent on these strategies was estimated for five broad roles: (a) project leaders and administrative support, (b) practice coaches, (c) clinical decision support programmers, (d) performance metric programmers, and (e) primary care local implementation team members.
PRINCIPAL FINDING: Implementation involved 286 persons, 18 131 person-hours, costing $1 587 139 or $5 per primary care visit with screening or $38 per primary care visit identifying depression, suicidal thoughts and/or alcohol or substance use disorders, in a single year. The majority of person-hours was devoted to project leadership (35%) and practice coaches (34%), and 36% of costs were for the first three sites.
CONCLUSIONS: When spread across patients screened in a single year, BHI implementation costs were well within the range for commonly used diagnostic assessments in primary care (eg, laboratory tests). This suggests that implementation costs alone should not be a substantial barrier to population-based BHI.

PMID: 33258127 [PubMed - in process]

Developments in Heart Failure With Reduced Ejection Fraction-Reply.

JAMA. 2020 12 01;324(21):2215-2216

Authors: Murphy SP, Ibhrahim NE, Januzzi JL

PMID: 33258887 [PubMed - indexed for MEDLINE]

A Pilot Study on Data-Driven Adaptive Deep Brain Stimulation in Chronically Implanted Essential Tremor Patients.

Front Hum Neurosci. 2020;14:541625

Authors: Castaño-Candamil S, Ferleger BI, Haddock A, Cooper SS, Herron J, Ko A, Chizeck HJ, Tangermann M

Abstract
Deep brain stimulation (DBS) is an established therapy for Parkinson's disease (PD) and essential-tremor (ET). In adaptive DBS (aDBS) systems, online tuning of stimulation parameters as a function of neural signals may improve treatment efficacy and reduce side-effects. State-of-the-art aDBS systems use symptom surrogates derived from neural signals-so-called neural markers (NMs)-defined on the patient-group level, and control strategies assuming stationarity of symptoms and NMs. We aim at improving these aDBS systems with (1) a data-driven approach for identifying patient- and session-specific NMs and (2) a control strategy coping with short-term non-stationary dynamics. The two building blocks are implemented as follows: (1) The data-driven NMs are based on a machine learning model estimating tremor intensity from electrocorticographic signals. (2) The control strategy accounts for local variability of tremor statistics. Our study with three chronically implanted ET patients amounted to five online sessions. Tremor quantified from accelerometer data shows that symptom suppression is at least equivalent to that of a continuous DBS strategy in 3 out-of 4 online tests, while considerably reducing net stimulation (at least 24%). In the remaining online test, symptom suppression was not significantly different from either the continuous strategy or the no treatment condition. We introduce a novel aDBS system for ET. It is the first aDBS system based on (1) a machine learning model to identify session-specific NMs, and (2) a control strategy coping with short-term non-stationary dynamics. We show the suitability of our aDBS approach for ET, which opens the door to its further study in a larger patient population.

PMID: 33250727 [PubMed]

Systems Biology Methods Applied to Blood and Tissue for a Comprehensive Analysis of Immune Response to Hepatitis B Vaccine in Adults.

Front Immunol. 2020;11:580373

Authors: Ben-Othman R, Cai B, Liu AC, Varankovich N, He D, Blimkie TM, Lee AH, Gill EE, Novotny M, Aevermann B, Drissler S, Shannon CP, McCann S, Marty K, Bjornson G, Edgar RD, Lin DTS, Gladish N, Maclsaac J, Amenyogbe N, Chan Q, Llibre A, Collin J, Landais E, Le K, Reiss SM, Koff WC, Havenar-Daughton C, Heran M, Sangha B, Walt D, Krajden M, Crotty S, Sok D, Briney B, Burton DR, Duffy D, Foster LJ, Mohn WW, Kobor MS, Tebbutt SJ, Brinkman RR, Scheuermann RH, Hancock REW, Kollmann TR, Sadarangani M

Abstract
Conventional vaccine design has been based on trial-and-error approaches, which have been generally successful. However, there have been some major failures in vaccine development and we still do not have highly effective licensed vaccines for tuberculosis, HIV, respiratory syncytial virus, and other major infections of global significance. Approaches at rational vaccine design have been limited by our understanding of the immune response to vaccination at the molecular level. Tools now exist to undertake in-depth analysis using systems biology approaches, but to be fully realized, studies are required in humans with intensive blood and tissue sampling. Methods that support this intensive sampling need to be developed and validated as feasible. To this end, we describe here a detailed approach that was applied in a study of 15 healthy adults, who were immunized with hepatitis B vaccine. Sampling included ~350 mL of blood, 12 microbiome samples, and lymph node fine needle aspirates obtained over a ~7-month period, enabling comprehensive analysis of the immune response at the molecular level, including single cell and tissue sample analysis. Samples were collected for analysis of immune phenotyping, whole blood and single cell gene expression, proteomics, lipidomics, epigenetics, whole blood response to key immune stimuli, cytokine responses, in vitro T cell responses, antibody repertoire analysis and the microbiome. Data integration was undertaken using different approaches-NetworkAnalyst and DIABLO. Our results demonstrate that such intensive sampling studies are feasible in healthy adults, and data integration tools exist to analyze the vast amount of data generated from a multi-omics systems biology approach. This will provide the basis for a better understanding of vaccine-induced immunity and accelerate future rational vaccine design.

PMID: 33250895 [PubMed - in process]

Circadian variation in sudden unexpected infant death in the United States.

