Search

Abstract Bone tissue engineering aims to harness materials to develop functional bone tissue to heal ‘critical-sized’ bone defects. This study examined a robust, coated poly(caprolactone) trimethacrylate (PCL-TMA) 3D-printable scaffold designed to augment bone formation. Following optimisation of the coatings, three bioactive coatings were examined, i) elastin-like polypeptide (ELP), ii) poly(ethyl acrylate) (PEA), fibronectin (FN) and bone morphogenetic protein-2 (BMP-2) applied sequentially (PEA/FN/BMP-2) and iii) both ELP and PEA/FN/BMP-2 coatings applied concurrently. The scaffold material was robust and showed biodegradability. The coatings demonstrated a significant (p

Abstract Background Fetal alcohol spectrum disorder (FASD) is a significant public health concern, yet there is no internationally agreed set of diagnostic criteria or summary of underlying evidence to inform diagnostic decision-making. This systematic review assesses associations of prenatal alcohol exposure (PAE) and outcomes of diagnostic assessments, providing an evidence base for the improvement of FASD diagnostic criteria. Methods Six databases were searched (inception–February 2023). Case-controls or cohort studies examining associations between participants with/without PAE or a FASD diagnosis and the domains of physical size, dysmorphology, functional neurodevelopment and/or brain structure/neurology were included. Excluded studies were non-empirical, sample size

This study images the base of the upper-plate lithosphere in the Nicaraguan subduction zone using common conversion point stacking of Sp phases and explores the relationships between deep upper-plate structure, subduction zone melting processes, and the arc-parallel transport of the Central American fore-arc sliver. We observe the negative velocity gradient associated with the upper-plate lithosphere–asthenosphere boundary in the Nicaraguan back-arc at depths of 60–80 km. However, the amplitude of the lithosphere–asthenosphere velocity gradient diminishes beneath the arc, consistent with a reduction in the shear-wave velocity of the deep upper-plate lithosphere. This zone lies above mantle wedge velocity anomalies which indicate upward-migrating partial melt, suggesting that ascending melt has altered and weakened the lithospheric mantle of the upper plate. In northwestern Nicaragua, the boundary of the Central American fore-arc sliver and the Caribbean plate, which is marked by a northeast decrease in geodetically measured arc-parallel surface velocities, lies above the northeast increase in the amplitude and localization of the lithosphere–asthenosphere velocity gradient. This correlation indicates that the kinematic margin of the Central American fore-arc sliver corresponds to a structural boundary that extends throughout the upper plate, and that is influenced by melt ascending from the mantle wedge.

Objective: To compare cumulative live birth rate (CLBR) and cost-effectiveness of intracytoplasmic sperm injection (ICSI) vs. conventional in vitro fertilization (cIVF). Design: Retrospective cohort study of cycles reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. Setting: Society for Assisted Reproductive Technology (SART) member IVF clinics in the United States. Patient(s): Patients with unexplained infertility who underwent first autologous retrieval cycles between January 2017 and December 2019 with linked fresh and frozen embryo transfers through December 2021. Intervention(s): ICSI vs. cIVF. Main Outcome Measure(s): The primary outcome was CLBR, defined as ≤1 live birth from a retrieval cycle and all linked embryo transfers. Secondary outcomes included two pronuclear (2PN) per oocyte retrieved, miscarriage rate, and total number of transferred or frozen embryos per 2PN. Subsamples with and without preimplantation genetic testing for aneuploidy (PGT-A) were analyzed. Outcomes were adjusted for age, body mass index, number of oocytes retrieved, length of follow-up, and clinic ICSI use rate. Result(s): A total of 18,805 patients with unexplained infertility were included. No difference in CLBR was found among cycles without genetic testing (54.4% ICSI vs. 57.5% cIVF) and with PGT-A (47.6% ICSI vs. 51.8% cIVF). Intracytoplasmic sperm injection cycles without genetic testing had a higher miscarriage rate (16.4% vs. 14.4%) but no difference was seen in cycles with PGT-A (13.9% ICSI vs. 13.2% cIVF). Intracytoplasmic sperm injection cycles had a significantly lower ratio of 2PN per oocyte retrieved without genetic testing (59.7% vs. 60.9%) and with PGT-A (63.3% vs. 65.8%). The ratio of embryos transferred or frozen per 2PN was not significantly different in cycles without genetic testing (49.4% vs. 49.6%) or with PGT-A (54.2% vs. 55.2%). Total fertilization failure occurred in 216 patients (4%) who underwent cIVF and in 153 patients (1.1%) who used ICSI.Compared with cIVF alone, an estimated additional $11,011,500 was charged to patients for ICSI without genetic testing and $9,010,500 was charged to patients for ICSI with PGT-A over 2 years by Society for Assisted Reproductive Technology clinics. On the basis of total fertilization failure rates, 35 patients would require treatment with routine ICSI to avoid a single cycle of total fertilization failure with cIVF. Conclusion(s): Routine use of ICSI in unexplained infertility is not warranted due to the additional cost and lack of CLBR benefit.

Abstract Background Innovative models of care have the potential to improve the sustainability of health systems by improving patient and provider experiences and population outcomes while simultaneously reducing costs. Yet, it is challenging to recognize the distinctive points during research and quality improvement processes that contribute to sustainment of effective interventions. The business concept of an inflection point—the position on the curve of a trajectory where the progress in implementation of an intervention is accelerated or decelerated—may be useful to understand implementation and improve sustainability and ultimately sustainment of effective interventions. The purpose of this study was to retrospectively identify and describe strategic inflection points that accelerated the sustainability process and led to the sustainment of Alberta Family Integrated Care. Methods This qualitative study was conducted in Alberta, Canada and employed an interpretive description design. Purposively sampled documents (proposals, project management plans, reports to funders and sponsors, meeting minutes, and fidelity audit and feedback checklists) from the Alberta Family Integrated Care cluster randomized controlled trial and quality improvement project constituted data for this study. Results To accelerate sustainability in the research context, we identified (1) alignment with strategic priorities, (2) iterative, user-centered co-design, and (3) contextualization of implementation as strategic inflection points. To accelerate sustainability in the health system context, we identified (1) the learning health system, (2) enduring partnerships, (3) responsivity to societal and system change, (4) embedded governance, and (5) intentional integration into the health system as strategic inflection points. Capitalizing on these strategic inflection points led to sustainment of Alberta Family Integrated Care in the provincial health system. Conclusions We identified key inflection points in the research and health system contexts that led to sustainment of Alberta Family Integrated Care. By anticipating, recognizing, and leveraging inflection points in the sustainability process, researchers may be able to accelerate implementation and achieve sustainment of multi-component interventions in complex systems. Trial registration ClinicalTrials.gov: NCT02879799. Registration date: May 27, 2016. Protocol version: June 9, 2016; version 2. Protocol publication: https://doi.org/10.1186/s13063-017-2181-3 .

Abstract The United States has seen increasing trends of maternal mortality in recent years. Within this health crisis there are large disparities whereby underserved and minoritized populations are bearing a larger burden of maternal morbidity and mortality. While new interventions to improve maternal health are being developed, there are opportunities for greater integration of existing evidence-based interventions into routine practice, especially for underserved populations, including those residing in maternity care deserts. In fact, over 80 percent of maternal deaths are preventable with currently available interventions. To spur equitable implementation of existing interventions, the National Heart, Lung, and Blood Institute launched the Maternal-Health Community Implementation Program (MH-CIP) in 2021. In 2023, the National Institutes of Health’s Implementing a Maternal health and PRegnancy Outcomes Vision for Everyone (IMPROVE) initiative partnered with the NHLBI to launch the IMPROVE Community Implementation Program (IMPROVE-CIP). By design, CIPs engage disproportionately impacted communities and partner with academic researchers to conduct implementation research. This commentary overviews the impetus for creating these programs, program goals, structure, and offers a high-level overview of the research currently supported. Lastly, the potential outcomes of these programs are contextualized within the landscape of maternal health initiatives in the United States.

