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The purpose of this study was to determine whether direct nursing care providers have decisional conflict about receiving influenza vaccinations and characteristics associated with decisional conflict. The researchers used a self-administered questionnaire mailed to direct nursing care providers in two long-term--care organizations. Most direct nursing care providers in both organizations (80% and 93%, respectively) intended to get the influenza vaccine. Unregulated direct nursing care providers had more decisional conflict than regulated providers, especially related to feeling uninformed about the pros and cons of influenza vaccination. Unclear valuing of the pros and cons of influenza vaccination was related to the age of the direct care providers in both organizations. Decisional conflict and influenza vaccination practices may be determined, in part, by age and by the culture of a health care organization. A decision aid to improve knowledge and clarify values may improve decision quality and increase influenza vaccination rates. [ABSTRACT FROM AUTHOR]

Objective: To identify patient and physician characteristics associated with family physicians recording blood pressure (BP) measurements in the medical charts of their elderly patients.Design: Retrospective review of patients' charts during a 12-month period and baseline questionnaire on the sociodemographic and practice characteristics of family physicians participating in the Community Hypertension Assessment Trial. The chart review collected data on patients' demographics, cardiovascular risk factors, antihypertensive medications, number of visits to family physicians, and number of BP readings recorded.Setting: Non-academic family practices in Hamilton and Ottawa, Ont.Participants: Data were abstracted from the charts of 55 randomly selected regular elderly patients (65 years old and older) from each of 28 participating family practices (N = 1540 charts).Main Outcome Measure: Number of recordings of BP measurements in medical charts during a 12-month period.Results: About 16% (241/1540) of elderly patients had not had their BP recorded in their charts during the 12-month review period. Among this 16%, almost half (47%, 114/241) had not had a BP measurement recorded during the previous 24 months. Multivariate analysis indicated that the likelihood of BP recording increased with the number of visits made to family physicians and was greater among patients taking antihypertensive medications or diagnosed with hypertension. Physicians who had more recently graduated from medical school (< or = 24 years) were more likely to record BP measurements.Conclusion: Hypertension guidelines recommend that, for patients at risk, BP be measured and recorded at each office visit. Although more than 84% of older patients had at least 1 BP reading documented in their charts, patients who were already diagnosed with hypertension or who made frequent visits to the office were more likely to have their BP measured and recorded. A more systematic approach to monitoring elderly patients who visit their family physicians less frequently or who are not currently diagnosed with hypertension is needed. [ABSTRACT FROM AUTHOR]

Filarial lymphedema (LE) remains a significant global problem despite the progress made toward elimination of lymphatic filariasis (LF). In Ghana, the main approach to LF is preventive chemotherapy, but this has minimal impact on individuals who have already developed LE. In 2018-2020, a 24-month randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of stringent hygiene measures using the Essential Package of Care with or without additional administration of doxycycline (DOX) to improve filarial leg LE. This study enrolled 356 participants with LE stages 1-3 from two districts in the Upper East Region of Ghana. In addition to regular training on appropriate care for their affected legs, participants were randomized to receive 6 weeks of either 200 mg/day DOX (n = 117), 100 mg/day DOX (n = 120), or matching placebo (n = 119). Participants were seen every 2 months, with clinical measurements done at 6, 12, 18, and 24 months to assess the status of affected legs. There was a trend toward later appearance of acute attacks after DOX, but surprisingly, DOX showed no effect on LE stage progression. In all groups, leg LE improvement was more common (DOX 200 mg: n = 23 [20%]; DOX 100 mg: n = 23 [19.5%]; placebo: n = 32 [27.4%]) than LE worsening (DOX 200 mg: n = 2 [1.7%]; DOX 100 mg: n = 3 [2.5%]; placebo: n = 2 [1.7%]). Overall, these data show a strong benefit from adherence to a strict hygiene protocol, with some added potential benefit for DOX in preventing acute attacks.

Lymphedema, hydrocele, and acute adenolymphangitis (ADL) are chronically disabling consequences in patients with lymphatic filariasis (LF). Provision of morbidity management and disability prevention and concurrent mass drug administration of anthelmintics are two pillars for elimination of LF. This study assessed the impact of strict hygiene protocols with or without doxycycline on the progression of filarial lymphedema. A randomized, placebo-controlled, double-blind trial was conducted in two regions in Tanzania. We enrolled 362 participants with lymphedema stages 1-3 assigned into three treatment groups of doxycycline 200 mg once daily, doxycycline 100 mg once daily, or matching placebo for 42 days in addition to hygiene measures. The participants were followed every 2 months for 2 years. Twenty-four months after treatment onset, 17.7% of participants displayed improved limb conditions, including 15/104 (14.4%) in the doxycycline 200 mg group, 16/105 (15.2%) in the doxycycline 100 mg group, and 25/107 (23.4%) in the placebo group. During the first 6 months after treatment, the number of participants experiencing an ADL attack was significantly lower in the doxycycline groups than in the placebo group. The study also found that hygiene was one of the factors associated with preventing the occurrence of acute attacks over the whole study period. Doxycycline 100 mg was a significant factor for the halt of progression (odds ratio: 0.53, P = 0.0239) when both legs if affected at baseline were considered. These findings emphasize the importance of practicing hygiene in reducing the occurrence of ADL attacks and the benefits of doxycycline with regards to acute attacks and halt of progression.

Background: After accounting for smoking history, lung cancer incidence is greater in African Americans than Whites. In the multiethnic cohort, total nicotine equivalents (TNE) are higher in African Americans than Whites at similar reported cigarettes per day. Greater toxicant uptake per cigarette may contribute to the greater lung cancer risk of African Americans., Methods: In a nested case-control lung cancer study within the Southern Community Cohort, smoking-related biomarkers were measured in 259 cases and 503 controls (40% White; 56% African American). TNE, the trans-3-hydroxycotinine/cotinine ratio, 4-(methylnitrosamino)-1-3-(pyridyl)-1-butanol (NNAL), mercapturic acid metabolites of volatile organic compounds, phenanthrene metabolites, cadmium (Cd), and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid were quantified in urine. Unconditional logistic regression was used to estimate the ORs and 95% confidence intervals (CI) for each biomarker and lung cancer risk., Results: TNE, NNAL, and Cd were higher in cases than controls (adjusted for age, race, sex, body mass index, and cigarettes per day). Among cases, these levels were higher in African Americans compared with Whites. After accounting for age, sex, body mass index, and pack-years, a one-SD increase in log-TNE (OR = 1.30; 95% CI, 1.10-1.54) and log-NNAL (OR = 1.27; 95% CI, 1.03-1.58 with TNE adjustment) was associated with lung cancer risk. In this study, in which NNAL concentration is relatively high, the association for log-TNE was attenuated after adjustment for log-NNAL., Conclusions: Smoking-related biomarkers provide additional information for lung cancer risk in smokers beyond smoking pack-years., Impact: Urinary NNAL, TNE, and Cd concentrations in current smokers, particularly African American smokers, may be useful for predicting lung cancer risk., (©2024 American Association for Cancer Research.)

Morbidity management of filarial lymphedema remains a challenge even during the post-lymphatic filariasis elimination era in Sri Lanka despite provision of the predominantly hygiene-based WHO Essential Package of Care. Because prior studies have suggested that 6 weeks of doxycycline may reduce progression of limb lymphedema, we conducted a randomized, placebo-controlled, superiority study to evaluate this possibility in Sri Lanka. Patients aged 14 to 65 years with lymphedema in one or both legs received either 200 mg of doxycycline daily for 6 weeks or matching placebo. The primary efficacy endpoint was improvement or lack of progression in lymphedema stage at 24 months postenrollment. Secondary endpoints included change in lymphedema stage at 12 and 24 months, frequency of acute adenolymphangitis episodes, and perceived disability measured by the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). Training and supplies for limb hygiene were provided throughout the study. Two hundred participants (100 in each arm) with lymphedema of Dreyer stages 1 to 3 were enrolled. By the end of the 2-year study, 29% of the doxycycline patients and 34% of those on placebo showed improvement (i.e., a decrease in lymphedema stage), whereas 11% and 15% of the two groups showed worsening of the lymphedema. Adenolymphangitis rates were comparable in the two groups (43 doxycycline and 38 placebo recipients), although attacks lasted slightly longer in placebo patients (6.5 days versus 5.2 days). In both groups, perceived disability improved initially, with partial rebound in the second year. Only 34 adverse events affecting 24 patients (11%) occurred during the 6-week treatment period. Although doxycycline did not significantly impact lymphedema progression in this study, the results clearly indicate that clinical and personal benefits can be obtained from intensive hygiene management alone.