Acta Paediatr. 2020 Nov 29;:

Authors: Anderson TM, Allen K, Ramirez JM, Mitchell EA

Abstract
AIM: To determine which factors are associated with sudden unexpected infant death (SUID) by time of day.
METHODS: Data were analyzed from the National Fatality Review Case Reporting System (2006-2015). Out of 20,005 SUID deaths in 37 states, 12,191 (60.9%) deaths had a recorded nearest hour of discovery of the infant. We compared distribution patterns between time of death and 118 variables to determine which were significantly correlated with SUID time of death using advanced statistical modelling techniques.
RESULTS: The 12-hour time periods which were most different were 10:00 to 21:00 (daytime) and 22:00 to 09:00 (nighttime). The main features that were associated with nighttime SUID were bed sharing, younger infants, non-white infants, placed supine to sleep, found supine, and caregiver was the parent. Daytime SUID was associated with older infants, daycare, white infants, sleeping in an adult bed, and prone sleep position. Factors not associated with time of death were sex of the infant, smoking, and breastfeeding.
CONCLUSION: SUID deaths that occur at night are associated with a separate set of risk factors compared to deaths that occur during the day. However, to minimize risk, it is important to practice safe sleep guidelines during both nighttime and daytime sleep.

PMID: 33251652 [PubMed - as supplied by publisher]

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

Lancet Oncol. 2021 01;22(1):107-117

Authors: Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, Bivalacqua TJ, Montgomery JS, Lerner SP, Busby JE, Poch M, Crispen PL, Steinberg GD, Schuckman AK, Downs TM, Svatek RS, Mashni J, Lane BR, Guzzo TJ, Bratslavsky G, Karsh LI, Woods ME, Brown G, Canter D, Luchey A, Lotan Y, Krupski T, Inman BA, Williams MB, Cookson MS, Keegan KA, Andriole GL, Sankin AI, Boyd A, O'Donnell MA, Sawutz D, Philipson R, Coll R, Narayan VM, Treasure FP, Yla-Herttuala S, Parker NR, Dinney CPN

Abstract
BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.
METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.
FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.
INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state.
FUNDING: FKD Therapies Oy.

PMID: 33253641 [PubMed - indexed for MEDLINE]

Strategies for writing a successful National Institutes of Health grant proposal for the early-career neurointerventionalist.

J Neurointerv Surg. 2020 Nov 25;:

Authors: Kan P, Mokin M, Mack WJ, Starke RM, Sheth KN, Albuquerque FC, Levitt MR

Abstract
OBJECTIVE: The goal of this article is to provide a succinct review of the key components of a NIH grant application and the NIH reviewprocess for the early career neurointerventionalist.
METHODS: The authors reviewed NIH rules and regulations and also reflected on their own collective experiencein writing NIH grant proposals in the area of cerebrovascular disease andneurointerventional surgery.
RESULTS: Key components of theresearch strategy include specific aims, significance, innovation and approach.The specific aims page is the most important page of the application and should be written first. The NIH review isbased on these key components along with an assessment of the appropriatenessof the investigators and environment for the research.
CONCLUSION: Detailed knowledge ofthe key components of the research grant is critical to a successful application.The information in the article may aid in the grant writing for early careerneurointerventionalists.

PMID: 33239307 [PubMed - as supplied by publisher]

National Institutes of Health grant opportunities for the neurointerventionalist: preparation and choosing the right mechanism.

J Neurointerv Surg. 2020 Nov 25;:

Authors: Kan P, Levitt MR, Mack WJ, Starke RM, Sheth KN, Albuquerque FC, Mokin M

Abstract
OBJECTIVE: The goal of this article is to provide recommendations for the early career neurointerventionalist in writing a successful grant application to the National Institutes of Health (NIH) and similar funding agencies.
METHODS: The authors reviewed NIH rules and regulations and also reflected on their own collective experience in writing NIH grant proposals in the area of cerebrovascular disease and neurointerventional surgery.
RESULTS: A strong proposal should address an important scientific problem where there is a gap in knowledge. The solution offered needs to be innovative but at the same time based on a strong scientific premise. The proposed research must be feasible to implement and investigate in the researcher's environment.
CONCLUSION: Successful grant writing is critical in funding and enhancing research. The information in the article may aid in the preparation stage of grant writing for early career neurointerventionalists.

PMID: 33239308 [PubMed - as supplied by publisher]

Rodent and fly models in behavioral neuroscience: an evaluation of methodological advances, comparative research, and future perspectives.

Neurosci Biobehav Rev. 2020 Nov 23;:

Authors: Moulin TC, Covill LE, Itskov PM, Williams MJ, Schiöth HB

Abstract
The assessment of behavioral outcomes is a central component of neuroscientific research, which has required continuous technological innovations to produce more detailed and reliable findings. In this article, we provide an in-depth review on the progress and future implications for three model organisms (mouse, rat, and Drosophila) essential to our current understanding of behavior. By compiling a comprehensive catalog of popular assays, we are able to compare the diversity of tasks and usage of these animal models in behavioral research. This compilation also allows for the evaluation of existing state-of-the-art methods and experimental applications, including optogenetics, machine learning, and high-throughput behavioral assays. We go on to discuss novel apparatuses and inter-species analyses for centrophobism, feeding behavior, aggression and mating paradigms, with the goal of providing a unique view on comparative behavioral research. The challenges and recent advances are evaluated in terms of their translational value, ethical procedures, and trustworthiness for behavioral research.

PMID: 33242563 [PubMed - as supplied by publisher]

Reply to Wenzel and Kubiak: Neuroticism is best defined by mean levels of negative emotion, not emotional variability.

Proc Natl Acad Sci U S A. 2020 12 29;117(52):32859-32860

Authors: Kalokerinos EK, Murphy SC, Koval P, Mestdagh M, Bastian B, Kuppens P

PMID: 33234570 [PubMed - indexed for MEDLINE]