Objective: Understanding both the positive and negative psychological outcomes among cancer patients during the pandemic is critical for planning post-pandemic cancer care. This study (1) examined levels of psychological distress and post-traumatic growth (PTG) among Canadian cancer patients during the COVID-19 pandemic and (2) explored variables that were associated with psychological distress and PTG during the pandemic using a biopsychosocial framework. Method: A cross-section survey was undertaken of patients receiving ongoing care at a regional cancer centre in Ontario, Canada, between February and December 2021. Self-reported questionnaires assessing sociodemographic information, social difficulties, psychological distress (depression, anxiety fear of recurrence, and emotional distress), PTG, illness perceptions, and behavioural responses to the pandemic were administered. Disease-related information was extracted from patient health records. Results: Prevalences of moderate to severe levels of depression, anxiety, fear of recurrence and emotional distress were reported by 26.0%, 21.2%, 44.2%, and 50.0% of the sample (N = 104), respectively. Approximately 43% of the sample reported experiencing high PTG, and these positive experiences were not associated with levels of distress. Social factors, including social difficulties, being female, lower education, and unemployment status were prominent associative factors of patient distress. Perceptions of the pandemic as threatening, adopting more health safety behaviours, and not being on active treatment also increased patient likelihood to experience severe psychological distress. Younger age and adopting more health safety behaviours increased the likelihood of experiencing high PTG. The discriminatory power of the predictive models was strong, with a C-statistic > 0.80. Conclusions: Examining both the positive and negative psychological patient outcomes during the pandemic has highlighted the complex range of coping responses. Interventions that adopt a multi-pronged approach to screen and address social distress, as well as to leverage health safety behaviours, may improve the adjustments in the pandemic aftermath.

Abstract Traumatic brain injury (TBI) affects millions globally, with a majority of TBI cases being classified as mild, in which diffuse pathologies prevail. Two of the pathological hallmarks of TBI are diffuse axonal injury (DAI) and microglial activation. While progress has been made investigating the breadth of TBI-induced axonal injury and microglial changes in rodents, the neuroinflammatory progression and interaction between microglia and injured axons in humans is less well understood. Our group previously investigated microglial process convergence (MPC), in which processes of non-phagocytic microglia directly contact injured proximal axonal swellings, in rats and micropigs acutely following TBI. These studies demonstrated that MPC occurred on injured axons in the micropig, but not in the rat, following diffuse TBI. While it has been shown that microglia co-exist and interact with injured axons in humans post-TBI, the occurrence of MPC has not been quantitatively measured in the human brain. Therefore, in the current study we sought to validate our pig findings in human postmortem tissue. We investigated MPC onto injured axonal swellings and intact myelinated fibers in cases from individuals with confirmed DAI and control human brain tissue using multiplex immunofluorescent histochemistry. We found an increase in MPC onto injured axonal swellings, consistent with our previous findings in micropigs, indicating that MPC is a clinically relevant phenomenon that warrants further investigation.

Abstract Background Our research team partnered with primary care and quality improvement staff in Federally Qualified Community Health Centers (CHCs) to develop Partnered and Equity Data-Driven Implementation (PEDDI) to promote equitable implementation of evidence-based interventions. The current study used a human-centered design methodology to evaluate the usability of PEDDI and generate redesign solutions to address usability issues in the context of a cancer screening intervention. Methods We applied the Cognitive Walkthrough for Implementation Strategies (CWIS), a pragmatic assessment method with steps that include group testing with end users to identify and prioritize usability problems. We conducted three facilitated 60-min CWIS sessions with end users (N = 7) from four CHCs that included scenarios and related tasks for implementing a colorectal cancer (CRC) screening intervention. Participants rated the likelihood of completing each task and identified usability issues and generated ideas for redesign solutions during audio-recorded CWIS sessions. Participants completed a pre-post survey of PEDDI usability. Our research team used consensus coding to synthesize usability problems and redesign solutions from transcribed CWIS sessions. Results Usability ratings (scale 0–100: higher scores indicating higher usability) of PEDDI averaged 66.3 (SD = 12.4) prior to the CWIS sessions. Scores averaged 77.8 (SD = 9.1) following the three CWIS sessions improving usability ratings from “marginal acceptability” to “acceptable”. Ten usability problems were identified across four PEDDI tasks, comprised of 2–3 types of usability problems per task. CWIS participants suggested redesign solutions that included making data fields for social determinants of health and key background variables for identifying health equity targets mandatory in the electronic health record and using asynchronous communication tools to elicit ideas from staff for adaptations. Conclusions Usability ratings indicated PEDDI was in the acceptable range following CWIS sessions. Staff identified usability problems and redesign solutions that provide direction for future improvements in PEDDI. In addition, this study highlights opportunities to use the CWIS methodology to address inequities in the implementation of cancer screening and other clinical innovations in resource-constrained healthcare settings.

Graduate education holds the potential to stimulate personal growth in individuals that leads to economically viable career opportunities. First-generation college students, underrepresented minorities (URM), and females often face unique obstacles that can undermine their progress in graduate programs. These obstacles may be more pervasive in fields where these students have lower enrollment, such as STEM graduate programs. The Graduate Student Success Survey+ (GSSS+) was broadly distributed to a national population of graduate students in the United States, with a particular focus on seeking the participation of students from universities that serve first-generation, URM, and female graduate students, capturing both STEM and non-STEM programs. Exploratory and confirmatory factor analyses were used to test the survey’s validity and reliability, with 648 participants from 23 universities. A 7-factor, 40-item model was determined with the following subscales: mentor support, imposter phenomenon, financial support, microaggressions (race and gender), access and opportunity, resilience, and peer support. Item analysis revealed differences in students’ perceptions of their graduate school experiences based on gender identity, racial and ethnic groups, residency status, enrollment type, program type, and program area. Findings lead to recommendations related to financial support, mental health counseling, and access and opportunity, to enhance graduate student success.

Abstract The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go related gene (HERG) potassium channels have uniquely rapid inactivation kinetics which are critical to the role they play in regulating cardiac electrical activity. Here, we exploit the K+ sensitivity of HERG inactivation to determine structures of both a conductive and non-conductive selectivity filter structure of HERG. The conductive state has a canonical cylindrical shaped selectivity filter. The non-conductive state is characterized by flipping of the selectivity filter valine backbone carbonyls to point away from the central axis. The side chain of S620 on the pore helix plays a central role in this process, by coordinating distinct sets of interactions in the conductive, non-conductive, and transition states. Our model represents a distinct mechanism by which ion channels fine tune their activity and could explain the uniquely rapid inactivation kinetics of HERG.

Abstract Background Older adult women often do not engage in sufficient physical activity (PA) and can encounter biological changes that exacerbate the negative effects of inadequate activity. Wearable activity monitors can facilitate PA initiation, but evidence of sustained behavior change is lacking. Supplementing wearable technologies with intervention content that evokes enjoyment, interest, meaning, and personal values associated with PA may support long term adherence. In this paper, we present the protocol of an NIA-funded study designed to evaluate the efficacy of CHALLENGE for increasing step count and motivation for PA in insufficiently active older women (Challenges for Healthy Aging: Leveraging Limits for Engaging Networked Game-based Exercise). CHALLENGE uses social media to supplement wearable activity monitors with the autonomy-supportive frame of a game. We hypothesize that CHALLENGE will engender playful experiences that will improve motivation for exercise and lead to sustained increases in step count. Methods We will recruit 300 healthy, community dwelling older adult women on a rolling basis and randomize them to receive either the CHALLENGE intervention (experimental arm) or an activity monitor-only intervention (comparison arm). Participants in both groups will receive a wearable activity monitor and personalized weekly feedback emails. In the experimental group, participants will also be added to a private Facebook group, where study staff will post weekly challenges that are designed to elicit playful experiences while walking. Assessments at baseline and 6, 12, and 18 months will measure PA and motivation-related constructs. We will fit linear mixed-effects models to evaluate differences in step count and motivational constructs, and longitudinal mediation models to evaluate if interventional effects are mediated by changes in motivation. We will also conduct thematic content analysis of text and photos posted to Facebook and transcripts from individual interviews. Discussion By taking part in a year-long intervention centered on imbuing walking behaviors with playful and celebratory experiences, participating older adult women may internalize changes to their identity and relationship with PA that facilitate sustained behavior change. Study results will have implications for how we can harness powerful and increasingly ubiquitous technologies for health promotion to the vast and growing population of older adults in the U.S. and abroad. Trial registration ClinicalTrials.gov Identifier NCT04095923. Registered September 17th, 2019.

