A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models.

Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6ßrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.

Mycoplasma hyorhinis infection promotes TNF-α signaling and SMAC mimetic-mediated apoptosis in human prostate cancer.

Growing evidence suggests an association between Mycoplasma infections and the development and progression of prostate cancer (PCa). In this study, we report that chronic and persistent M. hyorhinis infection induced robust TNF-α secretion from PCa cells. TNF-α secreted from M. hyorhinis-infected PCa cells subsequently led to activation of the NF-κB pathway. Chronic M. hyorhinis infection induced gene expression of pro-inflammatory cytokines and chemokines in a NF-κB-dependent manner and promoted cell proliferation, migration, and invasion in PCa cells. The elimination of M. hyorhinis in PCa cells significantly blocked TNF-α secretion, gene expression of cytokines and chemokines, migration, and invasion in PCa cells, suggesting M. hyorhinis-induced TNF-α plays an important role to promote malignant transformation of PCa. Furthermore, second mitochondria-derived activator of caspases (SMAC) mimetics potentiated caspase activation and cell death in M. hyorhinis-infected PCa by antagonizing inhibitor of apoptosis proteins (IAPs) activity. Tissue microarray analysis indicated that TNF-α is co-expressed in M. hyorhinis-infected human patient tissues. Findings from this study advance our understanding of the mycoplasma-oncogenesis process and suggest the potential for new approaches for preventions, diagnosis, and therapeutic approaches against prostate cancers.

Personal risk or societal benefit? Investigating adults' support for COVID-19 childhood vaccination.

Parental hesitancy poses a serious threat to the success of the COVID-19 childhood vaccination campaign. We investigate whether adults' opinions on childhood vaccination can be influenced via two survey experiments in Italy (n = 3,633 participants) and the UK (n = 3,314 participants). Respondents were randomly assigned to: a "risk treatment" that highlighted the potential risks of COVID-19 to a child, a "herd immunity treatment" that emphasized the community benefits of pediatric vaccination, or a control message. Participants' probability of supporting COVID-19 childhood vaccination was then assessed on a 0-100 scale. We find that the "risk treatment" reduced the proportion of Italian parents strongly against vaccination by up to 29.6 %, while increasing the proportion of neutral parents by up to 45.0 %. The "herd immunity treatment", instead, was only effective among non-parents, resulting in a lower proportion of individuals against pediatric vaccination and a higher proportion of individuals in favor (both shifted by around 20 %).

Survey of Orthopaedic Trauma Providers: Is MRI Superior to CT Scan for Evaluating and Preoperative Planning for Tibial Plateau Fractures?

A computerized tomography (CT) scan is the current advanced imaging standard of care for evaluation and preoperative planning for tibial plateau fractures, but magnetic resonance imaging (MRI) is emerging as a better method to identify soft tissue injuries. This study compares MRI and CT for fracture classification, associated soft tissue injuries, and preoperative planning for tibial plateau fractures. MRI offers lack of radiation and enhanced soft tissue evaluation, and as a result improved preoperative planning. MRI was favored among survey respondents for preoperative planning, Schatzker classification, and surgical approach planning.

Observation of ultracold atomic bubbles in orbital microgravity.

Substantial leaps in the understanding of quantum systems have been driven by exploring geometry, topology, dimensionality and interactions in ultracold atomic ensembles1-6. A system where atoms evolve while confined on an ellipsoidal surface represents a heretofore unexplored geometry and topology. Realizing an ultracold bubble-potentially Bose-Einstein condensed-relates to areas of interest including quantized-vortex flow constrained to a closed surface topology, collective modes and self-interference via bubble expansion7-17. Large ultracold bubbles, created by inflating smaller condensates, directly tie into Hubble-analogue expansion physics18-20. Here we report observations from the NASA Cold Atom Lab21 facility onboard the International Space Station of bubbles of ultracold atoms created using a radiofrequency-dressing protocol. We observe bubble configurations of varying size and initial temperature, and explore bubble thermodynamics, demonstrating substantial cooling associated with inflation. We achieve partial coverings of bubble traps greater than one millimetre in size with ultracold films of inferred few-micrometre thickness, and we observe the dynamics of shell structures projected into free-evolving harmonic confinement. The observations are among the first measurements made with ultracold atoms in space, using perpetual freefall to explore quantum systems that are prohibitively difficult to create on Earth. This work heralds future studies (in orbital microgravity) of the Bose-Einstein condensed bubble, the character of its excitations and the role of topology in its evolution.

Implementing patient navigation programs: Considerations and lessons learned from the Alliance to Advance Patient-Centered Cancer Care.

