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Summary: Tyrannosauroids are a clade of theropod dinosaur taxa that varied greatly in their body size distribution. We investigated the feeding performance of six tyrannosaur genera of variable body size and skull morphology. We used 3D finite element analysis to test whether skull shape becomes more or less resistant to feeding-induced forces. Cranial and mandibular models were scaled by adult Tyrannosaurus’s surface area to analyze the influence of shape on skull function. It was found that Tyrannosaurus experienced higher absolute stresses compared to small-bodied relatives. When surface area values were equalized across genera to account for the effect of size and test efficiency of skull shape, smaller individuals experience notably greater stresses than larger relatives due to the robust cranial osteology characterized in the allometry of tyrannosaurids. These results may indicate that the wide crania of tyrannosaurids convey a functional advantage that basal tyrannosauroids, juvenile tyrannosauroids, and alioramins lacked.

A subset of Nucleotide-binding and leucine-rich repeat-containing receptors (NLRs) function to mitigate overzealous pro-inflammatory signaling produced by NF-κB activation. Under normal pathophysiologic conditions, proper signaling by these NLRs protect against potential autoimmune responses. These NLRs associate with several different proteins within both the canonical and noncanonical NF-κB signaling pathways to either prevent activation of the pathway or inhibit signal transduction. Inhibition of the NF-κB pathways ultimately dampens the production of pro-inflammatory cytokines and activation of other downstream pro-inflammatory signaling mechanisms. Dysregulation of these NLRs, including NLRC3, NLRX1, and NLRP12, have been reported in human inflammatory bowel disease (IBD) and colorectal cancer patients, suggesting the potential of these NLRs as biomarkers for disease detection. Mouse models deficient in these NLRs also have increased susceptibility to colitis and colitis-associated colorectal cancer. While current standard of care for IBD patients and FDA-approved therapeutics function to remedy symptoms associated with IBD and chronic inflammation, these negative regulatory NLRs have yet to be explored as potential drug targets. In this review, we describe a comprehensive overview of recent studies that have evaluated the role of NLRC3, NLRX1, and NLRP12 in IBD and colitis-associated colorectal cancer.

Background: Safety and efficacy data for dupilumab beyond 1 year are lacking for patients from Japan with moderate-to-severe asthma. Methods: The TRAVERSE open-label extension (OLE) study (NCT02134028) assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in 2282 patients who completed a previous dupilumab asthma study. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included annualized severe exacerbation rate and change from parent study baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1), asthma control, quality of life, and blood eosinophil levels. Anti-drug antibodies (ADA) were evaluated. We report results in 160 (7.8% of exposed population) patients recruited from Japanese centers with non-oral corticosteroid (OCS)-dependent asthma rolled over from two parent studies, and in subgroups with a type 2 inflammatory phenotype. Results: TEAEs were consistent with the parent studies and the known safety profile of dupilumab. One patient permanently discontinued treatment due to TEAEs. Exacerbation rates remained low and were sustained to Week 96, as were improvements in pre-bronchodilator FEV1. Rapid, sustained improvements were observed in dupilumab-treated patients who previously received placebo in a parent study, while further improvements in exacerbation rates, asthma control, and asthma-related quality of life were observed in those continuing dupilumab. Blood eosinophil levels decreased progressively while on treatment. Treatment-emergent ADA responses were highest in patients who had previously received placebo. Efficacy results were consistent in patients with a type 2 phenotype. Conclusions: Long-term dupilumab treatment was well tolerated and efficacious in patients with non–OCS-dependent, moderate-to-severe asthma recruited from Japan.(Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov identifier, NCT02134028)

Introduction: Lung cancer is the deadliest cancer in the United States and worldwide, and lung adenocarcinoma (LUAD) is the most prevalent histologic subtype in the United States. LUAD exhibits a wide range of aggressiveness and risk of recurrence, but the biological underpinnings of this behavior are poorly understood. Past studies have focused on the biological characteristics of the tumor itself, but the ability of the immune response to contain tumor growth represents an alternative or complementary hypothesis. Emerging technologies enable us to investigate the spatial distribution of specific cell types within the tumor nest and characterize this immune response. This study aimed to investigate the association between immune cell density within the primary tumor and recurrence-free survival (RFS) in stage I and II LUAD. Methods: This study is a prospective collection with retrospective evaluation. A total of 100 patients with surgically resected LUAD and at least 5-year follow-ups, including 69 stage I and 31 stages II tumors, were enrolled. Multiplexed immunohistochemistry panels for immune markers were used for measurement. Results: Cox regression models adjusted for sex and EGFR mutation status revealed that the risk of recurrence was reduced by 50% for the unit of one interquartile range (IQR) change in the tumoral T-cell (adjusted hazard ratio per IQR increase = 0.50, 95% confidence interval: 0.27–0.93) and decreased by 64% in mast cell density (adjusted hazard ratio per IQR increase = 0.36, confidence interval: 0.15–0.84). The analyses were reported without the type I error correction for the multiple types of immune cell testing. Conclusions: Analysis of the density of immune cells within the tumor and surrounding stroma reveals an association between the density of T-cells and RFS and between mast cells and RFS in early-stage LUAD. This preliminary result is a limited study with a small sample size and a lack of an independent validation set.

Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease characterized by an eosinophilic inflammatory infiltrate in the esophagus, leading to remodeling, stricture formation, and fibrosis. Triggered by food and aeroallergens, type 2 cytokines interleukin (IL)-4, IL-13, IL-5 produced by CD4+ T helper 2 cells (Th2), eosinophils, mast cells, basophils, and type 2 innate lymphoid cells alter the esophageal epithelial barrier and increase inflammatory cell tissue infiltration. Clustering analysis based on the expression of type 2 inflammatory genes demonstrated the diversity of EoE endotypes. Despite the availability of treatment options for patients with EoE, which include dietary restriction, proton pump inhibitors, swallowed topical steroids, and esophageal dilation, there are still no Food and Drug Administration–approved medications for this disease; as such, there are clear unmet medical needs for these patients. A number of novel biologic therapies currently in clinical trials represent a promising avenue for targeted therapeutic approaches in EoE. This review summarizes our current knowledge on the role of type 2 inflammatory cells and mediators in EoE disease pathogenesis, as well as the future treatment landscape targeting underlying inflammation in EoE.

In this article, we compiled 13 etiological theories, 15 characteristics, and 81 observations/phenomena of peptic ulcers, reported in reproducible, peer-reviewed studies from the literature, to reflect the historical evolution of studies on peptic ulcers and to provide a multidisciplinary view of this disease. This data was collected during the systematic review of topics on peptic ulcers including genetics, etiology, epidemiology, psychology, anatomy, neurology, bacteriology, pathology, and clinical statistics. The data curated herein was extracted via application of recently published basic theories and methodologies. Keywords: Peptic ulcers, Etiological theory, Characteristics, Observations, Phenomena, Helicobacter pylori

Mumps outbreaks among vaccinated patients have become increasingly common in recent years. While there are multiple conditions driving this re-emergence, convention has suggested that these outbreaks are associated with waning immunity rather than vaccine escape. Molecular evidence from both the ongoing American and Dutch outbreaks in conjunction with recent structural biology studies challenge this convention, and suggest that emergent lineages of mumps virus exhibit key differences in antigenic epitopes from the vaccine strain employed: Jeryl-Lynn 5. The American and Dutch 2016–2017 outbreak lineages were examined using computational biology through the lens of diversity in immunogenic epitopes. Findings are discussed and the laboratory evidence indicating neutralization of heterologous mumps strains by serum from vaccinated individuals is reviewed. Taken together, it is concluded that the number of heterologous epitopes occurring in mumps virus in conjunction with waning immunity is facilitating small outbreaks in vaccinated patients, and that consideration of a polyvalent mumps vaccine is warranted.

Geographic ranges of many taxa have shifted poleward or up-slope under warming. Little is known, however, about the consistency of these dynamics among multiple mountains within a species’ geographic range. We assess climate tracking over the past century for four montane rodents, across the Ruby Mountains and Toiyabe Range within the Great Basin ecoregion of western North America. To do this, we generated species distribution models (SDMs, Maxent) in each mountain range during historical (1923–1940) and modern (2005–2015) time periods. Nineteen bioclimatic variables were derived from 800 m resolution monthly PRISM climate group data. SDMs trained on historic occurrences and climate were projected onto modern climates to estimate expected species distributions along each elevational gradient. Occurrence-based Observed Modern SDMs were compared to these Expected Modern SDMs, with congruence between the two representing the degree of climate tracking. Climate tracking predicted up-slope range expansions and contractions in the Ruby Mountains, while stasis or down-slope contractions were predicted in the Toiyabe Range. Observed Modern SDMs rarely matched climate tracking expectations, and the same species showed variable responses among mountains. Deviations are partially explained by changes in the contribution of temperature vs. precipitation over time. Additionally, optimal niche space in the Ruby Mountains shifted in elevation, but shifted in both elevation and latitude in the Toiyabe Range. Our results indicate that data from one elevational gradient may not be predictive of range dynamics elsewhere, even across similar environmental conditions and habitats, even for the same species. Conservation efforts will be better served by strategies that consider both inter- and intraspecific variation in responses to climate change over space and time.

Abstract Objective: To investigate the association between the mother‐infant relationship, defined as maternal‐infant emotional attachment, maternal separation anxiety and breastfeeding, and maternal employment status at 10 months following first childbirth. Method: Samples of employed, pregnant women, over 18 years of age and with sufficient English literacy were recruited systematically from one public and one private maternity hospital in Victoria. Data were collected by structured interview and self‐report questionnaire in the third trimester, and at 3 and 10 months postpartum. Socio‐demographic, employment, and breastfeeding information was collected. Participants completed standardised assessments of maternal separation anxiety and mother‐to‐infant emotional attachment. Results: Of 205 eligible women, 165 (81%) agreed to participate and 129 (78%) provided complete data. A reduced odds of employment participation was independently associated with continuing to breastfeed at 10 months (OR=0.22, p=0.004) and reporting higher maternal separation anxiety (OR=0.23, p=0.01) when maternal age, education, occupational status and use of paid maternity leave and occupational status were adjusted for in analyses. Conclusion: Employment participation in the first 10 months postpartum is associated with lower maternal separation anxiety, and shorter breastfeeding duration. Implications: Paid parental leave has public health implications for mothers and infants. These include permitting sufficient time to protect sustained breastfeeding, and the development of optimal maternal infant attachment, reflected in confidence about separation from her infant.

Tobacco product use is a risk factor in the development of oral cancer, although epidemiology studies show this risk is far less with smokeless tobacco product use than cigarette smoking. While smokeless tobacco contains harmful and potentially harmful constituents (HPHCs), the oral permeation of HPHCs in oral tobacco products is not completely understood. To improve the understanding, three different extract concentrations of the CORESTA reference products (CRP) for snus (CRP1.1) and moist snuff (CRP2.1) were applied to cellular tissue derived from two donors of EpiOral™ model, a 3D human buccal model, and permeation of nicotine and tobacco-specific nitrosamines (TSNAs) were measured over two hours. Permeation of 0.15% caffeine in complete artificial saliva and cell viability were also measured. Results showed that a consistent and concentration dependent cumulative permeation of nicotine and TSNAs was observed with high percent recovery in all conditions. A high degree of sensitivity was seen for all analytes, with minimal cytotoxicity for both CRPs. The data presented here show the EpiOral™ model is fit-for-purpose to evaluate the permeation of nicotine and TSNAs in nicotine-containing snus and moist snuff oral tobacco., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The data presented in this manuscript were generated and analyzed in studies commissioned by RAI Services Company and conducted under contract at LabCorp Early Development Laboratories Ltd. BMK, RAW, JR, and KJ were all full-time employees of RAI Services Company during the execution of this work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Amorphous solid dispersions (ASDs) are an attractive option to improve the bioavailability of poorly water-soluble compounds. However, the material attributes of ASDs can present formulation and processability challenges, which are often mitigated by the addition of excipients albeit at the expense of tablet size. In this work, an ASD manufacturing train combining co-precipitation and thin film evaporation (TFE) was used to generate high bulk-density co-precipitated amorphous dispersion (cPAD). The cPAD/TFE material was directly compressed into tablets at amorphous solid dispersion loadings up to 89 wt%, representing a greater than 60% reduction in tablet size relative to formulated tablets containing spray dried intermediate (SDI). This high ASD loading was possible due to densification of the amorphous dispersion during drying by TFE. Pharmacokinetic performance of the TFE-isolated, co-precipitated dispersion was shown to be equivalent to an SDI formulation. These data highlight the downstream advantages of this novel ASD manufacturing pathway to facilitate reduced tablet size via high ASD loading in directly compressed tablets., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D.S.F, H.N., J.R., and L.S. have filed a provisional patent on behalf of Merck & Co., Inc., Rahway, NJ, USA on thin film evaporation of co-precipitated dispersions as a method to improve bulk powder properties. All authors are employees of Merck & Co., Inc., Rahway, NJ, USA. Merck & Co., Inc., Rahway, NJ, USA had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initially infects the respiratory tract, it also directly or indirectly affects other organs, including the brain. However, little is known about the relative neurotropism of SARS-CoV-2 variants of concern (VOCs), including Omicron (B.1.1.529), which emerged in November 2021 and has remained the dominant pathogenic lineage since then. To address this gap, we examined the relative ability of Omicron, Beta (B.1.351), and Delta (B.1.617.2) to infect the brain in the context of a functional human immune system by using human angiotensin-converting enzyme 2 (hACE2) knock-in triple-immunodeficient NGC mice with or without reconstitution with human CD34 + stem cells. Intranasal inoculation of huCD34 + -hACE2-NCG mice with Beta and Delta resulted in productive infection of the nasal cavity, lungs, and brain on day 3 post-infection, but Omicron was surprisingly unique in its failure to infect either the nasal tissue or brain. Moreover, the same infection pattern was observed in hACE2-NCG mice, indicating that antiviral immunity was not responsible for the lack of Omicron neurotropism. In independent experiments, we demonstrate that nasal inoculation with Beta or with D614G, an ancestral SARS-CoV-2 with undetectable replication in huCD34 + -hACE2-NCG mice, resulted in a robust response by human innate immune cells, T cells, and B cells, confirming that exposure to SARS-CoV-2, even without detectable infection, is sufficient to induce an antiviral immune response. Collectively, these results suggest that modeling of the neurologic and immunologic sequelae of SARS-CoV-2 infection requires careful selection of the appropriate SARS-CoV-2 strain in the context of a specific mouse model., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To better define surrogate endpoints for neoadjuvant chemotherapy (NAC) trials in patients with muscle-invasive bladder cancer. We compared survival in patients with carcinoma in-situ (CIS) only vs. complete response following NAC and radical cystectomy (RC)., Materials and Methods: Patients with cT2-4N0M0 disease treated with NAC and RC between 2001 and 2018 were stratified by response: complete response (CR, pT0N0), partial response (PR, pTaN0, pT1N0+/-CIS), CIS-only (pTisN0), stable disease (SD, pT2N0), or progressive disease (PD, >pT2N0). Primary endpoints were overall survival (OS) and risk of recurrence in patients with CIS-only vs. CR. Multivariable Cox proportional hazards regression model was used for OS and a competing risks proportional hazards model was used for risk of recurrence., Results: Of 1,406 patients in our institution cohort, 340 patients met inclusion criteria. Kaplan-Meier mean estimates of OS for CR and CIS-only were 108.9 months (95% CI 89.7-127.9) and 125.8 months (95% CI 112.3-139.3), respectively (P = 0.13). Cox proportional hazards model found no difference in OS between patients with PR (HR 1.06, 95% CI 0.33-2.58, P = 0.897) or CIS-only (HR 0.422, 95% CI 0.15-1.18, P = 0.101) when compared to CR. The risk of recurrence was similar between patients with CIS-only (HR 0.73, 95% 0.29-1.84, P = 0.49) and PR (HR 1.32, 95% CI 0.54-3.29, P = 0.54) when compared to CR on competing risks analysis., Conclusions: Residual CIS-only after NAC and RC demonstrated similar survival outcomes when compared to patients with pathologic CR. Further study in large multi-institutional cohorts may further validate CIS-only as an additional surrogate endpoint after NAC and may inform future trials., Competing Interests: Conflict of interest The authors declared no conflict interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To determine whether peer companionship delivered by an aging services agency to socially-disconnected older adult primary care patients was associated with improvement in suicidal ideation depression, anxiety, and psychological connectedness., Design: Pragmatic, nonblinded, parallel-group, randomized controlled trial comparing peer companionship, The Senior Connection (TSC), to care-as-usual (CAU)., Setting: Lifespan, a nonmedical, community-based aging services agency., Participants: Adult primary care patients ages 60 years or older who endorsed feelings of loneliness or being a burden on others., Intervention: TSC was delivered by Lifespan volunteers who provided supportive visits and phone calls in the subjects' homes. CAU involved no peer companion assignment., Measurements: The primary outcome was suicidal ideation assessed by the Geriatric Suicide Ideation Scale; secondary outcomes were depression, anxiety, and feelings of belonging and being a burden on others. Data were collected at baseline, 3-, 6-, and 12-months., Results: Subjects (55% female) had a mean age of 71 years. There was no difference between groups in change in suicidal ideation or belonging. Subjects randomized to TSC had greater reduction in depression (PHQ-9; 2.33 point reduction for TSC versus 1.32 for CAU, p = 0.05), anxiety (GAD-7; TSC 1.52 versus CAU 0.28, p = 0.03), and perceived burden on others (INQ; 0.46 TSC versus 0.09 CAU, p <0.01)., Conclusions: TSC was superior to CAU for improving depression, anxiety, and perceived burden, but not suicidal ideation. Although effect sizes were small, the low-cost and nationwide availability of peer companionship justify further examination of its effectiveness and scalability in improving mental health outcomes of socially disconnected older adults., (Copyright © 2020. Published by Elsevier Inc.)

Background: Physical and emotional parent-infant closeness activate important neurobiological mechanisms involved in parenting. In a neonatal care context, most research focuses on physical (parental presence, skin-to-skin contact) aspects; insights into emotional closeness can be masked by findings that overemphasise the barriers or challenges to parenting an infant during neonatal care., Aim: To explore existing qualitative research to identify what facilitates and enables parents' experiences of emotional closeness to their infants while cared for in a neonatal unit., Study Design: A systematic review using meta-ethnographic methods. Search strategy involved searches on six databases, author runs, and backward and forward chaining. Reciprocal translation was used to identify and compare key concepts of parent-infant emotional closeness., Results: Searches identified 6992 hits, and 34 studies from 17 countries that involved 670 parents were included. Three overarching themes and associated sub-themes were developed. 'Embodied connections' describes how emotional closeness was facilitated by reciprocal parent-infant interactions, spending time as a family, and methods for parents to feel connected while physically separated. 'Inner knowing' concerns how knowledge about infant and maternal health and understanding the norms of neonatal care facilitated emotional closeness. 'Evolving parental role' relates to how emotional closeness was intertwined with parental identities of contributing to infant health, providing direct care, and being acknowledged as a parent., Conclusion: Parent-infant closeness evolves and is facilitated by multifaceted biopsychosocial factors. Practice implications include creating private and uninterrupted family time, strategies for parents to maintain an emotional connection to their infant when separated, and neurobiology education for staff., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Accidents and unintentional injuries account for the greatest number of adolescent deaths, often involving use of alcohol and other substances. This article describes the iterative design and development of Interactive Narrative System for Patient-Individualized Reflective Exploration (INSPIRE), a narrative-centered behavior change environment for adolescents focused on reducing alcohol use. INSPIRE is designed to serve as an extension to clinical preventive care, engaging adolescents in a theoretically grounded intervention for health behavior change by leveraging 3D game engine and interactive narrative technologies., Methods: Adolescents were engaged in all aspects of the iterative, multiyear development process of INSPIRE through over 20 focus groups and iterative pilot testing involving more than 145 adolescents. Qualitative findings from focus groups are reported, as well as quantitative findings from small-scale pilot sessions investigating adolescent engagement with a prototype version of INSPIRE using a combination of questionnaire and interaction trace log data., Results: Adolescents reported that they found INSPIRE to be engaging, believable, and relevant to their lives. The majority of participants indicated that the narrative's protagonist character was like them (84%) and that the narrative featured virtual characters that they could relate to (79%). In the interactive narrative, the goals most frequently chosen by adolescents were "stay in control" (60%) and "do not get in trouble" (55%)., Conclusions: With a strong theoretical framework (social-cognitive behavior change theory) and technology advances (narrative-centered learning environments), the field is well positioned to design health behavior change systems that can realize significant impacts on behavior change for adolescent preventive health., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

We have implemented the use of a small-scale, 7-vial Micro Freeze Dryer (MicroFD ® ; Millrock Technology, Inc.) that has the capability to accurately control heat transfer during lyophilization. We demonstrate the ability to fine-tune the MicroFD ® vial heat transfer coefficient (K v ) to match the K v of vials in a LyoStar III laboratory-scale unit. When the MicroFD ® is run under conditions that match the K v of the LyoStar III, the resulting lyophilization performance between scales results in equivalent product temperature profiles and critical quality attributes for the same drying process. The proposed workflow demonstrates how exploitation of K v control in the MicroFD ® enables cycle development of at-scale lyophilization processes using only 7 product vials. By changing the MicroFD ® K v , laboratory and, potentially, manufacturing cycles may be simulated using only 7 product vials for tremendous active pharmaceutical ingredient savings, as long as at-scale heat transfer coefficients are well characterized., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Introduction: Dorsal root ganglion stimulation (DRGS) is a powerful tool in the treatment of chronic, neuropathic pain. The premise of DRGS is similar to that of conventional spinal cord stimulation (cSCS), however, there is more variability in how it can be utilized. While it is this variability that likely gives it its versatility, DRGS is not as straightforward to implement as cSCS. The purpose of this study was to assess the efficacy of DRGS on a broad number of diagnoses, determine which dorsal root ganglia were associated with better outcomes for particular body parts/diagnoses, and evaluate what factors/parameters were associated with higher rates of trial success., Methods: This is a physician initiated, multicenter retrospective registry of 217 patients trialed with DRGS. Data were collected via an online questionnaire that assessed specifics regarding the patient's pain, distribution, size, and response to treatment. The data were analyzed to see if there were certain diagnoses and/or parameters that were more or less associated with trial success., Results: DRGS was found to be an effective treatment in all diagnoses evaluated within this study, most of which had statistically significant improvements in pain. The most important predictor of trial success was the amount of painful area covered by paresthesias during the programing phase. The number of leads utilized had a direct and indirect impact on trial success. Pain in the distribution of a specific peripheral nerve responded best and there was no statistical difference based on what body part was being treated., Conclusion: DRGS can be an effective treatment for a variety of neuropathic pain syndromes, in addition to CRPS. It is recommended that a minimum of 2 leads should be utilized per area being treated. In addition, this therapy was shown to be equally efficacious in any body part/region so long as the area being treated is focal and not widespread., (© 2018 International Neuromodulation Society.)

Development of optimal drug product (DP) lyophilization cycles is typically accomplished via multiple engineering runs to determine appropriate process parameters. These runs require significant time and product investments, which are especially costly during early phase development when the DP formulation and lyophilization process are often defined simultaneously. Even small changes in the formulation may require a new set of engineering runs to define lyophilization process parameters. To overcome these development difficulties, an 8 factor definitive screening design, including both formulation and process parameters, was executed on a fully human monoclonal antibody DP. The definitive screening design enables evaluation of several interdependent factors to define critical parameters that affect primary drying time and product temperature. From these parameters, a lyophilization development model is defined where near optimal process parameters can be derived for many different DP formulations. This concept is demonstrated on a monoclonal antibody DP where statistically predicted cycle responses agree well with those measured experimentally. This design of experiments approach for early phase lyophilization cycle development offers a workflow that significantly decreases the development time of clinically and potentially commercially viable lyophilization cycles for a platform formulation that still has variable range of compositions., (Published by Elsevier Inc.)