Abstract Background Stroke affects long-term physical and cognitive function; many survivors report unmet health needs, such as pain or depression. A hospital-led follow-up service designed to address ongoing health problems may avoid unplanned readmissions and improve quality of life. Methods This paper outlines the protocol for a registry-based, randomised controlled trial with allocation concealment of participants and outcome assessors. Based on an intention-to-treat analysis, we will evaluate the feasibility, acceptability, potential effectiveness and cost implications of a new tailored, codesigned, hospital-led follow-up service for people within 6–12 months of stroke. Participants (n = 100) from the Australian Stroke Clinical Registry who report extreme health problems on the EuroQol EQ-5D-3L survey between 90 and 180 days after stroke will be randomly assigned (1:1) to intervention (follow-up service) or control (usual care) groups. All participants will be independently assessed at baseline and 12–14-week post-randomisation. Primary outcomes for feasibility are the proportion of participants completing the trial and for intervention participants the proportion that received follow-up services. Acceptability is satisfaction of clinicians and participants involved in the intervention. Secondary outcomes include effectiveness: change in extreme health problems (EQ-5D-3L), unmet needs (Longer-term Unmet Needs questionnaire), unplanned presentations and hospital readmission, functional independence (modified Rankin Scale) and cost implications estimated from self-reported health service utilisation and productivity (e.g. workforce participation). To inform future research or implementation, the design contains a process evaluation including clinical protocol fidelity and an economic evaluation. Discussion The results of this study will provide improved knowledge of service design and implementation barriers and facilitators and associated costs and resource implications to inform a future fully powered effectiveness trial of the intervention. Trial registration ACTRN12622001015730pr. Trial sponsor Florey Institute of Neuroscience and Mental Health, 245 Burgundy Street, Heidelberg, VIC, 3084, PH: +61 3 9035 7032

Abstract Obesity is associated with increased cancer risk, yet the underlying mechanisms remain elusive. Obesity-associated cancers involve disruptions in metabolic and cellular pathways, which can lead to genomic instability. Repetitive DNA sequences capable of adopting alternative DNA structures (e.g., H-DNA) stimulate mutations and are enriched at mutation hotspots in human cancer genomes. However, it is not known if obesity impacts DNA repeat-mediated endogenous mutation hotspots. We address this gap by measuring mutation frequencies in obese and normal-weight transgenic reporter mice carrying either a control human B-DNA- or an H-DNA-forming sequence (from a translocation hotspot in c-MYC in Burkitt lymphoma). Here, we discover that H-DNA-induced DNA damage and mutations are elevated in a tissue-specific manner, and DNA repair efficiency is reduced in obese mice compared to those on the control diet. These findings elucidate the impact of obesity on cancer-associated endogenous mutation hotspots, providing mechanistic insight into the link between obesity and cancer.

Abstract Long-term reconstituting haematopoietic stem cells (LT-HSCs) are used to treat blood disorders via stem cell transplantation. The very low abundance of LT-HSCs and their rapid differentiation during in vitro culture hinders their clinical utility. Previous developments using stromal feeder layers, defined media cocktails, and bioengineering have enabled HSC expansion in culture, but of mostly short-term HSCs and progenitor populations at the expense of naive LT-HSCs. Here, we report the creation of a bioengineered LT-HSC maintenance niche that recreates physiological extracellular matrix organisation, using soft collagen type-I hydrogels to drive nestin expression in perivascular stromal cells (PerSCs). We demonstrate that nestin, which is expressed by HSC-supportive bone marrow stromal cells, is cytoprotective and, via regulation of metabolism, is important for HIF-1α expression in PerSCs. When CD34+ve HSCs were added to the bioengineered niches comprising nestin/HIF-1α expressing PerSCs, LT-HSC numbers were maintained with normal clonal and in vivo reconstitution potential, without media supplementation. We provide proof-of-concept that our bioengineered niches can support the survival of CRISPR edited HSCs. Successful editing of LT-HSCs ex vivo can have potential impact on the treatment of blood disorders.

Abstract Accelerated sea-level rise is an existential threat to coastal wetlands, but the timing and extent of wetland drowning are debated. Recent data syntheses have clarified future relative sea-level rise exposure and sensitivity thresholds for drowning. Here, we integrate these advances to estimate when and where rising sea levels could cross thresholds for initiating wetland drowning across the conterminous United States. Our results show that there is much spatial variation in relative sea-level rise rates, which impacts the potential timing and extent of wetlands crossing thresholds. High rates of relative sea-level rise along wetland-rich parts of the Gulf of Mexico and Atlantic coasts highlight areas where wetlands are already drowning or could begin to drown within decades, including large wetland landscapes within the Mississippi River delta, Greater Everglades, Chesapeake Bay, Texas, Georgia, and the Carolinas. Collectively, our results underscore the need to prepare for transformative coastal change.

Abstract Elucidating genetic diversity within wild forms of modern crops is essential for understanding domestication and the possibilities of wild germplasm utilization. Gossypium hirsutum is a predominant source of natural plant fibers and the most widely cultivated cotton species. Wild forms of G. hirsutum are challenging to distinguish from feral derivatives, and truly wild populations are uncommon. Here we characterize a population from Mound Key Archaeological State Park, Florida using genome-wide SNPs extracted from 25 individuals over three sites. Our results reveal that this population is genetically dissimilar from other known wild, landrace, and domesticated cottons, and likely represents a pocket of previously unrecognized wild genetic diversity. The unexpected level of divergence between the Mound Key population and other wild cotton populations suggests that the species may harbor other remnant and genetically distinct populations that are geographically scattered in suitable habitats throughout the Caribbean. Our work thus has broader conservation genetic implications and suggests that further exploration of natural diversity in this species is warranted.

The mechanisms contributing to age-related deterioration of the female reproductive system are complex, however aberrant protein homeostasis is a major contributor. We elucidated exceptionally stable proteins, structures, and macromolecules that persist in mammalian ovaries and gametes across the reproductive lifespan. Ovaries exhibit localized structural and cell-type-specific enrichment of stable macromolecules in both the follicular and extrafollicular environments. Moreover, ovaries and oocytes both harbor a panel of exceptionally long-lived proteins, including cytoskeletal, mitochondrial, and oocyte-derived proteins. The exceptional persistence of these long-lived molecules suggest a critical role in lifelong maintenance and age-dependent deterioration of reproductive tissues.

Lineage switch (LS) refers to the immunophenotypic transformation of one leukemia lineage to another (ie, lymphoid to myeloid) with retention of baseline genetics. This phenomenon was originally observed in infants with B-lymphoblastic leukemia (B-ALL) with KMT2A rearrangements following chemotherapy, but is now increasingly being observed as a form of immune escape following targeted therapies among children and adults with B-ALL with and without KMT2A rearrangements. In this report, we present two cases of adolescents with B-ALL harboring CRLF2 rearrangements (Philadelphia-like phenotype) who developed LS to acute myeloid leukemia following CD19 targeted therapy. To our knowledge, these are the first cases of LS to be reported in patients with CRLF2 rearranged acute lymphoblastic leukemia. In addition to raising awareness that this genetic mutation may associate with lineage plasticity, our cases illustrate the importance of multi-modal disease surveillance in the diagnosis of LS.