BACKGROUND: Six multidisciplinary cancer centers were selected and funded by the Merck Foundation (2017-2021) to collaborate in the Alliance to Advance Patient-Centered Cancer Care ("Alliance"), an initiative to improve patient access, minimize health disparities, and enhance the quality of patient-centered cancer care. These sites share their insights on implementation and expansion of their patient navigation efforts. METHODS: Patient navigation represents an evidence-based health care intervention designed to enhance patient-centered care and care coordination. Investigators at 6 National Cancer Institute-designated cancer centers outline their approaches to reducing health care disparities and synthesize their efforts to ensure sustainability and successful transferability in the management of patients with cancer and their families in real-world health care settings. RESULTS: Insights are outlined within the context of patient navigation program effectiveness and supported by examples from Alliance cancer center sites: 1) understand the patient populations, particularly underserved and high-risk patients; 2) capitalize on the existing infrastructure and institutional commitment to support and sustain patient navigation; and 3) build capacity by mobilizing community support outside of the cancer center. CONCLUSIONS: This process-level article reflects the importance of collaboration and the usefulness of partnering with other cancer centers to share interdisciplinary insights while undergoing intervention development, implementation, and expansion. These collective insights may be useful to staff at other cancer centers that look to implement, enhance, or evaluate the effectiveness of their patient navigation interventions.

Enhancing clinician participation in quality improvement training: implementation and impact of an evidence-based initiative to maximise antenatal clinician participation in training regarding women's alcohol consumption during pregnancy.

BACKGROUND: There are significant challenges in ensuring sufficient clinician participation in quality improvement training. Clinician capability has been identified as a barrier to the delivery of evidence-based care. Clinician training is an effective strategy to address this barrier, however, there are significant challenges in ensuring adequate clinician participation in training. This study aimed to assess the extent of participation by antenatal clinicians in evidence-based training to address alcohol consumption during pregnancy, and to assess differences in participation by profession. METHODS: A 7-month training initiative based on six evidence-based principles was implemented in a maternity service in New South Wales, Australia. Descriptive statistics described participation in training (% attending: any training; six evidence-based principles of training; all principles). Regression analyses examined differences by profession. RESULTS: Almost all antenatal clinicians participated in some training (182/186; 98%); 69% participated in ≥1 h of training (µ = 88.2mins, SD:56.56). The proportion of clinicians participating in training that satisfied each of the six principles ranged from 35% (training from peers and experts) to 82% (training was educational and instructional). Only 7% participated in training that satisfied all principles. A significantly higher proportion of midwifery compared to medical clinicians participated in training satisfying five of the six training principles. CONCLUSIONS: A training initiative based on evidence-based principles resulted in almost all clinicians receiving some training and 69% participating in at least 1 h of training. Variability between professions suggests training needs to be tailored to such groups. Further research is required to determine possible associations with care delivery outcomes. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, No. ACTRN12617000882325 (date registered: 16/06/2017).

Readability of Online Hand Surgery Patient Educational Materials: Evaluating the Trend Since 2008.

PURPOSE: Online patient educational materials have historically been written at a higher-than-recommended sixth grade reading level. The objectives of this study were to assess the readability of online hand surgery patient educational materials from the official online patient resource website of the American Society for Surgery of the Hand (ASSH) and to compare changes in the readability of the current ASSH online patient educational materials with those in 2008 and 2015. METHODS: An internet-based study of all 88 English language patient educational materials on HandCare.org, the official online patient resource website of the ASSH, was performed. The readability of each article was assessed using the Flesch reading ease formula, Flesch-Kincaid grade level, Coleman-Liau index, Gunning-Fog index, and Simple Measure of Gobbledygook grade level. To evaluate the trend in the readability of ASSH online hand surgery patient educational materials, the Flesch-Kincaid grade levels of articles published in 2020 were compared with those of data published in 2008 and 2015. RESULTS: The average Flesch reading ease score of the patient educational materials was 57.6, which is at the high-school reading level. The average reading grade level of patient educational materials ranged from 9.0 to 12.3 depending on the readability metric used. The average Flesch-Kincaid grade level of all the ASSH patient educational materials was 9.8 in 2020, which is significantly better than 10.4 in 2008 but significantly worse than 8.5 in 2015. CONCLUSIONS: Online hand surgery patient educational materials continue to be written for the general public at a higher-than-recommended reading grade level. There has been no substantial improvement in the readability of online hand surgery patient educational materials since 2008. CLINICAL RELEVANCE: Improvements are needed in the readability of online patient educational materials to ensure that patients with all health literacy levels are able to comprehend and benefit from health information.

Experimental evidence that changing beliefs about mask efficacy and social norms increase mask wearing for COVID-19 risk reduction: Results from the United States and Italy.

In the absence of widespread vaccination for COVID-19, governments and public health officials have advocated for the public to wear masks during the pandemic. The decision to wear a mask in public is likely affected by both beliefs about its efficacy and the prevalence of the behavior. Greater mask use in the community may encourage others to follow this norm, but it also creates an incentive for individuals to free ride on the protection afforded to them by others. We report the results of two vignette-based experiments conducted in the United States (n = 3,100) and Italy (n = 2,659) to examine the causal relationship between beliefs, social norms, and reported intentions to engage in mask promoting behavior. In both countries, survey respondents were quota sampled to be representative of the country's population on key demographics. We find that providing information about how masks protect others increases the likelihood that someone would wear a mask or encourage others to do so in the United States, but not in Italy. There is no effect of providing information about how masks protect the wearer in either country. Additionally, greater mask use increases intentions to wear a mask and encourage someone else to wear theirs properly in both the United States and Italy. Thus, community mask use may be self-reinforcing.

National interest may require distributing COVID-19 vaccines to other countries.

As immunization campaigns are accelerating, understanding how to distribute the scarce doses of vaccines is of paramount importance and a quantitative analysis of the trade-offs involved in domestic-only versus cooperative distribution is still missing. In this study we use a network Susceptible-Infected-Removed (SIR) model to show circumstances under which it is in a country's self-interest to ensure other countries can obtain COVID-19 vaccines rather than focusing only on vaccination of their own residents. In particular, we focus our analysis on the United States and estimate the internal burden of COVID-19 disease under different scenarios about vaccine cooperation. We show that in scenarios in which the US has reached the threshold for domestic herd immunity, the US may find it optimal to donate doses to other countries with lower vaccination coverage, as this would allow for a sharp reduction in the inflow of infected individuals from abroad.

Impact of Conventional and Open Access Publications in Orthopaedic Surgery.

INTRODUCTION: The academic impact of open access publications compared with conventional publications in orthopaedic surgery is not well described. The primary objective of this study was to compare the number of academic citations and social media posts between recent conventional and open access publications in orthopaedic surgery. Secondary objectives of this study were (1) to determine the correlation between academic citations and social media posts and (2) to study the trend of academic citations and social media posts over time. METHODS: An internet-based study was performed on 3,720 articles from five high-impact orthopaedic journals and their associated open access journals from March 2017 to February 2019, including 2,929 conventional and 791 open access journal publications. Academic citations were quantified using Google Scholar and Web of Science, and social media mentions using Twitter. The Mann-Whitney U test was used for comparisons of nonparametric data, and the Spearman rank correlation coefficient was calculated for correlations. RESULTS: The average number of academic citations per article was 10.1 on Google Scholar and 6.0 on Web of Science. The average number of Twitter posts per article was 1.6. Conventional publications had markedly more citations than open access publications on Google Scholar and Web of Science. Open access publications had markedly more Twitter posts, but the effect size was small and unimportant. Academic citations were weakly correlated with social media posts. On average, orthopaedic publications accrue 7.4 citations per year on Google Scholar and 4.6 citations per year on Web of Science. DISCUSSION: Our findings support a citation advantage to conventional publication. Publications in open access journals are cited less frequently and less rapidly compared with those in conventional journals. The use of social media for orthopaedic research is effectively equivalent between conventional and open access journals and continues to grow. LEVEL OF EVIDENCE: N/A.

Beliefs about Mask Efficacy and the Effect of Social Norms on Mask Wearing Intentions for COVID-19 Risk Reduction

In the absence of widespread vaccination for COVID-19, governments and public health officials have advocated for the public to wear masks during the pandemic. The decision to wear a mask in public is likely affected by both beliefs about its efficacy and the prevalence of the behavior. Greater mask use in the community may encourage others to follow this norm, but it also creates an incentive for individuals to free ride on the protection afforded to them by others. We report the results of two vignette-based experiments conducted in the United States and Italy to examine the causal relationship between beliefs, social norms, and reported intentions to engage in mask promoting behavior. We find that providing factual information about how masks protect others increases the likelihood that someone would wear a mask or encourage others to do so in the United States, but not in Italy. There is no effect of providing information about how masks protect the wearer in either country. Additionally, greater mask use increases intentions to wear a mask and encourage someone else to wear theirs properly in both the United States and Italy. Thus, community mask use may be self-reinforcing.

