Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort.

Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide metformin is the most common pharmaceutical therapy. Yet its full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of nondiabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared with nondiabetic subjects, changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study. SIGNIFICANCE STATEMENT: This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes.

Salvage of Nipple-Areolar Complex Ischemia With Dimethyl Sulfoxide: A Case Series.

BACKGROUND: Nipple-areolar complex (NAC) necrosis is a known risk of breast surgery, particularly mastectomy. Disruption of the underlying blood supply to the NAC can lead to ischemia and subsequent necrosis. Nitroglycerin paste is currently used to combat NAC ischemia but has limited efficacy and an unfavorable side effect profile. Topical dimethyl sulfoxide (DMSO) has been shown to increase tissue perfusion in microsurgery and various skin flaps, but its role in the treatment and prevention of NAC ischemia has not been reported. Through a prospective case series, this study aims to introduce DMSO as a safe treatment for NAC ischemia after breast surgery. METHODS: Patients treated by 2 breast surgeons and a single plastic surgeon who underwent nipple-sparing mastectomy or breast reduction and developed NAC ischemia were identified via a prospectively maintained database. Ischemic changes were diagnosed, and treatment to the affected NAC with DMSO was initiated at the conclusion of the procedure, or postoperative day 1 in most cases, and continued 4 times daily until ischemic changes had resolved clinically. Collected demographic, surgical, and outcome variables were analyzed using descriptive statistics. RESULTS: Eleven patients with a mean age of 47.8 ± 9.5 years (range, 35-61 years) and mean body mass index of 26.0 ± 4.4 kg/m2 (range, 20.7-33.4 kg/m2) were identified. The mean duration of time between surgery and the clinical diagnosis of NAC ischemia was 1.3 ± 2.8 days (range, 0-7 days). The average length of time from DMSO initiation to clinical improvement or resolution of NAC ischemia was 7.5 ± 2.5 days (range, 5-12 days). All patients demonstrated significant improvement or complete resolution of NAC ischemia following serial topical DMSO application. CONCLUSIONS: This study demonstrates DMSO is a safe treatment for threatened NACs. All patients in this series showed either dramatic improvement or resolution of NAC ischemia after DMSO application, and threatened NACs of all 11 patients were successfully salvaged. These promising results set the basis for ongoing randomized controlled studies to determine the efficacy of DMSO treatment for NAC ischemia.

Considerations for Surgical Treatment of Neurogenic Thoracic Outlet Syndrome: A Meta-Analysis of Patient-Reported Outcomes.

PURPOSE: It remains unclear whether first rib resection (FRR), performed via a supraclavicular (SCFRR) or transaxillary (TAFRR) approach, is necessary for patients with neurogenic thoracic outlet syndrome (nTOS). In a systematic review and meta-analysis, we performed a direct comparison of patient-reported functional outcomes following different surgical approaches for nTOS. METHODS: The authors searched PubMed, Embase, Web of Science, Cochrane Library, PROSPERO, Google Scholar, and the gray literature. Data were extracted based on the procedure type. Well-validated patient-reported outcome measures were analyzed in separate time intervals. Random-effects meta-analysis and descriptive statistics were used where appropriate. RESULTS: Twenty-two articles were included, with 11 discussing SCFRR (812 patients), 6 discussing TAFRR (478 patients), and 5 discussing rib-sparing scalenectomy (RSS; 720 patients). The mean difference between preoperative and postoperative Disabilities of the Arm, Shoulder and Hand score was significantly different comparing RSS (43.0), TAFRR (26.8), and SCFRR (21.8). The mean difference between preoperative and postoperative visual analog scale scores was significantly higher for TAFRR (5.3) compared to SCFRR (3.0). Derkash scores were significantly worse for TAFRR compared to RSS or SCFRR. RSS had a success rate of 97.4% based on Derkash score, followed by SCFRR and TAFRR at 93.2% and 87.9%, respectively. RSS had a lower complication rate compared to SCFRR and TAFRR. There was a difference in complication rates: 8.7%, 14.5%, and 3.6% for SCFRR, TAFRR, and RSS, respectively. CONCLUSIONS: Mean differences in Disabilities of the Arm, Shoulder and Hand scores and Derkash scores were significantly better for RSS. Higher complication rates were reported after FRR. Our findings suggest that RSS is an effective option for the treatment of nTOS. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Healing Exposed Calvarial Hardware Using Negative-Pressure Wound Therapy and Vashe Wound Solution: Case Report.