Polyamide-66 underwent substantial growth worldwide in the late 1930′s. It can be found in several public spaces. After 2019, due to the coronavirus disease (COVID-19), the sanitization of the interior of aircraft and public spaces by using UV light became important. Most of all, the effect of the far UVC 222 nm became a research hot spot and is still a research blank. In the present work, a comparative study on the post-exposure damage of polyamide- 66 occurred when controlled ultraviolet irradiation (UVC 254 nm, far UVC 222 nm, UVB 310 nm) and moisture-condensation were carried out. Chemical (FTIR), thermal (DMA), and nano-mechanical properties were evaluated. FTIR analysis showed the formation of O-H and/or N-H bonds since there appeared absorptions at 3400 cm−1 along with the vanishing of other signals related to C-N bonding. These changes are more evident in samples exposed to UVC 254 nm followed by samples that were irradiated with UVC 222 nm. Samples that were aged with UVA 313 nm didn't show a change in FTIR spectra. FTIR on spectra and nanoindentation showed that UVB 313 nm produced a lower aging effect on this material. In contrast, UVC 254 nm light caused the highest degree of surface chemical-mechanical change attributed to cleavage/crosslinking reactions initiated by free radicals produced by UV light and moisture. On the contrary, far UVC 222 nm light presented moderate effects on Polyamide-66. Glass-transition temperature (Tg) diminished as the time to exposure increased attributed to water absorption and surface damage, being the highest change at −16.05 °C for samples irradiated with 245 UVC nm. However, the potential of far UVC 222 nm light for COVID-19 sanitization, with no significant degradation effects on polymeric materials, is a promising finding that should be further explored and could provide a hopeful solution in the fight against the pandemic.

We present a patient with a post-pneumonectomy empyema refractory to surgical debridement and systemic antibiotics. The patient initially presented with a bronchopleural fistula and pneumothorax secondary to tuberculosis (TB) destroyed lung, which required a pneumonectomy with Eloesser flap. Ongoing pleural infection delayed the closure of the Eloesser flap, and thoracoscopic inspection of his chest cavity revealed a green, mucous biofilm-like structure lining the postpneumonectomy pleural cavity. Cultures identified pan-susceptible Pseudomonas aeruginosa. Despite debriding this biofilm-like structure and administering systemic antibiotics, the patient continued to show persistent signs of infection and regrowth of the film. We employed a novel approach to dissolve the biofilm-like structure using intrapleural dornase alfa followed by intrapleural antibiotic washes. After 3 weeks of daily washes, repeat inspection demonstrated the biofilm-like structure had completely resolved. Resolving the pseudomonas biofilm-like structure allowed permanent closure of his chest without further need for systemic antibiotics. At follow up 3 months later, he showed no sequalae. This treatment option can be an important adjunct to improve likelihood of chest closure in patients with post-pneumonectomy empyema that resists standard treatment options due to biofilm formation.

Abstract Fracture non‐union occurs due to various factors, leading to the development of potentially substantial bone defects. While autograft and allograft are the current gold standards for non‐union fractures, challenges related to availability and immune rejection highlight the need for improved treatments. A strategy in bone tissue engineering is to harness growth factors to induce an effect on cells to change their phenotype, behavior and initiate signaling pathways which lead to increased matrix deposition and tissue formation. Bone morphogenetic protein‐2 (BMP‐2) is a potent osteogenic growth factor however, given its rapid clearance time in vivo, there is a specific therapeutic window for efficacy while avoiding potential deleterious side‐effects. It is demonstrated that a Laponite nanoclay coating on a 3D printable and bioresorbable poly(caprolactone) trimethacrylate‐based resin enables binding of BMP‐2, decreases the rate of release, enabling reduced concentrations to be used while enhancing osteoinduction in both in vitro and in vivo models.

Background: Podcasts are a popular form of extracurricular education. They provide a range of benefits for listeners including an opportunity for learning whilst mobile. We aimed to assess the interest of medical students in a podcast series as a part of their formal paediatric surgery teaching resources; to determine the optimal format for such a podcast and, following their introduction, if they were considered to have a beneficial effect on student learning. Method: We conducted focus groups with medical students to explore interest in a podcast series and to determine the optimal format. Our findings guided production and introduction of 5 short-format podcast episodes as an adjunct to available formal learning resources. We ran student focus groups to evaluate the podcasts until data saturation was reached. Transcripts were analysed through thematic analysis by two researchers, who used the constant comparison process to produce a coding framework, through which they identified relevant themes. Results: Medical students utilised outsourced medical podcasts as an adjunct to formal medical school curricula. All students supported the introduction of a podcast series into formal teaching resources to extend paediatric surgical teaching. The preferred medical podcast format was a short, conversational style podcast that begins with a clinical case and ends with a summary. The introduction of podcasts increased student engagement in, and understanding of, podcast topics. Conclusion: Medical students enthusiastically embraced paediatric surgical podcasts in their curriculum. The addition of short-medium format podcasts enhances learning and engagement. Medical schools should utilize the teaching benefits that podcasts offer.

Abstract Chronic pain represents a significant unmet medical need, affecting one‐fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non‐opioid, non‐NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single‐ascending dose (SAD) study and a fed‐fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment‐emergent adverse events were considered related to EC5026. No apparent treatment‐ or dose‐related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near‐dose‐proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5–2 mg doses. Mean half‐lives ranged from 41.8 to 59.1 h. for doses of 8–24 mg, supporting a once‐daily dosing regimen. In the fed‐fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half‐lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.

Summary: The polymerase-associated factor 1 (Paf1) complex (Paf1C) is a conserved protein complex with critical functions during eukaryotic transcription. Previous studies showed that Paf1C is multi-functional, controlling specific aspects of transcription ranging from RNA polymerase II (RNAPII) processivity to histone modifications. However, it is unclear how specific Paf1C subunits directly impact transcription and coupled processes. We have compared conditional depletion to steady-state deletion for each Paf1C subunit to determine the direct and indirect contributions to gene expression in Saccharomyces cerevisiae. Using nascent transcript sequencing, RNAPII profiling, and modeling of transcription elongation dynamics, we have demonstrated direct effects of Paf1C subunits on RNAPII processivity and elongation rate and indirect effects on transcript splicing and repression of antisense transcripts. Further, our results suggest that the direct transcriptional effects of Paf1C cannot be readily assigned to any particular histone modification. This work comprehensively analyzes both the immediate and the extended roles of each Paf1C subunit in transcription elongation and transcript regulation.

There are few validated contextual measures predicting adoption of evidence-based programs. Variation in context at clinical sites can hamper dissemination. We examined organizational characteristics of Veterans Affairs hospitals implementing STRIDE, a hospital walking program, and characteristics’ influences on program adoption. Using a parallel mixed-method design, we describe context and organizational characteristics by program adoption. Organizational characteristics included: organizational resilience, implementation climate, organizational readiness to implement change, highest complexity sites versus others, material support, adjusted length of stay (LOS) above versus below national median, and improvement experience. We collected intake forms at hospital launch and qualitative interviews with staff members at 4 hospitals that met the initial adoption benchmark, defined as completing supervised walks with 5+ unique hospitalized Veterans during months 5 to 6 after launch with low touch implementation support. We identified that 31% (n = 11 of 35) of hospitals met adoption benchmarks. Seven percent of highest complexity hospitals adopted compared to 48% with lower complexity. Forty-three percent that received resources adopted compared to 29% without resources. Thirty-six percent of hospitals with above-median LOS adopted compared to 23% with below-median. Thirty-five percent with at least some implementation experience adopted compared to 0% with very little to no experience. Adopters reported higher organizational resilience than non-adopters (mean = 23.5 [SD = 2.6] vs 22.7 [SD = 2.6]). Adopting hospitals reported greater organizational readiness to change than those that did not (mean = 4.2 [SD = 0.5] vs 3.8 [SD = 0.6]). Qualitatively, all sites reported that staff were committed to implementing STRIDE. Participants reported additional barriers to adoption including challenges with staffing and delays associated with hiring staff. Adopters reported that having adequate staff facilitated implementation. Implementation climate did not have an association with meeting STRIDE program adoption benchmarks in this study. Contextual factors which may be simple to assess, such as resource availability, may influence adoption of new programs without intensive implementation support.

Introduction. Diabetes and stress hyperglycemia have been related with poorer clinical outcomes in patients infected by SARS-CoV-2 and at risk for severe disease. Objective. To evaluate clinical outcomes in three groups of patients (with diabetes, without diabetes and with stress hyperglycemia) with SARS-CoV-2 infection. Materials and methods. A retrospective cohort study was conducted in Cali (Colombia). We included patients 18 years old or older with a diagnosis of SARS-CoV-2 infection, managed in the emergency room, hospitalization, or intensive care unit between March 2020 and December 2021. Immunocompromised patients and pregnant women were excluded. Patients were classified into three groups: without diabetes, with diabetes, and with stress hyperglycemia. A comparison between the groups was performed. Results. A total of 945 patients were included (59.6% without diabetes, 27% with diabetes, and 13.4% with stress hyperglycemia). Fifty-five-point three percent required intensive care unit management, with a higher need in patients with stress hyperglycemia (89.8%) and diabetes (67.1%), with no difference between these groups (p = 0.249). We identified a higher probability of death in the group with stress hyperglycemia versus the one without diabetes (adjusted OR = 8.12; 95% CI: 5.12-12.88; p < 0.01). Frequency of acute respiratory distress syndrome, need for invasive mechanical ventilation, use of vasopressors and inotropes, need for de novo renal replacement therapy, and mortality was higher in patients with metabolic alterations (diabetes and stress hyperglycemia). Conclusions. Diabetes and stress hyperglycemia were associated with worse clinical outcomes and mortality in patients with COVID-19. These patients should be identified early and considered them high risk at the COVID-19 diagnosis to mitigate adverse outcomes.

Abstract Background Randomized clinical trials (RCTs) are the gold standard for assessing treatment effectiveness; however, they have been criticized for generalizability issues such as how well trial participants represent those who receive the treatments in clinical practice. We assessed the representativeness of participants from eight RCTs for chronic spine pain in the U.S., which were used for an individual participant data meta-analysis on the cost-effectiveness of spinal manipulation for spine pain. In these clinical trials, spinal manipulation was performed by chiropractors. Methods We conducted a retrospective secondary analysis of RCT data to compare trial participants’ socio-demographic characteristics, clinical features, and health outcomes to a representative sample of (a) U.S. adults with chronic spine pain and (b) U.S. adults with chronic spine pain receiving chiropractic care, using secondary data from the National Health Interview Survey (NHIS) and Medical Expenditure Panel Survey (MEPS). We assessed differences between trial and U.S. spine populations using independent t-tests for means and z-tests for proportions, accounting for the complex multi-stage survey design of the NHIS and MEPS. Results We found the clinical trials had an under-representation of individuals from health disparity populations with lower percentages of racial and ethnic minority groups (Black/African American 7% lower, Hispanic 8% lower), less educated (No high school degree 19% lower, high school degree 11% lower), and unemployed adults (25% lower) with worse health outcomes (physical health scores 2.5 lower and mental health scores 5.3 lower using the SF-12/36) relative to the U.S. population with spine pain. While the odds of chiropractic use in the U.S. are lower for individuals from health disparity populations, the trials also under-represented these populations relative to U.S. adults with chronic spine pain who visit a chiropractor. Conclusions Health disparity populations are not well represented in spine pain clinical trials. Embracing key community-based approaches, which have shown promise for increasing participation of underserved communities, is needed.

Abstract The gut microbiome (GM) modulates body weight/composition and gastrointestinal functioning; therefore, approaches targeting resident gut microbes have attracted considerable interest. Intermittent fasting (IF) and protein pacing (P) regimens are effective in facilitating weight loss (WL) and enhancing body composition. However, the interrelationships between IF- and P-induced WL and the GM are unknown. The current randomized controlled study describes distinct fecal microbial and plasma metabolomic signatures between combined IF-P (n = 21) versus a heart-healthy, calorie-restricted (CR, n = 20) diet matched for overall energy intake in free-living human participants (women = 27; men = 14) with overweight/obesity for 8 weeks. Gut symptomatology improves and abundance of Christensenellaceae microbes and circulating cytokines and amino acid metabolites favoring fat oxidation increase with IF-P (p

Abstract Background Translational efforts to increase uptake of evidence-based practices typically look at those outcomes in isolation of their impact on other aspects of care delivery. If we are in fact to “do no harm”, we must consider the possible negative impact of improving use of one practice on other quality measures. Alternatively, a focus on one practice could lead to spread of effective strategies to other practices, which would be highly beneficial. We studied the impact of a colorectal cancer (CRC) screening initiative on delivery of other preventive care measures. Methods We used an interrupted time series design with implementation year as the interruption point. The initiative was conducted between 2015 and 2020, with three staggered cohorts. Main outcomes were quality measures for colorectal cancer screening, cervical cancer screening, hypertension management, diabetes management, weight screening and follow-up, tobacco use screening and cessation treatment, and depression screening and follow-up. Results The initiative was associated with an increase in CRC screening (OR = 1.67, p ≤ 0.01; average marginal effect = 12.2% points), and did not reduce performance on other quality measures in the year of CRC program implementation or a change in their respective secular trends. Conclusions The initiative led to a clinically meaningful increase in CRC screening and was not associated with reductions in delivery of six other preventive services. Quality improvement (QI) initiatives typically approach implementation with an eye towards reducing unintended impact and leveraging existing staff and resources. Implementation research studies may benefit from considering how QI initiatives factor in the local context in implementation efforts.

Repetitive DNA sequences are abundant in the human genome and can adopt alternative (i.e., non-B) DNA structures. These sequences contribute to diverse biological functions, including genomic instability. Previously, we found that Z-DNA-, H-DNA- and cruciform DNA-forming sequences are mutagenic, implicating them in cancer etiology. These sequences can stimulate the formation of DNA double-strand breaks (DSBs), causing deletions via cleavage by the endonuclease ERCC1-XPF. Interestingly, the activity of ERCC1-XPF in H-DNA-induced mutagenesis is nucleotide excision repair (NER)-dependent, but its role in Z-DNA-induced mutagenesis is NER-independent. Instead, Z-DNA is processed by ERCC1-XPF in a mechanism dependent on the mismatch repair (MMR) complex, MSH2-MSH3. These observations indicate distinct mechanisms of non-B-induced genomic instability. However, the roles of NER and MMR proteins, as well as additional nucleases (CtIP and MRE11), in the processing of cruciform DNA remain unknown. Here, we present data on the processing of cruciform-forming short inverted repeats (IRs) by DNA repair proteins using mammalian cell-based systems. From this pilot study, we show that, in contrast to H-DNA and Z-DNA, short IRs are processed in a NER- and MMR-independent manner, and the nucleases CtIP and MRE11 suppress short IR-induced genomic instability in mammalian cells.

Abstract Background Healthcare workplace mistreatment has been documented globally. Poor workplace behaviour, ranging from incivility to bullying and harassment, is common in healthcare, and contributes significantly to adverse events in healthcare, poor mental health among healthcare workers, and to attrition in the healthcare workforce, particularly in junior years. Poor workplace behaviour is often normalised, and is difficult to address. Verbatim theatre, a form of research informed theatre in which plays are created from informants’ exact words only, is particularly suited to facilitating workplace culture change by raising awareness about issues that are difficult to discuss. The objective of this study was to assess the impact of the verbatim theatre play ‘Grace Under Pressure’ on workplace culture in NSW hospitals. Methods The intervention was conducted in 13 hospitals from 8 Local Health Districts (LHDs) in NSW, Australia, in October and November 2019, with aggregated impact across all sites measured by a bespoke survey (‘Pam McLean Centre (PMC) survey’) at the conclusion of the intervention. This study was conducted in 3 Local Health Districts (one urban, one regional, one remote), with data collection conducted in November–December 2019 and December 2020. The study design was a mixed methods assessment of the play’s impact using (1) validated baseline measures of psychosocial risk, analysed descriptively, (2) overall findings from the PMC survey above, analysed descriptively, (3) interviews conducted within a month of the intervention, analysed thematically and (4) interviews conducted one year later, analysed thematically. Results Half (51.5%) of the respondents (n = 149) to the baseline survey had scores indicating high risk of job strain and depressive symptoms. Of 478 respondents to the PMC survey (response rate 57%), 93% found the play important, 92% recommended others see the play, 89% considered that it stimulated thinking about workplace behaviour, and 85% that it made discussing these issues easier. Thematic analysis of interviews within one month (n = 21) showed that the play raised awareness about poor workplace behaviour and motivated behaviour change. Interviews conducted one year later (n = 6) attributed improved workplace culture to the intervention due to improved awareness, discussion and capacity to respond to challenging issues. Conclusions Verbatim theatre is effective in raising awareness about difficult workplace behaviour in ways that motivate behaviour change, and hence can be effective in catalysing real improvements in healthcare workplace culture. Creative approaches are recommended for addressing similarly complex challenges in healthcare workforce retention.

