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Mindy L Simpson,1 Roshni Kulkarni,2 Carmen Escuriola Ettingshausen,3 Rikke Medom Meldgaard,4 David L Cooper,5 Robert Klamroth6 1Pediatric Hematology/Oncology, Rush University Medical Center, Chicago, IL, USA; 2Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA; 3HZRM – Haemophilia Centre Rhein-Main, Frankfurt-Mörfelden, Mörfelden-Walldorf, Germany; 4Novo Nordisk A/S, Søborg, Denmark; 5Novo Nordisk Inc, Plainsboro, NJ, USA; 6Department for Internal Medicine, Vascular Medicine and Haemostaseology, Vivantes Klinikum, Berlin, GermanyCorrespondence: Mindy L SimpsonPediatric Hematology/Oncology, Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612, USATel +1 312 563 3995Email Mindy_L_Simpson@rush.eduAim/objective: Understanding pharmacokinetic (PK) differences between standard and extended half-life (EHL) products is important, particularly for factor IX (FIX), where differences are more significant than for factor VIII. Two single-dose PK trials showed N9-GP achieves higher FIX levels and greater area-under-the-curve than pdFIX, rFIX, and rFIXFc through higher recovery and longer terminal half-life. In paradigm 7, N9-GP demonstrated consistently favorable PK characteristics compared with rFIXFc. Collins et al explored population PK differences between N9-GP and pdFIX/rFIX based upon paradigm 1 data. This analysis uses population PK models based upon the paradigm 7 trial.Methods: 15 patients (21–65 years) with hemophilia B received single 50-IU/kg doses of N9-GP and rFIXFc ≥21 days apart. A population PK model developed from single-dose PK profiles simulated plasma FIX activity following dosing for surgery and on-demand treatment of bleeds. Simulations explored doses and frequencies required to sustain target World Federation of Hemophilia (WFH) factor activity levels.Results: PK profiles of N9-GP and rFIXFc were described by one- and three-compartment models, respectively. Simulations predicted significantly reduced dosing frequency and consumption for N9-GP than rFIXFc. For severe bleeds, a single N9-GP dose (80 IU/kg) is sufficient to maintain WFH-recommended FIX levels, whereas multiple rFIXFc doses are required. For surgery, redosing in the first week with N9-GP is modeled at day 6 vs rFIXFc dosing at 6, 30, 54, 78, and 126 hrs. For life-threatening bleeds, N9-GP is required at days 0, 3, 6, 13, and 18 vs rFIXFc redosing after 6 hrs with 10 additional doses at 24-, 48-, and 72 hr intervals.Conclusion: PK modeling approaches based upon direct comparative studies offer insights into PK differences between EHL FIX products. Model simulations show N9-GP may allow on-demand treatment and perioperative management with 55–75% fewer injections and 65–74% lower overall factor concentrate consumption than rFIXFc.Keywords: N9-GP, rFIXFc, population PK modeling, paradigm 7 trial

© 2015 Dar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Pro

It has long been hypothesized that behavioral reactions to epidemic severity autoregulate infection dynamics, for example when susceptible individuals self-sequester based on perceived levels of circulating disease. However, evidence for such 'behavioral autorepression' has remained elusive, and its presence could significantly affect epidemic forecasting and interventions. Here, we analyzed early COVID-19 dynamics at 708 locations over three epidemiological scales (96 countries, 50 US states, and 562 US counties). Signatures of behavioral autorepression were identified through: (i) a counterintuitive mobility-death correlation, (ii) fluctuation-magnitude analysis, and (iii) dynamics of SARS-CoV-2 infection waves. These data enabled calculation of the average behavioral-autorepression strength (i.e., negative feedback 'gain') across different populations. Surprisingly, incorporating behavioral autorepression into conventional models was required to accurately forecast COVID-19 mortality. Models also predicted that the strength of behavioral autorepression has the potential to alter the efficacy of non-pharmaceutical interventions. Overall, these results provide evidence for the long-hypothesized existence of behavioral autorepression, which could improve epidemic forecasting and enable more effective application of non-pharmaceutical interventions during future epidemics., Significance: Challenges with epidemiological forecasting during the COVID-19 pandemic suggested gaps in underlying model architecture. One long-held hypothesis, typically omitted from conventional models due to lack of empirical evidence, is that human behaviors lead to intrinsic negative autoregulation of epidemics (termed 'behavioral autorepression'). This omission substantially alters model forecasts. Here, we provide independent lines of evidence for behavioral autorepression during the COVID-19 pandemic, demonstrate that it is sufficient to explain counterintuitive data on 'shutdowns', and provides a mechanistic explanation of why early shutdowns were more effective than delayed, high-intensity shutdowns. We empirically measure autorepression strength, and show that incorporating autorepression dramatically improves epidemiological forecasting. The autorepression phenomenon suggests that tailoring interventions to specific populations may be warranted.

Background: The current study is a case study of a Māori (Indigenous people of New Zealand) organisation and their developmental processes in creating a kaumātua (older people) housing village for health and social wellbeing. This study identifies how a set of established co-design and culturally-centred principles were enacted when creating and developing the village., Method: A mixed-method concurrent design was used in creating the case with interviews (n = 4), focus groups (N = 4 with 16 total participants) and survey questionnaires (n = 56) involving kaumātua and organisation members., Results: Survey results illustrate that suitable and affordable housing are associated with self-rated health, loneliness, and life satisfaction. The primary purpose of the housing village was to enable kaumātua to be connected to the marae (community meeting house) as part of a larger vision of developing intergenerational housing around the marae to enhance wellbeing. Further, key themes around visioning, collaborative team and funding, leadership, fit-for-purpose design, and tenancy management were grounded in cultural elements using te ao Māori (Māori worldview)., Conclusion: This case study illustrates several co-design and culturally-centred principles from a previously developed toolkit that supported the project. This case study demonstrates how one community enacted these principles to provide the ground for developing a housing project that meets the health and social wellbeing of kaumātua., (© 2024. The Author(s).)