OBJECTIVE: The management of cranioplasty infections has historically been explantation followed by delayed reimplantation/reconstruction. This treatment algorithm necessitates surgery, tissue expansion, and prolonged disfigurement. In this report, the authors describe a treatment approach consisting of serial vacuum-assisted closure (VAC) with hypochlorous acid (HOCl) solution (Vashe Wound Solution; URGO Medical) as a salvage strategy. METHODS: A 35-year-old man who sustained head trauma, neurosurgical complications, and severe syndrome of the trephined (SOT; devastating neurologic decline treated by cranioplasty) underwent titanium cranioplasty with free flap. Three weeks postoperation, he presented with pressure-related wound dehiscence/partial flap necrosis, exposed hardware, and bacterial infection. Given the severity of his precranioplasty SOT, hardware salvage was critical. He was treated with serial VAC with HOCl solution for 11 days followed by VAC for 18 days and definitive split-thickness skin graft placement over resulting granulation tissue. Authors also conducted a literature review of cranial reconstruction infection management. RESULTS: The patient remained healed 7 months postoperatively without recurrent infection. Importantly, his original hardware was retained, and his SOT remained resolved. Findings from the literature review support the use of conservative modalities to salvage cranial reconstructions without hardware removal. CONCLUSIONS: This study investigates a new strategy for managing cranioplasty infections. The VAC with HOCl solution regimen was effective in treating the infection and salvaging the cranioplasty, thus obviating the complications associated with explantation, new cranioplasty, and recurrence of SOT. There is limited literature on the management of cranioplasty infections using conservative treatments. A larger study to better determine the efficacy of VAC with HOCl solution is underway.

Self-Reported Health Outcomes of Children and Youth with 10 Chronic Diseases.

OBJECTIVES: To identify pediatric patient-reported outcomes (PROs) that are associated with chronic conditions and to evaluate the effects of chronic disease activity on PROs. STUDY DESIGN: Participants (8-24 years old) and their parents were enrolled into 14 studies that evaluated Patient-Reported Outcome Measurement Information System PROs across 10 chronic conditions-asthma, atopic dermatitis, cancer, cancer survivors, chronic kidney disease, Crohn's disease, juvenile idiopathic arthritis, lupus, sickle cell disease, and type 1 diabetes mellitus. PRO scores were contrasted with the US general population of children using nationally representative percentiles. PRO-specific coefficients of variation were computed to illustrate the degree of variation in scores within vs between conditions. Condition-specific measures of disease severity and Cohen d effect sizes were used to examine PRO scores by disease activity. RESULTS: Participants included 2975 child respondents and 2392 parent respondents who provided data for 3409 unique children: 52% were 5-12 years old, 52% female, 25% African American/Black, and 14% Hispanic. Across all 10 chronic conditions, children reported more anxiety, fatigue, pain, and mobility restrictions than the general pediatric population. Variation in PRO scores within chronic disease cohorts was equivalent to variation within the general population, exceeding between-cohort variation by factors of 1.9 (mobility) to 5.7 (anxiety). Disease activity was consistently associated with poorer self-reported health, and these effects were weakest for peer relationships. CONCLUSIONS: Chronic conditions are associated with symptoms and functional status in children and adolescents across 10 different disorders. These findings highlight the need to complement conventional clinical evaluations with those obtained directly from patients themselves using PROs.

One Vax Two Lives: a social media campaign and research program to address COVID-19 vaccine hesitancy in pregnancy.