This paper describes oil spill stakeholder engagement in a recent comparative risk assessment (CRA) project that examined the tradeoffs associated with a hypothetical offshore well blowout in the Gulf of Mexico, with a specific focus on subsea dispersant injection (SSDI) at the wellhead. SSDI is a new technology deployed during the Deepwater Horizon (DWH) oil spill response. Oil spill stakeholders include decision makers, who will consider whether to integrate SSDI into future tradeoff decisions. This CRA considered the tradeoffs associated with three sets of response strategies: (1) no intervention; (2) mechanical recovery, in-situ burning, and surface dispersants; and, (3) SSDI in addition to responses in (2). For context, the paper begins with a historical review of U.S. policy and engagement with oil spill stakeholders regarding dispersants. Stakeholder activities throughout the project involved decision-maker representatives and their advisors to inform the approach and consider CRA utility in future oil spill preparedness., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Subsea dispersant injection (SSDI) was a new oil spill response (OSR) technology deployed during the Deepwater Horizon accident. To integrate SSDI into future OSR decisions, a hypothetical deepwater oil spill to the Gulf of Mexico was simulated and a comparative risk assessment (CRA) tool applied to contrast three response strategies: (1) no intervention; (2) mechanical recovery, in-situ burning, and surface dispersants; and, (3) SSDI in addition to responses in (2). A comparative ecological risk assessment (CRA) was applied to multiple valued ecosystem components (VECs) inhabiting different environmental compartments (ECs) using EC-specific exposure and relative VEC population density and recovery time indices. Results demonstrated the added benefit of SSDI since relative risks to shoreline, surface wildlife and most aquatic life VECs were reduced. Sensitivity of results to different assumptions was also tested to illustrate flexibility of the CRA tool in addressing different stakeholder priorities for mitigating the impacts of a deepwater blowout., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Despite the increasing importance of mini-tablet for its advantages as pediatric formulations and in modified-release applications, its popularity is limited due to the lack of formulation and processing knowledge in developing such dosage forms. In this study, common grades of microcrystalline cellulose and roller compacted granules with a range of powder properties were used to evaluate the critical material properties required for the successful manufacturing of 1.7-mm mini-tablets. It was found that blends with small particle size had poor flow properties that did not support consistent die filling and also tended to cause tooling jam and damage. While the granulation process was effective in improving blend flow properties by increasing particle size, it is imperative to avoid very large particles that could also cause inadequate flow by blocking the space within the die. Successful mini-tablet compression could be achieved by removing particles larger than roughly 1/3 of the die diameter or milling the granules using a screen less than 1/3 of the die diameter., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objectives: We sought to determine the predictors of next-day discharge (NDD) for selected patients undergoing elective transfemoral transcatheter aortic valve replacement (TF-TAVR)., Background: Techniques have rapidly evolved over the last several years to simplify TF-TAVR allowing for a subset of patients to be discharged the next day., Methods: Baseline and procedural characteristics, in-hospital and 30-day follow-up outcomes, complications and readmission rates of 100 TF-TAVR cases were assessed. Patients selected for NDD all met the following criteria: no procedural complications, same day ambulation, strong family support with home supervision, and access to our valve coordinator post discharge., Results: There were 22 patients in NDD and 78 in later-day discharge (LDD) groups respectively. The mean length of stay was 3.4days for LDD. There were no significant differences in baseline, pre-procedural characteristics, or frailty indices of the two groups. However, there were more baseline oxygen dependent patients in LDD (p=0.004). Procedural characteristics included more balloon expandable valves (p=0.005), less fluoroscopy time (p=0.008), and higher use of moderate sedation (p=0.0001) in NDD group. There were more minor vascular complications (p=0.04) and new permanent pacemaker implantations (p=0.016) in the LDD group. There were no vascular complications, stroke or blood transfusions in the NDD group. The 30-day re-admission and mortality rates were similar in both groups. In logistic analyses only moderate sedation was a strong predictor of next day discharge after TF-TAVR (p=0.003)., Conclusion: Carefully selected patients without complications following TF-TAVR can be discharged safely the next day., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: There is an expectation that midwifery practice is woman centred and promotes physiology. In addition, midwives must assess the wellbeing of mother and baby, and monitor the progress of labour. It is important to understand how midwifery actions and interactions influence the birth experience for women., Aim: The aim of this study was to explore midwifery practice during physiological birth from the perspective of both midwives and mothers., Method: A narrative inquiry involving face-to-face in-depth interviews was used to gather data. The participants were 10 midwives and 10 women who had recently attended or experienced an uncomplicated physiological birth. Data was analysed to identify themes occurring across the narratives., Findings: Two types of midwifery practice were identified from the data: rites of passage and rites of protection. Rites of passage were synergistic with women's needs during birth and involved managing distractions and reflecting internal wisdom. Rites of protection involved performing clinical assessments to determine wellbeing and labour progress. These practices could contradict the rites of passage by disrupting aloneness and reinforcing external wisdom., Conclusion: Midwives performed two types of practices which intersected with women's experience of birth in differing and contested ways. Conceptualising the role of the midwife as a 'ritual companion' and actions and words as rituals enables a deeper exploration of the values transmitted and reflected by midwifery practice. This study contributes to a discourse about midwifery practice during birth, women's experience of birth, and the influence of the institution on the nature of mother-midwife relationship., (Copyright © 2015 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