Exogenous antithrombin III (AT3) may be administered to pediatric patients supported by extracorporeal membrane oxygenation (ECMO) to achieve a greater systemic response to heparin. Antithrombin III administration and dosing practices vary between ECMO centers. This study compared the outcomes of two different AT3 replacement protocols used by a single pediatric ECMO center for 47 patients between December 2013 and August 2021. In May 2016, a weight-based continuous infusion protocol (WBP) was transitioned to a vial-sparing protocol (VSP) as a cost-saving measure. No difference was observed in the percentage of heparin monitoring levels within goal range, with a median of 56.5% therapeutic levels on the WBP compared with a median of 60.7% on the VSP ( p = 0.170). No significant differences were observed in amount of exogenous blood products administered, number of hemorrhagic or thrombotic events, number of mechanical failures, or number of circuit changes required. The VSP resulted in fewer AT3 dispenses ( p < 0.001) and units dispensed ( p = 0.005), resulting in a significant median cost reduction from $15,610.62 on the WBP to $7,765.56 on the VSP ( p = 0.005). A vial-sparing AT3 replacement protocol resulted in significant cost savings with similar efficacy and safety outcomes., Competing Interests: Disclosure: The views expressed in the submitted article are those of the authors and not an official position of the institution(s) which they represent. This article did not receive any sources of support including funding from a sponsor. The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Background: The study offers baseline data for a strengths-based approach emphasizing intergenerational cultural knowledge exchange and physical activity developed through a partnership with kaumātua (Māori elders) and kaumātua service providers. The study aims to identify the baseline characteristics, along with correlates of five key outcomes., Methods: The study design is a cross-sectional survey. A total of 75 kaumātua from six providers completed two physical functioning tests and a survey that included dependent variables based in a holistic model of health: health-related quality of life (HRQOL), self-rated health, spirituality, life satisfaction, and loneliness., Results: The findings indicate that there was good reliability and moderate scores on most variables. Specific correlates included the following: (a) HRQOL: emotional support ( β = 0.31), and frequent interaction with a co-participant ( β = 0.25); (b) self-rated health: frequency of moderate exercise ( β = 0.32) and sense of purpose ( β = 0.27); (c) spirituality: sense of purpose ( β = 0.46), not needing additional help with daily tasks ( β = 0.28), and level of confidence with cultural practices ( β = 0.20); (d) life satisfaction: sense of purpose ( β = 0.57), frequency of interaction with a co-participant ( β = -0.30), emotional support ( β = 0.25), and quality of relationship with a co-participant ( β = 0.16); and (e) lower loneliness: emotional support ( β = 0.27), enjoyment interacting with a co-participant ( β = 0.25), sense of purpose ( β = 0.24), not needing additional help with daily tasks ( β = 0.28), and frequency of moderate exercise ( β = 0.18)., Conclusion: This study provides the baseline scores and correlates of important social and health outcomes for the He Huarahi Tautoko (Avenue of Support) programme, a strengths-based approach for enhancing cultural connection and physical activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oetzel, Zhang, Nock, Meha, Huriwaka, Vercoe, Tahu, Urlich, Warbrick, Brown, Keown, Rewi, Erueti, Warbrick, Jackson, Perry, Reddy, Simpson, Cameron and Hokowhitu.)

Introduction: In recent years, there has been increased focus on individualizing treatment for persons with hemophilia including pharmacokinetic-guided (PK) dosing., Aims: In this retrospective study clinical outcomes before and after PK-guided prophylaxis were examined., Materials and Methods: Eight Haemophilia Treatment Centres from the United States participated in the study and included 132 patients classified into two cohorts: those undergoing a PK-assessment for product switch (switchers) or to optimize treatment (non-switchers). Subset analyses for the two most common products and patients with dosing per prescription label were included for annual bleeding rates (ABR), mean weekly consumption outcomes, and annualized cost of prophylaxis., Results: The most common products before and after index date were octocog alfa, rurioctocog alfa pegol, and efmoroctocog alfa. Seventy-four (56%) patients were identified as switchers and 58 (44%) patients were classified as non-switchers. The majority of patients (78.0%) experienced either a decrease in ABR post-index or maintained 0 ABR during pre- and post-index time periods, with similar proportions identified in both switchers (77.0%) and non-switchers (79.3%) populations. Non-switchers were identified as having no significant change in cost of therapy, while switchers experienced increased cost of therapy driven by higher price of extended half-life products. Within subset analyses, patients receiving rurioctocog alfa pegol and efmoroctocog alfa had mean ABR under 1 after index date., Conclusion: PK-guided prophylaxis has the potential to improve clinical outcomes without increase in cost of therapy for patients maintaining product and can aid in maintaining effective protection against bleeds in those switching product., (© 2023 Takeda Pharmaceuticals USA, Inc and The Authors. Haemophilia published by John Wiley & Sons Ltd.)

For much of the history of deaf education, spoken language bilingualism was not considered a viable goal. It was believed that given the challenges of meaningful auditory access, age-appropriate development in even one language would be daunting. However, implementation of universal newborn hearing screening during the early 2000s, along with early fitting of hearing technologies, including cochlear implants, has afforded significantly improved access to spoken language during the critical early years of language acquisition for most deaf children. In this context, it is timely to reconsider the possibilities of spoken language bilingualism in the education of deaf students. The present article therefore focuses on examining the available literature with a view to summarizing current understandings and reflecting on how these understandings can inform future research and practice and the multiple ways in which bilingualism can be operationalized in the education of deaf students.

Objectives: This study examined a Māori (Indigenous people of Aotearoa New Zealand) age-friendly housing development. Two Māori community groups worked with multiple stakeholders to codesign a culture-centered, kaumātua (older adults) urban housing community. The purpose was to identify codesign and culture-centered principles in the development., Methods: Kaupapa Māori (Māori-centered) and participatory research methodologies guided the culture-centered research design. Data collection included 27 interviews with 19 residents and 12 organizational stakeholders; three focus groups with residents' families, service providers, and nonresident kaumātua (n = 16); and project documents. Data analysis used the framework method., Results: Three codesign process themes emerged: (a) Kaumātua-centered vision; (b) realizing the vision; and (c) living the shared vision., Discussion: Accounting for cultural practices in codesigning age-friendly and culture-centered housing for and with Indigenous older adults helps meet their cultural, social, health, and economic needs. The research offers a practical pathway to developing age-friendly housing environments for Māori kaumātua, their communities, wider society, and other Indigenous people., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Health inequities experienced by kaumātua (older Māori) in Aotearoa, New Zealand, are well documented. Examples of translating and adapting research into practice that identifies ways to help address such inequities are less evident. The study used the He Pikinga Waiora (HPW) implementation framework and the Consolidated Framework for Implementation Research (CFIR) to explore promising co-design and implementation practices in translating an evidence-based peer-education programme for older Māori to new communities., Methods: The study was grounded in an Indigenous methodology (Kaupapa Māori) and a participatory research approach. Data were collected from research documentation, community meeting and briefing notes, and interviews with community researchers., Results: The data analysis resulted in several key promising practices: Kaumātua mana motuhake (kaumātua independence and autonomy) where community researchers centred the needs of kaumātua in co-designing the programme with researchers; Whanaungatanga (relationships and connectedness) which illustrated how community researchers' existing and emerging relationships with kaumātua, research partners, and each other facilitated the implementation process; and Whakaoti Rapanga (problem-solving) which centred on the joint problem-solving undertaken by the community and university researchers, particularly around safety issues. These results illustrate content, process, and relationship issues associated with implementation effectiveness., Conclusions: This study showed that relational factors are central to the co-design process and also offers an example of a braided river, or He Awa Whiria, approach to implementation. The study offers a valuable case study in how to translate, adapt, and implement a research-based health programme to Indigenous community settings through co-design processes., Trial Registration: The project was registered on 6 March 2020 with the Australia New Zealand Clinical Trial Registry: ACTRN12620000316909 . Prospectively registered., (© 2022. The Author(s).)