The COVID-19 pandemic has disproportionately affected pregnant people by increasing health risks of maternal morbidity and mortality, stillbirth, and preterm birth. Although numerous studies have supported the safety and efficacy of COVID-19 vaccination in pregnancy in preventing or mitigating the risk for these adverse outcomes, many pregnant people remain hesitant. Approximately half of US adults regularly consume news from social media platforms, which are a fertile ground for the spread of vaccine disinformation. The lack of information regarding COVID-19 vaccine safety early in the pandemic fueled vaccine myths targeting the fears of pregnant people about vaccination risks. Saddened by the spike in maternal deaths of unvaccinated individuals during the COVID-19 Delta variant surge in the fall of 2021, we created a social media campaign to promote scientific communication regarding the risks of COVID-19 disease in pregnancy and the benefits of vaccination. We called the campaign "One Vax Two Lives," which refers to the ability of 1 maternal vaccine to benefit the health and lives of both the pregnant individual and their fetus. We present a blueprint of how we leveraged a large, interdisciplinary student workforce to create a social media campaign and research program studying vaccine hesitancy, which can be replicated by other groups. Community engagement and partnerships with key stakeholders, such as the Washington State Department of Health, were essential for amplifying the campaign and providing our team with feedback on content and approach. We present the analytics of our social media advertisements, web articles, and video content that helped inform the iterative design process of the multimedia content. Moving forward, we are launching collaborative research programs to study vaccine hesitancy and inform the development of new social media content designed for pregnant individuals who are: (1) Spanish-speaking Hispanic/Latina/x, (2) Black or Afro-Latinx, and (3) residents of rural communities in the State of Washington. Data from these mixed methods studies will inform new communication campaigns to reach vaccine-hesitant individuals. Finally, we discuss lessons learned and how the most impactful elements of the campaign can be translated to related areas of maternal public health.

Characteristics and Treatment of Patients Diagnosed With Paradoxical Adipose Hyperplasia After Cryolipolysis: A Case Series and Scoping Review.

BACKGROUND: Paradoxical adipose hyperplasia (PAH), a rare side effect of CoolSculpting (cryolipolysis), is characterized by fatty enlargement of the treatment area occurring months after the procedure. OBJECTIVES: The purpose of this study was to report a retrospective case series of patients diagnosed with PAH at the authors' institution, increase the collective understanding of this complication and subsequent management, and raise the question of who should ethically perform cryolipolysis. METHODS: All participants diagnosed with PAH by a plastic surgeon at a large academic medical center were identified. Demographic information, medical history, procedure details, time to PAH diagnosis, and corrective surgical intervention details were collected. Mean duration of time from cryolipolysis treatment to diagnosis of PAH was calculated, along with other descriptive statistics. A scoping review of all PAH literature published in PubMed, Embase, and Web of Science was also conducted. RESULTS: Four patients diagnosed with PAH after cryolipolysis were identified for inclusion in this study. The calculated incidence of PAH at our center was 0.67%. All patients requested therapy for PAH and subsequently underwent either liposuction, abdominoplasty, or both. The mean duration of in-person follow-up time after final surgical treatment of PAH was 13.8 + 19.8 months (range, 2.8-43.5). Fortunately, no patients showed signs of PAH recurrence, and 3 out of 4 patients did not show signs of residual deformity. CONCLUSIONS: Findings from this patient cohort and scoping review provide evidence that although revisions may be required, conventional body contouring methods, not in the armamentarium of non-plastic surgeon practitioners, effectively alleviated PAH.

Ultrahigh-Resolution Mass Spectrometry-Based Platform for Plasma Metabolomics Applied to Type 2 Diabetes Research.

Metabolomics-the endpoint of the omics cascade-is increasingly recognized as a preferred method for understanding the ultimate responses of biological systems to stress. Flow injection electrospray (FIE) mass spectrometry (MS) has advantages for untargeted metabolic fingerprinting due to its simplicity and capability for high-throughput screening but requires a high-resolution mass spectrometer to resolve metabolite features. In this study, we developed and validated a high-throughput and highly reproducible metabolomics platform integrating FIE with ultrahigh-resolution Fourier transform ion cyclotron resonance (FTICR) MS for analysis of both polar and nonpolar metabolite features from plasma samples. FIE-FTICR MS enables high-throughput detection of hundreds of metabolite features in a single mass spectrum without a front-end separation step. Using plasma samples from genetically identical obese mice with or without type 2 diabetes (T2D), we validated the intra and intersample reproducibility of our method and its robustness for simultaneously detecting alterations in both polar and nonpolar metabolite features. Only 5 min is needed to acquire an ultra-high resolution mass spectrum in either a positive or negative ionization mode. Approximately 1000 metabolic features were reproducibly detected and annotated in each mouse plasma group. For significantly altered and highly abundant metabolite features, targeted tandem MS (MS/MS) analyses can be applied to confirm their identity. With this integrated platform, we successfully detected over 300 statistically significant metabolic features in T2D mouse plasma as compared to controls and identified new T2D biomarker candidates. This FIE-FTICR MS-based method is of high throughput and highly reproducible with great promise for metabolomics studies toward a better understanding and diagnosis of human diseases.