Background: The pedunculopontine nucleus (PPN) is a part of the mesencephalic locomotor region and, in recent years, it has been considered a new surgical target for deep brain stimulation (DBS) for movement disorders including atypical parkinsonian syndromes such as progressive supranuclear palsy (PSP) and multiple system atrophy. Involvement of the PPN may play an important role in gait impairment in these disorders and the development of PPN DBS could potentially provide treatment for this disabling problem. However, the role of the PPN and the specific pathways involved in gait control and other motor functions are poorly understood., Methods: We present a chronological account of our group's experience in the use of PPN DBS. This entails the treatment of four patients with disabling movement disorders who all exhibited either marked damage or disconnection of the nigro-striatal pathway., Results: Within our series, the results were variable in that 2 of the 4 patients benefited greatly from DBS but the other 2 did not., Conclusions: Our findings suggest that in carefully selected patients, PPN DBS can potentially alleviate symptoms due to dopaminergic striatal inactivity; symptoms that are typically resistant to stimulation of other subcortical targets used for parkinsonian syndromes and movement disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In June 2010 the Australian Health Practitioner Agency unified the national registration of health professionals in Australia and introduced a separate register for midwives. Standard registration renewal requirements aimed to provide safe, competent practitioners. These new conditions created the impetus for practitioners to consider how they meet the re-registration standards for either their nurse or midwifery register/s., Question: How are midwives responding to the changed re-registration conditions for registration renewal?, Methods: Longitudinal case study design. A purposive sample of 24 midwives from five states was recruited. 20 took part in individual interviews over two re-registration periods. 4 midwives were interviewed in a focus group to verify the findings., Findings: Three themes captured issues and tensions about registration and midwifery practice. They are Rotation, Restriction and Extension., Conclusion: This paper has shown how the re-registration conditions and standards post 2010 have generated discourse around registration renewal. The simultaneous introduction of regulatory and legislative changes has resulted in the construction of categories within contemporary midwifery practice that do not necessarily align with the Nursing and Midwifery Board of Australia (NMBA) requirements for re-registration. Further research is recommended to examine the continuing influence and impact of the changes on the Australian midwifery workforce., (Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.)

Objectives: There is a general concern that hypnotic medications in patients with respiratory disorders have the potential to decrease respiratory effort and blunt the arousal response to hypoxemia which may lead to sleep breathing disorders. We investigated whether suvorexant, an orexin receptor antagonist approved for treatment of insomnia at a maximum daily dose of 20 mg in the US, causes sleep breathing disorders in patients with chronic obstructive pulmonary disease (COPD)., Design: This was a randomized, double-blind, placebo-controlled, 2-period, cross-over, study performed in 9 sleep laboratories/clinical research units in the United States. The participants were 25 COPD patients aged 39-72 y with mild-to-moderate airflow limitation based on GOLD spirometry criteria. In each period, patients received suvorexant (40 mg in <65 y-olds; 30 mg in ≥65 y-olds) or placebo for four consecutive nights. Respiratory function during sleep was measured by oxygen saturation using pulse oximetry (SpO2, primary endpoint) and Apnea Hypopnea Index (AHI, secondary endpoint). The study was powered to rule out a difference between treatments of -2 percentage points in SpO2 on Day 4., Results: There was no treatment effect following single and multiple doses of suvorexant on mean SpO2 during total sleep time (Day 1: suvorexant = 93.14%, placebo = 93.24%, difference = -0.10 [90% CI: -0.50, 0.31]; Day 4: suvorexant = 93.38%, placebo = 92.99%, difference = 0.39 [90% CI: -0.12, 0.91]). There was no clinically meaningful increase in mean AHI by suvorexant compared with placebo on Day 1 (difference = 0.72 [90% CI: -0.60, 2.04]) or Day 4 (difference = 2.05 [90% CI: 0.33, 3.77])., Conclusions: These data do not suggest an overt respiratory depressant effect with 30-40 mg daily doses of suvorexant, up to twice the maximum recommended dose for treating insomnia in the US, in patients with mild-to-moderate COPD. Trial registration Clinicaltrials.gov identifier: NCT01293006., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the reliability of estimates of bladder volume (BV) in children with the BladderScan BVI 9400 (BS) compared with the volume obtained at catheterization (CV)., Materials and Methods: BV was measured using the BS in 50 children (age range 6 weeks-14 years) who required urinary catheter placement during surgery or urodynamic studies. BS measurements were taken prior to catheter insertion. BV was compared with CV., Results: BS volumes ranged from 0 to 513 mL (mean = 79 mL, median = 34 mL) and CV from 0 to 500 mL (mean = 81 mL, median = 31 mL). There was high correlation between the BS and CV measures (rho = 0.96). The mean difference between BS and CV volumes was -2.1 mL (SD 21). Where the CV ≤ 100 mL the BS volumes ranged from 0 to 84 mL (mean = 74 mL, median = 30 mL) and the CV from 0 to 88 mL (mean = 76 mL, median = 25 mL) (rho = 0.89). The mean difference = 0.5 mL (95% limits of agreement ± 23 mL). In a small sample of 12 children <36 months, correlation between BS and CV volumes was not as strong with rho = 0.82., Conclusions: Overall the BladderScan showed a high correlation with catheter volume and there was good clinical agreement between the measures., (Copyright © 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: Elderly patients with cancer are under-represented in clinical trials, and there is especially scant data on their participation in early-phase trials. In an effort to provide more data, we reviewed our Phase I experience., Methods: We conducted a retrospective analysis of 461 patients enrolled in Phase I clinical trials at the Cancer Therapy Research Center (CTRC) from 2009 to 2011 to determine the rate of completion of at least 12 weeks of treatment, incidence of adverse events, prevalence of co-morbidities, functional status, and survival. Elderly (E) was defined as ≥70 years; non-elderly (NE) was defined as ≤69 years., Results: The elderly represented 15% (69/461) of enrolled patients. The most common malignancies were colon (20%), hematologic (18%), lung (15%), and breast (8%). The median age of E was 72 years (range 70-85, SD 3.15), and 49% of the E was female. Co-morbidities (E vs. NE) include diabetes (28% vs. 23%), hypertension (65% vs. 44%), and chronic kidney disease (91% vs. 48%). Thirty-two percent of E vs. 37% of NE completed at least 12 weeks of treatment. Reasons for not completing in E vs. NE respectively were progression of disease (43% vs. 61%), toxicity (28% vs. 9%), and self-withdrawal (11% vs. 7%). Reasons for not completing the protocol was significantly associated with being elderly (p = 0.005). There were non-significant differences in toxicity in E vs., Ne Conclusion: Elderly patients have a higher likelihood of not completing trials for reasons including toxicity. This highlights the need for better Phase I trial-designs incorporating ideal geriatric assessment tools., (© 2013. Published by Elsevier Ltd. All rights reserved.)