Background: Women aged ≥40 years diagnosed with a malignant ovarian germ cell tumor are more likely to have poor outcomes than their younger counterparts (aged 15-39 years)., Objective: We used the National Cancer Database (NCDB) to evaluate patterns of care and overall survival for individuals diagnosed with one of the four most common histologic subtypes of malignant ovarian germ cell tumor by age group., Methods: We identified women aged 15-90 diagnosed with ovarian germ cell tumors in the NCDB (2004-2016). Logistic regression was used to compare patterns of care, demographic, and disease characteristics by age group. Cox proportional hazards regression was used to evaluate associations between a range of demographic, clinical, and treatment characteristics with overall survival., Results: A total of n=2998 patients who were diagnosed with one of the four most common histologic subtypes (immature teratoma, dysgerminoma, yolk sac tumor, and mixed germ cell) of ovarian germ cell tumor were included in the analysis. Patients aged ≥40 years diagnosed with ovarian germ cell tumors were more likely to have co-morbidities, a bilateral tumor, higher stage of disease, receive chemotherapy only, and have a residual tumor after resection as compared with patients aged <40 years. Moreover, women aged ≥40 years had the highest risk of death (reference: 15-24 year olds; HR=5.37, 95% CI 3.76 to 7.66) after adjustment for demographic characteristics, tumor histology, and treatment received. In stratified analyses, women aged ≥40 years had significantly worse overall survival at each disease stage and histologic subtype., Conclusion: Findings suggest that women aged ≥40 years who are diagnosed with ovarian germ cell tumors have worse overall survival than those aged <40, independent of stage, disease characteristics, and treatment. Our study highlights the need for future research to better understand reasons for poorer outcomes in women aged ≥40 years., Competing Interests: Competing interests: LF has acted as a paid consultant for Decibel Therapeutics for work performed outside of the current study., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine whether John Henryism Active Coping (JHAC) is a protective risk factor for distress during the COVID-19 pandemic and whether this association differs by race/ethnicity., Methods: Data were collected as part of the 2020 National Blair Center Poll. Higher scores on JHAC measured a greater behavioral predisposition to cope actively and persistently with difficult psychosocial stressors and barriers of everyday life., Results: High JHAC was associated with lower odds for feeling worried and for feeling afraid when thinking about COVID-19. These associations differed across race/ethnicity such that having a greater JHAC behavioral predisposition to coping was inversely associated with feelings of distress when thinking about the COVID-19 pandemic only among Whites and Hispanics, but not among African Americans., Conclusion: Our findings have important implications as the COVID-19 pandemic continues into 2022 and psychological distress may linger and increase due to unprecedented economic and social impacts., Competing Interests: Declarations of interest: None.

Maintenance of telomere length has long been established to play a role in the biology of cancer and several studies suggest that it may be especially important in myeloid malignancies. To overcome potential bias in confounding and reverse causation of observational studies, we use both a polygenic risk score (PRS) and inverse-variance weighted (IVW) Mendelian randomization (MR) analyses to estimate the relationship between genetically predicted leukocyte telomere length (LTL) and acute myeloid leukemia (AML) risk in 498 cases and 2099 controls and myelodysplastic syndrome (MDS) risk in 610 cases and 1759 controls. Genetic instruments derived from four recent studies explaining 1.23-4.57% of telomere variability were considered. We used multivariable logistic regression to estimate odds ratios (OR, 95% confidence intervals [CI]) as the measure of association between individual single-nucleotide polymorphisms and myeloid malignancies. We observed a significant association between a PRS of longer predicted LTL and AML using three genetic instruments (OR = 4.03 per ~1200 base pair [bp] increase in LTL, 95% CI: 1.65, 9.85 using Codd et al. [Codd, V., Nelson, C.P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J.L., Hottenga, J.J., Fischer, K., Esko, T., Surakka, I. et al. (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat. Genet., 45, 422-427 427e421-422.], OR = 3.48 per one-standard deviation increase in LTL, 95% CI: 1.74, 6.97 using Li et al. [Li, C., Stoma, S., Lotta, L.A., Warner, S., Albrecht, E., Allione, A., Arp, P.P., Broer, L., Buxton, J.L., Alves, A.D.S.C. et al. (2020) Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length. Am. J. Hum. Genet., 106, 389-404.] and OR = 2.59 per 1000 bp increase in LTL, 95% CI: 1.03, 6.52 using Taub et al. [Taub, M.A., Conomos, M.P., Keener, R., Iyer, K.R., Weinstock, J.S., Yanek, L.R., Lane, J., Miller-Fleming, T.W., Brody, J.A., Raffield, L.M. et al. (2022) Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom., 2.] genetic instruments). MR analyses further indicated an association between LTL and AML risk (PIVW ≤ 0.049) but not MDS (all PIVW ≥ 0.076). Findings suggest variation in genes relevant to telomere function and maintenance may be important in the etiology of AML but not MDS., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A combined Haemophilus influenzae type b (Hib)/meningococcal serogroup C (MenC) vaccine will soon be unavailable in the UK immunisation schedule due to discontinuation by the manufacturer. An interim statement by the Joint Committee on Vaccination and Immunisation (JCVI) advises stopping MenC immunisation at 12 months of age when this occurs. We undertook an analysis of the public health impact of various potential meningococcal vaccination strategies in the UK in the absence of the Hib/MenC vaccine. A static population-cohort model was developed evaluating the burden of IMD (using 2005-2015 epidemiological data) and related health outcomes (e.g., cases, cases with long-term sequelae, deaths), which allows for the comparison of any two meningococcal immunisation strategies. We compared potential strategies that included different combinations of infant and/or toddler MenACWY immunisations with the anticipated future situation in which a 12-month MenC vaccine is not used, but the MenACWY vaccine is routinely given in adolescents. The most effective strategy is combining MenACWY immunisation at 2, 4, and 12 months of age with the incumbent adolescent MenACWY immunisation programme, resulting in the prevention of an additional 269 IMD cases and 13 fatalities over the modelling period; of these cases, 87 would be associated with long-term sequelae. Among the different vaccination strategies, it was observed that those with multiple doses and earlier doses provided the greatest protection. Our study provides evidence suggesting that the removal of the MenC toddler immunisation from the UK schedule would potentially increase the risk of unnecessary IMD cases and have a detrimental public health impact if not replaced by an alternate infant and/or toddler programme. This analysis supports that infant and toddler MenACWY immunisation can provide maximal protection while complementing both infant/toddler MenB and adolescent MenACWY immunisation programmes in the UK.