Cell-free protein synthesis is an important tool for studying gene expression and harnessing it for applications. In cells, gene expression is regulated in part by the spatial organization of transcription and translation. Unfortunately, current cell-free approaches are unable to control the organization of molecular components needed for gene expression, which limits the ability to probe and utilize its effects. Here, we show, using complementary computational and experimental approaches, that macromolecular crowding can be used to control the spatial organization and translational efficiency of gene expression in cell-sized vesicles. Computer simulations and imaging experiments reveal that, as crowding is increased, DNA plasmids become localized at the inner surface of vesicles. Ribosomes, in contrast, remain uniformly distributed, demonstrating that crowding can be used to differentially organize components of gene expression. We further carried out cell-free protein synthesis reactions in cell-sized vesicles and quantified mRNA and protein abundance. At sufficiently high levels of crowding, we observed localization of mRNA near vesicle surfaces, a decrease in translational efficiency and protein abundance, and anomalous scaling of protein abundance as a function of vesicle size. These results are consistent with high levels of crowding causing altered spatial organization and slower diffusion. Our work demonstrates a straightforward way to control the organization of gene expression in cell-sized vesicles and provides insight into the spatial regulation of gene expression in cells.

Background: There is growing interest in palliative care within Indigenous communities, and within Aotearoa New Zealand, of the significant role that Māori (Indigenous people) families play in caring for older relatives. This study explored the centrality of culture in how Māori extended families ( whānau ) in Aotearoa New Zealand interpret and enact family-based care roles within the Māori world ( Te Ao Māori )., Methods: Applying Māori-centered and community-based participatory research principles, we examined 17 interviews with older Māori who shared experiences of palliative care for a partner or family member. The thematic analysis used a cultural-discursive framework incorporating Māori principles of wellbeing and values expressed within the care relationship., Results: The findings centered on three whānau roles in palliative care: whānau as (1) Holders and protectors of Māori knowledge; (2) Weavers of spiritual connection; and (3) Navigators in different worlds., Conclusion: The study problematizes the notion of a single 'primary caregiver', privileges whānau as an inter-woven relational, dynamic care network, and encourages health professionals to recognize the cultural embeddedness of dominant approaches to palliative care., Competing Interests: Competing interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: Knowledge of the challenges unpaid caregivers faced providing care to older people during the COVID-19 pandemic is limited. Challenges may be especially pronounced for those experiencing inequitable access to health and social care. This participatory action research study, located in New Zealand, has four main objectives, (i) to understand the challenges and rewards associated with caregiving to older care recipients during the COVID-19 pandemic restrictions; (ii) to map and collate resources developed (or mobilised) by organisations during the pandemic; (iii) to co-produce policy recommendations, identify useful caregiver resources and practices, prioritise unmet needs (challenges); and, (iv) to use project results in knowledge translation, in order to improve caregivers access to resources, and raise the profile and recognition of caregivers contribution to society., Methods and Analysis: Māori, Pacific and rural-dwelling caregivers to 30 older care-recipients, and 30 representatives from organisations supporting caregivers in New Zealand will be interviewed. Combining data from the interviews and caregivers letters (from an archive of older people's pandemic experiences), framework analysis will be used to examine the interrelated systems of the human ecological model and the impact on caregiving experiences during the pandemic. Resources that service providers had created or used for caregivers and older people will be collated and categorised. Through co-production with caregivers and community partners we will produce three short films describing caregivers' pandemic experiences; identify a suite of resources for caregivers to use in future events requiring self-isolation, and in everyday life; and generate ideas to address unresolved issues., Competing Interests: The authors have declared that no competing interest exist.

Hemophilia is an X-linked, recessive bleeding disorder. Improvements in factor replacement therapy and overall approach to hemophilia management have increased the lifespan and quality of life for patients with hemophilia. Thus, they are presenting for cardiac surgery related to age-related atherosclerosis, vascular disorders, and degenerative valvular disease. Although challenging, cardiac surgery can be performed safely with appropriate planning, using a multidisciplinary approach. This article provides a narrative review and framework for the perioperative management of patients with hemophilia A and B undergoing cardiac surgery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Māori kaumātua (elders) face stark health and social inequities compared to non-Māori New Zealanders. The tuakana-teina (older sibling-younger sibling) peer education programme is a strengths-based approach to enhance well-being and social connectedness. The purpose of this study is to present the baseline data from this programme and identify correlates of well-being outcomes. Method: Participants included 128 kaumātua who completed a self-report survey about health-related quality of life, spirituality, social connection and loneliness, life satisfaction, cultural identity and connection, elder abuse, health service utilisation and demographics. Findings: Multiple regression models illustrated the following correlates of outcomes: (a) self-rated health: needing more help with daily tasks (β = -0.36) and housing problems (β = -0.17); (b) health-related quality of life: needing more help with daily tasks (β = -0.31), housing problems (β = -0.21), and perceived autonomy (β = 0.19); (c) spiritual well-being: understanding of tikanga (cultural protocols) (β = 0.32) and perceived autonomy (β = 0.23); (d) life satisfaction: social support (β = 0.23), sense of purpose (β = 0.23), cultural identity (β = 0.24), trouble paying bills (β = -0.16), and housing problems (β = -0.16); (e) loneliness: elder abuse (β = 0.27), social support (β = -0.21), and missing pleasure of being with whānau (extended family) (β = 0.19). Conclusions: Key correlates for outcomes centred on social support, housing problems, cultural connection and perceived autonomy. These correlates are largely addressed through the programme where tuakana/peer educators provide support and links to social and health services to teina/peer recipients in need. This study illustrates needs and challenges for kaumātua, whilst the larger programme represents a strengths-based and culturally-centred approach to address health issues related to ageing in an Indigenous population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Oetzel, Ruru, Zhang, Simpson, Nock, Meha, Holmes, Clark, Adams, Akapita, Ngaia, Murphy, Moses, Reddy and Hokowhitu.)

As unpaid family caregiving of older adults becomes increasingly prevalent, it is imperative to understand how family caregivers are socialized and how they understand the caregiving role. This PRISMA-ScR-based scoping review examines the published literature between 1995-2019 on the socialization of potential and current unpaid family caregivers of older adults. Of 4,599 publications identified, 47 were included. Three perspectives of socialization were identified: (1) role acculturation ; (2) role negotiation and identification ; and (3) specialized role learning . The findings show how socialization involves different contexts (e.g., cultures), imperatives for action (e.g., circumstances), socialization agents (e.g., family), processes (e.g., modeling), and internal (e.g., normalization) and external (e.g., identification) consequences for caregivers. Future research could fruitfully explore how caregivers manage key turning points within the socialization process, disengage from the caregiving role, and negotiate the socialization and individualization processes within diverse cultural and funding contexts.