There is a pressing public health need to find interventions that reduce suicide risk in later life. Psychiatric and physical illness, functional decline, and social factors place seniors at risk for suicide. Reflecting this body of evidence, the Centers for Disease Control and Prevention (CDC) has identified the promotion and strengthening of social connectedness, between and within the individual, family, community, and broader societal levels, as a key strategy for suicide prevention. The Senior Connection, a randomized trial of peer companionship for older adults, is described here, with an emphasis on the most novel features of the study design-grounding in a psychological theory of suicide and intervening at an early stage in the suicide risk trajectory by linking primary care patients with the Aging Services Provider Network., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Hematopoietic cell transplantation (HCT) and prolonged chemotherapy are standard postremission strategies for adult acute lymphoblastic leukemia in first complete remission, but the optimal strategy remains controversial. There are no randomized trials of allogeneic HCT. In the present study, updated individual patient data were collected and analyzed from studies with information on availability of matched sibling donor (used to mimic randomization) and from randomized trials of autograft versus chemotherapy. Data from 13 studies including 2962 patients, excluding Philadelphia chromosome-positive patients, showed a survival benefit for having a matched sibling donor for patients < 35 years of age (OR = 0.79; 95% CI, 0.70-0.90, P = .0003) but not for those ≥ 35 years of age (OR = 1.01; 95% CI, 0.85-1.19, P = .9; heterogeneity P = .03) because of the higher absolute risk of nonrelapse mortality for older patients. No differences were seen by risk group. There was a trend toward inferior survival for autograft versus chemotherapy (OR = 1.18; 95% CI, 0.99-1.41; P = .06). No beneficial effect of autografting was seen compared with chemotherapy in this analysis. We conclude that matched sibling donor myeloablative HCT improves survival only for younger patients, with an absolute benefit of approximately 10% at 5 years. Improved chemotherapy outcomes and reduced nonrelapse mortality associated with allogeneic HCT may change the relative effects of these treatments in the future.

Point mutations of dehaloperoxidase-hemoglobin A (DHP A) that affect the surface charge have been prepared to study the interaction between DHP A with its substrate 2,4,6-trichlorophenol (TCP). Kinetic studies of these surface mutations showed a correlation, in which the more positively charged mutants have increased catalytic efficiency compared with wild type DHP A. As a result, the hypothesis of this study is that there is a global electrostatic interaction between DHP A and TCP. The electrostatic nature of substrate binding was further confirmed by the result that kinetic assays of DHP A were affected by ionic strength. Furthermore, isoelectric focusing (IEF) gel study showed that the pI-6.8 for DHP A, which indicates that DHP A has a slight negative charge pH 7, consistent with the kinetic observations., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The integration of all-trans-retinoic acid (ATRA) with anthracycline chemotherapy into up-front regimens for acute promyelocytic leukemia (APL) has produced striking improvements in clinical outcomes, making APL one of the most curable forms of hematologic malignancies in adults. In addition, arsenic trioxide has proven efficacy in relapse and when combined with ATRA in frontline regimens has demonstrated high efficacy in a number of trials and the potential to replace chemotherapy, which would thereby reduce chemotherapy-related adverse events. Cure in APL is also largely dependent on timely and effective supportive care measures that counteract such life-threatening emergencies as coagulopathy and APL differentiation syndrome. The risk of mortality during induction and the risk of relapse following frontline therapy are related to the individual's initial clinical presentation and relapse-risk score at diagnosis; however, these risks are now quite low even in high-risk patients as long as appropriate therapy is initiated expeditiously. Multiple European and North American trials have investigated risk-adapted approaches to the treatment of APL and have reported high success rates. Further refinement of risk-adapted strategies is ongoing and will likely contribute to better patient care. A roundtable conference was conducted to discuss risk-adapted therapy for APL and to develop a consensus statement and approach for clinical oncologists. Expert opinions and evidence-based strategies presented during the roundtable are summarized herein.