Coronavirus disease-19 (Covid-19) pandemic have demonstrated the importantance of vaccines in disease prevention. Self-amplifying mRNA vaccines could be another option for disease prevention if demonstrated to be safe and immunogenic. Phase 1 of this randomized, double-blinded, placebo-controlled trial (N = 42) assessed the safety, tolerability, and immunogenicity in healthy young and older adults of ascending levels of one-dose ARCT-021, a self-amplifying mRNA vaccine against Covid-19. Phase 2 (N = 64) tested two-doses of ARCT-021 given 28 days apart. During phase 1, ARCT-021 was well tolerated up to one 7.5 μg dose and two 5.0 μg doses. Local solicited AEs, namely injection-site pain and tenderness were more common in ARCT-021vaccinated, while systemic solicited AEs, mainly fatigue, headache and myalgia were reported in 62.8% and 46.4% of ARCT-021 and placebo recipients, respectively. Seroconversion rate for anti-S IgG was 100% in all cohorts, except for the 1 μg one-dose in younger adults and the 7.5 μg one-dose in older adults. Anti-S IgG and neutralizing antibody titers showed a general increase with increasing dose, and overlapped with titers in Covid-19 convalescent patients. T-cell responses were also observed in response to stimulation with S-protein peptides. Taken collectively, ARCT-021 is immunogenic and has favorable safety profile for further development., (© 2022. The Author(s).)

Background The onset and mechanisms of endothelial-to-mesenchymal transition (EndMT) in mitral valve (MV) leaflets following myocardial infarction (MI) are unknown, yet these events are closely linked to stiffening of leaflets and development of ischemic mitral regurgitation. We investigated whether circulating molecules present in plasma within days after MI incite EndMT in MV leaflets. Methods and Results We examined the onset of EndMT in MV leaflets from 9 sheep with inferior MI, 8 with sham surgery, and 6 naïve controls. Ovine MVs 8 to 10 days after inferior MI displayed EndMT, shown by increased vascular endothelial cadherin/α-smooth muscle actin-positive cells. The effect of plasma on EndMT in MV endothelial cells (VECs) was assessed by quantitative polymerase chain reaction, migration assays, and immunofluorescence. In vitro, post-MI plasma induced EndMT marker expression and enhanced migration of mitral VECs; sham plasma did not. Analysis of sham versus post-MI plasma revealed a significant drop in the Wnt signaling antagonist sFRP3 (secreted frizzled-related protein 3) in post-MI plasma. Addition of recombinant sFRP3 to post-MI plasma reversed its EndMT-inducing effect on mitral VECs. RNA-sequencing analysis of mitral VECs exposed to post-MI plasma showed upregulated FOXM1 (forkhead box M1). Blocking FOXM1 reduced EndMT transcripts in mitral VECs treated with post-MI plasma. Finally, FOXM1 induced by post-MI plasma was downregulated by sFRP3. Conclusions Reduced sFRP3 in post-MI plasma facilitates EndMT in mitral VECs by increasing the transcription factor FOXM1. Restoring sFRP3 levels or inhibiting FOXM1 soon after MI may provide a novel strategy to modulate EndMT in the MV to prevent ischemic mitral regurgitation and heart failure.

Importance: Migraine is a common neurological disease that often begins in childhood and continues into adulthood; approximately 6 million children and adolescents in the United States cope with migraine, and many frequently experience significant disability and multiple headache days per week. Although pharmacological preventive treatments have been shown to offer some benefit to youth with migraine, additional research is needed to understand whether and how these benefits are sustained., Objective: To survey clinical status of youth with migraine who participated in the 24-week Childhood and Adolescent Migraine Prevention (CHAMP) trial over a 3-year follow-up period., Design, Setting, and Participants: This survey study used internet-based surveys collected from youth ages 8 to 17 years at 3, 6, 12, 18, 24, and 36 months after completion of the CHAMP trial, which randomized participants to amitriptyline, topiramate, or placebo. At the end of the trial, the study drug was stopped, and participants received clinical care of their choice thereafter. The CHAMP trial was conducted between May 2012 and November 2015, and survey follow-up was conducted June 2013 to June 2018. Participants in this survey study were representative of those randomized in the trial. Data were analyzed from March 2020 to April 2021., Exposures: Survey completion., Main Outcomes and Measures: Headache days, disability (assessed using the Pediatric Migraine Disability Scale [PedMIDAS]), and self-report of ongoing use of prescription preventive medication., Results: A total of 205 youth (mean [SD] age, 14.2 [2.3] years; 139 [68%] girls; mean [SD] history of migraine, 5.7 [3.1] years) participated in the survey. Retention of participants was 189 participants (92%) at month 6, 182 participants (88%) at month 12, 163 participants (80%) at month 18, 165 participants (80%) at month 24, and 155 participants (76%) at month 36. Over the course of the 3-year follow-up, participants consistently maintained meaningful reductions in headache days (mean [SD] headache days per 28 days: CHAMP baseline, 11.1 [6.0] days; CHAMP completion, 5.0 [5.7] days; 3-year follow-up, 6.1 [6.1] days) and disability (mean [SD] score: CHAMP baseline, 40.9 [26.4]; CHAMP completion, 17.9 [22.1]; 3-year follow-up, 12.3 [20.0]). At 3 years after completion of the CHAMP trial, headache days were approximately 1.5 per week (changed from about 3 per week at trial baseline) and disability had improved from the moderate range to the low mild range on the PedMIDAS. Longitudinal analyses showed that amitriptyline and topiramate did not explain intercept random effects for either mean rate of headache days per week (amitriptyline: estimate [SE], 0.07 [0.05]; P = .16; topiramate: estimate [SE], 0.04 [0.05]; P = .50) or headache disability PedMIDAS total score (amitriptyline: estimate [SE], 0.25 [0.38]; P = .52; topiramate: estimate [SE], -0.09 [0.39]; P = .82) changes over time. Of 153 participants who reported on prescription drug use at 3 years, only 1 participant (1%) reported using prevention medication, and most participants reported no medication use at most time points., Conclusions and Relevance: These findings suggest that children and adolescents with longer than 5 years history of migraine who participated in the CHAMP trial may sustain positive clinical outcomes over time, even after discontinuing preventive pill-based treatment. This survey study could inform use and discontinuation timing of pharmacological preventive therapies for migraine in youth ages 8 to 17 years. Research is needed to examine mechanisms of treatment improvement and maintenance for preventive therapies, as well as placebo, in the pediatric population.

During 1995-2011, the overall incidence of hepatitis A decreased by 95% in the United States from 12 cases per 100,000 population during 1995 to 0.4 cases per 100,000 population during 2011, and then plateaued during 2012─2015. The incidence increased by 294% during 2016-2018 compared with the incidence during 2013-2015, with most cases occurring among populations at high risk for hepatitis A infection, including persons who use illicit drugs (injection and noninjection), persons who experience homelessness, and men who have sex with men (MSM) (1-3). Previous outbreaks among persons who use illicit drugs and MSM led to recommendations issued in 1996 by the Advisory Committee on Immunization Practices (ACIP) for routine hepatitis A vaccination of persons in these populations (4). Despite these long-standing recommendations, vaccination coverage rates among MSM remain low (5). In 2017, the New York City Department of Health and Mental Hygiene contacted CDC after public health officials noted an increase in hepatitis A infections among MSM. Laboratory testing* of clinical specimens identified strains of the hepatitis A virus (HAV) that subsequently matched strains recovered from MSM in other states. During January 1, 2017-October 31, 2018, CDC received reports of 260 cases of hepatitis A among MSM from health departments in eight states, a substantial increase from the 16 cases reported from all 50 states during 2013-2015. Forty-eight percent (124 of 258) of MSM patients were hospitalized for a median of 3 days. No deaths were reported. In response to these cases, CDC supported state and local health departments with public health intervention efforts to decrease HAV transmission among MSM populations. These efforts included organizing multistate calls among health departments to share information, providing guidance on developing targeted outreach and managing supplies for vaccine campaigns, and conducting laboratory testing of clinical specimens. Targeted outreach for MSM to increase awareness about hepatitis A infection and improve access to vaccination services, such as providing convenient locations for vaccination, are needed to prevent outbreaks among MSM., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8 + T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4 + T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 μg and 10 μg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine., Competing Interests: Declaration of interests D.M., E.C.A., P.H., K.-J.J.P., M.A., H.B., A.D., Y.B., B.C., J.V., S.R, J.A.G., M.S., R.Y., W.T., K.T., S.P., P.K., J.D., S.M.S., B.M.S, S.G.H., and P.C. are employees of Arcturus Therapeutics, Inc. E.E.O is an unpaid member of the Scientific Advisory Board of Arcturus Therapeutics, Inc., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

[Figure: see text].