Abstract Background The field of implementation science has significantly expanded in size and scope over the past two decades, although work related to understanding implementation processes have of course long preceded the more systematic efforts to improve integration of evidence-based interventions into practice settings. While this growth has had significant benefits to research, practice, and policy, there are some clear challenges that this period of adolescence has uncovered. Main body This invited commentary reflects on the development of implementation science, its rapid growth, and milestones in its establishment as a viable component of the biomedical research enterprise. The authors reflect on progress in research and training, and then unpack some of the consequences of rapid growth, as the field has grappled with the competing challenges of legitimacy among the research community set against the necessary integration and engagement with practice and policy partners. The article then enumerates a set of principles for the field's next developmental stage and espouses the aspirational goal of a “big tent” to support the next generation of impactful science. Conclusion For implementation science to expand its relevance and impact to practice and policy, researchers must not lose sight of the original purpose of the field—to support improvements in health and health care at scale, the importance of building a community of research and practice among key partners, and the balance of rigor, relevance, and societal benefit.

Objective: The purpose of this study was to investigate how parents of children with complex care needs conceptualize burnout from the perspective of parents themselves. Methods: We conducted semi-structured interviews with 38 parents, selected for maximal variation in parental, child, and family characteristics. Inductive thematic analysis was employed. Results: Burnout was conceptualized as encompassing three themes: having a reoccurring long-term nature, commencing with symptoms of stress progressing into exhaustion, and ending in a survival mode wherein parents worked hard to project an image of everything being well and under control (fighting) while distancing physically and emotionally from others and themselves (fleeing). Conclusion: Burnout involves specific aspects of caregiving and parenting, such as long-term responsibility for the child, which cannot be relinquished. Furthermore, burnout may also be ‘hidden’: not always showing to the outside world, which requires extra attention and vigilance among parent's informal and formal networks. Awareness of the various interpretations of the term may foster constructive communication. Innovation: Focusing on parents’ individual experiences has illuminated new aspects of burnout. By purposively sampling a variety of parents of children with complex care needs, a broader understanding of the meaning of the term ‘burnout’ from the perspective of parents was achieved.

AbstractThis mixed methods study examined students’ perceptions of EcoJustice and Social Justice curriculum in an undergraduate children’s literature course. Data included beginning-course and end-course Likert scale questions and open-ended responses, student reflective writings, and assignments. This study also examined survey responses from faculty teaching children’s literature. Results showed that students, primarily preservice teacher candidates, want EcoJustice topics in the curriculum and believe such teaching is more important than educators do. Students and teachers viewed Social Justice and EcoJustice pedagogy as separate and had much less understanding of EcoJustice topics and pedagogy compared to those of Social Justice; however, after experiencing an EcoJustice inclusive curriculum, the end-course results demonstrate that students had a much better understanding and a stronger belief in the importance of EcoJustice topics. Student participants reported a better understanding of how connected justice topics and pedagogy are and how they could incorporate such pedagogy into their own K-12 teaching using children’s literature. The author made her children’s literature courses more ecologically inclusive and justice-focused and provides brief recommendations for incorporating EcoJustice pedagogy in undergraduate children’s literature courses.

Abstract Background Food insecurity, an economic and social condition of limited food access, is associated with poor diet quality—a risk factor for several common cancers. The University of Texas MD Anderson Cancer Center supports healthy food access through community‐led evidence translation by actively partnering with community‐based organizations (CBOs). These partnerships aim to enhance the capacity of food assistance CBOs to effectively implement evidence‐based food insecurity mitigation programs in the cancer center's area of influence. Methods This case study aims to describe the cancer center's model for local food access capacity building and detail operationalization in the context of a whole‐community cancer prevention effort (Be Well Baytown) in Baytown, Texas. Results Elements central to the capacity building model include (i) assessment of baseline needs and capacity, (ii) empowering a community champion within a relevant CBO, (iii) mapping inter‐sectoral community partnerships, collaborations, and linkages, and (iv) leveraging systems, connections, and resources to provide an enabling environment for overall food access systems growth. Through this process, Be Well Baytown enhanced the capacity of a local food pantry leading to increases in total reach, pounds of food distributed, and number of food distribution events in collaboration with intersectoral partners from 2018 to 2023. Conclusion This case study highlights the model's implementation as a co‐benefit community partnership strategy to maximize the impact of food security programs integrated with comprehensive cancer center prevention efforts.

Background Fecal shedding of SARS-CoV-2 occurs during infection, particularly in pediatric populations. The gut microbiota are associated with resistance to enteric pathogens. COVID-19 is associated with alterations to the gut microbiome. We hypothesized that the gut microbiome of infants born to SARS-CoV-2+ mothers differs between infants with and without fecal shedding of the virus. Methods We enrolled 10 infants born to SARS-CoV-2+ mothers. We used qPCR on fecal RNA to test for SARS-CoV-2 and 16S rRNA gene sequencing of the V4 region to assess the gut microbiome. Infant SARS-CoV-2 status from nasal swabs was abstracted from medical records. Results Of the 10 included infants, nine were tested for SARS-CoV-2 by nasal swab with 1 testing positive. Four infants, including the nasal swab positive infant, had at least one sample with detectable levels of SARS-CoV-2 fecal shedding. Detection of both SARS-CoV-2 genes in feces was associated with increased gut alpha diversity compared to no detection by a linear mixed effects model (p

Introduction The cornerstone in the management of type 2 diabetes (T2D) is lifestyle modification including a healthy diet, typically one in which carbohydrate provides 45%–60% of total energy intake (E%). Nevertheless, systematic reviews and meta-analyses of trials with low carbohydrate diets (which are increased in protein and/or fat) for T2D have found improved glycaemic control in the first months relative to comparator diets with higher carbohydrate content. Studies lasting ≥1 year are inconclusive, which could be due to decreased long-term dietary adherence. We hypothesise that glucometabolic benefits can be achieved following 12 months of carbohydrate-restricted dieting, by maximising dietary adherence through delivery of meal kits, containing fresh, high-quality ingredients for breakfast, dinner and snacks, combined with nutrition education and counselling.Methods and analysis This protocol describes a 12-month investigator-initiated randomised controlled, open-label, superiority trial with two parallel groups that will examine the effect of a carbohydrate-reduced high-protein (CRHP) diet compared with a conventional diabetes (CD) diet on glucometabolic control (change in glycated haemoglobin being the primary outcome) in 100 individuals with T2D and body mass index (BMI) >25 kg/m2. Participants will be randomised 1:1 to receive either the CRHP or the CD diet (comprised 30/50 E% from carbohydrate, 30/17 E% from protein and 40/33 E% from fat, respectively) for 12 months delivered as meal kits, containing foods covering more than two-thirds of the participants’ estimated daily energy requirements for weight maintenance. Adherence to the allocated diets will be reinforced by monthly sessions of nutrition education and counselling from registered clinical dietitians.Ethics and dissemination The trial has been approved by the National Committee on Health Research Ethics of the Capital Region of Denmark. The trial will be conducted in accordance with the Declaration of Helsinki. Results will be submitted for publication in international peer-reviewed scientific journals.Trial registration number NCT05330247.Protocol version The trial protocol was approved on 9 March 2022 (study number: H-21057605). The latest version of the protocol, described in this manuscript, was approved on 23 June 2023.

BackgroundAdolescence is a key developmental period that affects lifelong health and is impacted by adolescents regularly engaging with digital health information. Adolescents need digital health literacy (DHL) to effectively evaluate the quality and credibility of such information, and to navigate an increasingly complex digital health environment. Few educational resources exist to improve DHL, and few have involved adolescents during design. The co-design approach may hold utility through developing interventions with participants as design partners. ObjectiveThis project aimed to explore the co-design approach in developing an educational resource to improve adolescents’ DHL. MethodsAdolescents (12-17 years old) attended 4 interactive co-design workshops (June 2021-April 2022). Participant perspectives were gathered on DHL and the design of educational resources to improve it. Data generated were analyzed through content analysis to inform educational resource development. ResultsIn total, 27 participants from diverse backgrounds attended the workshops. Insight was gained into participants’ relationship with digital health information, including acceptance of its benefits and relevance, coupled with awareness of misinformation issues, revealing areas of DHL need. Participants provided suggestions for educational resource development that incorporated the most useful aspects of digital formats to develop skills across these domains. The following 4 themes were derived from participant perspectives: ease of access to digital health information, personal and social factors that impacted use, impacts of the plethora of digital information, and anonymity offered by digital sources. Initial participant evaluation of the developed educational resource was largely positive, including useful suggestions for improvement. ConclusionsCo-design elicited and translated authentic adolescent perspectives and design ideas into a functional educational resource. Insight into adolescents’ DHL needs generated targeted educational resource content, with engaging formats, designs, and storylines. Co-design holds promise as an important and empowering tool for developing interventions to improve adolescents’ DHL.

ABSTRACT Riboflavin (vitamin B2) is the precursor of the flavin coenzymes, FAD and FMN, which play a central role in cellular redox metabolism. While humans must obtain riboflavin from dietary sources, certain microbes, including Mycobacterium tuberculosis (Mtb), can biosynthesize riboflavin de novo. Riboflavin precursors have also been implicated in the activation of mucosal-associated invariant T (MAIT) cells which recognize metabolites derived from the riboflavin biosynthesis pathway complexed to the MHC-I-like molecule, MR1. To investigate the biosynthesis and function of riboflavin and its pathway intermediates in mycobacterial metabolism and physiology, we constructed conditional knockdowns (hypomorphs) in riboflavin biosynthesis and utilization genes in Mycobacterium smegmatis (Msm) and Mtb by inducible CRISPR interference. Using this comprehensive panel of hypomorphs, we analyzed the impact of gene silencing on viability, on the transcription of (other) riboflavin pathway genes, on the levels of the pathway proteins, and on riboflavin itself. Our results revealed that (i) despite lacking a canonical transporter, both Msm and Mtb assimilate exogenous riboflavin when supplied at high concentration; (ii) there is functional redundancy in lumazine synthase activity in Msm; (iii) silencing of ribA2 or ribF is profoundly bactericidal in Mtb; and (iv) in Msm, ribA2 silencing results in concomitant knockdown of other pathway genes coupled with RibA2 and riboflavin depletion and is also bactericidal. In addition to their use in genetic validation of potential drug targets for tuberculosis, this collection of hypomorphs provides a useful resource for future studies investigating the role of pathway intermediates in MAIT cell recognition of mycobacteria.IMPORTANCEThe pathway for biosynthesis and utilization of riboflavin, precursor of the essential coenzymes, FMN and FAD, is of particular interest in the flavin-rich pathogen, Mycobacterium tuberculosis (Mtb), for two important reasons: (i) the pathway includes potential tuberculosis (TB) drug targets and (ii) intermediates from the riboflavin biosynthesis pathway provide ligands for mucosal-associated invariant T (MAIT) cells, which have been implicated in TB pathogenesis. However, the riboflavin pathway is poorly understood in mycobacteria, which lack canonical mechanisms to transport this vitamin and to regulate flavin coenzyme homeostasis. By conditionally disrupting each step of the pathway and assessing the impact on mycobacterial viability and on the levels of the pathway proteins as well as riboflavin, our work provides genetic validation of the riboflavin pathway as a target for TB drug discovery and offers a resource for further exploring the association between riboflavin biosynthesis, MAIT cell activation, and TB infection and disease.

IntroductionMigraine is a debilitating neurological disorder, with a wide range of symptoms and disease burden, underscoring the heterogeneity of patients’ disease characteristics and treatment needs. To characterize the profile of migraine patients in the US who may be eligible for preventive treatment with an anti-CGRP pathway mAb and to better understand treatment patterns and real-world use of acute and preventive medications for migraine, we conducted a retrospective cohort study of adult patients.MethodsThese patients were identified as having migraine using diagnosis codes or migraine-specific medication use (first = index) in the IQVIA PharMetrics® Plus database. Patients were required to have ≥ 12 months of continuous enrollment in medical and pharmacy benefits prior to index (baseline) and after index (follow-up). Patients were stratified into chronic migraine (CM) and non-chronic migraine (non-CM) by diagnosis codes. Based on acute migraine-specific medication dispensing data in the follow-up period, non-CM patients were divided into 3 cohorts: highest, middle, and lowest tertile of total units of dispensed acute migraine-specific medication (gepants, ditans, ergot derivatives, and triptans). Migraine medication use was captured in the baseline and follow-up periods.ResultsA total of 22,584 CM and 216,807 non-CM patients (72,269 patients in each tertile) were identified and included in the study. Over the follow-up, CM patients had a mean of 70 units of acute migraine-specific medications dispensed, while the highest, middle, and lowest tertile of non-CM patients had a mean of 92, 29, and 10 units, respectively. Anti-calcitonin gene-related peptide pathway mAbs were dispensed for 28.9% of CM patients, and for 6.9%, 4.1%, and 2.9% of non-CM patients in the highest, middle, and lowest tertiles, respectively.ConclusionA lower proportion of non-CM patients had use of anti-calcitonin gene-related peptide pathway mAbs compared to CM patients, confirming the unmet need with appropriate preventive medication. There appears to be a persistent gap in management of patients without a diagnosis of CM who are dispensed high quantities of acute migraine-specific medications.

IntroductionHealth systems like the Veterans Health Administration (VA) face challenges in recruiting and retaining a primary care physician workforce. This cross-sectional study of recent or current VA medical residents sought to identify determinants of intent to pursue primary care practice in VA after residency training.MethodsResidents were identified from administrative data between 2020 and 2021 and recruited via an emailed self-administered survey. Multivariable logistic regression, accounting for survey non-response, was applied to examine the association between intent to pursue VA practice and two sets of measures: VA training experiences and individual preferences for work conditions.ResultsOf 268 responses received, 141 (56%) of the sample reported inclination to consider VA employment post-residency. Experiences with training in VA were rated more positively in the VA-inclined group compared to the not-inclined group. In the multivariable model, intent to practice primary care was the strongest predictor (OR 4.04, p

Mutations in the epidermal growth factor receptor (EGFR) are common in non-small cell lung cancer (NSCLC), particularly in never-smoker patients. However, these mutations are not always carcinogenic, and have recently been reported in histologically normal lung tissue from patients with and without lung cancer. To investigate the outcome of EGFR mutation in healthy lung stem cells, we grow murine alveolar type II organoids monoclonally in a three-dimensional Matrigel. Our experiments show that the EGFR-L858R mutation induces a change in organoid structure: mutated organoids display more ‘budding’, in comparison with non-mutant controls, which are nearly spherical. We perform on-lattice computational simulations, which suggest that this can be explained by the concentration of division among a small number of cells on the surface of the mutated organoids. We are currently unable to distinguish the cell-based mechanisms that lead to this spatial heterogeneity in growth, but suggest a number of future experiments which could be used to do so. We suggest that the likelihood of L858R-fuelled tumorigenesis is affected by whether the mutation arises in a spatial environment that allows the development of these surface protrusions. These data may have implications for cancer prevention strategies and for understanding NSCLC progression.

