Heparin-binding epidermal growth factor and fibroblast growth factor 2 rescue Müller glia-derived progenitor cell formation in microglia- and macrophage-ablated chick retinas.

Recent studies have demonstrated the impact of pro-inflammatory signaling and reactive microglia/macrophages on the formation of Müller glial-derived progenitor cells (MGPCs) in the retina. In chick retina, ablation of microglia/macrophages prevents the formation of MGPCs. Analyses of single-cell RNA-sequencing chick retinal libraries revealed that quiescent and activated microglia/macrophages have a significant impact upon the transcriptomic profile of Müller glia (MG). In damaged monocyte-depleted retinas, MG fail to upregulate genes related to different cell signaling pathways, including those related to Wnt, heparin-binding epidermal growth factor (HBEGF), fibroblast growth factor (FGF) and retinoic acid receptors. Inhibition of GSK3ß, to simulate Wnt signaling, failed to rescue the deficit in MGPC formation, whereas application of HBEGF or FGF2 completely rescued the formation of MGPCs in monocyte-depleted retinas. Inhibition of Smad3 or activation of retinoic acid receptors partially rescued the formation of MGPCs in monocyte-depleted retinas. We conclude that signals produced by reactive microglia/macrophages in damaged retinas stimulate MG to upregulate cell signaling through HBEGF, FGF and retinoic acid, and downregulate signaling through TGFß/Smad3 to promote the reprogramming of MG into proliferating MGPCs.

ID factors regulate the ability of Müller glia to become proliferating neurogenic progenitor-like cells.

The purpose of this study was to investigate how ID factors regulate the ability of Müller glia (MG) to reprogram into proliferating MG-derived progenitor cells (MGPCs) in the chick retina. We found that ID1 is transiently expressed by maturing MG (mMG), whereas ID4 is maintained in mMG in embryonic retinas. In mature retinas, ID4 was prominently expressed by resting MG, but following retinal damage ID4 was rapidly upregulated and then downregulated in MGPCs. By contrast, ID1, ID2, and ID3 were low in resting MG and then upregulated in MGPCs. Inhibition of ID factors following retinal damage decreased numbers of proliferating MGPCs. Inhibition of IDs, after MGPC proliferation, significantly increased numbers of progeny that differentiated as neurons. In damaged or undamaged retinas inhibition of IDs increased levels of p21Cip1 in MG. In response to damage or insulin+FGF2 levels of CDKN1A message and p21Cip1 protein were decreased, absent in proliferating MGPCs, and elevated in MG returning to a resting phenotype. Inhibition of notch- or gp130/Jak/Stat-signaling in damaged retinas increased levels of ID4 but not p21Cip1 in MG. Although ID4 is the predominant isoform expressed by MG in the chick retina, id1 and id2a are predominantly expressed by resting MG and downregulated in activated MG and MGPCs in zebrafish retinas. We conclude that ID factors have a significant impact on regulating the responses of MG to retinal damage, controlling the ability of MG to proliferate by regulating levels of p21Cip1, and suppressing the neurogenic potential of MGPCs.

Indole Nucleophile Triggers Mechanistic Divergence in Ni-Photoredox N-Arylation.

This study presents a Ni-photoredox method for indole N-arylation, broadening the range of substrates to include indoles with unprotected C3-positions and base-sensitive groups. Through detailed mechanistic inquiries, a Ni(I/III) mechanism was uncovered, distinct from those commonly proposed for Ni-catalyzed amine, thiol, and alcohol arylation, as well as from the Ni(0/II/III) cycle identified for amide arylation under almost identical conditions. The key finding is the formation of a Ni(I) intermediate bearing the indole nucleophile as a ligand prior to oxidative addition, which is rare for Ni-photoredox carbon-heteroatom coupling and has a profound impact on the reaction kinetics and scope. The pre-coordination of indole renders a more electron-rich Ni(I) intermediate, which broadens the scope by enabling fast reactivity even with challenging electron-rich aryl bromide substrates. Thus, this work highlights the often-overlooked influence of X-type ligands on Ni oxidative addition rates and illustrates yet another mechanistic divergence in Ni-photoredox C-heteroatom couplings.

Leveraging the Redox Promiscuity of Nickel To Catalyze C-N Coupling Reactions.

This perspective details advances made in the field of Ni-catalyzed C-N bond formation. The use of this Earth abundant metal to decorate amines, amides, lactams, and heterocycles enables direct access to a variety of biologically active and industrially relevant compounds in a sustainable manner. Herein, different strategies that leverage the propensity of Ni to facilitate both one- and two-electron processes will be surveyed. The first part of this Perspective focuses on strategies that facilitate C-N couplings at room temperature by accessing oxidized Ni(III) intermediates. In this context, advances in photochemical, electrochemical, and chemically mediated processes will be analyzed. A special emphasis has been put on providing a comprehensive explanation of the different mechanistic avenues that have been proposed to facilitate these chemistries; either Ni(I/III) self-sustained cycles or Ni(0/II/III) photochemically mediated pathways. The second part of this Perspective details the ligand designs that also enable access to this reactivity via a two-electron Ni(0/II) mechanism. Finally, we discuss our thoughts on possible future directions of the field.

The Characteristics and HIV-Related Outcomes of People Living with Co-occurring HIV and Mental Health Conditions in the United States: A Systematic Review of Literature from 2016 to 2021.

Considering advances in HIV prevention and treatment, jurisdictional efforts to end the HIV/AIDS epidemic, and reduced stigma towards people living with HIV infection and mental health conditions, the authors systematically reviewed studies published between 2016 and 2021 and identified 45 studies that met the eligibility criteria. The review found that stigma towards mental health conditions still acts as a barrier to accessing HIV treatment, which impacts treatment outcomes. Additionally, social determinants of health, such as housing instability and poverty, appear to impact mental health and, therefore, HIV-related outcomes. The review also highlighted the mutually reinforcing effects of HIV, mental health, and substance use conditions, providing valuable insights into the syndemic effects of these co-occurring conditions. Overall, the review highlights the need to address stigma and social determinants of health in HIV prevention and treatment efforts and to integrate mental health services into HIV care to improve outcomes for people living with both HIV and mental health conditions.

Shaping research for people living with co-existing mental and physical health conditions: A research priority setting initiative from the United Kingdom.

INTRODUCTION: Those with severe and enduring mental ill health are at greater risk of long-term physical health conditions and have a reduced life expectancy as a result. Multiple factors compound this health inequality, and the need for setting research priorities in this area is highlighted with physical and mental healthcare services being separate, and limited multimorbidity research. METHODS: The aim of this exercise was to work in partnership with healthcare professionals and carers, family, friends and individuals with lived experience of both mental and physical health conditions, to set research priorities to help people with mental health conditions to look after their physical health. The exercise was guided by the James Lind Alliance approach. For this, a steering group was set up, two surveys were completed and a final priority workshop was conducted. RESULTS: This priority setting exercise guided by people's needs and lived experience has produced a set of well-defined research topics. Initially, 555 research questions were suggested in the first survey, which were refined to 54 questions for the second survey. A priority setting workshop was then conducted to get the final 10 priorities. CONCLUSIONS: Taking these topics forward to improve services and treatment for both mental and physical ill health may in turn improve physical health and lessen the reduced life expectancy of those living with mental ill health. PATIENT OR PUBLIC CONTRIBUTION: This work was completed in collaboration with people who have lived experience of mental ill health and physical health conditions, as well as carers, family and friends. Their contribution has been significant for this work from piloting surveys, amending language used and educating the researchers and contributing to this paper. The initial work was completed with a steering group and continued with surveys and workshops.

Chronic Stress Impairs the Structure and Function of Astrocyte Networks in an Animal Model of Depression.

Now astrocytes appear to be the key contributors to the pathophysiology of major depression. Evidence in rodents shows that chronic stress is associated with a decreased expression of astrocytic GFAP-immunoreactivity within the cortex in addition to changes in the complexity and length of astrocyte processes. Furthermore, postmortem brains of individuals with depression have revealed a decrease in astrocyte density. Notably, astrocytes are extensively coupled to one another through gap junctions to form a network, or syncytium, and we have previously demonstrated that syncytial isopotentiality is a mechanism by which astrocytes function as an efficient system with respect to brain homeostasis. Interestingly, the question of how astrocyte network function changes following chronic stress is yet to be elucidated. Here, we sought to examine the effects of chronic stress on network-level astrocyte (dys)function. Using a transgenic aldh1l1-eGFP astrocyte reporter mouse, a six-week unpredictable chronic mild stress (UCMS) paradigm as a rodent model of major depression, and immunohistochemical approaches, we show that the morphology of individual astrocytes is altered by chronic stress exposure. Additionally, in astrocyte syncytial isopotentiality measurement, we found that UCMS impairs the syncytial coupling strength of astrocytes within the hippocampus and prefrontal cortex-two brain regions that have been implicated in the regulation of mood. Together, these findings reveal that chronic stress leads to astrocyte atrophy and impaired gap junction coupling, raising the prospect that both individual and network-level astrocyte functionality are important in the etiology of major depression and other neuropsychiatric disorders.

The policy landscape and challenges of disaster risk financing: navigating risk and uncertainty.

A more anticipatory, pre-agreed response is a shared goal of many in the disaster management and humanitarian communities. This paper considers the emerging policy landscape of disaster risk financing (DRF), which is taken here to include mechanisms that allow agencies to act in advance of disasters occurring, as well as those that aim to respond earlier to disasters which have already happened. What they both have in common is no longer waiting for needs to become apparent before responding; however, this creates a challenge for practitioners because of the potential for acting erroneously. This paper provides a more cohesive way of understanding approaches in this policy area through the shared challenge of decision-making under the condition of uncertainty. Drawing on expert interviews and science and technology studies theory, it sets out some recommendations on how practitioners can navigate risk and uncertainty better within DRF and in a more nuanced way.

Program Implementation Approaches to Build and Sustain Health Care Coordination for Type 2 Diabetes.

BACKGROUND: As more people enter the U.S. health care system under the Affordable Care Act (ACA), it is increasingly critical to deliver coordinated, high-quality health care. The ACA supports implementation and sustainability of efficient health care models, given expected limits in available resources. This article highlights implementation strategies to build and sustain care coordination, particularly ones consistent with and reinforced by the ACA. It focuses on disease self-management programs to improve the health of patients with type 2 diabetes, exemplified by grantees of the Alliance to Reduce Disparities in Diabetes. METHOD: We conducted interviews with grantee program representatives throughout their 5-year programs and conducted a qualitative framework analysis of data to identify key themes related to care coordination. RESULTS: The most promising care coordination strategies that grantee programs described included establishing clinic-community collaborations, embedding community health workers within care management teams, and sharing electronic data. Establishing provider buy-in was crucial for these strategies to be effective. DISCUSSION: This article adds new insights into strategies promoting effective care coordination. The strategies that grantees implemented throughout the program align with ACA requirements, underscoring their relevance to the changing U.S. health care environment and the likelihood of further support for program sustainability.

Peer-Generated Health Information: The Role of Online Communities in Patient and Caregiver Health Decisions.

Individuals increasingly access peer-generated health information (PGHI) through social media, especially online health communities (OHCs). Previous research has documented PGHI topics, credibility assessment strategies, and PGHI's connection with well-being. However, there is limited evidence on where, when, and why individuals seek PGHI and how they use PGHI in health decisions. We conducted in-person and online focus groups with verified OHC members (N = 89)-representing 50 different medical conditions and 77 OHCs-to explore these topics. Two researchers independently coded transcripts with NVivo 9.2 and thematically analyzed responses. Most individuals accidentally discovered PGHI during Web searches rather than intentionally seeking it. Individuals valued PGHI primarily as an alternative information source about treatment options, self-care activities, and health care provider questions rather than a source of emotional support, and they acknowledged PGHI's limitation as anecdotal evidence. Individuals used PGHI as a springboard for additional research and patient-provider discussions, ultimately making treatment decisions alongside providers. These findings suggest that individuals use PGHI in much the same way they use traditional online health information and that PGHI facilitates, rather than obstructs, shared decision making with health care providers.

In vivo quantification of the [(11)C]DASB binding in the normal canine brain using positron emission tomography.

BACKGROUND: [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB) is currently the mostly used radiotracer for positron emission tomography (PET) quantitative studies of the serotonin transporter (SERT) in the human brain but has never been validated in dogs. The first objective was therefore to evaluate normal [(11)C]DASB distribution in different brain regions of healthy dogs using PET. The second objective was to provide less invasive and more convenient alternative methods to the arterial sampling-based kinetic analysis. RESULTS: A dynamic acquisition of the brain was performed during 90 min. The PET images were coregistered with the magnetic resonance images taken prior to the study in order to manually drawn 20 regions of interest (ROIs). The highest radioactivity concentration of [(11)C]DASB was observed in the hypothalamus, raphe nuclei and thalamus and lowest levels in the parietal cortex, occipital cortex and cerebellum. The regional radioactivity in those 20 ROIs was quantified using the multilinear reference tissue model 2 (MRTM2) and a semi-quantitative method. The values showed least variability between 40 and 60 min and this time interval was set as the optimal time interval for [(11)C]DASB quantification in the canine brain. The correlation (R(2)) between the MRTM2 and the semi-quantitative method using the data between 40 and 60 min was 99.3% (two-tailed p-value < 0.01). CONCLUSIONS: The reference tissue models and semi-quantitative method provide a more convenient alternative to invasive arterial sampling models in the evaluation of the SERT of the normal canine brain. The optimal time interval for static scanning is set at 40 to 60 min after tracer injection.

Traumatic brain injury and adverse life events: Group differences in young adults injured as children.

OBJECTIVES: To investigate whether individuals with a history of traumatic brain injury (TBI) experience a greater number of adverse life events (ALE) compared to controls, to identify significant predictors of experiencing ALE and whether the severity of childhood TBI negatively influences adult life outcomes. DESIGN: A total of 167 individuals, injured prior to age 18, 5 or more years post-injury and 18 or more years of age, were recruited in the Canterbury region of New Zealand, with 124 having sustained childhood TBI (62 mild, 62 moderate/severe) and 43 orthopaedic injury controls. Participants were asked about ALE they had experienced and other adult life outcomes. RESULTS: Individuals with a history of TBI experienced more ALE compared to controls. The number of ALE experienced by an individual was associated with more visits to the doctor, lower education level and lower satisfaction with material standard of living. CONCLUSIONS: Childhood TBI is associated with an increased number of ALE and adult negative life outcomes. Understanding factors that contribute to negative outcomes following childhood TBI will provide an avenue for rehabilitation and support to reduce any problems in adulthood.

Improving the implementation of diabetes self-management: findings from the Alliance to Reduce Disparities in Diabetes.

To enhance the health and well-being of patients managing type 2 diabetes, the five grantees comprising the Alliance to Reduce Disparities in Diabetes implemented evidence-based approaches to patient self-management education as part of their programs. This article describes strategies implemented by the grantees that may help explain program success, defined as improvement in clinical values and patient-reported outcomes. A process evaluation of grantee programs included interviews and document review at the beginning, midpoint, and end of the Alliance initiative. A total of 97 interviews were conducted over time with 65 program representatives. The Alliance programs served 2,328 people from diverse racial and ethnic backgrounds and provided 36,826 diabetes self-management sessions across the intervention sites. Framework analysis of the interviews identified four key themes that emerged across time and program sites that may help account for program success: empowerment, increasing access and support, addressing local needs and barriers, and care coordination. The overall evaluation findings may help other diabetes self-management programs seeking to translate and implement evidence-based approaches to reduce disparities and enhance patient well-being.

Sphingosine-1-phosphate signaling regulates the ability of Müller glia to become neurogenic, proliferating progenitor-like cells.

The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. S1PR1 is highly expressed by resting MG and is rapidly downregulated following acute retinal damage. Drug treatments that activate S1PR1 or increase levels of S1P suppressed the formation of MGPCs, whereas treatments that inhibit S1PR1 or decreased levels of S1P stimulated the formation of MGPCs. Inhibition of S1PR1 or SPHK1 significantly enhanced the neuronal differentiation of the progeny of MGPCs. Further, ablation of microglia from the retina, wherein the formation of MGPCs in damaged retinas is impaired, has a significant impact upon expression patterns of S1P-related genes in MG. Inhibition of S1PR1 and SPHK1 partially rescued the formation of MGPCs in damaged retinas missing microglia. Finally, we show that TGFß/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs and activation of S1P signaling depends, in part, on signals produced by reactive microglia.

Association of Fitzpatrick Skin Type with metastatic risk from uveal melanoma in 854 consecutive patients at a single center.

OBJECTIVE: To assess the association of skin color using Fitzpatrick Skin Type (FST) with metastatic risk of uveal melanoma. SUBJECTS: 854 consecutive patients with uveal melanoma and documented FST. METHODS: Retrospective detailed review of patient charts was performed for FST (type I- white, II-fair, III-average, IV-light brown, V-brown, VI-black), clinical details of the patient and the uveal melanoma, tumor cytogenetic classification according to The Cancer Genome Atlas (TCGA), and outcome of melanoma-related metastasis and death. RESULTS: The FST classification was type I (n = 97 patients), type II (n = 665), type III (n = 79), type IV (n = 11), type V (n = 2), type VI (n = 0). A comparison of patient FST (type I vs. II vs. III-V) revealed significant differences in mean age at presentation (64.1 vs. 58.5 vs. 49.8 years, p < 0.001), race white (100% vs. 98% vs. 75%, p < 0.001), presence of ocular melanocytosis (3% vs. 3% vs. 10%, p = 0.01), visual acuity <20/200 at presentation (6% vs. 7% vs. 13%, p = 0.03), genetic results showing TCGA group B tumors (11% vs. 14% vs. 26%, p = 0.01) or TCGA group D tumors (22% vs. 11% vs. 9%, p = 0.01), 10-year incidence of melanoma-related metastasis (25% vs. 15% vs. 14%, p = 0.02) and 10-year incidence of melanoma-related death (9% vs. 3% vs. 4%, p = 0.04). FST was a significant predictor of melanoma-related metastasis (p = 0.02, Hazard ratio 2.3). CONCLUSIONS: Fitzpatrick skin type may be a predictor of melanoma-related metastasis, with metastasis and TCGA Group D tumors being more common in patients with FST I.

Impact of Social Stories on social and emotional health of autism spectrum primary school children: the ASSSIST2 RCT with economic evaluation.

Background: Differences in the way autistic children experience the world can contribute to anxiety and stress. Carol Gray's Social Stories™ are a highly personalised intervention to support children by providing social information about specific situations in an individual story. Objectives: This randomised controlled trial aimed to establish whether Social Stories are clinically effective and cost-effective in improving social responsiveness and social and emotional health in children on the autism spectrum in schools. Design: A multisite pragmatic cluster randomised controlled trial comparing Social Stories with care as usual. Setting: Eighty-seven schools (clusters) across Yorkshire and the Humber. Participants: Two hundred and forty-nine children were randomised via a bespoke system hosted at York Trials Unit (129 Social Stories and 120 care as usual). Recruitment was completed in May 2021. Participants were children aged 4-11 years with a diagnosis of autism, alongside teachers, interventionists and caregivers. Recruitment was via schools, NHS trusts, support groups and local publicity. Intervention: The intervention included training for educational professionals and caregivers covering psychoeducation and implementation of Social Stories. Stories were written around contextualised goals around the child's need for social information. Interventionists read the Social Story™ with the child at least six times over 4 weeks during school. Main outcome measure: The primary outcome was the Social Responsiveness Scale-2 completed by teachers at 6 months (the primary end point), which measures social awareness, cognition, communication and behaviour. Data were collected from caregivers and educational professionals at 6 weeks and 6 months through questionnaires. Blinding of participants was not possible. Results: At 6 months, the estimated difference in expected teacher-reported Social Responsiveness Scale-2 T-score (the primary end point) was -1.61 (95% confidence interval -4.18 to 0.96, p = 0.220), slightly favouring the intervention group. The estimated differences for the parent-reported secondary outcomes at 6 months were small and generally favoured the control group except the measure of children's quality-adjusted life-year (+ 0.001, 95% confidence interval -0.032 to 0.035) and parental stress (-1.49, 95% confidence interval -5.43 to 2.46, p = 0.460), which favoured the intervention group. Children in the intervention group met their individual goals more frequently than children who received usual care alone (0.97 confidence interval 0.21 to 1.73, p = 0.012). The intervention is likely to save small costs (-£191 per child, 95% confidence interval -767.7 to 337.7) and maintain a similar quality of life compared to usual care. The probability of Social Stories being a preferred option is 75% if the society is willing to pay £20,000 per quality-adjusted life-year gained. Limitations include considerable disruptions during the coronavirus disease 2019 pandemic. Conclusion: Social Stories are used in schools and represent a low-cost intervention. There is no clinically evident impact on social responsiveness, anxiety and/or depression, parental stress or general health. Benefits were observed for specific behavioural goals as assessed by the teacher, and Social Stories may serve as a useful tool for facilitating dialogue between children and school staff to address specific behavioural challenges. Usage should be at the school's discretion. Future work: Given the uncertainty of the results in light of coronavirus disease 2019, further work to establish the impact of Social Stories is merited. Trial registration: This trial is registered as ISRCTN11634810. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/111/91) and is published in full in Health Technology Assessment; Vol. 28, No. 39. See the NIHR Funding and Awards website for further award information.

Autism affects the way children experience the world, and some children find social situations stressful. We wanted to know whether Social Stories™, developed by Carol Gray, helped children with their social skills and behaviour in school and whether they offered value for money. A randomised controlled trial design was used, which gave schools an equal chance of being asked to deliver Social Stories or to continue providing care as usual. Two hundred and forty-nine children from 87 schools took part and we trained school staff and parents to write and deliver Social Stories. We agreed with teachers and parents, what each child needed help with and wrote stories with this in mind. Trained staff read the Social Story with the child at least six times over 4 weeks. Follow-up information was collected from parents and school staff at the start of the study, after 6 weeks and 6 months. After 6 months, teachers completed a questionnaire called the Social Responsiveness Scale-2 which measures the child's social skills. Using these measures, the results suggest that Social Stories do not lead to any significant changes in social skills, mental health, parent stress, general health or quality of life but children in schools allocated to Social Stories met their goal more frequently and incurred less costs than children who did not. Parents and educational professionals found the Social Stories intervention and training beneficial. Based on our findings, Social Stories do not appear to improve general social skills in primary-aged autistic children. Benefits were observed for specific goals, and school-based costs were reduced.

The Use of MRI-Derived Radiomic Models in Prostate Cancer Risk Stratification: A Critical Review of Contemporary Literature.

The development of precise medical imaging has facilitated the establishment of radiomics, a computer-based method of quantitatively analyzing subvisual imaging characteristics. The present review summarizes the current literature on the use of diagnostic magnetic resonance imaging (MRI)-derived radiomics in prostate cancer (PCa) risk stratification. A stepwise literature search of publications from 2017 to 2022 was performed. Of 218 articles on MRI-derived prostate radiomics, 33 (15.1%) generated models for PCa risk stratification. Prediction of Gleason score (GS), adverse pathology, postsurgical recurrence, and postradiation failure were the primary endpoints in 15 (45.5%), 11 (33.3%), 4 (12.1%), and 3 (9.1%) studies. In predicting GS and adverse pathology, radiomic models differentiated well, with receiver operator characteristic area under the curve (ROC-AUC) values of 0.50-0.92 and 0.60-0.92, respectively. For studies predicting post-treatment recurrence or failure, ROC-AUC for radiomic models ranged from 0.73 to 0.99 in postsurgical and radiation cohorts. Finally, of the 33 studies, 7 (21.2%) included external validation. Overall, most investigations showed good to excellent prediction of GS and adverse pathology with MRI-derived radiomic features. Direct prediction of treatment outcomes, however, is an ongoing investigation. As these studies mature and reach potential for clinical integration, concerted effort to validate these radiomic models must be undertaken.

Dysphagia and Lung Disease in Children With Spinal Muscular Atrophy Treated With Disease-Modifying Agents.

OBJECTIVES: Disease-modifying agents (DMAs) for the treatment of spinal muscular atrophy (SMA) have evolved the SMA phenotype with improved survival. Ongoing oropharyngeal dysphagia and respiratory complications are reported. The extent of dysphagia and respiratory morbidity in this population, since DMAs' introduction, has not been well described. METHODS: A whole-population study involved all children with treated SMA types 1-3 in our facility. Videofluoroscopic swallow studies (type 1 alone), chest CT scans, and clinical data were collected. RESULTS: Thirty-six children were included (n = 9 type 1, n = 14 type 2, and n = 13 type 3; age range 0.3-15.4 years). Abnormal swallowing characteristics were demonstrated in all children with type 1 (n = 8; 100%). Bronchiectasis was found on chest CT: 3 of 9 (33.3%), 2 of 14 (14.3%), and 2 of 13 (15.4%) of type 1, 2, and 3, respectively. Atelectasis, mucus plugging, bronchial wall thickening, and parenchymal changes were common. DISCUSSION: Swallow impairments were universal in children with type 1. Bronchiectasis was common in all pediatric SMA types, with a prevalence of 1 in 5. Routine monitoring and management of dysphagia/recurrent respiratory infection should be implemented for improvement in lung health.

Telephone informed consent in a pragmatic point-of-care clinical trial embedded in primary care.

BACKGROUND: One benefit of pragmatic clinical trials is reduction of the burden on patients and clinical staff while facilitating a learning healthcare system. One way to decrease the work of clinical staff is through decentralized telephone consent. METHODS: The Diuretic Comparison Project (DCP) was a nationwide Point of Care pragmatic clinical trial conducted by the VA Cooperative Studies Program. The purpose of the trial was to compare the clinical effectiveness on major CV outcomes of two commonly used diuretics, hydrochlorothiazide and chlorthalidone, in an elderly patient population. Telephone consent was allowed for this study because of its minimal risk designation. Telephone consent was more difficult than initially anticipated and the study team constantly adjusted methods to find timely solutions. RESULTS: The major challenges can be categorized as call center-related, telecommunications, operational, and study population based. In particular, the possible technical and operational pitfalls are rarely discussed. By presenting hurdles here, future studies may avoid these challenges and start studies with a more effective system in place. CONCLUSIONS: DCP is a novel study designed to answer an important clinical question. The lessons learned from implementing a centralized call center for the Diuretic Comparison Project helped the study reach enrollment goals and develop a centralized telephone consent system that can be utilized for future pragmatic and explanatory clinical trials. CLINICAL TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov; NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417]. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

ß-Blocker Use and Cardiovascular Outcomes in Hemodialysis: A Systematic Review.

Rationale & Objective: There is conflicting evidence regarding the type of ß-blockers to use in dialysis patients. This systematic review seeks to determine whether highly dialyzable ß-blockers are associated with higher rates of cardiovascular events and mortality in hemodialysis patients than poorly dialyzable ß-blockers. Study Design: A systematic review of the existing literature was conducted. A meta-analysis was performed using data from the selected studies. Setting & Study Populations: Participants were from the United States, Canada, and Taiwan. The mean ages of participants ranged from 55.9-75.7 years. Selection Criteria for Studies: We searched the Ovid MEDLINE database from 1990 to September 2020. Studies without adult hemodialysis participants and without comparisons of at least 2 ß-blockers of different dialyzability were excluded. Data Extraction: Baseline and adjusted outcome data were extracted from each study. Analytical Approach: Random-effects models were used to calculate pooled risk ratios using fully adjusted models from individual studies. Results: Four cohort studies were included. Pooling fully adjusted models, highly dialyzable ß-blockers did not influence mortality (HR, 0.94; 95% CI, 0.81-1.08; I2 = 0.84) compared with poorly dialyzable ß-blockers but were associated with a reduction in cardiovascular events (HR, 0.88; 95% CI, 0.83-0.93). There was significant heterogeneity between studies (I2 = 0.35). Only 1 study reported on adverse events. Intradialytic hypotension was more common in those on carvedilol (a poorly dialyzable ß-blocker) compared with those on metoprolol (a highly dialyzable ß-blocker; adjusted incidence rate ratio, 1.10; 95% CI, 1.09-1.11). Limitations: No randomized controlled trials were identified. Each study used different analytic methods and different definitions for outcomes. Classifications of ß-blockers varied. Only 1 study reported on adverse events. Conclusions: Pooled data suggest highly dialyzable ß-blockers are associated with similar mortality events and fewer cardiovascular events compared with poorly dialyzable ß-blockers.