The aim of this study was to survey an international group of temporomandibular joint surgeons regarding their outcomes with alloplastic total joint replacement in skeletally immature patients and to review the literature linked to autogenous reconstruction and alloplastic replacement of the temporomandibular joint (TMJR) in this population. A total of 24 custom/patient-specific TMJ Concepts devices were implanted into 14 patients (eight male and six female). Their mean age was 14 years (range 7-17 years). Nine (64.3%) had bilateral devices and five (35.7%) had unilateral devices. The most prevalent diagnosis was idiopathic condylar resorption (33.3%), followed by ankylosis (16.7%). Concurrent orthognathic surgery was performed in four patients (28.6%). The TMJR was completed as a one-stage procedure in 11 patients (78.6%) and in two stages in three patients (21.4%). All surgeons reported improvements in maximum incisal opening with good function. The respondents reported no asymmetric mandibular growth or retrognathia after either bilateral or unilateral TMJR implantation. This pilot study indicates that the use of TMJR in the growing patient may be a useful modality in select cases. The encouraging results of experienced surgeons demonstrate and support the need for further studies on the utilization of TMJR in this patient population., (Copyright © 2020. Published by Elsevier Ltd.)

Drosophila melanogaster possesses a complex nervous system, regulating sophisticated behavioral outputs, that serves as a powerful model for dissecting molecular mechanisms underlying neuronal function and neurodegenerative disease. Immunofluorescence techniques provide a way to visualize the spatiotemporal organization of these networks, permitting observation of their development, functional location, remodeling and, eventually, degradation. However, basic immunostaining techniques do not always result in efficient antibody penetration through the brain, and supplemental techniques to enhance permeability can compromise structural integrity, altering spatial organization. Here, slow freezing of brains is shown to facilitate antibody permeability without loss of antibody specificity or brain integrity. To demonstrate the advantages of this freezing technique, the results of two commonly used permeation methods - detergent-based and partial proteolytic digestion - are compared.

VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal in vitro activity, and potent in vivo activity against Aspergillus fumigatus , including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study, was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (i.v.) doses of VL-2397. All dosing cohorts were fully enrolled; all subjects completed the safety follow-up. A safety committee reviewed the safety data for each dosing cohort prior to recommending the initiation of each subsequent cohort. No serious adverse events (SAEs) occurred; the majority of treatment-emergent adverse events (TEAEs) were mild and self-limited. The most common drug-related TEAEs were infusion site reactions. No clinically concerning trends were noted in vital signs, electrocardiograms, physical examinations, or safety laboratory results. Following single infusions of VL-2397, the overall and maximum exposures rose less than proportionally with increasing doses from 3 mg to 1,200 mg as indicated by area under the concentration-time curve over 24 h (AUC 24 ) and maximum concentration ( C max ). No signs of VL-2397 accumulation were observed following i.v. infusions of 300, 600, and 1,200 mg every 24 h (q24h) for 7 days. Renal elimination played a major role in total body clearance, with up to 47% of unmetabolized drug in urine 24 h after administration at single doses of >30 mg. Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK, and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis., (Copyright © 2019 American Society for Microbiology.)

VL-2397 (previously termed ASP2397) is an antifungal, aluminum-chelating cyclic hexapeptide with a structure analogous to that of ferrichrome-type siderophores, whereby replacement of aluminum by iron was shown to decrease the antifungal activity of this compound. Here, we found that inactivation of an importer for ferrichrome-type siderophores, termed Sit1, renders Aspergillus fumigatus resistant to VL-2397. Moreover, expression of the endogenous sit1 gene under the control of a xylose-inducible promoter (to uncouple sit1 expression from iron repression) combined with C-terminal tagging with a fluorescent protein demonstrated localization of Sit1 in the plasma membrane and xylose-dependent VL-2397 susceptibility. This underlines that Sit1-mediated uptake is essential for VL-2397 susceptibility. Under xylose-induced sit1 expression, VL-2397 also retained antifungal activity after replacing aluminum with iron, which demonstrates that VL-2397 bears antifungal activity independent of cellular aluminum importation. Analysis of sit1 expression indicated that the reduced antifungal activity of the iron-chelated VL-2397 is caused by downregulation of sit1 expression by the imported iron. Furthermore, we demonstrate that defects in iron homeostatic mechanisms modulate the activity of VL-2397. In contrast to A. fumigatus and Candida glabrata , Saccharomyces cerevisiae displays intrinsic resistance to VL-2397 antifungal activity. However, expression of sit1 from A. fumigatus , or its homologue from C. glabrata , resulted in susceptibility to VL-2397, which suggests that the intrinsic resistance of S. cerevisiae is based on lack of uptake and that A. fumigatus , C. glabrata , and S. cerevisiae share an intracellular target for VL-2397., (Copyright © 2019 American Society for Microbiology.)

The extracellular matrix (ECM) of tissues is an important mediator of cell function. Moreover, understanding cellular dynamics within their specific tissue context is also important for developmental biology, cancer research, and regenerative medicine. However, robust in vitro models that incorporate tissue-specific microenvironments are lacking. Here we describe a novel mammary-specific culture protocol that combines a self-gelling hydrogel comprised solely of ECM from decellularized rat or human breast tissue with the use of our previously described 3D bioprinting platform. We initially demonstrate that undigested and decellularized mammary tissue can support mammary epithelial and tumor cell growth. We then describe a methodology for generating mammary ECM extracts that can spontaneously gel to form hydrogels. These ECM hydrogels retain unique structural and signaling profiles that elicit differential responses when normal mammary and breast cancer cells are cultured within them. Using our bioprinter, we establish that we can generate large organoids/tumoroids in the all mammary-derived hydrogel. These findings demonstrate that our system allows for growth of organoids/tumoroids in a tissue-specific matrix with unique properties, thus providing a suitable platform for ECM and epithelial/cancer cell studies. STATEMENT OF SIGNIFICANCE: Factors within extracellular matrices (ECMs) are specific to their tissue of origin. It has been shown that tissue specific factors within the mammary gland's ECM have pronounced effects on cellular differentiation and cancer behavior. Understanding the role of the ECM in controlling cell fate has major implications for developmental biology, tissue engineering, and cancer therapy. However, in vitro models to study cellular interactions with tissue specific ECM are lacking. Here we describe the generation of 3D hydrogels consisting solely of human or mouse mammary ECM. We demonstrate that these novel 3D culture substrates can sustain large 3D bioprinted organoid and tumoroid formation. This is the first demonstration of an all mammary ECM culture system capable of sustaining large structural growths., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: To compare a phenobarbital-adjunct versus benzodiazepine-only approach for the management of alcohol withdrawal syndrome in the emergency department (ED) with regard to the need for intensive care unit (ICU) admission, severity of symptoms on ED discharge, and complications., Methods: This was a retrospective cohort study conducted in two academic EDs in the United States. Adult patients seen in the ED with a diagnosis of alcohol withdrawal syndrome were included. Patients were categorized into two groups based on whether phenobarbital was administered in the ED: 1) phenobarbital group (with or without benzodiazepines) or 2) non-phenobarbital group. The primary outcome measure was the need for ICU admission. Secondary outcomes included Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at ED discharge, and complications. Complications were a composite of death, need for intubation, hypotension or vasopressor use, seizures, and hospital acquired pneumonia., Results: The study cohort included 209 patients (phenobarbital = 97, non-phenobarbital = 112). The mean (standard deviation) age was 49 (12) years and 85% (n = 178) were male. A similar proportion of patients in the phenobarbital (14%, n = 14) and non-phenobarbital (11%, n = 12) groups required ICU admission (p = 0.529). The median CIWA-Ar score on ED discharge was 7 (IQR 4-12) points in the phenobarbital group and 7 (IQR 4-14) points in the non-phenobarbital group (p = 0.752). The occurrence of complications was also similar in the phenobarbital (9%, n = 9) and non-phenobarbital groups (11%, n = 10)., Conclusion: Adjunctive phenobarbital use in the ED for alcohol withdrawal syndrome did not result in decreased ICU admission, severity of symptoms, or complications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

VL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus species. Plasma concentrations from a phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397. Healthy subjects aged 18 to 55 years received single doses of VL-2397, ranging from 3 to 1,200 mg, multiple daily doses of 300, 600, or 1,200 mg for 7 days, or 300 mg three times/day for 7 days followed by 600 mg daily for 21 days. Plasma samples were collected throughout the dosing intervals. Sixty-six subjects provided 1,908 concentrations. Drug concentrations over time were increased less than dose proportionally for doses above 30 mg. Dose-normalized concentrations plotted over time did not overlap. A 3-compartment nonlinear saturable binding model fit the data well. Clearance increased with dose, and mean values ranged from 0.4 liters/h at 3 mg to 8.5 liters/h at 1,200 mg. Mean volume in the central compartment ranged from 4.8 to 6.9 liters across doses. In the first 24 h, once-daily dosing results in a rapid decrease in concentrations by hour 16 to approximately 1 mg/liter, regardless of dose, with slow clearance over time. Administration of 300 mg every 8 h achieved concentrations above 1 mg/liter over an entire 24-h period. There was a significant relationship between body surface area and clearance. The data suggest that VL-2397 has nonlinear saturable binding kinetics. Protein binding is the likely primary source of the nonlinearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets., (Copyright © 2019 American Society for Microbiology.)

Neighborhood socioeconomic status (nSES) is associated with cardiovascular morbidity and mortality in the general population; however, its effect on high-risk patients with prevalent coronary artery disease (CAD) is unclear. We hypothesized "double jeopardy," whereby the association between nSES and adverse outcomes would be greater in high-risk patients with heart failure (HF) and/or previous myocardial infarction (MI) compared with those without. We followed 3,635 patients (mean age 63.2 years, 42% with HF, 25% with previous MI) with known or suspected CAD over a median of 3.3 years for all-cause death and cardiovascular death or nonfatal MI. Patients were categorized by a composite nSES score, and proportional hazards models were used to determine the association between nSES and outcomes. Cross-product interaction terms for previous MI × nSES and HF × nSES were analyzed. Compared with high nSES patients, low nSES patients had increased risk of all-cause death (hazard ratio [HR] = 1.61; 95% confidence interval [CI] = 1.20, 2.15) and cardiovascular death or MI (subdistribution HR [sHR] = 1.82; 95% CI = 1.30, 2.54). Associations were more pronounced among patients without HF or previous MI. Low nSES patients without HF had a higher risk of all-cause death (HR = 2.27; 95% CI = 1.41, 3.65) compared with those with HF (HR = 1.21; 95% CI = 0.82, 1.77, P interaction = 0.04). Similarly, low nSES patients without previous MI had a higher risk of cardiovascular death or MI (sHR = 2.72; 95% CI = 1.73, 4.28) compared with those with previous MI (sHR = 1.02; 95% CI = 0.58, 1.81, P interaction = 0.02). In conclusion, low nSES was independently associated with all-cause death and cardiovascular death or MI in patients with CAD; however, associations were greater in patients without HF or previous MI compared with those with HF or MI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We compared geographic information system (GIS)- and Census-based approaches for measuring the physical and social neighborhood environment at the census tract-level versus and audit approach on associations with body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR). Data were used from the 2012-2014 Women and Their Children's Health (WaTCH) Study ( n =940). Generalized linear models were used to obtain odds ratios (ORs) for BMI (≥30 kg/m 2 ), WC (>88 cm), and WHR (>0.85). Using an audit approach, more adverse neighborhood characteristics were associated with a higher odds of WC (OR: 1.10; 95% CI: 1.05, 1.15) and WHR (OR: 1.09; 95% CI: 1.05, 1.14) after adjustment for age, race/ethnicity, income, and oil spill exposure. There were no significant associations between GIS- and Census- based measures with obesity in adjusted models. Quality aspects of the neighborhood environment captured by audits at the individual-level may be more relevant to obesity than physical or social aspects at the census-tract level., Competing Interests: Conflict of interest None declared.

Ischemic mitral regurgitation (IMR) is a common complication of ischemic heart disease that doubles mortality after myocardial infarction and is a major driving factor increasing heart failure. IMR is caused by left ventricular (LV) remodeling which displaces the papillary muscles that tether the mitral valve leaflets and restrict their closure. IMR frequently recurs even after surgical treatment. Failed repair associates with lack of reduction or increase in LV remodeling, and increased heart failure and related readmissions. Understanding mechanistic and molecular mechanisms of IMR has largely attributed to the development of large animal models. Newly developed therapeutic interventions targeted to the primary causes can also be tested in these models. The sheep is one of the most suitable models for the development of IMR. In this chapter, we describe the protocols for inducing IMR in sheep using surgical ligation of obtuse marginal branches. After successful posterior myocardial infarction involving posterior papillary muscle, animals develop significant mitral regurgitation around 2 months after the surgery.

Purpose: The Deepwater Horizon Oil Spill is the largest marine oil spill in US history. Few studies have evaluated the potential health effects of this spill on the Gulf Coast community. The Women and Their Children's Health (WaTCH) study is a prospective cohort designed to investigate the midterm to long-term physical, mental and behavioural health effects of exposure to the oil spill., Participants: Women were recruited by telephone from pre-existing lists of individuals and households using an address-based sampling frame between 2012 and 2014. Baseline interviews obtained information on oil spill exposure, demographics, physical and mental health, and health behaviours. Women were also asked to provide a household roster, from which a child between 10 and 17 years was randomly selected and recruited into a child substudy. Telephone respondents were invited to participate in a home visit in which blood samples, anthropometrics and neighbourhood characteristics were measured. A follow-up interview was completed between 2014 and 2016., Findings to Date: 2852 women completed the baseline interview, 1231 of whom participated in the home visit, and 628 children participated in the child's health substudy. The follow-up interview successfully reinterviewed 2030 women and 454 children., Future Plans: WaTCH continues to conduct follow-up surveys, with a third wave of interviews planned in 2017. Also, we are looking to enhance the collection of spatially related environmental data to facilitate assessment of health risks in the study population. In addition, opportunities to participate in behavioural interventions for subsets of the cohort have been initiated. There are ongoing studies that examine the relationship between genetic and immunological markers with mental health., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