Considerations to Support Use of Patient-Reported Outcomes Measurement Information System Pediatric Measures in Ambulatory Clinics.

OBJECTIVE: To identify challenges to the use of Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric measures in the ambulatory pediatric setting and possible solutions to these challenges. STUDY DESIGN: Eighteen semistructured telephone interviews of health system leaders, measurement implementers, and ambulatory pediatric clinicians were conducted. Five coders used applied thematic analysis to iteratively identify and refine themes in interview data. RESULTS: Most interviewees had roles in leadership or the implementation of patient-centered outcomes; 39% were clinicians. Some had experience using PROMIS clinically (44%) and 6% were considering this use. Analyses yielded 6 themes: (1) selection of PROMIS measures, (2) method of administration, (3) use of PROMIS Parent Proxy measures, (4) privacy and confidentiality of PROMIS responses, (5) interpretation of PROMIS scores, and (6) using PROMIS scores clinically. Within the themes, interviewees illuminated specific unique considerations for using PROMIS with children, including care transitions and privacy. CONCLUSIONS: Real-world challenges continue to hamper PROMIS use. Ongoing efforts to disseminate information about the integration of PROMIS measures in clinical care is critical to impacting the health of children.

Influences of health and environmental deprivation on family relationships among children with chronic disease.

PURPOSE: Families play a key role in managing chronic illness. Among chronically ill children, we describe the Patient-Reported Outcomes Measurement Information System (PROMIS) Family Relationships measure over time and its associations with sociodemographics, environmental deprivation, and health. METHODS: Parents of children aged 8-18 years with asthma (n = 171), type 1 diabetes (n = 199), or sickle cell disease (n = 135), recruited in pediatric clinics and emergency departments (ED), completed demographic surveys. Every six months for up to three years, children completed PROMIS Family Relationships, Anxiety, and Depressive Symptoms short forms (T-scores; mean 50, SD = 10), and a 5-level health status item. Linear mixed models were fit to estimate associations. RESULTS: Older baseline age was associated with weaker family relationships. For example, for each 3-year higher baseline age, relationships were 3 points weaker for males (- 3.0; 95%CI - 5.7 to - .0.2) and females (- 3.1; 95%CI - 6.0 to - 0.3) with asthma recruited in the ED. For each 1-unit higher mean overall health, relationships were 4.6 points (95%CI 3.2-6.1) stronger for children with diabetes and about 2 points stronger for children with asthma (2.3; 0.7-3.9) and sickle cell disease (2.1; 0.3-3.9). Family relationships were 0.3-0.5 points weaker for each 1-unit increment in mean anxiety or depressive symptoms across all three diseases. Relationships were not significantly associated with environmental deprivation and generally stable over time. CONCLUSIONS: Family relationships were weaker among older children and generally stable over time, yet fluctuated with physical and mental health. Monitoring PROMIS Family Relationships scores may facilitate referrals for chronically ill children who need support.

Reliability and validity of PROMIS® pediatric family relationships short form in children 8-17 years of age with chronic disease.

PURPOSE: Families play a key role in managing pediatric chronic illness. The PROMIS® pediatric family relationships measure was developed primarily within the general pediatric population. We evaluated the Family Relationships short form in the context of pediatric chronic diseases. METHODS: Children aged 8-17 years with asthma (n = 73), type 1 diabetes (n = 122), or sickle cell disease (n = 80) completed the Family Relationships 8a short form and the PROMIS Pediatric Profile-25's six domains representing physical, mental, and social health. Parents (N = 275) of these children completed the parent versions of the same measures. We evaluated reliability of the Family Relationships measure using Cronbach's alpha and IRT-based marginal reliability, and the standard error of measurement (SEM). Convergent/discriminant validity were assessed from correlations between the Family Relationships domain and the PROMIS-25 domains. RESULTS: SEM increased for scores above the normative mean of 50. Cronbach's alpha and IRT-estimated marginal reliabilities exceeded 0.80 for children and parents across diseases, except in asthma, where marginal reliability was 0.75 for parents. Scores displayed small to large correlations in the expected directions with social and mental health domains. The largest correlations occurred with parents' proxy reports of children's depressive symptoms in sickle cell disease and asthma, r = - 0.60 (95% CI - 0.74, - 0.48) and r = - 0.58 (95% CI - 0.68, - 0.48) respectively. CONCLUSIONS: The Family Relationships 8-item short form demonstrated adequate reliability and convergent/discriminant validity for use in pediatric chronic conditions, though scores above the mean displayed greater uncertainty. Evidence of the measure's reliability and validity in multiple contexts furthers the case for its use.

