A Platform for Sustainable Scale: The Challenge Initiative's Innovative Approach to Scaling Proven Interventions.

INTRODUCTION: The global health community continues to face barriers in scaling up evidence-based interventions for widespread adoption. Although many effective interventions have been developed over the years, expanding their reach to benefit broader populations has happened slowly or not at all. OVERVIEW: The Challenge Initiative (TCI) is a nontraditional development platform that supports local urban governments to rapidly scale up proven family planning (FP) and adolescent and youth sexual and reproductive health (AYSRH) interventions for the urban poor. TCI prioritizes sustainability and local ownership and uses a health systems approach when planning for and managing scale. TCI strengthens urban health systems with seed funding, coaching, and technical assistance (TA), and TCI University houses "how-to" guidance and tools for implementing the interventions. In turn, local governments commit political will and financial and human resources while using TCI coaching to integrate interventions into routine practice and systems to achieve widespread and sustained impact at scale. RESULTS: As of June 2021, TCI has supported 104 local governments across 11 countries in scaling up effective FP and AYSRH interventions, while also mobilizing about US$28 million from those local governments to facilitate their implementation. TCI has increased capacity and bolstered urban health systems, with 39 local governments "graduating" from TCI support and 2.02 million additional FP clients across 4 regional TA hubs. CONCLUSION: TCI aims to change how local governments coordinate, finance, and implement proven interventions to improve access to quality FP information and services. With built-in incentives for local governments, partners, and donors to participate, TCI is generating significant learning on how local governments can realize sustainable scale and demonstrating how organizations like TCI that facilitate governments to scale up effective interventions can accelerate the scale-up of these interventions across multiple geographies.

"Empowering Us": A community-led survey of real-world perspectives of adults with type 1 diabetes using insulin pumps and continuous glucose monitoring to manage their glucose levels.

OBJECTIVE: To conduct an Australian community-led survey of adults with type 1 diabetes (T1D), identifying priorities for, and barriers to, optimal use of advanced glucose management technologies. RESEARCH DESIGN AND METHODS: A 30-question online survey of current or past users of insulin pump therapy (IPT), real-time continuous glucose monitoring (RT-CGM), or intermittently scanned CGM (isCGM) explored perceptions regarding device design, access, education, outcomes, and support. RESULTS: Between November 2021 and January 2022, surveys were completed by 3,380 participants (age [mean ± SD] 45 ± 16 years; 62% female; 20 ± 14 years diabetes), with 55%, 82%, and 55% reporting experience with IPT, RT-CGM, and isCGM, respectively. Overall, most considered diabetes technology '(extremely) important' for maintaining target glucose levels (98%) and reducing hypoglycaemia severity and frequency (93%). For most, technology contributed positively to emotional well-being (IPT 89%; RT-CGM 91%; isCGM 87%), which was associated with device effectiveness in maintaining glucose in range, comfort, and convenience. Barriers included affordability (IPT 68%; RT-CGM 81%; isCGM 69%) and insufficient information for informed choices about device suitability (IPT 39%; RT-CGM 41%; isCGM 36%). CONCLUSIONS: Technology is perceived by adults with T1D as important for managing glycaemia and emotional well-being. Modifiable barriers to use include affordability, and information regarding device suitability.

Scaling Access to Contraception for Youth in Urban Slums: The Challenge Initiative's Systems-Based Multi-Pronged Strategy for Youth-Friendly Cities.

INTRODUCTION: More than half of all adolescents globally live in Asia, with India having the largest adolescent population in the world at 253 million. In sub-Saharan Africa, adolescents make up the greatest proportion of the population, with 23% of the population aged 10-19. And these numbers are predicted to grow rapidly-particularly in urban areas as rural youth migrate to cities for economic opportunities. While adolescents and youth are subject to high sexual and reproductive health risks, few efforts have been documented for addressing these in urban settings, especially in poor settlements. METHODS: The Challenge Initiative (TCI) is a demand-driven, family planning platform for sustainable scale and impact that lets city governments-in particular urban slums-lead implementation. It is currently active in 11 countries in Africa and Asia. In June 2018, TCI heightened its focus on adolescent and youth sexual and reproductive health (AYSRH) for youth living in urban slums. It now supports 39 city governments. TCI dedicates technical and program support to married (including first-time parents) and unmarried youth ages 15-24 years. Using an innovative coaching model and an online learning platform (TCI University), TCI supports city governments as they implement AYSRH interventions to accelerate the impact of TCI's model for rapid scale. RESULTS: TCI has been assessing the performance of cities implementing its AYSRH approaches using its RAISE tool and has found considerable improvement over two rounds of assessments through TCI coaching and support for adaptation of its high-impact interventions between the first and second round. CONCLUSIONS: TCI's AYSRH approach scaled rapidly to 39 cities and multiple urban slums since 2018, using its evidence-based interventions and coaching model. In the context of universal health coverage, TCI has supported segmented demand generation and improved access to quality and affordable contraceptive as well as youth-friendly health services. It provides a menu of interventions for cities to implement for youth-including such approaches as public-private partnerships with pharmacies and quality assurance using quick checklists-along with an innovative coaching model. This approach has facilitated greater access to contraceptive methods of choice for youth.