We investigated whether associations of neighborhood social environment attributes and physical activity differed among 12 countries and levels of economic development using World Bank classification (low/lower-middle-, upper-middle- and high- income countries) among 9-11 year old children (N=6161) from the International Study of Childhood Obesity, Lifestyle, and the Environment (ISCOLE). Collective efficacy and perceived crime were obtained via parental/guardian report. Moderate-to-vigorous physical activity (MVPA) was assessed with waist-worn Actigraph accelerometers. Neighborhood environment by country interactions were tested using multi-level statistical models, adjusted for covariates. Effect estimates were reported by country and pooled estimates calculated across World Bank classifications for economic development using meta-analyses and forest plots. Associations between social environment attributes and MVPA varied among countries and levels of economic development. Associations were more consistent and in the hypothesized directions among countries with higher levels economic development, but less so among countries with lower levels of economic development., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Adequate nutrition is essential for growth in children with cystic fibrosis (CF). The new CF Foundation Clinical Practice Guidelines bring attention to monitoring macronutrient intake as well as total energy., Methods: Dietary intake of 75 preschool children with CF and pancreatic insufficiency was examined and compared to the Clinical Practice Guidelines. Regression analyses examined relationships between macronutrient intake and growth., Results: Approximately 45% of children met the 110% minimum recommended dietary allowance (RDA) recommendation. Children consumed 35.3% (6.1) of total daily energy intake from fat, 12.7% (1.7) from protein, and 52.0% (6.1) from carbohydrates. Percent energy from protein was associated with height growth., Conclusions: Many preschoolers with CF are not meeting nutrition benchmarks for total energy and fat. To optimize nutrition early, dietary monitoring with frequent individualized feedback is needed. Optimizing intake of macronutrients that promote growth, especially fat and protein, should be a primary clinical target., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Dam removal is an increasingly popular restoration tool, but our understanding of ecological responses to dam removal over time is still in the early stages. We quantified seasonal benthic macroinvertebrate density, taxonomic composition, and functional traits for three years after lowhead dam removal in three reaches of the Olentangy River (Ohio, USA): two upstream of former dam (one restored, one unrestored), and one downstream of former dam. Macroinvertebrate community density, generic richness, and Shannon-Wiener diversity decreased between ∼9 and ∼15 months after dam removal; all three variables consistently increased thereafter. These threshold responses were dependent on reach location: density and richness increased ∼15 months after removal in upstream reaches versus ∼19 months downstream of the former dam. Initial macroinvertebrate density declines were likely related to seasonality or life-history characteristics, but density increased up to 2.27× from year to year in three out of four seasons (late autumn, early spring, summer) across all reaches. Macroinvertebrate community composition was similar among the three reaches, but differed seasonally based on non-metric multidimensional scaling (NMDS) and analysis of similarity (ANOSIM). Seasonal differences among communities tended to decrease after dam removal. We detected community-wide shifts in functional traits such as multivoltinism, depositional habitat use, burrowing, and collector-gatherer feeding mode. We observed that these traits were expressed most strongly with Chironomidae, which was the most abundant family. Our results suggest that seasonal environmental conditions can play a role in the response and recovery of macroinvertebrate communities-often used to monitor ecosystem condition-following dam removal. In particular, macroinvertebrate density and diversity can show recovery after dam removal, especially in seasons when macroinvertebrate density is typically lowest, with concomitant changes to functional trait abundance. Thus, we recommend scientists and managers consider responses to dam removal throughout the year. Further, similar density, generic richness, and functional traits among reaches suggest that channel restoration after dam removal may initially have equivocal effects on invertebrate communities., Competing Interests: The authors declare there are no competing interests.

Background: Network meta-analysis (NMA) has become a popular method to compare more than two treatments. This scoping review aimed to explore the characteristics and methodological quality of knowledge synthesis approaches underlying the NMA process. We also aimed to assess the statistical methods applied using the Analysis subdomain of the ISPOR checklist., Methods: Comprehensive literature searches were conducted in MEDLINE, PubMed, EMBASE, and Cochrane Database of Systematic Reviews from inception until April 14, 2015. References of relevant reviews were scanned. Eligible studies compared at least four different interventions from randomised controlled trials with an appropriate NMA approach. Two reviewers independently performed study selection and data abstraction of included articles. All discrepancies between reviewers were resolved by a third reviewer. Data analysis involved quantitative (frequencies) and qualitative (content analysis) methods. Quality was evaluated using the AMSTAR tool for the conduct of knowledge synthesis and the ISPOR tool for statistical analysis., Results: After screening 3538 citations and 877 full-text papers, 456 NMAs were included. These were published between 1997 and 2015, with 95% published after 2006. Most were conducted in Europe (51%) or North America (31%), and approximately one-third reported public sources of funding. Overall, 84% searched two or more electronic databases, 62% searched for grey literature, 58% performed duplicate study selection and data abstraction (independently), and 62% assessed risk of bias. Seventy-eight (17%) NMAs relied on previously conducted systematic reviews to obtain studies for inclusion in their NMA. Based on the AMSTAR tool, almost half of the NMAs incorporated quality appraisal results to formulate conclusions, 36% assessed publication bias, and 16% reported the source of funding. Based on the ISPOR tool, half of the NMAs did not report if an assessment for consistency was conducted or whether they accounted for inconsistency when present. Only 13% reported heterogeneity assumptions for the random-effects model., Conclusions: The knowledge synthesis methods and analytical process for NMAs are poorly reported and need improvement.

Rationale: Ischemic mitral regurgitation, a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to ischemic mitral regurgitation., Objective: Endothelial, interstitial, and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post MI, was analyzed in vitro., Methods and Results: Ovine MVs, harvested 6 months after inferior MI, showed CD45, a protein tyrosine phosphatase, colocalized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45 + endothelial cells (VE-cadherin + /CD45 + /α-smooth muscle actin [SMA] + and VE-cadherin + /CD45 + /αSMA- cells) and possible fibrocytes (VE-cadherin - /CD45 + /αSMA + ) in inferior MI compared with sham-operated and normal sheep. CD45 + cells correlated with MV fibrosis and mitral regurgitation severity. VE-cadherin + /CD45 + /αSMA + cells suggested that CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with transforming growth factor-β1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and transforming growth factor-β1 to 3, not observed in transforming growth factor-β1-treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers and inhibited EndMT-associated migration of MV endothelial cells., Conclusions: MV endothelial cells express CD45, both in vivo post MI and in vitro in response to transforming growth factor-β1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45 + endothelial cells to MV adaptation and fibrosis post MI warrants investigation., (© 2016 American Heart Association, Inc.)

Seizures are a common manifestation of hypoxic-ischaemic brain injury in the neonate. In status epilepticus models alterations to GABA A R subunit expression have been suggested to contribute to (i) abnormal development of the GABAergic system, (ii) why seizures become self-sustaining and (iii) the development of pharmacoresistance. Detailed investigation of GABA A R subunit protein expression after neonatal hypoxia-ischaemia (HI) is currently insufficient. Using our pig model of HI and subsequent spontaneous neonatal seizures, we investigated changes in protein expression of the three predominant α-subunits of the GABA A R; α 1 , α 2 and α 3 . Anaesthetized, ventilated newborn pigs (< 24 h old) were subjected to 30 min HI and subsequently recovered to 24 or 72 h. Amplitude-integrated electroencephalography was used to monitor brain activity and identify seizure activity. Brain tissue was collected post-mortem and GABA A R α-subunit protein expression was analysed using western blot and immunohistochemistry. GABA A R α 1 and α 3 protein expression was significantly reduced in animals that developed seizures after HI; HI animals that did not develop seizures did not exhibit the same reductions. Immunohistochemistry revealed decreased α 1 and α 3 expression, and α 1 redistribution from the cell membrane to the cytosol, in the hippocampus of seizure animals. Multivariate analyses, controlling for HI severity and neuronal injury, revealed that seizures were independently associated with significant GABA A R α 3 reduction. This is the first study to show loss and redistribution of GABA A R α-subunits in a neonatal brain experiencing seizures. Our findings are similar to those reported in models of SE and in chronic epilepsy., (© 2016 International Society for Neurochemistry.)

Introduction: Economic evaluations conducted in children have unique features compared to adults. Important developments in pediatric economic evaluation in recent years include new options for valuing health states for cost-utility analysis (CUA) and shifting child health priorities. The Pediatric Economic Database Evaluation (PEDE) project includes a comprehensive database of pediatric health economic evaluations published since 1980. The objective of this scoping review was to identify trends over time in the use of CUA and other analytic techniques, and the therapeutic areas chosen for study. Areas covered: Medical and grey literature were searched, key characteristics were extracted, frequencies were tabulated and cross-tabulations were performed. Differences between early (1980 and 1999) and late (2000 and 2014) periods were assessed using a chi-squared statistic. Of the 2,776 pediatric economic evaluations published between 1980 and 2014, substantially more were cost-effectiveness analyses (CEAs) and CUAs than cost benefit analyses and cost minimization analyses (63.9 and 24.9% versus 7.6 and 3.6%, respectively). This pattern was consistent regardless of the type of intervention, disease or age group studied. A trend toward higher proportions of CUAs and CEAs was evident in the later period (X 2 p < 0.0001). Other significant trends included a higher proportion of studies of preventive interventions (X 2 p < 0.0001), and more studies in children aged 1 to 12 years and fewer in perinates in the later period (X 2 p < 0.0001). Overall the most common disease class studied was infectious diseases (29.2%). Expert commentary: Pediatric economic evaluation continues to grow in volume and methodologic complexity. While CUAs have increased, whether their quality has improved remains unknown. Although most studies are in infectious disease, the volume of publications may not align with emerging child health priorities such as adolescent health, injury, developmental disabilities, mental health, and the use of personalized medicine. Increasing economic evaluations in these areas will enhance pediatric decision-making.

Objective: The purpose of this investigation was to examine treatment adherence to medication and lifestyle recommendations among pediatric migraine patients using electronic monitoring systems., Background: Nonadherence to medical treatment is a significant public health concern, and can result in poorer treatment outcomes, decreased cost-effectiveness of medical care, and increased morbidity. No studies have systematically examined adherence to medication and lifestyle recommendations in adolescents with migraine outside of a clinical trial., Methods: Participants included 56 adolescents ages 11-17 who were presenting for clinical care. All were diagnosed with migraine with or without aura or chronic migraine and had at least 4 headache days per month. Medication adherence was objectively measured using electronic monitoring systems (Medication Event Monitoring Systems technology) and daily, prospective self-report via personal electronic devices. Adherence to lifestyle recommendations of regular exercise, eating, and fluid intake were also assessed using daily self-report on personal electronic devices., Results: Electronic monitoring indicates that adolescents adhere to their medication 75% of the time, which was significantly higher than self-reported rates of medication adherence (64%). Use of electronic monitoring of medication detected rates of adherence that were significantly higher for participants taking once daily medication (85%) versus participants taking twice daily medication (59%). Average reported adherence to lifestyle recommendations of consistent noncaffeinated fluid intake (M = 5 cups per day) was below recommended levels of a minimum of 8 cups per day. Participants on average also reported skipping 1 meal per week despite recommendations of consistently eating three meals per day., Conclusions: Results suggest that intervention focused on adherence to preventive treatments (such as medication) and lifestyle recommendations may provide more optimal outcomes for children and adolescents with migraine and their families. Once daily dosing of medication may be preferred to twice daily medication for increased medication adherence among children and adolescents., (© 2016 American Headache Society.)

Although many studies have reported associations between characteristics of the neighborhood environment and obesity, little is understood about the pathways or mechanisms through which these associations operate. The purpose of this study was to examine possible behavioral and stress pathways hypothesized to mediate the association between neighborhood environments and obesity and whether pathways contribute to different obesity outcomes. Cross-sectional data were used from the 2012-2014 Women and Their Children's Health Study (WaTCH) in Louisiana (N = 909). Participants' neighborhoods, body mass index (BMI) and waist circumference (WC) were objectively measured. The causal inference approach to mediation analysis was used to obtain indirect estimates for self-reported measures of physical activity, low access to food, and depression. The mean BMI was 32.0 kg/m(2) and the mean WC was 98.6 cm. The (adverse) neighborhood environment was significantly associated BMI (β = 0.17 kg/m(2); 95% Confidence Interval (CI): 0.03, 0.31) and WC (β = 0.64; 95% CI: 0.34, 0.95, after adjusting for covariates. Neither depression, physical activity, nor low food access mediated those associations. Further research that investigates and uses better measures of the behavioral and stress pathways through which the neighborhood environment influences obesity is warranted.

Objective: To describe baseline headache characteristics of children and adolescents participating in a multicenter, randomized, double-blinded, placebo-controlled, comparative effectiveness study of amitriptyline, topiramate, and placebo for the prevention of migraine (CHAMP Study)., Methods: Children and adolescents (age 8-17 years old, inclusive) diagnosed with migraine with or without aura, having headaches at least four times per month were enrolled from 2012 through 2014. The trial involved a baseline period (minimum of 28 days) during which prospective diaries were completed and demographics and headache features obtained., Results: A total of 488 children and adolescents (mean age 14.0 ± 2.4 years) agreed to participate in the trial, with 361 randomized and 127 not randomized. Randomized subjects had a 5.5 ± 3.1 year history of headaches, with 15.1 ± 7.1 headache days per month (based upon retrospective report at screening visit). Prospective diaries reported 11.5 ± 6.1 headache days per 28 day baseline. Across this 28 day period, reported headache days per week were stable (about 3 headache days per week). Recording of individual headache features by diary (n = 4136 headache days) showed characteristics consistent with migraine (mean duration 10.5 ± 8.1 hours, mean severity 6.0 ± 2.1, 60% throbbing, 55% with activity worsening headaches, 55% with photophobia, and 47% with phonophobia)., Conclusions: Baseline data from the CHAMP Study suggested that the randomized sample was representative of the real world population of children and adolescents that present for treatment of migraine. Headaches in children and adolescents recorded during a 28 day prospective baseline period in this multi-site comparative effectiveness study did not change over the course of the baseline period, even though a clear diagnosis, recommendation for effective acute treatment, and standardized education about healthy habits occurred prior to the diary collection period., (© 2016 American Headache Society.)

A series of piperazin-1-yl substituted unfused heterobiaryls was synthesized as ligands of the 5-HT₇ receptors. The goal of this project was to elucidate the structural features that affect the 5-HT₇ binding affinity of this class of compounds represented by the model ligand 4-(3-furyl)-2-(4-methylpiperazin-1-yl)pyrimidine (2). The SAR studies included systematical structural changes of the pyrimidine core moiety in 2 to quinazoline, pyridine and benzene, changes of the 3-furyl group to other heteroaryl substituents, the presence of various analogs of the 4-methylpiperazin-1-yl group, as well as additional substitutions at positions 5 and 6 of the pyrimidine. Substitution of position 6 of the pyrimidine in the model ligand with an alkyl group results in a substantial increase of the binding affinity (note a change in position numbers due to the nomenclature rules). It was also demonstrated that 4-(3-furyl) moiety is crucial for the 5-HT₇ binding affinity of the substituted pyrimidines, although, the pyrimidine core can be replaced with a pyridine ring without a dramatic loss of the binding affinity. The selected ethylpyrimidine (12) and butylpyrimidine (13) analogs of high 5-HT₇ binding affinity showed antagonistic properties in cAMP functional test and varied selectivity profile-compound 12 can be regarded as a dual 5-HT₇/5-HT2AR ligand, and 13 as a multi-receptor (5-HT₇, 5-HT2A, 5-HT₆ and D₂) agent.

Over the last decade, the biomarkers procalcitonin and C-reactive protein have gained interest in sepsis research. Procalcitonin is a unique biomarker that is specific to bacterial infection and has demonstrated utility in the risk stratification of patients with potential life-threatening bacterial infections. In addition, procalcitonin has been documented as having a role in reducing the rate of unnecessary antibiotics while positively impacting antibiotic resistance rates and cost savings. The purposes of this review article are to discuss the clinical relevance of C-reactive protein and procalcitonin as diagnostic and prognostic markers for sepsis with a focus on the use of serial procalcitonin levels as a component of antibiotic stewardship programs. The federal government has recently become invested in combating the progression of antibiotic resistance; a 5-year national plan has been developed to address these concerns. Establishing a reliable antibiotic stewardship program is one of the goals of this national plan.