National interest may require distributing COVID-19 vaccines to other countries

As the clinical trials for COVID-19 vaccine progress, understanding how to distribute the initially scarce doses is of paramount importance and a quantitative analysis of the trade-offs involved in domestic-only versus cooperative distribution is still missing. In this study we use a network Susceptible-Infected-Removed (SIR) model to show under which circumstances it is in a countrys self-interest to ensure other countries can also obtain a COVID-19 vaccine rather than focusing only on vaccination of their own residents. In particular, we focus our analysis on the USs decision and estimate the internal burden of COVID-19 disease under different scenarios about vaccine cooperation. We show that in scenarios in which the US has reached the threshold for domestic herd immunity, the US may find it optimal to donate doses to other countries with lower vaccination coverage, as this would allow for a sharp reduction in the inflow of infected individuals from abroad.

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B.

BACKGROUND: Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan-McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular vesicle that contains important molecular information of the cell and are used for cell-to-cell communication. Within the fraction of the extracellular vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect. METHODS: Exosomes derived from MSC (MSC-exo) were purified, characterized, and given via intranasal administration to Shank3B KO mice (in the concentration of 107 particles/ml). Three weeks post treatment, the mice were tested for behavioral scoring, and their results were compared with saline-treated control and their wild-type littermates. RESULTS: Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization, and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex. CONCLUSIONS: Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mouse model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model of autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.

Community Priority setting for Fetal Alcohol Spectrum Disorder Research in Australia.

INTRODUCTION: Fetal Alcohol Spectrum Disorder (FASD) is a neurodevelopmental disorder caused by prenatal alcohol exposure (PAE). FASD research is a rapidly growing field that crosses multiple disciplines. To ensure research is relevant and meaningful for people living with FASD, their families, and the broader public there is a need to engage community members in setting priorities for research. OBJECTIVES: Our primary objective was to formally identify the views of people living with FASD, their parents/caregivers, service providers, and the general community on the research priorities for FASD and alcohol use in pregnancy in Australia. Our secondary objective was to provide an overview of current research in the highest priority areas identified. METHODS: The approach for this study involved two community surveys and a consensus workshop, followed by a rapid literature review. Survey responses (n = 146) were collected and grouped using qualitative thematic analysis. The themes identified were then ranked in a second survey (n = 45). The 22 highest ranked themes were considered in a workshop with 21 community members, and consensus on the top ten priority areas was sought. The priority areas were grouped into conceptually similar topics and rapid literature reviews were undertaken on each. RESULTS: A diverse range of priorities was identified within key areas of prevention, diagnosis, and therapy. On request from participants, separate priority lists were developed by Aboriginal and non-Aboriginal participants. CONCLUSION: There is need for a national network of researchers to take forward the research commenced by the Centre of Research Excellence, FASD Research Australia, in addressing community priorities. KEY WORDS: Community, priorities, FASD, rapid review, Australia.

Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis.

AIMS: Clusterin is a topologically dynamic chaperone protein with the ability to participate in both intra- and extacellular proteostasis. Clusterin has been shown to be upregulated in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) and has been shown to protect against TDP-43 protein misfolding in animal and cell models. Previous studies have demonstrated an association between the pathological burden of TDP-43 misfolding and cognitive deficits in ALS, demonstrating high specificity, but correspondingly low sensitivity owing to a subset of individuals with no evidence of cognitive deficits despite a high burden of TDP-43 pathology, called mismatch cases. METHODS: Hypothesizing that differences in the ability to cope with protein misfolding in these cases may be due to differences in expression of protective mechanisms such as clusterin expression, we assessed the spatial expression of clusterin and another chaperone protein, HspB8, in post mortem brain tissue of mismatch cases. We employed a modified in situ hybridization technique called BaseScope, with single cell, single transcript resolution. RESULTS: Mismatch cases demonstrated differential spatial expression of clusterin, with a predominantly neuronal pattern, compared to cases with cognitive manifestations of their TDP-43 pathology who demonstrated a predominantly glial distribution of expression. CONCLUSIONS: Our data suggest that, in individuals with TDP-43 pathology, predominantly neuronal expression of clusterin in extra-motor brain regions may indicate a cell protective mechanism delaying clinical manifestations such as cognitive dysfunction.

Toward the improvement of total nitrogen deposition budgets in the United States.