A customized allogenic bone block for alveolar reconstruction quantitated by a 3D matching technique: A case report.

After initial resorption, the bone volume showed long-term stability following loading of the implant. Furthermore, 3D matching was a suitable quantification method to analyze the volume development of bone augmentation.

Effects of mechanical abrasion challenge on sound and demineralized dentin surfaces treated with SDF.

This study evaluated the effect of mechanical abrasion on the surface integrity, color change (ΔE) and antibacterial properties of demineralized and sound dentin surfaces treated with silver-diammine-fluoride (SDF). The dentin specimens were divided into two groups: sound and demineralized dentin, then divided into three sub-groups, control (no-treatment), SDF, and SDF + potassium-iodide (KI). Each sub-group was further divided into two groups, one exposed to mechanical brushing and the other without brushing. Specimens were analyzed for the ΔE, surface roughness/surface loss and antibacterial properties (CFU, optical density and fluorescent microscope). Repeated Measures ANOVA was used for statistical analysis of color change while one-way ANOVA was used for CFU analysis. SDF and SDI + KI groups showed significant reduction in ΔE with brushing in the sound dentin group unlike the demineralized group. The surface roughness values were higher for both SDF and SDF + KI groups but roughness values significantly decreased after brushing. Both SDF and SDF + KI groups revealed significantly less surface loss than control. The SDF group showed high anti-bacterial effect after brushing, unlike SDF + KI group. So, we concluded that mechanical brushing improved the esthetic outcome. While, SDF and SDF + KI could protect the dentin surface integrity. SDF-treated dentin possesses an antibacterial property even after mechanical brushing.

MINDSET: Clinical feasibility of utilizing the revised epilepsy self-management tool for Spanish speaking patients.

This paper describes the expanded English/Spanish version of the Management Information and Decision Support Epilepsy Tool (MINDSET) as well as the methods and findings from a feasibility study conducted from July 2016 through February 2017 with 43 Spanish and English-speaking Hispanic people living with epilepsy (PWE) in Arizona (n = 23) and Texas (n = 20) over two consecutive regular clinic visits. The expansion of MINDSET added goal setting and strategy selection to improve self-management (S-M) in PWE. The previous study tested the feasibility of English MINDSET, which was designed to facilitate the identification and discussion of S-M issues between the patient and healthcare provider (HCP) during a regular clinic visit. Results indicate MINDSET feasibility for use in the following: 1) identifying S-M issues across several domains; 2) selecting and assessing confidence in tailored S-M goals/strategies for improvement; 3) discussing S-M issues/goals/strategies/confidence with a HCP; and 4) creating an action plan (AP) and tracking achievement during regular clinic visits. Across two visits, 80-90% of patients agreed that the revised version of MINDSET was helpful, understandable, trustworthy, promoted careful thinking about management, was of appropriate duration, and would be helpful in future management and communication with HCP. Participating HCPs agreed that MINDSET improved the ease, thoroughness, and accuracy in identifying patient S-M issues and establishing a plan for improvement.

Anterior and Lateral Lumbar Interbody Fusion With Supplemental Interspinous Process Fixation: Outcomes from a Multicenter, Prospective, Randomized, Controlled Study.