BAY 94-9027 (damoctocog alfa pegol, Jivi) is an extended-half-life recombinant factor VIII (rFVIII) shown to be well-tolerated and efficacious in bleeding prevention in previously treated patients with severe hemophilia A. During the PROTECT VIII study, prophylaxis patients received BAY 94-9027 at intervals determined based on their bleeding phenotype, observed during a 10-week run-in treatment period with twice-weekly dosing. Those with ≤ 1 spontaneous joint or muscle bleed were randomized to either 45 to 60 IU/kg every 5 days or 60 IU/kg every 7 days; patients could increase dosing frequency to every 5 days or twice weekly in the case of bleeds. Those enrolled after the randomization arms were full, and those with ≥ 2 bleeds in the run-in period, received 30 to 40 IU/kg twice weekly. Patients completing the main study could receive open-label BAY 94-9027 in the extension phase. Dosing regimen, total, and joint annualized bleeding rates were analyzed over three periods: prestudy, main study, and extension. A total of 80 patients who were on prophylaxis treatment prior to and during the study and had prior bleed data available were evaluated in this post hoc analysis of PROTECT VIII. Most patients (> 80%) required fewer infusions with BAY 94-9027 prophylaxis versus their previous standard-half-life (SHL) rFVIII product. Lower bleeding and joint bleeding rates were observed over time from the prestudy to the extension study period in all treatment regimens. Compared with SHL FVIII, BAY 94-9027 prophylaxis allows patients to reduce infusion frequency with maintained or improved protection from bleeds., Competing Interests: M.E.M. has received consultancy fees from Bayer Healthcare, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi, Shire, Octapharma, Kedrion, and Grifols. M.T.R. has received institutional research support from Bayer and BioMarin, and received honoraria for serving on advisory boards and speakers bureaus for Bayer, Novo Nordisk, Sanofi Genzyme, and Takeda. C.N. has received grant/research support, honoraria, or consultation fees from Alnylam, Baxalta/Shire, Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Roche, Pfizer, and Sobi. B.A.K. has received research support from CSL Behring and Novo Nordisk, and received honoraria for serving on advisory boards and speaker bureaus from Bayer, BioMarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, and Takeda. S.R. has received institutional research grants from Sangamo, and participated in speaker bureaus for Shire. M.L.S. has received institutional research grants from Bayer, Bioverativ/Sanofi, Daichii-Sankyo, Octapharma, Novo Nordisk, Baxalta (Shire, Takeda), and Roche (Genentech), and received honoraria and consultation fees from Bayer, BioMarin, Pfizer, Roche, Spark, and Novo Nordisk., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Macromolecular crowding is a feature of cellular and cell-free systems that, through depletion effects, can impact the interactions of semiflexible biopolymers with surfaces. In this work, we use computer simulations to study crowding-induced adsorption of semiflexible polymers on otherwise repulsive surfaces. Crowding particles are modeled explicitly, and we investigate the interplay between the bending stiffness of the polymer and the volume fraction and size of crowding particles. Adsorption to flat surfaces is promoted by stiffer polymers, smaller crowding particles, and larger volume fractions of crowders. We characterize transitions from non-adsorbed to partially and strongly adsorbed states as a function of bending stiffness. The crowding-induced transitions occur at smaller values of the bending stiffness as the volume fraction of crowders increases. Concomitant effects on the size and shape of the polymer are reflected by crowding- and stiffness-dependent changes to the radius of gyration. For various polymer lengths, we identify a critical crowding fraction for adsorption and analyze its scaling behavior in terms of polymer stiffness. We also consider crowding-induced adsorption in spherical confinement and identify a regime in which increasing the bending stiffness induces desorption. The results of our simulations shed light on the interplay of crowding and bending stiffness on the spatial organization of biopolymers in encapsulated cellular and cell-free systems.

Objective: The aim of this study was to examine ways that older Māori (New Zealand's Indigenous people) enhanced their ability to be peer educators and how this role impacted on their sense of purpose and well-being in later life., Method: Kaupapa Māori and community-based participatory research principles guided the peer intervention involving 26 Māori kaumātua (older people 55 years and older) as peer educators (tuakana) for 121 other kaumātua (teina) facing transitions in later life. Each pair held up to 3 conversations; independent coders rated tuakana communication skills. We used mixed methods in a pre- and post-test, clustered staggered design. Participants completed baseline and post-intervention assessments of health and well-being consistent with Māori worldviews. 5 focus groups involving 22 teina and 1 with 5 tuakana were held., Results: Tuakana communication skills were rated as high by teina and independent coders. Qualitative analysis supported the importance of Māori communication processes for the role. Further, three measures increased significantly from the baseline to the final period for tuakana accounting for about 15% of the variance in these variables: sense of purpose (p = .07), self-rated health (p = .05), and health-related quality of life (p = .04). The qualitative analysis supported the benefits of the peer educator role for older Māori including enhanced sense of identity, well-being, and social connectedness., Discussion: The results demonstrated that kaumātua had strong communication in the peer educator role and that the intervention has positive impacts for them. The study contributes to peer intervention research that may help to improve experiences ofIndigenous and other older people., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Health literacy (HL) and health numeracy (HN) are underestimated barriers to treatment adherence in patients with haemophilia., Aim: To test the ability of an educational intervention to improve knowledge, HL, HN, adherence and joint health in adolescent and young adult (AYA) males with haemophilia., Methods: We performed a longitudinal pilot study of 41 participants aged 12-21 years with haemophilia A or B during two clinic visits 6-12 months apart. The first visit included a comprehensive pre-intervention assessment: demographics, knowledge survey, Montreal Cognitive Assessment testing, 5-question tool to assess baseline HN, assessment of HL with the Rapid Estimate of Adolescent Literacy in Medicine tool, history of adherence and Haemophilia Joint Health Score (HJHS). An educational intervention using a visual aid explained basic pharmacokinetic (PK) concepts and personal teaching regarding haemophilia treatment regimens was used during this visit. The second visit included a post-intervention assessment: a reassessment of knowledge, HL, HN, HJHS, adherence to prescribed therapy and number of joint bleeds since the pre-intervention visit., Results: Forty-one males with haemophilia A or B were enrolled in the study. Of these, 33 completed the post-intervention assessment. Knowledge (p = .002) and HN (p = .05) were significantly improved post-intervention, although the HL, number of joint bleeds, adherence to prescribed therapy and HJHS were not., Conclusions: Participants with low HL and/or HN may benefit from alternate methods of education such as audiovisual material. Education using audiovisual materials improved knowledge and HN in this study; however, this did not affect adherence to prescribed therapy., (© 2021 John Wiley & Sons Ltd.)

Macromolecular crowding and the presence of surfaces can significantly impact the spatial organization of biopolymers. While the importance of crowding-induced depletion interactions in biology has been recognized, much remains to be understood about the effect of crowding on biopolymers such as DNA plasmids. A fundamental problem highlighted by recent experiments is to characterize the impact of crowding on polymer-polymer and polymer-surface interactions. Motivated by the need for quantitative insight, we studied flexible ring polymers in crowded environments using Langevin dynamics simulations. The simulations demonstrated that crowding can lead to compaction of isolated ring polymers and enhanced interactions between two otherwise repulsive polymers. Using umbrella sampling, we determined the potential of mean force (PMF) between two ring polymers as a function of their separation distance at different volume fractions of crowding particles, φ. An effective attraction emerged at φ≈ 0.4, which is similar to the degree of crowding in cells. Analogous simulations showed that crowding can lead to strong adsorption of a ring polymer to a wall, with an effective attraction to the wall emerging at a smaller volume fraction of crowders (φ≈ 0.2). Our results reveal the magnitude of depletion interactions in a biologically-inspired model and highlight how crowding can be used to tune interactions in both cellular and cell-free systems.

Background: The Aotearoa New Zealand population is ageing accompanied by health and social challenges including significant inequities that exist between Māori and non-Māori around poor ageing and health. Although historically kaumātua (elder Māori) faced a dominant society that failed to realise their full potential as they age, Māori culture has remained steadfast in upholding elders as cultural/community anchors. Yet, many of today's kaumātua have experienced 'cultural dissonance' as the result of a hegemonic dominant culture subjugating an Indigenous culture, leading to generations of Indigenous peoples compelled or forced to dissociate with their culture. The present research project, Kaumātua Mana Motuhake Pōī (KMMP) comprises two interrelated projects that foreground dimensions of wellbeing within a holistic Te Ao Māori (Māori epistemology) view of wellbeing. Project 1 involves a tuakana-teina/peer educator model approach focused on increasing service access and utilisation to support kaumātua with the greatest health and social needs. Project 2 focuses on physical activity and cultural knowledge exchange (including te reo Māori--Māori language) through intergenerational models of learning., Methods: Both projects have a consistent research design and common set of methods that coalesce around the emphasis on kaupapa kaumatua; research projects led by kaumātua and kaumātua providers that advance better life outcomes for kaumātua and their communities. The research design for each project is a mixed-methods, pre-test and two post-test, staggered design with 2-3 providers receiving the approach first and then 2-3 receiving it on a delayed basis. A pre-test (baseline) of all participants will be completed. The approach will then be implemented with the first providers. There will then be a follow-up data collection for all participants (post-test 1). The second providers will then implement the approach, which will be followed by a final data collection for all participants (post-test 2)., Discussion: Two specific outcomes are anticipated from this research; firstly, it is hoped that the research methodology provides a framework for how government agencies, researchers and relevant sector stakeholders can work with Māori communities. Secondly, the two individual projects will each produce a tangible approach that, it is anticipated, will be cost effective in enhancing kaumātua hauora and mana motuhake., Trial Registration: Australia New Zealand Clinical Trial Registry ( ACTRN12620000316909 ). Registered 6 March 2020.

Background: Patients with hemophilia A are commonly treated with replacement recombinant factor VIII (rFVIII) products, which can be standard-acting or long-acting. Long-acting products have modifications, offering the potential for reduced dosing frequency while maintaining therapeutic benefit. Extended dosing intervals reduce patient burden and can improve quality of life and adherence., Objective: To assess real-world data for the use of 6 commonly prescribed standard-acting and long-acting FVIII products in the United States: octocog alfa, BAY 14-2222, BAY 81-8973, rVIII-SingleChain, rFVIIIFc, and polyethylene glycol (PEG)-rFVIII. We summarized annualized bleeding rates (ABRs), dosing frequency, and factor consumption in patients treated with each product, with subgroup analyses for patients with severe disease., Methods: De-identified patient data were collected from 11 hemophilia treatment centers in the United States. Patients treated with octocog alfa, BAY 14-2222, BAY 81-8973, rVIII-SingleChain, rFVIIIFc, or PEG-rFVIII prophylaxis for ≥ 8 weeks at the time of data collection were included in the analysis. Among the 6 treatment groups, matching was attempted for patient age and disease severity where possible., Results: Data were obtained for 240 patients, of whom 191 patients had severe disease. Patients receiving long-acting FVIII products were dosed less frequently than those receiving standard-acting FVIII products. The proportion of patients dosed 2 times weekly or less was 65.0%, 70.0%, 72.5%, 25.0%, 40.0%, and 47.5% with rVIII-SingleChain, rFVIIIFc, PEG-rFVIII, octocog alfa, BAY 14-2222, and BAY 81-8973, respectively. Median ABRs ranged from 2.0 to 3.0 (mean 2.6 to 4.4) across the 6 products for all patients and were similar for patients with severe disease (median 2.0 to 3.0 and mean 2.5 to 4.8). The proportion of patients experiencing 0 bleeding episodes ranged from 7.5% to 25.0% for all patients and 12.0% to 28.6% for patients with severe disease. For all patients, median (mean) weekly FVIII product consumption was lowest for rVIII-SingleChain among the 6 products ( P = 0.045); 91.9 (91.1) IU per kg per week for rVIII-SingleChain, 108.5 (103.6) for rFVIIIFc, 97.6 (111.0) for PEG-rFVIII, 114.0 (117.5) for octocog alfa, 102.5 (102.6) for BAY 14-2222, and 95.1 (100.7) for BAY 81-8973. Similar differences in weekly consumption among the 6 products were observed for patients with severe disease ( P = 0.014)., Conclusions: Real-world data demonstrate that long-acting products may be beneficial compared with standard-acting products because of reduced dosing frequency while maintaining effectiveness. The 6 products evaluated showed statistically comparable ABRs and percentage of patients with 0 bleeds for all patients including those with severe disease. rVIII-SingleChain demonstrated lowest mean consumption for all patients, as well as for patients with severe hemophilia A, which may lead to potential savings in health care costs., Disclosures: This study was funded by CSL Behring. Simpson reports consulting honoraria for participation in advisory boards for Bayer, CSL Behring, HEMA Biologics, Novo Nordisk, Octapharma, and Takeda and speakers bureau for Bayer and Novo Nordisk. Yan and Desai are employees of CSL Behring. Maro is an employee of Adivo Associates, which conducted the analyses for this study. Data were presented in part at the Hemostasis and Thrombosis Research Society; May 9-11, 2019; New Orleans, LA; at the International Society on Thrombosis and Haemostasis; July 6-10, 2019; Melbourne, Australia; and have been published in part in "Comparing Factor Use and Bleed Rates in U.S. Hemophilia A Patients Receiving Prophylaxis with 3 Different Long-Acting Recombinant Factor VIII Products," by Mindy L. Simpson, Vidhi Desai, Géraldine S. Maro, Songkai Yan ( J Manag Care Spec Pharm. 2020;26[4]:504-12).

Macromolecular crowding is known to modulate chemical equilibria, reaction rates, and molecular binding events, both in aqueous solutions and at lipid bilayer membranes, natural barriers that enclose the crowded environments of cells and their subcellular compartments. Previous studies on the effects of macromolecular crowding in aqueous compartments on conduction through membranes have focused on single-channel ionic conduction through previously formed pores at thermodynamic equilibrium. Here, the effects of macromolecular crowding on the mechanism of pore formation itself were studied using the droplet interface bilayer (DIB) technique with the voltage-dependent pore-forming peptide alamethicin (alm). Macromolecular crowding was varied using 8 kDa molecular weight polyethylene glycol (PEG8k) or 500 kDa dextran (DEX500k) in two aqueous droplets on both sides of the bilayer membrane. In general, voltage thresholds for pore formation in the presence of crowders in the droplets decreased compared to their values in the absence of crowders, due to excluded volume effects, water binding by PEG, and changes in the ordering of water molecules and hydrogen-bonding interactions involving the polar lipid headgroups. In addition, asymmetric crowder loading (e.g., PEG8k-DEX500k on either side of the membrane) resulted in transmembrane osmotic pressure gradients that either enhanced or degraded the ionic conduction through the pores.

Introduction: BAY 94-9027 is a newly developed extended half-life product to treat haemophilia, allowing for fewer injections than with standard products. This post hoc analysis aimed to compare physicians' and patients' opinions on BAY 94-9027 prophylaxis, and explore how qualitative interview data is aligned with the data from the Haemophilia-specific Quality of Life questionnaire for Adults (Haemo-QoL-A)., Methods: Exploratory qualitative interviews were conducted with physicians and patients by phone upon the exit of patients from the PROTECT VIII extension phase following a semi-directed guide. In this post hoc analysis, all transcripts were reviewed and reported concepts were compared to assess the level of concordance between physicians and patients. These qualitative data were compared with the Haemo-QoL-A mean global and subscale scores at baseline and end of main phase (36 weeks later)., Results: Ten physicians and 16 patients (mean age 47 years) from Israel, the Netherlands and the USA were interviewed. Significant improvements were reported by all physicians from baseline [e.g. lower frequency of bleeds (80%), improvement in emotional functioning (90%)], which is in concordance with patients' reports. The improved confidence reported by physicians cascaded to greater participation in various activities, resulting in a better perceived emotional state and a significant improvement on the Haemo-QoL-A emotional impact subscale score (p = 0.04) between baseline and end of main phase. Most physicians (80%) reported improvement in bleed frequency, as patients did (88%). Improvement in physical functioning or mobility was not consistently reported in this 8-month study., Conclusion: Interviewed physicians and patients generally agreed on the beneficial impact of BAY 94-9027, specifically regarding the increased level of self-confidence in patients and its subsequent positive impact on patients' lives. These findings supported the observed improvement on the Haemo-QoL-A emotional impact subscale. Overall, this study highlights the concordance between physician and patient perspective on the positive experience with BAY 94-9027.

Background: Aotearoa/New Zealand has a population that is ageing and there are challenges to health and social outcomes related to related to key life transitions (e.g., retirement, change in health conditions, loss of spouse). Further, there are significant inequities between Māori (Indigenous people) and non-Māori in ageing outcomes. The purpose of this study was to test the impacts and cost effectiveness of a tuakana/teina (peer education) intervention on kaumātua (elders) receiving the intervention. This study was framed by a strengths-based approach based on the key cultural concept of mana motuhake (autonomy and self-actualisation)., Methods: This study was grounded in principles of Kaupapa Māori and community-based participatory research to bring together a diverse group of stakeholders to co-develop and co-evaluate the intervention. The intervention had tuakana (peer educators) having conversations with up to six teina (recipients) and providing information related to health and social services. The research design was a pre- and post-test, clustered staggered design. Participants completed a baseline assessment of health and mana motuhake measures consistent with Māori worldviews along with two follow-up assessments (one after the first intervention group completed its activities and a second after the second intervention group completed its activities). Additionally, five focus groups and open-ended questions on the assessments were used to provide qualitative evaluation., Findings: A total of 180 kaumātua were recruited to the intervention with 121 completing it. The analysis revealed improvements over time in the expected direction on most of the variables. However, only three of the variables had statistically significant intervention effects: received support, tribal identity, and trouble paying bills. Qualitative results supported impacts of the intervention on mana motuhake, social connectedness, and tangible/information support related to services. Cost-effectiveness analysis showed that the intervention is cost effective, with a cost per QALY of less than the conventional threshold of three times gross domestic product per capita., Conclusions: The findings support the relevancy and importance of kaumātua knowledge to create a strengths-based approach to improve health and social outcomes. This study demonstrates that a contextually based and culturally safe age-friendly environments can facilitate engagement and participation by kaumātua for kaumātua., Trial Registry: Australia New Zealand Clinical Trial Registry (ACTRN12617001396314); Date Registered: 3 October 2017 (retrospectively registered); https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373733&isClinicalTrial=False.

Background: Recombinant factor VIII (rFVIII) products have been developed with improved pharmacokinetics, offering some patients the potential to extend dosing intervals, thereby reducing their dosing frequency while minimizing the occurrence of bleeding events. No clinical trials have been conducted to compare the bleeding rates and use of these long-acting products., Objectives: To (a) assess real-world use of prophylaxis regimens in patients using 1 of 3 different long-acting products-rVIII-SingleChain, rFVIIIFc, or PEG-rFVIII; and (b) compare bleeding rates, dosing frequency, and factor consumption in 3 cohorts of patients. For rVIII-SingleChain patients, these measures were also compared with the prior products these patients used., Methods: De-identified patient chart data were collected from 11 hemophilia treatment centers in the United States. Patients were included if they had been treated with rVIII-SingleChain, rFVIIIFc, or PEG-rFVIII prophylaxis for ≥ 8 weeks at the time of data collection. Matching for age and disease severity was attempted between the 3 patient groups. Data were also collected for patients who switched from their prior FVIII product to prophylaxis with rVIII-SingleChain., Results: Data were obtained for 120 male patients. The majority of patients were dosing 2 times per week or less frequently (rVIII-SingleChain 65.0%, rFVIIIFc 70.0%, and PEG-rFVIII 72.5%). Annualized bleeding rates were comparable among the 3 cohorts, with median (mean) values of 2.0 (2.6) with rVIII-SingleChain and rFVIIIFc, and 3.0 (3.7) with PEG-rFVIII. The overall median (mean) FVIII consumption in IU per kg per week (IU/kg/week) was 91.9 (91.1) with rVIII-SingleChain, 108.5 (103.6) with rFVIIIFc, and 97.6 (111.0) with PEG-rFVIII, resulting in expected mean annual consumption of 322,140 IU, 361,816 IU, and 373,100 IU, respectively, for a 70 kg patient aged ≥12 years. The mean consumption was significantly different among the 3 products for all patients ( P = 0.0164) and for those dosed 2 times per week ( P < 0.0001). Among patients infusing 2 times per week, median (mean) consumption with rVIII-SingleChain was 83.8 (81.2) IU/kg/week, compared with 109.6 (104.4) IU/kg/week for rFVIIIFc and 92.1 (91.5) IU/kg/week for PEG-rFVIII. Additionally, switching from prophylaxis with prior FVIII products to rVIII-SingleChain increased the proportion of patients dosing ≤ 2 times per week (20% to 65%), decreased mean consumption (103.3 to 91.9 IU/kg/week; P = 0.0164), and maintained the mean annualized bleeding rates (2.9 to 2.6; P = 0.5665)., Conclusions: Results for rVIII-SingleChain confirm the findings from its pivotal trial. Analyses of annualized bleeding rates demonstrate comparable clinical outcomes of rVIII-SingleChain to the other 2 long-acting products assessed. In patients aged ≥ 12 years, rVIII-SingleChain prophylaxis may result in an 11.0% and 13.7% lower mean factor consumption than rFVIIIFc and PEG-rFVIII, respectively, representing a potential cost-saving opportunity of 34% in both cases-at the current wholesale acquisition cost of the corresponding products. In addition, in patients using rVIII-SingleChain prophylactically, consumption was reduced compared with their prior products, while bleeding control was well maintained., Disclosures: This study was funded by CSL Behring. Analyses were conducted by Adivo Associates. Maro is an employee of Adivo Associates. Desai and Yan are employees of CSL Behring. Simpson has received consulting honoraria for participation in advisory boards for CSL Behring, Genentech, Octapharma, and Bioverativ and speakers bureau for Bayer and Novo Nordisk. Data were presented in part at the Hemostasis and Thrombosis Research Society; May 9-11, 2019; New Orleans, LA, and at the International Society on Thrombosis and Haemostasis; July 6-10, 2019; Melbourne, Australia.