Frameworks for limiting ecosystem exposure to excess nutrients and acidity require accurate and complete deposition budgets of reactive nitrogen (Nr). While much progress has been made in developing total Nr deposition budgets for the U.S., current budgets remain limited by key data and knowledge gaps. Analysis of National Atmospheric Deposition Program Total Deposition (NADP/TDep) data illustrates several aspects of current Nr deposition that motivate additional research. Averaged across the continental U.S., dry deposition contributes slightly more (55%) to total deposition than wet deposition and is the dominant process (>90%) over broad areas of the Southwest and other arid regions of the West. Lack of dry deposition measurements imposes a reliance on models, resulting in a much higher degree of uncertainty relative to wet deposition which is routinely measured. As nitrogen oxide (NOx) emissions continue to decline, reduced forms of inorganic nitrogen (NHx = NH3 + NH4+) now contribute >50% of total Nr deposition over large areas of the U.S. Expanded monitoring and additional process-level research are needed to better understand NHx deposition, its contribution to total Nr deposition budgets, and the processes by which reduced N deposits to ecosystems. Urban and suburban areas are hotspots where routine monitoring of oxidized and reduced Nr deposition is needed. Finally, deposition budgets have incomplete information about the speciation of atmospheric nitrogen; monitoring networks do not capture important forms of Nr such as organic nitrogen. Building on these themes, we detail the state of the science of Nr deposition budgets in the U.S. and highlight research priorities to improve deposition budgets in terms of monitoring and flux measurements, leaf- to regional-scale modeling, source apportionment, and characterization of deposition trends and patterns.

Return to Play after Patellar Stabilization.

PURPOSE OF REVIEW: The purpose of this review is to evaluate the existing literature regarding return to play (RTP) and return to prior performance (RPP) following patellar stabilization surgery. It will also discuss suggested guidelines regarding RTP, and finally, to encourage future patellofemoral instability research to report and publish results of RTP rates using standardized RTP guidelines. RECENT FINDINGS: There is a lack of validation and universal adoption of standardized RTP guidelines. This has led to a dearth of high-quality studies on RTP and RPP after patellar stabilization. The best available studies to date would suggest high RTP rates (84%-100%), average RPP rates (33%-77%), and a highly variable timeframe for return (3-12 months). Patellofemoral instability can be a persistent and challenging problem, particularly in the young and active population for which it most often occurs. Much of the previous studies on patellofemoral instability evaluated success and failure as prevention of recurrent dislocation. However, prevention of recurrence alone may not be enough for many patients. The best available data on RTP and RPP following patellofemoral instability is based on lower quality of evidence studies, expert opinion, and published societal guidelines. Future research on this topic should include clinical validation of the International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine (ISAKOS) RTP guidelines and reporting of outcomes based on these guidelines in patellofemoral instability publications.

The creative turn in evidence for public health: community and arts-based methodologies.

Background: We propose that arts based methodologies can be of value in the production and exchange of evidence in supporting public health related policy. This article reports on a collaborative piece of work resulting from two projects which took place in a former coal mining town in South Wales. Methods: We used a participatory framework whereby researchers, community members and artists co-produced 'evidence' through the creative arts to inform public policy. We collected a range of data using a number of different techniques, including interviews, focus groups and observation, but also included an extensive range of creative activities. Results: The data provided a diverse range of perspectives on how people of different ages live their lives. The People's Platform was a performance-based debate which was the culmination of the collaboration. The show involved a series of short performances with time for facilitated discussion in-between. It was felt that the show facilitated knowledge exchange on health and wellbeing issues that are usually difficult to express and understand through traditional forms of evidence. Conclusion: Whilst arts-based approaches are not free from risk, they offer an alternative form of knowledge as a necessary complement to the range of data available to policy makers.

Integrin alpha V beta 3 targeted dendrimer-rapamycin conjugate reduces fibroblast-mediated prostate tumor progression and metastasis.

Therapeutic strategies targeting both cancer cells and associated cells in the tumor microenvironment offer significant promise in cancer therapy. We previously reported that generation 5 (G5) dendrimers conjugated with cyclic-RGD peptides target cells expressing integrin alpha V beta 3. In this study, we report a novel dendrimer conjugate modified to deliver the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In vitro analyses demonstrated that this drug conjugate, G5-FI-RGD-rapamycin, binds to prostate cancer (PCa) cells and fibroblasts to inhibit mTOR signaling and VEGF expression. In addition, G5-FI-RGD-rapamycin inhibits mTOR signaling in cancer cells more efficiently under proinflammatory conditions compared to free rapamycin. In vivo studies established that G5-FI-RGD-rapamycin significantly inhibits fibroblast-mediated PCa progression and metastasis. Thus, our results suggest the potential of new rapamycin-conjugated multifunctional nanoparticles for PCa therapy.