The prevalence of obesity has increased dramatically worldwide and has become a critical public health priority. Obesity is associated with many co-morbid conditions, including hypertension, diabetes, and cardiovascular disease. Although the physiology of obesity is complex, a healthy diet and sufficient exercise are two elements known to be critical to combating this condition. Years of research on the Mediterranean diet, which is high in fresh fruits and vegetables, nuts, fish, and olive oil, have demonstrated a reduction in numerous non-communicable chronic diseases associated with this diet. There is strong evidence to support an anti-inflammatory effect of the diet, and inflammation is a key driver of obesity. Changes in diet alter the gut microbiota which are intricately intertwined with human physiology, as gut microbiota-derived metabolites play a key role in biological pathways throughout the body. This review will summarize recent published studies that examine the potential role of gut metabolites, including short-chain fatty acids, bile acids, trimethylamine-N-oxide, and lipopolysaccharide, in modulating inflammation after consumption of a Mediterranean-like diet. These metabolites modulate pathways of inflammation through the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, toll-like receptor 4 signaling, and macrophage driven effects in adipocytes, among other mechanisms.

Introduction: More brands are using tobacco-free nicotine (TFN) in electronic cigarettes (e-cigarettes) and these products are becoming increasingly popular. The term TFN and claims about its properties can mislead consumers about the harms and addictiveness of TFN e-cigarettes, which may increase initiation of these products among non-smokers or influence current smokers’ decisions to adopt TFN e-cigarettes as a harm reduction measure. Methods: We conducted an observational, cross-sectional survey of 777 adolesc aged 13–17 and 655 current adult cigarette smokers residing in Massachusetts, Connecticut, New Hampshire, Rhode Island, or Vermont about their TFN e-cigarette awareness, use, perceptions, and susceptibility. We examined the association between prior awareness of TFN and use, perceptions, and susceptibility. Results: One-third of adolescents and adults reported being aware of TFN. TFN e-cigarette use was less common than tobacco-derived nicotine (TDN) e-cigarette use among adolescents (8.9 % vs. 30.5 %) and adults (21.1 % vs. 79.4 %). Compared to unaware adolescents, adolescents who were aware of TFN more frequently reported being more likely to use TFN compared to TDN e-cigarettes and that TFN e-cigarettes are more addictive than those containing TDN. Aware adult smokers more frequently reported that TFN e-cigarettes are more addictive than TDN e-cigarettes, TFN e-cigarettes cause some harm, TDN e-cigarettes cause little harm, and that TFN and TDN e-cigarettes are equally harmful than those who were unaware previously. Conclusion: Public health education campaigns are needed to educate consumers about the harms and addictiveness of TFN e-cigarettes.

ABSTRACT Motility promotes biofilm initiation during the early steps of this process: microbial surface association and attachment. Motility is controlled in part by chemotaxis signaling, so it seems reasonable that chemotaxis may also affect biofilm formation. There is a gap, however, in our understanding of the interactions between chemotaxis and biofilm formation, partly because most studies analyzed the phenotype of only a single chemotaxis signaling mutant, e.g., cheA. Here, we addressed the role of chemotaxis in biofilm formation using a full set of chemotaxis signaling mutants in Helicobacter pylori, a class I carcinogen that infects more than half the world’s population and forms biofilms. Using mutants that lack each chemotaxis signaling protein, we found that chemotaxis signaling affected the biofilm initiation stage, but not mature biofilm formation. Surprisingly, some chemotaxis mutants elevated biofilm initiation, while others inhibited it in a manner that was not tied to chemotaxis ability or ligand input. Instead, the biofilm phenotype correlated with flagellar rotational bias. Specifically, mutants with a counterclockwise bias promoted biofilm initiation, e.g., ∆cheA, ∆cheW, or ∆cheV1; in contrast, those with a clockwise bias inhibited it, e.g., ∆cheZ, ∆chePep, or ∆cheV3. We tested this correlation using a counterclockwise bias-locked flagellum, which induced biofilm formation independent of the chemotaxis system. These CCW flagella, however, were not sufficient to induce biofilm formation, suggesting there are downstream players. Overall, our work highlights the new finding that flagellar rotational direction promotes biofilm initiation, with the chemotaxis signaling system operating as one mechanism to control flagellar rotation.IMPORTANCEChemotaxis signaling systems have been reported to contribute to biofilm formation in many bacteria; however, how they regulate biofilm formation remains largely unknown. Chemotaxis systems are composed of many distinct kinds of proteins, but most previous work analyzed the biofilm effect of loss of only a few. Here, we explored chemotaxis’ role during biofilm formation in the human-associated pathogenic bacterium Helicobacter pylori. We found that chemotaxis proteins are involved in biofilm initiation in a manner that correlated with how they affected flagellar rotation. Biofilm initiation was high in mutants with counterclockwise (CCW) flagellar bias and low in those with clockwise bias. We supported the idea that a major driver of biofilm formation is flagellar rotational direction using a CCW-locked flagellar mutant, which stays CCW independent of chemotaxis input and showed elevated biofilm initiation. Our data suggest that CCW-rotating flagella, independent of chemotaxis inputs, are a biofilm-promoting signal.

Photothermal therapy (PTT) has garnered extensive attention as an efficient strategy for cancer therapy. Unfortunately, there are currently no suitable photothermal agents (PTAs) capable of effectively treating HER2-positive breast cancer (HER2+ BC) due to the challenges in addressing blood circulation and tumor accumulation. Here, we propose a HER2-specific macrophage biomimetic nanoplatform IR820@ZIF-8@EM (AMBP) for enhanced bio-photothermal therapy of HER2+ BC. An anti-HER2 antibody was expressed in engineered macrophages using the transmembrane expression technique. As an efficient PTAs, IR820 dyes were assembled into ZIF-8 as to develop a “nano-thermal-bomb”. Homology modeling methods support that the expressed anti-HER2 antibody can specifically recognize the HER2 receptor. Moreover, antibody-dependent cell-mediated cytotoxicity can also be induced in HER2+ BC cells by AMBP. In vitro fluorescence confocal imaging showed that AMBP promoted the uptake of HER2+ cancer cells while in vivo anti-tumor experiments demonstrated that AMBP efficiently accumulates in the tumor regions. Finally, under spatiotemporally controlled near-infrared (NIR) irradiation, three of the six tumors were eradicated in AMBP-treated mice, demonstrating a safe and effective strategy. In conclusion, our research opens a new paradigm for antibody-specific macrophage, and it is expected that these characteristics will have substantial clinical translation potential for BC treatment.

Abstract Background Sustainability of evidence-based interventions (EBIs) is suboptimal in healthcare. Evidence on how knowledge translation (KT) strategies are used for the sustainability of EBIs in practice is lacking. This study examined what and how KT strategies were used to facilitate the sustainability of Alberta Family Integrated Care (FICare)™, a psychoeducational model of care scaled and spread across 14 neonatal intensive care units, in Alberta, Canada. Methods First, we conducted an environmental scan of relevant documents to determine the use of KT strategies to support the sustainability of Alberta FICare™. Second, we conducted semi-structured interviews with decision makers and operational leaders to explore what and how KT strategies were used for the sustainability of Alberta FICare™, as well as barriers and facilitators to using the KT strategies for sustainability. We used the Expert Recommendations for Implementation Change (ERIC) taxonomy to code the strategies. Lastly, we facilitated consultation meetings with the Alberta FICare™ leads to share and gain insights and clarification on our findings. Results We identified nine KT strategies to facilitate the sustainability of Alberta FICare™: Conduct ongoing training; Identify and prepare local champions; Research co-production; Remind clinicians; Audit and provide feedback; Change record systems; Promote adaptability; Access new funding; and Involve patients/consumers and family members. A significant barrier to the sustainability of Alberta FICare™ was a lack of clarity on who was responsible for the ongoing maintenance of the intervention. A key facilitator to sustainability of Alberta FICare was its alignment with the Maternal, Newborn, Child & Youth Strategic Clinical Network (MNCY SCN) priorities. Co-production between researchers and health system partners in the design, implementation, and scale and spread of Alberta FICare™ was critical to sustainability. Conclusion This research highlights the importance of clearly articulating who is responsible for continued championing for the sustainability of EBIs. Additionally, our research demonstrates that the adaptation of interventions must be considered from the onset of implementation so interventions can be tailored to align with contextual barriers for sustainability. Clear guidance is needed to continually support researchers and health system leaders in co-producing strategies that facilitate the long-term sustainability of effective EBIs in practice.