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Background This study aims to compare dosimetrically and radiobiologically 3 D conformal, intensity modulated radiation therapy ( IMRT), RapidArc ( RA) volumetric modulated arc therapy and proton therapy techniques for early-stage glottic cancer. Methods Ten patients were retrospectively selected. Photon treatment planning was performed using Eclipse External Beam Planning, and proton planning was performed using CMS Xio. The minimum, mean and maximum dose values for planning target volume ( PTV), mean and maximum dose values for organ at risk, % of volume of PTV receiving at least 95% of the prescription dose, and D20, D50 and D90 of carotid arteries were compared. Biological response models of tumour control probabilities and normal tissue complication probabilities were calculated. Results IMRT, RA and proton plans versus three-dimensional conformal radiotherapy (3 D-CRT) plans consistently provided superior PTV coverage and decreased mean dose to the thyroid and carotid arteries. Conclusion All these three modalities showed superiority with less variation among themselves compared with 3 D-CRT plans. Clinical investigation is warranted to determine if these treatment approaches will translate into a reduction in radiation therapy-induced toxicities. [ABSTRACT FROM AUTHOR]

Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Despite this association, the mechanisms underlying the increased susceptibility to respiratory virus infection are poorly understood. Retinoic acid-inducible gene I (RIG-I) is an important regulator of influenza virus-induced expression of antiviral cytokines, mainly interferons (IFNs), which are necessary to clear viral infections. In this study, we compared the innate cytokine responses of two mouse CS exposure models following a challenge with influenza A virus (IAV): 1) exposure of the mice to cigarette smoke extract (CSE) intratracheally and 2) exposure of the mice to CS in a whole body exposure chamber. Both intratracheal CSE treatment and whole body CS exposure caused antiviral immunosuppression in these mice, and both CS exposure methods inhibited RIG-I induction. CS attenuated influenza-induced antiviral IFNs and IP-10 expression in vivo. However, we did not find that CS inhibited induction of the proinflammatory cytokines IL-6 and TNF-α, whose expression was induced by IAV. Interestingly, IAV infection also increased Toll-like receptor 3 (TLR3) expression in mouse lung, but CS exposure did not impact TLR3 induction in these mice. Together, the results support our previous finding in a human lung organ culture model that the suppression of RIG-I induction and antiviral cytokine responses by CS are likely important in the enhanced susceptibility of smokers to influenza infection in the lung. [ABSTRACT FROM AUTHOR]

Proton T2 relaxation times of metabolites in the human brain were measured using point resolved spectroscopy at 3T in vivo. Four echo times (54, 112, 246 and 374 ms) were selected from numerical and phantom analyses for effective detection of the glutamate multiplet at ~ 2.35 ppm. In vivo data were obtained from medial and left occipital cortices of five healthy volunteers. The cortices contained predominantly gray and white matter, respectively. Spectra were analyzed with LCModel software using volume-localized calculated spectra of brain metabolites. The estimate of the signal strength vs. TE was fitted to a monoexponential function for estimation of apparent T2 (T2†). T2† was estimated to be similar between the brain regions for creatine, choline, glutamate and myo-inositol, but significantly different for N-acetylaspartate singlet and multiplet. T2†s of glutamate and myo-inositol were measured as 181 ± 16 and 197 ± 14 ms (mean ± SD, N = 5) for medial occipital cortices, and 180 ± 12 and 196 ± 17 ms for left occipital cortices, respectively. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this paper we study sample size calculation methods for the asymptotic Wilcoxon-Mann-Whitney test for data with or without ties. The existing methods are applicable either to data with ties or to data without ties but not to both cases. While the existing methods developed for data without ties perform well, the methods developed for data with ties have limitations in that they are either applicable to proportional odds alternatives or have computational difficulties. We propose a new method which has a closed-form formula and therefore is very easy to calculate. In addition, the new method can be applied to both data with or without ties. Simulations have demonstrated that the new sample size formula performs very well as the corresponding actual powers are close to the nominal powers. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

BACKGROUND: Blood pressure (BP) screening in adults has been identified by the US Preventive Services Task Force as a Grade A recommendation.OBJECTIVE: To compare BP screening rates in adult patients among payer sources and provider types in two national probability samples of outpatient office visits.DESIGN/METHODS: An analysis of visit data for all patients 18 years and older in the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey-Outpatient Department (OPD) during the years 2005-2009 was performed. Data on 279,510 patient visits were analyzed, including adults seen in ambulatory or office-based settings (NAMCS, N=147,675) and hospital outpatient departments (OPD, N=131,835). BP screening rates were compared based on provider type (Family Practice, Internal Medicine, Obstetrics-Gynecology, and Cardiovascular Specialist) and payer source (Private Insurance, Medicare, Medicaid, and Self Pay).Results: Overall, BP screening rates were higher in the OPD sample (65.70% vs, 55.83%, p < .001), despite a higher mean age and higher proportion of privately insured or Medicare patients in the NAMCS sample. The odds ratio for BP screening was 1.538 for insured patients compared to self-pay in the NAMCS sample (95% CI: 1.473-1.606); however, the disparity was not observed in the OPD data. Cardiovascular specialists demonstrated the most adherence to BP screening, regardless of payer source. Overall BP screening rates are shown in Table 1.Conclusions: Analysis of two national probability samples reflected marked disparity in BP screening in adult patients based on payer source and provider type. [ABSTRACT FROM AUTHOR]

BACKGROUND: It has been suggested by national data and popular media that prevalence of obesity and elevated Blood Pressure (BP) has increased in the United States over time.OBJECTIVE: To assess the trends in the prevalence of elevated BP and obesity in adult patients, and to quantify any correlation between them using national probability data sets.DESIGN/METHODS: An analysis of visit data for all patients 18 years and older included in the 2005-09 National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey-Outpatient Department (OPD) was performed. BP data from 160,380 patient visits were analyzed, including adults seen in ambulatory or office-based settings (NAMCS, N=74,645) and hospital outpatient departments (OPD, N=85,735). Correlation between BP and BMI were calculated using the Pearson Correlation method.Results: Overall, the prevalence of hypertension decreased over time, while the prevalence of obesity increased. This data is represented in Table 1.Conclusions: This analysis suggests that while the prevalence of obesity may be increasing, the prevalence of elevated BP has actually decreased over time. This seemingly counter-intuitive finding may reflect improved BP control rates, despite obesity, which is suggested in contemporary NHANES data. [ABSTRACT FROM AUTHOR]

Background: Screening for maternal anogenital Group B streptococci (GBS) colonization in pregnancy with initiation of intravenous intrapartum antibiotic prophylaxis as indicated has led to a significant reduction in the incidence of neonatal GBS infection. This study aims to evaluate the agreement between vaginal-perianal or vaginal-perineal culture and the more typically used vaginal-rectal culture for screening for maternal anogenital GBS colonization in the third trimester of pregnancy.Methods: Eligible English-language studies published until January 2020 were retrieved from Scopus, Web of Science, PubMed, Embase, and ClinicalTrials.gov databases. Studies were compiled that assessed for GBS colonization utilizing vaginal-perianal or vaginal-perineal culture and vaginal-rectal culture during the third trimester of pregnancy. Nonoriginal research articles and studies that did not assess pregnant patients, did not use culture-based screening, or did not compare vaginal-perianal or vaginal-perineal culture with vaginal-rectal culture were excluded. The search identified 559 articles with three prospective cohort studies that met inclusion criteria, including 643 participants. Quality was assessed using the Newcastle-Ottawa Scale, and risk of bias was assessed using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Patient characteristics and associated pain with specimen collection were abstracted. Meta-analyses of both the raw agreement and the Cohen's kappa statistic were performed.Results: Within the three included studies, the range of GBS detection was 17.6-34.0%, consistent with the anticipated prevalence of GBS colonization reported in earlier publications. For both raw agreement and Cohen's kappa coefficient, the test for heterogeneity was not significant, indicating low heterogeneity among studies. The pooled estimate of the raw agreement was 0.97 (95%CI 0.95-0.98) and of the Cohen's kappa coefficient was 0.91 (95% CI: 0.87-0.95), indicating (according to the Landis and Koch criteria) an "almost perfect" agreement between the compared clinical tests. In the two studies that assessed procedure-related patient discomfort, vaginal-rectal swabbing caused more discomfort.Conclusion: Use of vaginal-perineal culture for assessment of maternal GBS colonization is comparable to the more typically utilized vaginal-rectal culture and is associated with less discomfort. [ABSTRACT FROM AUTHOR]

We sought to understand how the coronavirus disease 2019 pandemic has affected the neurosurgical workforce. We created a survey consisting of 22 questions to assess the respondent's operative experience, location, type of practice, subspecialty, changes in clinic and operative volumes, changes to staff, and changes to income since the pandemic began. The survey was distributed electronically to neurosurgeons throughout the United States and Puerto Rico. Of the 724 who opened the survey link, 457 completed the survey. The respondents were from throughout the United States and Puerto Rico and represented all practices types and subspecialties. Nearly all respondents reported hospital restrictions on elective surgeries. Most reported a decline in clinic and operative volume. Nearly 70% of respondents saw a decrease in the work hours of their ancillary providers, and almost one half (49.1%) of the respondents had had to downsize their practice staff, office assistants, nurses, schedulers, and other personnel. Overall, 43.6% of survey respondents had experienced a decline in income, and 27.4% expected a decline in income in the upcoming billing cycle. More senior neurosurgeons and those with a private practice, whether solo or as part of a group, were more likely to experience a decline in income as a result of the pandemic compared with their colleagues. The coronavirus disease 2019 pandemic will likely have a lasting effect on the practice of medicine. Our survey results have described the early effects on the neurosurgical workforce. Nearly all neurosurgeons experienced a significant decline in clinical volume, which led to many downstream effects. Ultimately, analysis of the effects of such a pervasive pandemic will allow the neurosurgical workforce to be better prepared for similar events in the future. [ABSTRACT FROM AUTHOR]

Mebendazole and other anti-parasitic drugs are being used off-prescription based on social media and unofficial accounts of their anti-cancer activity. The purpose of this study was to conduct a controlled evaluation of mebendazole's therapeutic efficacy in cell culture and in vivo models of ovarian cancer. The majority of ovarian cancers harbor p53 null or missense mutations, therefore the effects of p53 mutations and a mutant p53 reactivator, PRIMA-1MET (APR246) on mebendazole activity were evaluated. Mebendazole was evaluated in cisplatin-resistant high grade serous stage 3C ovarian cancer patient derived xenograft (PDX) models: PDX-0003 (p53 null) and PDX-0030 (p53 positive), and on ovarian cancer cell lines: MES-OV (p53 R282W), ES2 (p53 S241F), A2780 (p53 wild type), SKOV3 parental (p53 null) and isogenic sublines, SKOV3 R273H p53 and SKOV3 R248W p53. Drug synergy and mechanisms were evaluated in cell cultures using isobolograms, clonogenic assays and western blots. Prevention of tumor establishment was studied in a MES-OV orthotopic model. Mebendazole inhibited growth of ovarian cancer cell cultures at nanomolar concentrations and PDXs at doses up to 50 mg/kg, and reduced orthotopic tumor establishment at 50 mg/kg. The mechanism of mebendazole was associated with p53-independent induction of p21 and tubule depolymerization. PRIMA-1MET also inhibited tumor establishment and worked synergistically with mebendazole in cell culture to inhibit growth and induce intrinsic apoptosis through a p53- and tubule destabilization-independent mechanism. This work demonstrates the therapeutic potential of repurposing mebendazole and supports clinical development of mebendazole for ovarian cancer therapy and maintenance. Unlabelled Image • Mebendazole inhibits growth of ovarian cancer cell lines and high grade serous ovarian PDX tumors. • Mebendazole inhibits tumor establishment in an orthotopic ovarian cancer model of maintenance therapy. • Mebendazole's activity is related to p21 elevation and tubule destabilization, and complemented by mutant p53 reactivation. [ABSTRACT FROM AUTHOR]

Background: The clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts.Methods: We used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated with Tmeff2, an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analyses were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SigCheck software.Results: Low levels of TMEFF2 mRNA significantly (p < 0.0001) correlated with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. We identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression was significantly associated with time to recurrence after prostatectomy in four geographically different patient cohorts (2.9 ≤ HR ≥ 4.1; p ≤ 0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96 ≤ HR ≥ 4.28; p ≤ 0.032) and improved the prognostic value of standard clinicopathological markers. The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p = 0.00017).Conclusions: This study provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, like Tmeff2, as guides to discover prognostic indicators, and suggests the possibility that low Tmeff2 expression marks a distinct subclass of PCa. [ABSTRACT FROM AUTHOR]

Background: Currently, endovascular treatment of intracranial aneurysms (ICAs) is limited by low complete occlusion rates. The advent of novel endovascular technology has expanded the applicability of endovascular therapy; however, the superiority of novel embolic devices over the traditional Guglielmi detachable coils (GDCs) is still debated. We performed a systematic review of literature that reported Raymond-Roy occlusion classification (RROC) rates of modern endovascular devices to determine their immediate and follow-up occlusion effectiveness for the treatment of unruptured saccular ICAs., Methods: A search was conducted using electronic databases (PUBMED, Cochrane, ClinicalTrials.gov, Web of Science). We retrieved studies published between 2000-2022 reporting immediate and follow-up RROC rates of subjects treated with different endovascular ICA therapies. We extracted demographic information of the treated patients and their reported angiographic RROC rates., Results: A total of 80 studies from 15 countries were included for data extraction. RROC rates determined from angiogram were obtained for 21,331 patients (72.5% females, pooled mean age: 58.2 (95% CI: 56.8-59.6), harboring 22,791 aneurysms. The most frequent aneurysm locations were the internal carotid artery (46.4%, 95% CI: 41.9%-50.9%), the anterior communicating artery (26.4%, 95% CI: 22.5%-30.8%), the middle cerebral artery (24.5%, 95% CI:19.2%-30.8%) and the basilar tip (14.4%, 95% CI:11.3%-18.3%). The complete occlusion probability (RROC-I) was analyzed for GDCs, the Woven EndoBridge (WEB), and flow diverters. The RROC-I rate was the highest in balloon-assisted coiling (73.9%, 95% CI: 65.0%-81.2%) and the lowest in the WEB (27.8%, 95% CI:13.2%-49.2%). The follow-up RROC-I probability was homogenous in all analyzed devices., Conclusions: We observed that the coil-based endovascular therapy provides acceptable rates of complete occlusion, and these rates are improved in balloon-assisted coils. Out of the analyzed devices, the WEB exhibited the shortest time to achieve >90% probability of follow-up complete occlusion (~18 months). Overall, the GDCs remain the gold standard for endovascular treatment of unruptured saccular aneurysms.

Most nanomedicines require efficient in vivo delivery to elicit diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, we propose the term "nanoparticle blood removal pathways" (NBRP), which summarizes the interactions between nanoparticles and the body's various cell-dependent and cell-independent blood clearance mechanisms. We reviewed nanoparticle design and biological modulation strategies to mitigate nanoparticle-NBRP interactions. As these interactions affect nanoparticle delivery, we studied the preclinical literature from 2011-2021 and analyzed nanoparticle blood circulation and organ biodistribution data. Our findings revealed that nanoparticle surface chemistry affected the in vivo behavior more than other nanoparticle design parameters. Combinatory biological-PEG surface modification improved the blood area under the curve by ~418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle-NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines., Competing Interests: Competing interests The authors declare no competing interests.

Chemotherapy and radiotherapy resistance are major obstacles in the long-term efficacy of head and neck squamous cell carcinoma (HNSCC) treatment. Secondhand smoke (SHS) exposure is common and has been proposed as an independent predictor of HNSCC recurrence and disease-free survival. However, the underlying mechanisms responsible for these negative patient outcomes are unknown. To assess the effects of SHS exposure on cisplatin efficacy in cancer cells, three distinct HNSCC cell lines were exposed to sidestream (SS) smoke, the main component of SHS, at concentrations mimicking the nicotine level seen in passive smokers' saliva and treated with cisplatin (0.01-100 µM) for 48 h. Compared to cisplatin treatment alone, cancer cells exposed to both cisplatin and SS smoke extract showed significantly lower cisplatin-induced cell death and higher cell viability, IC 50 , and indefinite survival capacity. However, SS smoke extract exposure alone did not change cancer cell viability, cell death, or cell proliferation compared to unexposed control cancer cells. Mechanistically, exposure to SS smoke extract significantly reduced the expression of cisplatin influx transporter CTR1, and increased the expression of multidrug-resistant proteins ABCG2 and ATP7A. Our study is the first to document that exposure to SHS can increase cisplatin resistance by altering the expression of several proteins involved in multidrug resistance, thus increasing the cells' capability to evade cisplatin-induced cell death. These findings emphasize the urgent need for clinicians to consider the potential role of SHS on treatment outcomes and to advise cancer patients and caregivers on the potential benefits of avoiding SHS exposure.