Objective: Considerable research indicates that individuals with dementia have deficits in the ability to recognize emotion in other people. The present study examined ability to detect emotional qualities of objects., Method: Fifty-two patients with frontotemporal dementia (FTD), 20 patients with Alzheimer's disease (AD), 18 patients awaiting surgery for intractable epilepsy, and 159 healthy controls completed a newly developed test of ability to recognize emotional qualities of art (music and paintings), and pleasantness in simple sensory stimuli (tactile, olfactory, auditory), and to make aesthetic judgments (geometric shapes, room décor). A subset of participants also completed a test of ability to recognize emotions in other people., Results: Patients with FTD showed a marked deficit in ability to recognize the emotions conveyed in art, compared with both healthy individuals and patients with AD (relative to controls, deficits in patients with AD only approached significance). This deficit remained robust after controlling for FTD patients' ability to recognize pleasantness in simple sensory stimuli, make aesthetic judgments, identify odors, and identify emotions in other people. Neither FTD nor AD patients showed deficits in recognizing pleasant sensory stimuli or making aesthetic judgments. Exploratory analysis of patients with epilepsy revealed no deficits in any of these domains., Conclusion: Patients with FTD (but not AD) showed a significant, specific deficit in ability to interpret emotional messages in art, echoing FTD-related deficits in recognizing emotions in other people. This finding adds to our understanding of the impact these diseases have on the lives of patients and their caregivers. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background and Objective: Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are extended half-life rFIX compounds. We report the first single-dose pharmacokinetic trial of N9-GP and rFIXFc., Patients/methods: Paradigm 7 was a multicenter, open-label, randomized, crossover trial in previously treated (>150 exposure days) adults with congenital hemophilia B (FIX activity ≤2%). Patients received single intravenous injections (50 IU/kg) of N9-GP and rFIXFc with at least 21 days between doses. Plasma FIX activity, predose, and at serial time points up to 240 hours postdose, was measured using validated one-stage clotting assays (SynthAFax for N9-GP; Actin FSL for rFIXFc) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity-time curve from 0 to infinity, dose-normalized to 50 IU/kg (AUC 0-inf,norm )., Results: Fifteen patients received study treatment. Based on FIX activity results from the one-stage clotting assays, estimated AUC 0-inf,norm was significantly greater for N9-GP than rFIXFc (ratio: 4.39; P  <   0.0001, based on a two-sided test on 5% significance level). In addition, N9-GP had a longer terminal half-life, two times higher incremental recovery at 30 minutes and maximum FIX activity (dose-normalized to 50 IU/kg) and six times higher FIX activity at 168 hours than rFIXFc. These findings were largely comparable with the chromogenic assay data and are consistent with published data for each compound., Conclusions: In this comparison, N9-GP demonstrated favorable pharmacokinetic characteristics versus rFIXFc, helping clinicians to understand differences between N9-GP and rFIXFc., Registration: This trial is registered with clinicaltrials.gov (NCT03075670) and the European Clinical Trials Database (EudraCT: 2016-001149-25).

Transcription is an episodic process characterized by probabilistic bursts, but how the transcriptional noise from these bursts is modulated by cellular physiology remains unclear. Using simulations and single-molecule RNA counting, we examined how cellular processes influence cell-to-cell variability (noise). The results show that RNA noise is higher in the cytoplasm than the nucleus in ∼85% of genes across diverse promoters, genomic loci, and cell types (human and mouse). Measurements show further amplification of RNA noise in the cytoplasm, fitting a model of biphasic mRNA conversion between translation- and degradation-competent states. This multi-state translation-degradation of mRNA also causes substantial noise amplification in protein levels, ultimately accounting for ∼74% of intrinsic protein variability in cell populations. Overall, the results demonstrate how noise from transcriptional bursts is intrinsically amplified by mRNA processing, leading to a large super-Poissonian variability in protein levels., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Diverse biological systems utilize fluctuations ("noise") in gene expression to drive lineage-commitment decisions. However, once a commitment is made, noise becomes detrimental to reliable function, and the mechanisms enabling post-commitment noise suppression are unclear. Here, we find that architectural constraints on noise suppression are overcome to stabilize fate commitment. Using single-molecule and time-lapse imaging, we find that-after a noise-driven event-human immunodeficiency virus (HIV) strongly attenuates expression noise through a non-transcriptional negative-feedback circuit. Feedback is established through a serial cascade of post-transcriptional splicing, whereby proteins generated from spliced mRNAs auto-deplete their own precursor unspliced mRNAs. Strikingly, this auto-depletion circuitry minimizes noise to stabilize HIV's commitment decision, and a noise-suppression molecule promotes stabilization. This feedback mechanism for noise suppression suggests a functional role for delayed splicing in other systems and may represent a generalizable architecture of diverse homeostatic signaling circuits., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Recent superresolution microscopy studies in E. coli demonstrate that the cytoplasm has highly variable local concentrations where macromolecular crowding plays a central role in establishing membrane-less compartmentalization. This spatial inhomogeneity significantly influences molecular transport and association processes central to gene expression. Yet, little is known about how macromolecular crowding influences gene expression bursting-the episodic process where mRNA and proteins are produced in bursts. Here, we simultaneously measured mRNA and protein reporters in cell-free systems, showing that macromolecular crowding decoupled the well-known relationship between fluctuations in the protein population (noise) and mRNA population statistics. Crowded environments led to a 10-fold increase in protein noise even though there were only modest changes in the mRNA population and fluctuations. Instead, cell-like macromolecular crowding created an inhomogeneous spatial distribution of mRNA ("spatial noise") that led to large variability in the protein production burst size. As a result, the mRNA spatial noise created large temporal fluctuations in the protein population. These results highlight the interplay between macromolecular crowding, spatial inhomogeneities, and the resulting dynamics of gene expression, and provide insights into using these organizational principles in both cell-based and cell-free synthetic biology.

Introduction: Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis., Aim: Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs)., Methods: A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 μg/kg or 225 μg/kg initial doses with 75 μg/kg subsequent doses by schedule were administered until clinical response., Results: The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 μg/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 μg/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins., Conclusion: The dose-dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population., (© 2017 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Fundamental to biological decision-making is the ability to generate bimodal expression patterns where 2 alternate expression states simultaneously exist. Here, we use a combination of single-cell analysis and mathematical modeling to examine the sources of bimodality in the transcriptional program controlling HIV's fate decision between active replication and viral latency. We find that the HIV transactivator of transcription (Tat) protein manipulates the intrinsic toggling of HIV's promoter, the long terminal repeat (LTR), to generate bimodal ON-OFF expression and that transcriptional positive feedback from Tat shifts and expands the regime of LTR bimodality. This result holds for both minimal synthetic viral circuits and full-length virus. Strikingly, computational analysis indicates that the Tat circuit's noncooperative "nonlatching" feedback architecture is optimized to slow the promoter's toggling and generate bimodality by stochastic extinction of Tat. In contrast to the standard Poisson model, theory and experiment show that nonlatching positive feedback substantially dampens the inverse noise-mean relationship to maintain stochastic bimodality despite increasing mean expression levels. Given the rapid evolution of HIV, the presence of a circuit optimized to robustly generate bimodal expression appears consistent with the hypothesis that HIV's decision between active replication and latency provides a viral fitness advantage. More broadly, the results suggest that positive-feedback circuits may have evolved not only for signal amplification but also for robustly generating bimodality by decoupling expression fluctuations (noise) from mean expression levels.

Objectives: To evaluate the safety of outpatient induction with dinoprostone insert in low-risk labour inductions for premature rupture of membranes or postdates gestation., Methods: This retrospective cohort study compared outpatient labour induction priming with inpatient induction in terms of neonatal safety, mode of delivery, and obstetrical parameters. The sample included all inductions for premature rupture of membranes or postdate gestation. The analysis used logistic regression. The statistical power of the sample was 80% to detect a difference of 5.6% for the composite neonatal safety outcome (5-minute Apgar score <7 and NICU admission for >12 hours or transfer to a level III nursery)., Results: Compared with the inpatient cohort (n = 568), the outpatient cohort (n = 611) included more postdate gestations (93% vs. 67%) with less cervical dilatation (0.5 cm vs. 1.0 cm) and larger infants (3705 g vs. 3551 g). There were no differences in measures of neonatal safety or mode of delivery. The outpatient cohort required more dinoprostone inserts (1.59 vs. 1.23) and were less likely to deliver within 24 hours (OR 0.24, 95% CI 0.17 to 0.34) but were also less likely to deliver by CS (OR 0.71, 95% CI 0.54 to 0.95), after adjusting for obstetrical parameters., Conclusion: An outpatient model of labour induction using dinoprostone inserts is feasible and safe., (Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Episodic gene expression, with periods of high expression separated by periods of no expression, is a pervasive biological phenomenon. This bursty pattern of expression draws from a finite reservoir of expression machinery in a highly time variant way, i.e., requiring no resources most of the time but drawing heavily on them during short intense bursts, that intimately links expression bursting and resource sharing. Yet, most recent investigations have focused on specific molecular mechanisms intrinsic to the bursty behavior of individual genes, while little is known about the interplay between resource sharing and global expression bursting behavior. Here, we confine Escherichia coli cell extract in both cell-sized microfluidic chambers and lipid-based vesicles to explore how resource sharing influences expression bursting. Interestingly, expression burst size, but not burst frequency, is highly sensitive to the size of the shared transcription and translation resource pools. The intriguing implication of these results is that expression bursts are more readily amplified than initiated, suggesting that burst formation occurs through positive feedback or cooperativity. When extrapolated to prokaryotic cells, these results suggest that large translational bursts may be correlated with large transcriptional bursts. This correlation is supported by recently reported transcription and translation bursting studies in E. coli. The results reported here demonstrate a strong intimate link between global expression burst patterns and resource sharing, and they suggest that bursting plays an important role in optimizing the use of limited, shared expression resources.

Low utilization of palliative care services by Māori remains despite increases in services designed to meet Māori needs. The purpose of this study is to explore palliative care information brochures in the context of Māori principles of well-being and communication protocols, and health literacy. We examined 99 brochures from palliative care services in New Zealand and held two focus groups with 12 Māori elders (kaumātua) and extended family (whanau) members. Taking a cultural-discursive approach incorporating Māori worldviews, we analysed textual and conceptual features of the brochures. The findings centred on cultural connection and disconnection within the brochures and serve as a critique of the prominent messages currently presented in these brochures. The findings raise questions about the capacity of agencies to convey culturally resonant messages to kaumātua and their whānau. We identify implications of palliative care brochures for health literacy of provider organizations as well as kaumātua and whanau., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Recent analysis demonstrates that the HIV-1 Long Terminal Repeat (HIV LTR) promoter exhibits a range of possible transcriptional burst sizes and frequencies for any mean-expression level. However, these results have also been interpreted as demonstrating that cell-to-cell expression variability (noise) and mean are uncorrelated, a significant deviation from previous results. Here, we re-examine the available mRNA and protein abundance data for the HIV LTR and find that noise in mRNA and protein expression scales inversely with the mean along analytically predicted transcriptional burst-size manifolds. We then experimentally perturb transcriptional activity to test a prediction of the multiple burst-size model: that increasing burst frequency will cause mRNA noise to decrease along given burst-size lines as mRNA levels increase. The data show that mRNA and protein noise decrease as mean expression increases, supporting the canonical inverse correlation between noise and mean.

The structure and function of microbial communities is deeply influenced by the physical and chemical architecture of the local microenvironment and the abundance of its community members. The complexity of this natural parameter space has made characterization of the key drivers of community development difficult. In order to facilitate these characterizations, we have developed a microwell platform designed to screen microbial growth and interactions across a wide variety of physical and initial conditions. Assembly of microbial communities into microwells was achieved using a novel biofabrication method that exploits well feature sizes for control of innoculum levels. Wells with incrementally smaller size features created populations with increasingly larger variations in inoculum levels. This allowed for reproducible growth measurement in large (20 μm diameter) wells, and screening for favorable growth conditions in small (5, 10 μm diameter) wells. We demonstrate the utility of this approach for screening and discovery using 5 μm wells to assemble P. aeruginosa colonies across a broad distribution of innoculum levels, and identify those conditions that promote the highest probability of survivial and growth under spatial confinement. Multi-member community assembly was also characterized to demonstrate the broad potential of this platform for studying the role of member abundance on microbial competition, mutualism and community succession.

Protein noise measurements are increasingly used to elucidate biophysical parameters. Unfortunately noise analyses are often at odds with directly measured parameters. Here we show that these inconsistencies arise from two problematic analytical choices: (i) the assumption that protein translation rate is invariant for different proteins of different abundances, which has inadvertently led to (ii) the assumption that a large constitutive extrinsic noise sets the low noise limit in gene expression. While growing evidence suggests that transcriptional bursting may set the low noise limit, variability in translational bursting has been largely ignored. We show that genome-wide systematic variation in translational efficiency can-and in the case of E. coli does-control the low noise limit in gene expression. Therefore constitutive extrinsic noise is small and only plays a role in the absence of a systematic variation in translational efficiency. These results show the existence of two distinct expression noise patterns: (1) a global noise floor uniformly imposed on all genes by expression bursting; and (2) high noise distributed to only a select group of genes.

Cell-free systems provide a flexible platform for probing specific networks of biological reactions isolated from the complex resource sharing (e.g., global gene expression, cell division) encountered within living cells. However, such systems, used in conventional macro-scale bulk reactors, often fail to exhibit the dynamic behaviors and efficiencies characteristic of their living micro-scale counterparts. Understanding the impact of internal cell structure and scale on reaction dynamics is crucial to understanding complex gene networks. Here we report a microfabricated device that confines cell-free reactions in cellular scale volumes while allowing flexible characterization of the enclosed molecular system. This multilayered poly(dimethylsiloxane) (PDMS) device contains femtoliter-scale reaction chambers on an elastomeric membrane which can be actuated (open and closed). When actuated, the chambers confine Cell-Free Protein Synthesis (CFPS) reactions expressing a fluorescent protein, allowing for the visualization of the reaction kinetics over time using time-lapse fluorescent microscopy. Here we demonstrate how this device may be used to measure the noise structure of CFPS reactions in a manner that is directly analogous to those used to characterize cellular systems, thereby enabling the use of noise biology techniques used in cellular systems to characterize CFPS gene circuits and their interactions with the cell-free environment.