Further resolving physicochemical-fish associations would be of considerable benefit to advancing both scientific research and monitoring programs in the Baltic states. We collected 3 years of coordinated hydrogeomorphic, water-chemistry, and fish assemblage data at 11 study reaches along the Nevėžis River of central Lithuania and assessed their relative influence on fish assemblages. Of the 23 fish species surveyed in the Nevėžis River, omnivorous and tolerant species were most common. Both water chemistry and physical, hydrogeomorphic characteristics emerged as predictors of fish assemblage descriptors. The strength of evidence for biological oyxgen demand as a strong environmental driver was compelling for both the Lithuanian Fish Index (LFI) and percentage of simple lithophils. Channel substrate emerged in multiple models as a strong predictor variable (LFI, % intolerant species, % simple lithophils, % omnivores). Measures of channel size (drainage area, mean depth) contributed to models for multiple fish metrics including percentage of lithophils, percentage of omnivores, and percentage of intolerant species. This research represents novel work in the region, and our results are an important step in supporting the development of a comprehensive physicochemical research and monitoring program in Lithuania.

Introduction: Maxillary surgery on a bone segment enables movement in the sagittal and vertical planes. When performed on multiple segments, it further provides movement in the transverse plane. Typical sites for interdental osteotomies are between laterals and canines, premolars and canines, or between incisors. Additionally, osteotomies can be bilateral, unilateral or asymmetric. The ability to control intercanine width, buccolingual angulation of incisors, and correct Bolton discrepancy are some of the advantages of maxillary segmentation between laterals and canines., Objective: This article describes important features to be considered in making a clinical decision to segment the maxilla between laterals and canines when treating a dentoskeletal deformity. It further discusses the history of this surgical approach, the indications for its clinical use, the technique used to implement it, as well as its advantages, disadvantages, complications and stability. It is therefore hoped that this paper will contribute to disseminate information on this topic, which will inform the decision-making process of those professionals who wish to make use of this procedure in their clinical practice., Conclusions: Segmental maxillary osteotomy between laterals and canines is a versatile technique with several indications. Furthermore, it offers a host of advantages compared with single-piece osteotomy, or between canines and premolars.

Objectives: To systematically review health economic guidelines for information on how to present health economic evaluations and consider implications for nontechnical audiences such as policymakers., Methods: Electronic databases and supplementary sources were searched for economic evaluation guidelines. Guidelines were critically appraised. Descriptive characteristics, standard formats, supports for nontechnical audiences, presentation approaches, and common reporting recommendations were extracted. Frequencies were tabulated and trends identified., Results: Thirty-one guidelines were included. Twenty-two guidelines include a standard reporting format with some sample tables and graphs. Common presentation approaches include well-cited tables of data sources, transparent model diagrams and descriptions, disaggregated results, and tabular and graphical displays of sensitivity analyses. Despite most guidelines being funded by policymakers, only five guidelines provided advice on presenting economic evaluations to noneconomists. However, 11 guidelines included a glossary of economic terminology for nontechnical readers. Common concepts that may require further explanation include differences in economic perspectives, appropriateness of time horizons, how economic outcomes such as quality-adjusted life-years relate to their component clinical outcomes, and choice of sensitivity analyses., Conclusions: Health economists have consistent presentation formats and common reporting elements that should be considered when developing user-friendly explanations for general audiences. These overlap with policymakers' informational needs but may not be sufficient for understanding by nontechnical audiences. Developing presentation formats and tools that incorporate viewpoints of both economists and noneconomists will allow for better application of the results of economic evaluations and enhance the transparency and legitimacy of decision-making processes that are informed by economic evaluations., (Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Importance: Evidence-based treatments that achieve optimal energy intake and improve growth in preschool-aged children with cystic fibrosis (CF) are a critical need., Objective: To test whether behavioral and nutritional treatment (intervention) was superior to an education and attention control treatment in increasing energy intake, weight z (WAZ) score, and height z (HAZ) score., Design, Setting, and Participants: This randomized clinical trial included 78 children aged 2 to 6 years (mean age, 3.8 years) with CF and pancreatic insufficiency (intervention, n = 36 and control, n = 42). The study was conducted at 7 CF centers between January 2006 and November 2012; all 78 participants who met intent-to-treat criteria completed through follow-up., Interventions: Behavioral intervention combined individualized nutritional counseling targeting increased energy intake and training in behavioral child management skills. The control arm provided education and served as a behavioral placebo controlling for attention and contact frequency. Both treatments were delivered in person or telehealth (via telephone). Sessions occurred weekly for 8 weeks then monthly for 4 months (6 months). Participants then returned to standard care for 1 year, with 12-month follow-up thereafter., Main Outcomes and Measures: Changes in energy intake and WAZ score were examined from pretreatment to posttreatment (6 months) and change in HAZ score was assessed pretreatment to follow-up (18 months). Covariates included sex, Pseudomonas aeruginosa status at baseline, and treatment modality (in person vs telehealth)., Results: At baseline, mean (SD) energy intake was 1462 (329) kcals/d, WAZ score was -0.44 (0.81), and HAZ score was -0.55 (0.84). From pretreatment to posttreatment, the intervention increased daily energy intake by 485 calories vs 58 calories for the control group (adjusted difference, 431 calories; 95% CI, 282 to 581; P < .001) and increased the WAZ score by 0.12 units vs 0.06 for the control (adjusted difference, 0.09; 95% CI, -0.06 to 0.24; P = .25). From pretreatment to follow-up, the intervention increased the HAZ score by 0.09 units vs -0.02 for the control (adjusted difference, 0.14 units; 95% CI, 0.001 to 0.27; P = .049). Measured treatment integrity and credibility were high for both groups., Conclusions and Relevance: Behavioral and nutritional intervention improved energy intake and HAZ score outcomes but not WAZ score outcomes. Our results provide evidence that behavioral and nutritional treatment may be efficacious as a nutritional intervention for preschoolers aged 2 to 6 years with CF and pancreatic insufficiency., Trial Registration: clinicaltrials.gov Identifier:NCT00241969.

Introduction: Findings from early cephalometric studies on airway changes after 2-jaw orthognathic surgery have been challenged because the previous anteroposterior interpretation of airway changes can now be evaluated in 3 dimensions. The aims of this study were to use cone-beam computed tomography to quantify the nasopharynx, oropharynx, and total airway volume changes associated with skeletal movements of the maxilla and mandible in a sample of patients undergoing 2-jaw orthognathic surgery for correction of skeletal malocclusion., Methods: Skeletal movements and airway volumes of 71 postpubertal patients (31 male, 40 female; mean age, 18.8 years) were measured. They were divided into 2 groups based on ANB angle, overjet, and occlusion (Class II: ANB, >2°; overjet, >1 mm; total, 35 subjects; and Class III: ANB, <1°; overjet, <1 mm; total, 36 subjects). Presurgical and postsurgical measurements were collected for horizontal, vertical, and transverse movements of the maxilla and the mandible, along with changes in the nasopharynx, oropharynx, and total airways. Associations between the directional movements of skeletal structures and the regional changes in airway volume were quantified. Changes in the most constricted area were also noted., Results: Horizontal movements of D-point were significantly associated with increases in both total airway (403.6 ± 138.6 mm(3); P <0.01) and oropharynx (383.9 ± 127.9 mm(3); P <0.01) volumes. Vertical movements of the posterior nasal spine were significantly associated with decreases in total airway volume (-459.2 ± 219.9 mm(3); P = 0.04) and oropharynx volume (-639.7 ± 195.3 mm(3); P <0.01), increases in nasopharynx (187.2 ± 47.1 mm(3); P <0.01) volume, and decreases in the most constricted area (-10.63 ± 3.69 mm(2); P <0.01). In the Class III patients only, the vertical movement of D-point was significantly associated with decreases in both total airway (-724.0 ± 284.4 mm(3); P = 0.02) and oropharynx (-648.2 ± 270.4 mm(3); P = 0.02) volumes. A similar negative association was observed for the most constricted area for the vertical movement of D-point (-15.45 ± 4.91 mm(2); P <0.01)., Conclusions: Optimal control of airway volume is through management of the mandible in the horizontal direction and the vertical movement of the posterior maxilla for all patients. The surgeon and the orthodontist should optimally plan these movements to control gains or losses in airway volume as a result of orthognathic surgery., (Copyright © 2015 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)