BACKGROUND: Rigid interspinous process fixation (ISPF) has received consideration as an efficient, minimally disruptive technique in supporting lumbar interbody fusion. However, despite advantageous intraoperative utility, limited evidence exists characterizing midterm to long-term clinical outcomes with ISPF. The objective of this multicenter study was to prospectively assess patients receiving single-level anterior (ALIF) or lateral (LLIF) lumbar interbody fusion with adjunctive ISPF. METHODS: This was a prospective, randomized, multicenter (11 investigators), noninferiority trial. All patients received single-level ALIF or LLIF with supplemental ISPF (n = 66) or pedicle screw fixation (PSF; n = 37) for degenerative disc disease and/or spondylolisthesis (grade ≤2). The randomization patient ratio was 2:1, ISPF/PSF. Perioperative and follow-up outcomes were collected (6 weeks, 3 months, 6 months, and 12 months). RESULTS: For ISPF patients, mean posterior intraoperative outcomes were: blood loss, 70.9 mL; operating time, 52.2 minutes; incision length, 5.5 cm; and fluoroscopic imaging time, 10.4 seconds. Statistically significant improvement in patient Oswestry Disability Index scores were achieved by just 6 weeks after operation (P < .01) and improved out to 12 months for the ISPF cohort. Patient-reported 36-Item Short Form Health Survey and Zurich Claudication Questionnaire scores were also significantly improved from baseline to 12 months in the ISPF cohort (P < .01). A total of 92.7% of ISPF patients exhibited interspinous fusion at 12 months. One ISPF patient (1.5%) required a secondary surgical intervention of possible relation to the posterior instrumentation/procedure. CONCLUSION: ISPF can be achieved quickly, with minimal tissue disruption and complication. In supplementing ALIF and LLIF, ISPF supported significant improvement in early postoperative (≤12 months) patient-reported outcomes, while facilitating robust posterior fusion.

Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and In Vitro Cytomegalovirus Infection Reveal Plastic and Robust Immune Pathway Biology Responses.

Neonates and especially premature infants are highly susceptible to infection but still can have a remarkable resilience that is poorly understood. The view that neonates have an incomplete or deficient immune system is changing. Human neonatal studies are challenging, and elucidating host protective responses and underlying cognate pathway biology, in the context of viral infection in early life, remains to be fully explored. In both resource rich and poor settings, human cytomegalovirus (HCMV) is the most common cause of congenital infection. By using unbiased systems analyses of transcriptomic resources for HCMV neonatal infection, we find the systemic response of a preterm congenital HCMV infection, involves a focused IFN regulatory response associated with dendritic cells. Further analysis of transcriptional-programming of neonatal dendritic cells in response to HCMV infection in culture revealed an early dominant IFN-chemokine regulatory subnetworks, and at later times the plasticity of pathways implicated in cell-cycle control and lipid metabolism. Further, we identify previously unknown suppressed networks associated with infection, including a select group of GPCRs. Functional siRNA viral growth screen targeting 516-GPCRs and subsequent validation identified novel GPCR-dependent antiviral (ADORA1) and proviral (GPR146, RGS16, PTAFR, SCTR, GPR84, GPR85, NMUR2, FZ10, RDS, CCL17, and SORT1) roles. By contrast a gene family cluster of protocadherins is significantly differentially induced in neonatal cells, suggestive of possible immunomodulatory roles. Unexpectedly, programming responses of adult and neonatal dendritic cells, upon HCMV infection, demonstrated comparable quantitative and qualitative responses showing that functionally, neonatal dendritic cell are not overly compromised. However, a delay in responses of neonatal cells for IFN subnetworks in comparison with adult-derived cells are notable, suggestive of subtle plasticity differences. These findings support a set-point control mechanism rather than immaturity for explaining not only neonatal susceptibility but also resilience to infection. In summary, our findings show that neonatal HCMV infection leads to a highly plastic and functional robust programming of dendritic cells in vivo and in vitro. In comparison with adults, a minimal number of subtle quantitative and temporal differences may contribute to variability in host susceptibility and resilience, in a context dependent manner.

2- and 3-dimensional synthetic large-scale de novo patterning by mammalian cells through phase separation.

Synthetic biology provides an opportunity for the construction and exploration of alternative solutions to biological problems - solutions different from those chosen by natural life. To this end, synthetic biologists have built new sensory systems, cellular memories, and alternative genetic codes. There is a growing interest in applying synthetic approaches to multicellular systems, especially in relation to multicellular self-organization. Here we describe a synthetic biological system that confers large-scale de novo patterning activity on 2-D and 3-D populations of mammalian cells. Instead of using the reaction-diffusion mechanisms common in real embryos, our system uses cadherin-mediated phase separation, inspired by the known phenomenon of cadherin-based sorting. An engineered self-organizing, large-scale patterning system requiring no prior spatial cue may be a significant step towards the construction of self-assembling synthetic tissues.

A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication.

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome.