Bifunctional Immunity Proteins Protect Bacteria against FtsZ-Targeting ADP-Ribosylating Toxins.

ADP-ribosylation of proteins can profoundly impact their function and serves as an effective mechanism by which bacterial toxins impair eukaryotic cell processes. Here, we report the discovery that bacteria also employ ADP-ribosylating toxins against each other during interspecies competition. We demonstrate that one such toxin from Serratia proteamaculans interrupts the division of competing cells by modifying the essential bacterial tubulin-like protein, FtsZ, adjacent to its protomer interface, blocking its capacity to polymerize. The structure of the toxin in complex with its immunity determinant revealed two distinct modes of inhibition: active site occlusion and enzymatic removal of ADP-ribose modifications. We show that each is sufficient to support toxin immunity; however, the latter additionally provides unprecedented broad protection against non-cognate ADP-ribosylating effectors. Our findings reveal how an interbacterial arms race has produced a unique solution for safeguarding the integrity of bacterial cell division machinery against inactivating post-translational modifications.

Nanoparticle-mediated delivery of tetrahydrobiopterin restores endothelial function in diabetic rats.

Endothelial dysfunction, underlying the vascular complications of diabetes and other cardiovascular disorders, may result from uncoupling of endothelial nitric oxide synthase (eNOS) activity due to decreased levels of tetrahydrobiopterin (BH4), a critical co-factor for eNOS. Some clinical trials attempting to deliver exogenous BH4 as a potential therapeutic strategy in vascular disease states have failed due to oxidation of BH4 in the circulation. We sought to develop a means of protecting BH4 from oxidation while delivering it to dysfunctional endothelial cells. Polymeric and solid lipid nanoparticles (NPs) loaded with BH4 were delivered by injection or oral gavage, respectively, to streptozotocin-induced diabetic rats. BH4 was measured in coronary endothelial cells and endothelium-dependent vascular reactivity was assessed in vascular rings. Lymphatic uptake of orally delivered lipid NPs was verified by sampling mesenteric lymph. BH4-loaded polymeric NPs maintained nitric oxide production by cultured endothelial cells under conditions of oxidative stress. BH4-loaded NPs, delivered via injection or ingestion, increased coronary endothelial BH4 concentration and improved endothelium-dependent vasorelaxation in diabetic rats. Pharmacodynamics assessment indicated peak concentration of solid lipid NPs in the systemic bloodstream 6 hours after ingestion, with disappearance noted by 48 hours. These studies support the feasibility of utilizing NPs to deliver BH4 to dysfunctional endothelial cells to increase nitric oxide bioavailability. BH4-loaded NPs could provide an innovative tool to restore redox balance in blood vessels and modulate eNOS-mediated vascular function to reverse or retard vascular disease in diabetes.

Integrated Cytometry With Machine Learning Applied to High-Content Imaging of Human Kidney Tissue for In Situ Cell Classification and Neighborhood Analysis.

The human kidney is a complex organ with various cell types that are intricately organized to perform key physiological functions and maintain homeostasis. New imaging modalities, such as mesoscale and highly multiplexed fluorescence microscopy, are increasingly being applied to human kidney tissue to create single-cell resolution data sets that are both spatially large and multidimensional. These single-cell resolution high-content imaging data sets have great potential to uncover the complex spatial organization and cellular makeup of the human kidney. Tissue cytometry is a novel approach used for the quantitative analysis of imaging data; however, the scale and complexity of such data sets pose unique challenges for processing and analysis. We have developed the Volumetric Tissue Exploration and Analysis (VTEA) software, a unique tool that integrates image processing, segmentation, and interactive cytometry analysis into a single framework on desktop computers. Supported by an extensible and open-source framework, VTEA's integrated pipeline now includes enhanced analytical tools, such as machine learning, data visualization, and neighborhood analyses, for hyperdimensional large-scale imaging data sets. These novel capabilities enable the analysis of mesoscale 2- and 3-dimensional multiplexed human kidney imaging data sets (such as co-detection by indexing and 3-dimensional confocal multiplexed fluorescence imaging). We demonstrate the utility of this approach in identifying cell subtypes in the kidney on the basis of labels, spatial association, and their microenvironment or neighborhood membership. VTEA provides an integrated and intuitive approach to decipher the cellular and spatial complexity of the human kidney and complements other transcriptomics and epigenetic efforts to define the landscape of kidney cell types.

A Case Series on the Use of Brentuximab Vedotin for the Treatment of Mycosis Fungoides.

BACKGROUND: Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody that appears to be more effective against CD30-expressing cutaneous T-cell lymphoma (CTCL) compared to current standard-of-care treatments.   Objective: To determine the real-world efficacy and adverse effects of BV use in patients with mycosis fungoides (MF) who were treated with BV at Atrium Health Wake Forest Baptist Medical Center. METHODS: Study staff performed a retrospective chart review of patients diagnosed with MF who were prescribed BV at Atrium Health Wake Forest Baptist Comprehensive Cancer Center. RESULTS:   Regardless of their response to BV, all patients in our cohort had higher CD30 positivity on subsequent biopsies compared to their initial skin biopsy.  Conclusions: Improved understanding of appropriate CD30 testing and evaluation will allow for quicker invention of patients with BV responsive CTCL.  J Drugs Dermatol. 2023;22(12):e33-e34.    doi:10.36849/JDD.6981e.

The Patient-Physician Relationship and Adherence: Observations From a Clinical Study.

Improved patient-physician relationships (PPR) are associated with better patient satisfaction and disease outcomes, however, there is limited literature assessing how PPR affects adherence in dermatology. We recruited 30 subjects with a clinical diagnosis of rosacea. Subjects were instructed to use ivermectin 1% cream once daily for 3 months and adherence was measured using the Medication Event Monitoring System cap. The Patient-Doctor Relationship Questionnaire (PDRQ-9), a validated questionnaire assessing patients’ perceived strength of the relationship with their doctor, was completed. Mean adherence for all subjects over three months of the study was 62%. PDRQ-9 scores positively correlated with adherence rates for 3 months of treatment (r(26)=0.52; P=0.006). The perceived strength of the PPR may have a role in patients’ adherence to their medications. Improving the PPR, through empathy and effective communication, may facilitate better medication adherence and treatment outcomes. Perche PO, Singh R, Cook MK, et al. The patient-physician relationship and adherence: observations from a clinical study. J Drugs Dermatol. 2023;22(8):838-839. doi:10.36849/JDD.7103.

Topical Moisturizer Meaningfully Reduces Disease Severity in Atopic Patients With Xerosis.

BACKGROUND: Repairing the epidermal barrier is critically important in atopic dermatitis (AD), but the effect of moisturizer on quality of life (QOL) is not well characterized.  Objective: To assess whether the use of a moisturizer improves QOL in atopic patients with xerosis.  Methods: Thirty-five (35) adults with xerosis and AD received a moisturizer designed for AD to apply daily for three months. Adherence was assessed with electronic monitors. Quality of life (QOL) was assessed with the Dermatology Life Quality Index (DLQI) at baseline and follow-up.  Results: Mean adherence to the moisturizer was 46%. Dryness improved from 1.9 at baseline to 1.4 at follow-up (P=0.02). DLQI improved from 3.3 at baseline to 1.5 at 3 months (P=0.005). The "feeling self-conscious or embarrassed due to their skin condition" DLQI item improved from 0.79 at baseline to 0.14 at 3 months (P=0.0009).  Conclusion: Moisturizers are the foundation of AD treatment. Even non-medicated topical emollients can improve QOL in patients with AD.  J Drugs Dermatol. 2023;22(12):e51-e52.     doi:10.36849/JDD.7036e.

Topical Ivermectin Is Associated With Improved Erythematotelangiectatic, Papulopustular, and Phymatous Rosacea in a Secondary Analysis.

Rosacea has variable clinical presentation consisting of four overlapping phenotypes: erythematotelangiectatic, papulopustular, phymatous, and ocular.1 Rosacea's pathogenesis involves increased cutaneous density of Demodex folliculorum mites, which drive inflammation through activation of Toll-like receptor-2.1,2 Thus, topical ivermectin (IVM) 1.0% cream's anti-inflammatory and acaricidal activity provides an effective and targeted treatment for moderate-to-severe rosacea. However, literature assessing IVM is limited to efficacy in treating the papulopustular presentation, limiting generalizability.1,3,4 Although our primary endpoint was to assess patient adherence, the objective of this secondary analysis was to assess IVM efficacy in rosacea, regardless of clinical presentation.

The genogram as a recruitment tool for identifying primary caregivers of youth living with sickle cell disease preparing for transition.

AIMS: The purpose of this secondary analysis was to describe the impact of using genograms to identify family caregivers from an original research study which used family caregiver-adolescents/young adults (AYA) dyads. BACKGROUND: Research to improve transition preparation for AYA with chronic disease is essential as 90% will survive into adulthood. Family-based transition research is specifically needed as a majority of transition preparation will occur in the home setting. Dyadic research on transition has not previously described strategies for recruiting appropriate family caregivers. DESIGN: A descriptive, secondary analysis was conducted using genograms developed during the original study conducted between October 2019 and February 2020. METHODS: For this secondary analysis conducted between July 2020 and August 2021, 50 genograms were analysed using descriptive statistics to describe family structures, relationships and responsibilities in families of AYAs living with sickle cell disease. RESULTS: In 43 genograms, there was only one primary caregiver in the family. In seven genograms, there were multiple primary caregivers who met the inclusion criteria for primary caregiver in a single family. In five genograms, there were two appropriate primary caregivers in a single family, and in two genograms, there were three appropriate individuals in a single family who met study criteria as a primary caregiver. CONCLUSIONS: Findings from the analysis of the genograms used in the original study demonstrated potential ability to improve on dyad recruitment by more specifically identifying the family member most involved in supporting the AYA's disease management. IMPACT: Genograms are an established tool for gathering information on families and application with recruitment could improve research in the realm of transition and other family-based research. NO PATIENT OR PUBLIC CONTRIBUTION: This was a secondary analysis that assessed already existing data.

Examining the influence of positive childhood experiences on childhood overweight and obesity using a national sample.

Positive childhood experiences (PCEs) promote healthy social development, improve overall wellness, and help to moderate and prevent exposure to adverse childhood experiences. There has been limited research examining the association between positive childhood experiences and overweight or obesity status in children. The purpose of this study was to examine whether experiencing positive childhood experiences are associated with lower rates of overweight or obesity status in children between 10 and 17 years of age, using cross-sectional data from the 2018-2019 National Survey of Children's Health (n = 28,771), a nationally representative mail and online survey. Frequencies, proportions, and unadjusted associations for each variable were calculated using descriptive statistics and bivariate analyses. To examine the association between overweight or obesity and PCEs, multivariable regression models were used. Compared to children who were underweight or had a healthy weight, children who were overweight or obese were less likely to: participate after school activities (78.1%, p < 0.0001), volunteer in their community, school, or church (45.6%, p < 0.0001), have a mentor they feel comfortable going to for guidance (87.0%, p = 0.02), live in a safe neighborhood (61.3%, p < 0.0001), live in a supportive neighborhood (50.4%, p < 0.0001), and to live with a resilient family (78.3%; p = 0.0099). In adjusted analysis, among children exposed to two or more ACEs, children residing in a supportive neighborhood were less likely to be overweight or obese (aOR 0.87; 0.77-0.98). Our findings suggest that certain PCEs may mitigate overweight and obesity when children have experienced at least some childhood trauma.

Decision-Making Involvement, Self-Efficacy, and Transition Readiness in Youth With Sickle Cell Disease.

BACKGROUND: Transition to adult healthcare is a critical time for adolescents and young adults (AYAs) with sickle cell disease, and preparation for transition is important to reducing morbidity and mortality risks associated with transition. OBJECTIVE: We explored the relationships between decision-making involvement, self-efficacy, healthcare responsibility, and overall transition readiness in AYAs with sickle cell disease prior to transition. METHODS: This cross-sectional, correlational study was conducted with 50 family caregivers-AYAs dyads receiving care from a large comprehensive sickle cell clinic between October 2019 and February 2020. Participants completed the Decision-Making Involvement Scale, the Sickle Cell Self-Efficacy Scale, and the Readiness to Transition Questionnaire. Multiple linear regression was used to assess the relationships between decision-making involvement, self-efficacy, healthcare responsibility, and overall transition readiness in AYAs with sickle cell disease prior to transition to adult healthcare. RESULTS: Whereas higher levels of expressive behaviors, such as sharing opinions and ideas in decision-making, were associated with higher levels of AYA healthcare responsibility, those behaviors were inversely associated with feelings of overall transition readiness. Self-efficacy was positively associated with overall transition readiness but inversely related to AYA healthcare responsibility. Parent involvement was negatively associated with AYA healthcare responsibility and overall transition readiness. DISCUSSION: While increasing AYAs' decision-making involvement may improve AYAs' healthcare responsibility, it may not reduce barriers of feeling unprepared for the transition to adult healthcare. Facilitating active AYA involvement in decision-making regarding disease management, increasing self-efficacy, and safely reducing parent involvement may positively influence their confidence and capacity for self-management.

Tracking the evolution of CNS remyelinating lesion in mice with neutral red dye.

Animal models of central nervous system (CNS) demyelination, including toxin-induced focal demyelination and immune-mediated demyelination through experimental autoimmune encephalomyelitis (EAE), have provided valuable insights into the mechanisms of neuroinflammation and CNS remyelination. However, the ability to track changes in transcripts, proteins, and metabolites, as well as cellular populations during the evolution of a focal lesion, has remained challenging. Here, we developed a method to label CNS demyelinating lesions by the intraperitoneal injection of a vital dye, neutral red (NR), into mice before killing. We demonstrate that NR-labeled lesions can be easily identified on the intact spinal cord in both lysolecithin- and EAE-mediated demyelination models. Using fluorescence microscopy, we detected NR in activated macrophages/microglia and astrocytes, but not in oligodendrocytes present in lesions. Importantly, we successfully performed RT-qPCR, Western blot, flow cytometry, and mass spectrometry analysis of precisely dissected NR-labeled lesions at 5, 10, and 20 d postlesion (dpl) and found differential changes in transcripts, proteins, cell populations, and metabolites in lesions over the course of remyelination. Therefore, NR administration is a simple and powerful method to track and analyze the detailed molecular, cellular, and metabolic changes that occur within the lesion microenvironment over time following CNS injury. Furthermore, this method can be used to identify molecular and metabolic pathways that regulate neuroinflammation and remyelination and facilitate the development of therapies to promote repair in demyelinating disorders such as multiple sclerosis.

Student, Faculty, and Coach Perspectives on Why Athletes Excel in Medical School: A Qualitative Analysis.

Phenomenon Medical schools are tasked with selecting applicants who will excel in a rigorous curriculum and successfully perform as future physicians. While many studies have assessed quantitative prematriculation data for predicting success in medical school, fewer studies have assessed for qualitative prematriculation factors influencing medical school performance. A recent study revealed that medical students with at least one year of varsity level college athletics participation outperformed their peers on United States Medical Licensing board exams and clinical clerkships. The current study sought to explore medical student, medical school faculty, and college coach perspectives about factors explaining why medical students with collegiate athletic experience succeed in medical school. Approach: In 2019, the authors conducted semi-structured interviews with medical students with collegiate athletic experience, medical school faculty with experience educating student athletes, and college coaches with experience training student athletes who matriculated into medical school. The interview transcripts were systematically coded and analyzed for themes using a grounded theory approach. Participants were recruited and interviewed until saturation of data was reached. Findings: Fifteen medical students with collegiate athletic experience, five medical school faculty, and three collegiate coaches participated in the study. Six themes were identified as important factors explaining the academic success of these students in medical school and each of these themes appeared in student, faculty, and coach interviews: goal setting, goal pursuit, and performance appraisal; development of time management, planning, and organizational skills; development of team values and teamwork skills; development of communication and interpersonal skills; acceptance of, coping strategies for, and resilient response to stress and adversity; and prioritization of personal wellness. Participants described meaningful connections between these attributes and skills, suggesting the students' development, transfer, and application of them is interrelated. Insights: In this study, academic success of medical students with collegiate athletic experience was attributed to specific skills and attributes developed during college. The grounded theory life skills transfer model can explain transfer of these attributes and skills from college to the medical school setting. Theoretical frameworks and empirical study findings from the sociology, educational psychology, sports psychology, and medical education literature provide helpful lenses for understanding why these skills and attributes confer success among student athletes in medical school. These findings offer important insights on skill development that may support the academic success of all medical students.

Large-scale, three-dimensional tissue cytometry of the human kidney: a complete and accessible pipeline.

The advent of personalized medicine has driven the development of novel approaches for obtaining detailed cellular and molecular information from clinical tissue samples. Tissue cytometry is a promising new technique that can be used to enumerate and characterize each cell in a tissue and, unlike flow cytometry and other single-cell techniques, does so in the context of the intact tissue, preserving spatial information that is frequently crucial to understanding a cell's physiology, function, and behavior. However, the wide-scale adoption of tissue cytometry as a research tool has been limited by the fact that published examples utilize specialized techniques that are beyond the capabilities of most laboratories. Here we describe a complete and accessible pipeline, including methods of sample preparation, microscopy, image analysis, and data analysis for large-scale three-dimensional tissue cytometry of human kidney tissues. In this workflow, multiphoton microscopy of unlabeled tissue is first conducted to collect autofluorescence and second-harmonic images. The tissue is then labeled with eight fluorescent probes, and imaged using spectral confocal microscopy. The raw 16-channel images are spectrally deconvolved into 8-channel images, and analyzed using the Volumetric Tissue Exploration and Analysis (VTEA) software developed by our group. We applied this workflow to analyze millimeter-scale tissue samples obtained from human nephrectomies and from renal biopsies from individuals diagnosed with diabetic nephropathy, generating a quantitative census of tens of thousands of cells in each. Such analyses can provide useful insights that can be linked to the biology or pathology of kidney disease. The approach utilizes common laboratory techniques, is compatible with most commercially-available confocal microscope systems and all image and data analysis is conducted using the VTEA image analysis software, which is available as a plug-in for ImageJ.

In Situ Classification of Cell Types in Human Kidney Tissue Using 3D Nuclear Staining.

To understand the physiology and pathology of disease, capturing the heterogeneity of cell types within their tissue environment is fundamental. In such an endeavor, the human kidney presents a formidable challenge because its complex organizational structure is tightly linked to key physiological functions. Advances in imaging-based cell classification may be limited by the need to incorporate specific markers that can link classification to function. Multiplex imaging can mitigate these limitations, but requires cumulative incorporation of markers, which may lead to tissue exhaustion. Furthermore, the application of such strategies in large scale 3-dimensional (3D) imaging is challenging. Here, we propose that 3D nuclear signatures from a DNA stain, DAPI, which could be incorporated in most experimental imaging, can be used for classifying cells in intact human kidney tissue. We developed an unsupervised approach that uses 3D tissue cytometry to generate a large training dataset of nuclei images (NephNuc), where each nucleus is associated with a cell type label. We then devised various supervised machine learning approaches for kidney cell classification and demonstrated that a deep learning approach outperforms classical machine learning or shape-based classifiers. Specifically, a custom 3D convolutional neural network (NephNet3D) trained on nuclei image volumes achieved a balanced accuracy of 80.26%. Importantly, integrating NephNet3D classification with tissue cytometry allowed in situ visualization of cell type classifications in kidney tissue. In conclusion, we present a tissue cytometry and deep learning approach for in situ classification of cell types in human kidney tissue using only a DNA stain. This methodology is generalizable to other tissues and has potential advantages on tissue economy and non-exhaustive classification of different cell types.

Clinical, histopathologic and molecular features of idiopathic and diabetic nodular mesangial sclerosis in humans.

BACKGROUND: Idiopathic nodular mesangial sclerosis, also called idiopathic nodular glomerulosclerosis (ING), is a rare clinical entity with an unclear pathogenesis. The hallmark of this disease is the presence of nodular mesangial sclerosis on histology without clinical evidence of diabetes mellitus or other predisposing diagnoses. To achieve insights into its pathogenesis, we queried the clinical, histopathologic and transcriptomic features of ING and nodular diabetic nephropathy (DN). METHODS: All renal biopsy reports accessioned at Indiana University Health from 2001 to 2016 were reviewed to identify 48 ING cases. Clinical and histopathologic features were compared between individuals with ING and DN (n = 751). Glomeruli of ING (n = 5), DN (n = 18) and reference (REF) nephrectomy (n = 9) samples were isolated by laser microdissection and RNA was sequenced. Immunohistochemistry of proline-rich 36 (PRR36) protein was performed. RESULTS: ING subjects were frequently hypertensive (95.8%) with a smoking history (66.7%). ING subjects were older, had lower proteinuria and had less hyaline arteriolosclerosis than DN subjects. Butanoate metabolism was an enriched pathway in ING samples compared with either REF or DN samples. The top differentially expressed gene, PRR36, had increased expression in glomeruli 248-fold [false discovery rate (FDR) P = 5.93 × 10-6] compared with the REF and increased 109-fold (FDR P = 1.85 × 10-6) compared with DN samples. Immunohistochemistry revealed a reduced proportion of cells with perinuclear reaction in ING samples as compared to DN. CONCLUSIONS: Despite similar clinical and histopathologic characteristics in ING and DN, the uncovered transcriptomic signature suggests that ING has distinct molecular features from nodular DN. Further study is warranted to understand these relationships.

Neighborhood Socioeconomic Status and Mechanical Thrombectomy Outcomes.

BACKGROUND/PURPOSE: Our study aimed to assess the impacts of neighborhood socioeconomic status on mechanical thrombectomy (MT) outcomes for acute ischemic stroke (AIS). METHODS: We conducted a prospective observational study of consecutive adult AIS patients treated with MT at one US comprehensive stroke center from 2012 to 2018. A composite neighborhood socioeconomic score (nSES) was created using patient home address, median household income, percentage of households with interest, dividend, or rental income, median value of housing units, percentage of persons 25 or older with high school degrees, college degrees or holding executive, managerial or professional specialty occupations. Using this score, patients were divided into low, middle and high nSES tertiles. Outcomes included 90-day functional independence, in-hospital mortality, length of hospital stay, discharge location, time to recanalization, successful recanalization, and symptomatic intracranial hemorrhage (sICH). RESULTS: 328 patients were included. Between the three nSES groups, proportion of White patients, time-to-recanalization and admission NIH stroke scale differed significantly (p<0.05). Patients in the high nSES tertile were more likely to be functionally dependent at 90 days (unadjusted OR, 95% CI, 1.91 [1.10, 3.36]) and were less likely to die in the hospital (unadjusted OR, 95% CI, 0.46, [0.20, 0.98]). Further, patients in the high nSES tertile had decreased times to recanalization (median time in minutes, low=335, mid=368, high=297, p=0.04). However, after adjusting for variance in race and severity of stroke, the differences in clinical outcomes were not significant. CONCLUSION: This study highlights how unadjusted neighborhood socioeconomic status is significantly associated with functional outcome, mortality, and time-to-recanalization following MT for AIS. Since adjustment modifies the significant association, the socioeconomic differences may be influenced by differences in pre-hospital factors that drive severity of stroke and time to recanalization. Better understanding of the interplay of these factors may lead to timelier evaluation and improvement in patient outcomes.

Barriers to Transition to Home From the Neonatal Intensive Care Unit: A Qualitative Perspectives of Parents and Healthcare Providers.

The objective of this study was to explore the challenges faced by parents of former neonatal intensive care unit (NICU) patients in transitioning home from parents' and healthcare providers' perspective. We conducted semistructured individual and group interviews with parents of former NICU patients and healthcare providers. Themes from the individual interviews framed the group interviews' contents. The group interviews were recorded and transcribed, and thematic analysis was performed to identify themes. We conducted individual and group interviews with 16 parents and 33 inpatient and outpatient providers from November 2017 to June 2018. Individual interview participants identified several barriers experienced by parents when transitioning their infant home from the NICU including parental involvement and engagement during NICU stay and during the discharge process. Further exploration within group interviews revealed opportunities to improve discharge communication and processes, standardization of parental education that was lacking due to NICU resource constraints, support for parents' emotional state, and use of technology for infant care in the home. Parents of NICU patients face serious emotional, logistical, and knowledge challenges when transitioning their infant home from the NICU. Understanding and mitigating the challenges of transitioning infants from NICU to home require multistakeholder input from both parents and providers.

Uncovering Family Treatment Decision-Making Processes: The Value and Application of Case Study Methods to Family Research.

Research on how and why family processes influence phenomena is essential to advancing many areas of science. Case study methods offer an approach that overcomes some of the sampling and analysis obstacles researchers face when studying families. This article aims to illustrate the benefits of case study methods for studying complex family processes using an example from treatment decision-making in sickle cell disease. Using survey, observation, and interview data from various family members within multiple family units, we detail our application of the following analytic strategies: (a) proposition-building, (b) pattern-matching, and (c) cross-case synthesis. Incorporating propositions from a conceptual framework assisted us in study development, data collection, and analysis. Development of graphs and matrices to create thematic family profiles uncovered how and why treatment decision-making occurred as a family process in a pediatric chronic illness. Case study methods are an established, but innovative approach to investigating various phenomena in families.

Kidney Histopathology and Prediction of Kidney Failure: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: The use of kidney histopathology for predicting kidney failure is not established. We hypothesized that the use of histopathologic features of kidney biopsy specimens would improve prediction of clinical outcomes made using demographic and clinical variables alone. STUDY DESIGN: Retrospective cohort study and development of a clinical prediction model. SETTING & PARTICIPANTS: All 2,720 individuals from the Biopsy Biobank Cohort of Indiana who underwent kidney biopsy between 2002 and 2015 and had at least 2 years of follow-up. NEW PREDICTORS & ESTABLISHED PREDICTORS: Demographic variables, comorbid conditions, baseline clinical characteristics, and histopathologic features. OUTCOMES: Time to kidney failure, defined as sustained estimated glomerular filtration rate ≤ 10mL/min/1.73m2. ANALYTICAL APPROACH: Multivariable Cox regression model with internal validation by bootstrapping. Models including clinical and demographic variables were fit with the addition of histopathologic features. To assess the impact of adding a histopathology variable, the amount of variance explained (r2) and the C index were calculated. The impact on prediction was assessed by calculating the net reclassification index for each histopathologic variable and for all combined. RESULTS: Median follow-up was 3.1 years. Within 5 years of biopsy, 411 (15.1%) patients developed kidney failure. Multivariable analyses including demographic and clinical variables revealed that severe glomerular obsolescence (adjusted HR, 2.03; 95% CI, 1.51-2.03), severe interstitial fibrosis and tubular atrophy (adjusted HR, 1.99; 95% CI, 1.52-2.59), and severe arteriolar hyalinosis (adjusted HR, 1.53; 95% CI, 1.14-2.05) were independently associated with the primary outcome. The addition of all histopathologic variables to the clinical model yielded a net reclassification index for kidney failure of 5.1% (P < 0.001) with a full model C statistic of 0.915. Analyses addressing the competing risk for death, optimism, or shrinkage did not significantly change the results. LIMITATIONS: Selection bias from the use of clinically indicated biopsies and exclusion of patients with less than 2 years of follow-up, as well as reliance on surrogate indicators of kidney failure onset. CONCLUSIONS: A model incorporating histopathologic features from kidney biopsy specimens improved prediction of kidney failure and may be valuable clinically. Future studies will be needed to understand whether even more detailed characterization of kidney tissue may further improve prognostication about the future trajectory of estimated glomerular filtration rate.

Youths' Experiences of Transition from Pediatric to Adult Care: An Updated Qualitative Metasynthesis.

PROBLEM: Improvements in chronic disease management has led to increasing numbers of youth transitioning to adult healthcare. Poor transition can lead to high risks of morbidity and mortality. Understanding adolescents and young adults (AYA) perspectives on transition is essential to developing effective transition preparation. The aim of this metasynthesis was to synthesize qualitative studies assessing the experiences and expectations of transition to adult healthcare settings in AYAs with chronic diseases to update work completed in a prior metasynthesis by Fegran, Hall, Uhrenfeldt, Aagaard, and Ludvigsen (2014). ELIGIBILITY CRITERIA: A search of PubMed, Medline, PsycINFO, and CINAHL was conducted to gather articles published after February 2011 through June 2019. SAMPLE: Of 889 articles screened, a total of 33 articles were included in the final analysis. RESULTS: Seven main themes were found: developing transition readiness, conceiving expectations based upon pediatric healthcare, transitioning leads to an evolving parent role, transitioning leads to an evolving youth role, identifying barriers, lacking transition readiness, and recommendations for improvements. CONCLUSIONS: Findings of this metasynthesis reaffirmed previous findings. AYAs continue to report deficiencies in meeting the Got Transition® Six Core Elements. The findings highlighted the need to create AYA-centered transition preparation which incorporate support for parents. IMPLICATIONS: Improvements in transition preparation interventions need to address deficiencies in meeting the Got Transition® Six Core Elements. More research is needed to identify and address barriers implementing the transition process.