Antecedent group A streptococcal pharyngitis is a well-established cause of acute rheumatic fever (ARF) where rheumatic valvular heart disease (RHD) and Sydenham chorea (SC) are major manifestations. In ARF, crossreactive antibodies and T cells respond to streptococcal antigens, group A carbohydrate, N-acetyl-β- D -glucosamine (GlcNAc), and M protein, respectively, and through molecular mimicry target heart and brain tissues. In this translational human study, we further address our hypothesis regarding specific pathogenic humoral and cellular immune mechanisms leading to streptococcal sequelae in a small pilot study. The aims of the study were to (1) better understand specific mechanisms of pathogenesis in ARF, (2) identify a potential early biomarker of ARF, (3) determine immunoglobulin G (IgG) subclasses directed against GlcNAc, the immunodominant epitope of the group A carbohydrate, by reaction of ARF serum IgG with GlcNAc, M protein, and human neuronal cells (SK-N-SH), and (4) determine IgG subclasses deposited on heart tissues from RHD. In 10 pediatric patients with RHD and 6 pediatric patients with SC, the serum IgG2 subclass reacted significantly with GlcNAc, and distinguished ARF from 7 pediatric patients with uncomplicated pharyngitis. Three pediatric patients who demonstrated only polymigrating arthritis, a major manifestation of ARF and part of the Jones criteria for diagnosis, lacked the elevated IgG2 subclass GlcNAc-specific reactivity. In SC, the GlcNAc-specific IgG2 subclass in cerebrospinal fluid (CSF) selectively targeted human neuronal cells as well as GlcNAc in the ELISA. In rheumatic carditis, the IgG2 subclass preferentially and strongly deposited in valve tissues ( n = 4) despite elevated concentrations of IgG1 and IgG3 in RHD sera as detected by ELISA to group A streptococcal M protein. Although our human study of ARF includes a very small limited sample set, our novel research findings suggest a strong IgG2 autoantibody response against GlcNAc in RHD and SC, which targeted heart valves and neuronal cells. Cardiac IgG2 deposition was identified with an associated IL-17A/IFN-γ cooperative signature in RHD tissue which displayed both IgG2 deposition and cellular infiltrates demonstrating these cytokines simultaneously. GlcNAc-specific IgG2 may be an important autoantibody in initial stages of the pathogenesis of group A streptococcal sequelae, and future studies will determine if it can serve as a biomarker for risk of RHD and SC or early diagnosis of ARF., Competing Interests: MC, discloses her affiliation as chief scientific officer/consultant and co-founder of Moleculera Labs in Oklahoma City, OK where the company offers diagnostic testing for anti-neuronal autoantibodies in autoimmune neurologic and psychiatric disorders. SS, has no financial conflicts of interest. Although she is a co-inventor on the anti-neuronal autoantibodies/CaMKII panel, neither she nor the NIMH receive any royalties from the patent. CK, discloses holding in part a patent for development of the anti-neuronal autoantibody assays and receives royalties from Moleculera Labs. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kirvan, Canini, Swedo, Hill, Veasy, Jankelow, Kosanke, Ward, Zhao, Alvarez, Hedrick and Cunningham.)

Introduction: The purpose of this study was to compare the metabolism of Streptococcus mutans biofilms after 1-7 days of growth on different orthodontic adhesives., Methods: Specimens of 6 commercial orthodontic adhesives were fabricated in custom-made molds and polymerized using a light-emitting diode light-curing unit. Bioluminescent S mutans (UA159:JM10) biofilms were grown on ultraviolet-sterilized specimens for 1, 3, 5, and 7 days (n = 18 biofilms/d/product) in anaerobic conditions at 37°C. The metabolism of biofilms (relative luminescence unit [RLU]) was measured 0, 2, 4, and 6 minutes after exposure to D-luciferin solution using a microplate reader. A linear mixed-effects model was used to analyze the logarithm of RLU (log RLU). The model included fixed effects of products, days, and minutes. Tukey-Kramer post-hoc tests were then performed on the significant predictors of log RLU (α = 0.05)., Results: Days (P <0.0001) and minutes (P <0.0001) were independent predictors of log RLU, but the products were not (P = 0.5869). After adjusting for minutes, the log RLU was analyzed with a post-hoc test, and all differences between days were significant with the exceptions of day 3 from day 5 (P = 0.0731) and day 5 from day 7 (P = 0.8802). After adjusting for day, log RLU was analyzed with a post-hoc test and all differences in minutes were significant., Conclusions: No significant differences in the metabolism of S mutans biofilms were observed among the 6 orthodontic adhesives. Biofilms that were grown for 3 days demonstrated the highest levels of biofilm metabolism as evidenced by higher mean log RLU values relative to 1, 5, and 7-day growth durations., (Copyright © 2021 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Background: Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation., Methods and Results: We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 μs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement., Conclusions: Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has had a tremendous impact on the healthcare system. Owing to restrictions in elective surgery and social distancing guidelines, the training curriculum for neurosurgical trainees has been rapidly evolving. This evolution could have significant long-term effects on the training of neurosurgery residents. The objective of the present study was to assess the effects of COVID-19 on neurosurgical training programs and residents., Methods: A survey consisting of 31 questions assessing changes to resident clinical and educational workload and their sentiment regarding how these changes might affect their careers was distributed electronically to neurosurgery residents in the United States and Canada., Results: The survey respondents were from 29 states and Canada and were relatively evenly spread across all levels of residency. Nearly 82% reported that the inpatient and outpatient volumes had been either greatly (44.0%) or moderately (37.8%) reduced. Greater than 91% reported that their work responsibilities or access to the hospital had been reduced, with a significant reduction in work hours and a significant increase in resident didactics (P < 0.001). Senior residents expressed concern about their educational experience and their future career prospects as a result of the pandemic., Conclusion: Universally, residents have experienced reduced work hours and a reduction in their operative case volumes. Programs have adapted by increasing didactic time and using electronic platforms. It is quite possible that this remarkable period will prompt a critical reappraisal of the pre-COVID-19 adequacy of educational content in our training programs and that the enhanced educational efforts driven by this pandemic could be lasting., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Proper blood flow through the atrioventricular heart valves (AHVs) relies on the holistic function of the valve and subvalvular structures, and a failure of any component can lead to life-threatening heart disease. A comprehension of the mechanical characteristics of healthy valvular components is necessary for the refinement of heart valve computational models. In previous studies, the chordae tendineae have been mechanically characterized as individual structures, usually in a clamping-based approach, which may not accurately reflect the in vivo chordal interactions with the leaflet insertion and papillary muscles. In this study, we performed uniaxial mechanical testing of strut chordae tendineae of the AHVs under a unique tine-based leaflet-chordae-papillary muscle testing to observe the chordae mechanics while preserving the subvalvular component interactions. Results of this study provided insight to the disparity of chordae tissue stress-stretch responses between the mitral valve (MV) and the tricuspid valve (TV) under their respective emulated physiological loading. Specifically, strut chordae tendineae of the MV anterior leaflet had peak stretches of 1.09-1.16, while peak stretches of 1.08-1.11 were found for the TV anterior leaflet strut chordae. Constitutive parameters were also derived for the chordae tissue specimens using an Ogden model, which is useful for AHV computational model refinement. Results of this study are beneficial to the eventual improvement of treatment methods for valvular disease.

Objective: Inflammatory and immunologic cytokines and vagal activity have important roles in health and mental health, and may influence each other. The authors assessed relationships of representative biomarkers linked to disaster exposure-heart rate variability (HRV) with Interleukin-2 (IL-2, cell-medicated immunity) and Interleukin-6 (IL-6, pro-inflammatory and pro-immunologic), stratified by psychiatric diagnosis., Design: Participants were assessed for psychiatric diagnosis, IL-2, IL-6, HRV, and HR reactivity to trauma reminders., Setting: Outpatient university psychiatry clinics in Oklahoma City and Tulsa., Participants: Relocated Katrina survivors and demographically matched controls, not on psychiatric, cardiovascular, or inflammatory medications., Main Outcome Measures: SCID-IV, baseline serum IL-2 and IL-6, HRV through power spectral analysis., Results: Survivors had higher sympathetic and lower parasympathetic activity at baseline and lower parasympathetic HR reactivity than controls, with flattened parasympathetic reactivity in the presence of depression and of post-traumatic stress disorder (PTSD). Survivors' IL-2 and IL-6 did not differ from controls and did not differ in PTSD or depression. Depressed survivors' sympathetic reactivity correlated negatively with IL-2 and parasympathetic reactivity correlated positively with IL-2., Conclusions: HRV differed after hurricane exposure and with survivors& depression and/or PTSD, more sensitively capturing somatic sequelae than assessed cytokines. Higher sympathetic HR reactivity associated with lower immuno-logic IL-2 may indicate a double biological "hit" in depressed disaster survivors, possibly rendering them more vulnerable to cardiovascular and immunologic illness as well as depression. Associations of HRV with IL-2 may support reciprocal influences of cytokines and vagal activity. Lack of significant correlations of IL-6 with HRV measures is consistent with its pleiotropic role.

Co-administration of functionally distinct anti-cancer agents has emerged as an efficient strategy in lung cancer treatment. However, a specially designed drug delivery system is required to co-encapsulate functionally different agents, such as a combination of siRNA and chemotherapy, for targeted delivery. We developed a folic acid (FA)-conjugated polyamidoamine dendrimer (Den)-based nanoparticle (NP) system for co-delivery of siRNA against HuR mRNA (HuR siRNA) and cis-diamine platinum (CDDP) to folate receptor-α (FRA) -overexpressing H1299 lung cancer cells. The co-delivery of HuR siRNA and CDDP using the FRA-targeted NP had a significantly greater therapeutic effect than did individual therapeutics. Further, the FRA-targeted NP exhibited improved cytotoxicity compared to non-targeted NP against lung cancer cells. Finally, the NP showed negligible toxicity towards normal MRC9 lung fibroblast cells. Thus, the present study demonstrates FRA-targeted Den nanoparticle system as a suitable carrier for targeted co-delivery of siRNA and chemotherapy agents in lung cancer cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the use of radiotherapy (RT) in older patients with triple-negative breast cancer (TNBC)., Patients and Methods: The National Cancer Data Base (NCDB) is a comprehensive national database that captures approximately 70% of newly diagnosed cancer patients in the United States. Data for patients meeting the criteria of nonmetastatic TNBC were extracted and analyzed., Results: A total of 44,731 TNBC patients with indications for postoperative RT were identified. Median patient age was 59 (range, 19-90) years. Maximum RT use occurred between the ages of 46 and 70, with rapid decline in patients older than 70 years. Overall, there was a statistically significant improvement in overall survival (OS) with the addition of RT. Of the 24 variables evaluated, 23 were statistically significant on univariate analysis. On multivariate analysis a majority of these factors including facility location, age, Charlson/Deyo comorbidity condition score, and tumor characteristics (lymph node status, pathologic T stages, and use of systemic chemotherapy) remained significant. The use of RT was associated with improved OS rates in both the older (5-year OS, 66.4% vs. 42.6%, P < .001) and younger (5-year OS, 77.3% vs. 63.2%, P < .001) patient groups., Conclusion: In this group of high-risk patients, there was decreased use of RT in older patients. In our study of a large patient population with TNBC, RT was associated with increased OS rates in both younger and older patients, and RT should be strongly considered, when indicated by clinicopathologic factors, in patients with TNBC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Despite this association, the mechanisms underlying the increased susceptibility to respiratory virus infection are poorly understood. Retinoic acid-inducible gene I (RIG-I) is an important regulator of influenza virus-induced expression of antiviral cytokines, mainly interferons (IFNs), which are necessary to clear viral infections. In this study, we compared the innate cytokine responses of two mouse CS exposure models following a challenge with influenza A virus (IAV): 1) exposure of the mice to cigarette smoke extract (CSE) intratracheally and 2) exposure of the mice to CS in a whole body exposure chamber. Both intratracheal CSE treatment and whole body CS exposure caused antiviral immunosuppression in these mice, and both CS exposure methods inhibited RIG-I induction. CS attenuated influenza-induced antiviral IFNs and IP-10 expression in vivo. However, we did not find that CS inhibited induction of the proinflammatory cytokines IL-6 and TNF-α, whose expression was induced by IAV. Interestingly, IAV infection also increased Toll-like receptor 3 (TLR3) expression in mouse lung, but CS exposure did not impact TLR3 induction in these mice. Together, the results support our previous finding in a human lung organ culture model that the suppression of RIG-I induction and antiviral cytokine responses by CS are likely important in the enhanced susceptibility of smokers to influenza infection in the lung.

Proton T(2) relaxation times of metabolites in the human brain were measured using point resolved spectroscopy at 3T in vivo. Four echo times (54, 112, 246 and 374 ms) were selected from numerical and phantom analyses for effective detection of the glutamate multiplet at ~ 2.35 ppm. In vivo data were obtained from medial and left occipital cortices of five healthy volunteers. The cortices contained predominantly gray and white matter, respectively. Spectra were analyzed with LCModel software using volume-localized calculated spectra of brain metabolites. The estimate of the signal strength vs. TE was fitted to a monoexponential function for estimation of apparent T(2) (T(2)(†)). T(2)(†) was estimated to be similar between the brain regions for creatine, choline, glutamate and myo-inositol, but significantly different for N-acetylaspartate singlet and multiplet. T(2)(†)s of glutamate and myo-inositol were measured as 181 ± 16 and 197 ± 14 ms (mean ± SD, N = 5) for medial occipital cortices, and 180 ± 12 and 196 ± 17 ms for left occipital cortices, respectively., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: To evaluate short- and long-term safety and efficacy of duloxetine in women with predominant stress urinary incontinence (SUI)., Research Design and Methods: The study was a 6-week, double-blind, randomised, parallel, placebo-controlled study followed by an uncontrolled open-label extension (OLE) run in 342 study centres in 16 European countries. Women with predominant SUI were randomly assigned to placebo (n = 1380) or duloxetine 40 mg twice daily (n = 1378) for 6 weeks. Completers of the acute phase were enrolled in the OLE, which had a minimum duration of 6 weeks and ended, based on the approval status of duloxetine in the participating country., Main Outcome Measures: The primary outcome measure was the change in incontinence episode frequency (IEF) over 6 weeks. Secondary outcome measures were the long-term maintenance of effect on IEF and Patient Global Impression of Improvement (PGI-I), the short- and long-term impact on quality of life using the King's Health Questionnaire (KHQ), and the long-term safety of duloxetine., Results: After 6 weeks, the decrease in weekly IEF was significantly greater with duloxetine treatment compared to placebo (-50.0 vs. -29.9%; p < 0.001). The percentage of responders (defined as > or =50% decrease in IEF) was significantly higher with duloxetine treatment than with placebo (50.6 vs. 31.2%; p < 0.001). Duloxetine treatment was associated with improvements in weekly pad use (-31.4%), PGI-I ratings (63.6%), and KHQ score (-6.25) compared to placebo (-12.5%, 48.5% and -3.13, respectively, all p < 0.001). Treatment-emergent adverse events were significantly more common during duloxetine treatment (48.3%) than placebo (33.3%), (p < 0.001). Of the 2290 patients continuing into the OLE, 1165 (42.2%) completed the available duration, and 592 (21.5%) discontinued because of an adverse event (percentages relative to total randomised patients). Long-term efficacy in the OLE was assessed over a 72-week period and was maintained over that time. However, the results should be interpreted within the context that better responding patients are more likely to remain on duloxetine, while patients responding poorly are more likely to discontinue over time., Conclusions: Duloxetine seems to be an efficacious treatment with an acceptable safety profile for women with SUI. Achieved improvement is maintained over the longer term in those women who remain on therapy.

Purpose: We primarily compared the effectiveness of combined pelvic floor muscle training (PFMT) and duloxetine with imitation PFMT and placebo for 12 weeks in women with stress urinary incontinence (SUI). In addition, we compared the effectiveness of combined treatment with single treatments, single treatments with each other and single treatments with no treatment., Materials and Methods: This blinded, doubly controlled, randomized trial enrolled 201 women 18 to 75 years old with SUI at 17 incontinence centers in the Netherlands, United Kingdom and United States. Women averaged 2 or more incontinence episodes daily and were randomized to 1 of 4 combinations of 80 mg duloxetine daily, placebo, PFMT and imitation PFMT, including combined treatment (in 52), no active treatment (in 47), PFMT only (in 50) and duloxetine only (in 52). The primary efficacy measure was incontinence episode frequency. Other efficacy variables included the number of continence pads used and the Incontinence Quality of Life questionnaire score., Results: The intent to treat population incontinence episode frequency analysis demonstrated the superiority of duloxetine with or without PFMT compared with no treatment or with PFMT alone. However, pad and Incontinence Quality of Life analyses suggested greater improvement with combined treatment than single treatment. A completer population analysis demonstrated the efficacy of duloxetine with or without PFMT and suggested combined treatment was more effective than either treatment alone., Conclusions: The data support significant efficacy of combined PFMT and duloxetine in the treatment of women with SUI. We hypothesize that complementary modes of action of duloxetine and PFMT may result in an additive effect of combined treatment.