Impact of family-centered tailoring of pediatric diabetes self-management resources.

BACKGROUND: The American Diabetes Association recommends a family-centered approach that addresses each family's specific type 1 diabetes self-management barriers. OBJECTIVE: To assess an intervention that tailored delivery of self-management resources to families' specific self-management barriers. SUBJECTS: At two sites, 214 children 8-16 years old with type 1 diabetes and their parent(s) were randomized to receive tailored self-management resources (intervention, n = 106) or usual care (n = 108). METHODS: Our intervention (1) identified families' self-management barriers with a validated survey, (2) tailored self-management resources to identified barriers, and (3) delivered the resources as four group sessions coordinated with diabetes visits. Mixed effects models with repeated measures were fit to A1c as well as parent and child QOL during the intervention and 1 year thereafter. RESULTS: Participants were 44% youth (8-12 years) and 56% teens (13-16 years). No intervention effect on A1c or QOL was shown, combining data from sites and age groups. Analyzing results by site and age group, post-intervention A1c for teens at one site declined by 0.06 more per month for intervention teens compared to usual care (P < 0.05). In this group, post-intervention A1c declined significantly when baseline A1c was >8.5 (-0.08, P < 0.05), with an even larger decline when baseline A1c was >10 (-0.19, P < 0.05). In addition, for these teens, the significant improvements in A1c resulted from addressing barriers related to motivation to self-manage. Also at this site, mean QOL increased by 0.61 points per month more during the intervention for parents of intervention youth than for usual care youth (P < 0.05). CONCLUSIONS: Tailored self-management resources may improve outcomes among specific populations, suggesting the need to consider families' self-management barriers and patient characteristics before implementing self-management resources.

Testing Young Adults' Reactions to Facebook Cues and Their Associations with Alcohol Use.

Background: Alcohol cues on social media may influence young adults' drinking patterns, these cues may be pro-social or pro-alcohol in nature. The influence of individual Facebook cues on young adults' drinking intentions and behaviors remains unknown. Objectives: The purpose of this study was to assess how Facebook cues influence intention to drink, and how intention was associated with Theory of Reasoned Action constructs including alcohol-related attitudes and norms, and future behavior. Methods: Incoming university students completed a pre-college and a 2-year follow-up phone interview. A vignette presented individual Facebook cues representing "pro-social" or "pro-alcohol" sentiments. Participants indicated intention to drink alcohol and their rationale for this intention after each cue. Additional measures included TRA constructs of alcohol-related attitudes and norms, and problem alcohol use. Analyses included a qualitative approach to examine rationales for intention to drink in response to Facebook cues, and linear mixed effects models. Results: Of 338 participants, 56.1% were female, 74.8% were Caucasian. Alcohol-related attitudes and norms were positively associated with intention to drink in response to pro-social and pro-alcohol Facebook cues. Participants' intention to drink in response to pro-alcohol cues was positively associated with problem alcohol use two years later. Conclusions/importance: Findings illuminate the influence of social media on alcohol-related behaviors and highlight potential future screening approaches.

Impact of X/Y genes and sex hormones on mouse neuroanatomy.

Biological sex influences brain anatomy across many species. Sex differences in brain anatomy have classically been attributed to differences in sex chromosome complement (XX versus XY) and/or in levels of gonadal sex steroids released from ovaries and testes. Using the four core genotype (4CG) mouse model in which gonadal sex and sex chromosome complement are decoupled, we previously found that sex hormones and chromosomes influence the volume of distinct brain regions. However, recent studies suggest there may be more complex interactions between hormones and chromosomes, and that circulating steroids can compensate for and/or mask underlying chromosomal effects. Moreover, the impact of pre vs post-pubertal sex hormone exposure on this sex hormone/sex chromosome interplay is not well understood. Thus, we used whole brain high-resolution ex-vivo MRI of intact and pre-pubertally gonadectomized 4CG mice to investigate two questions: 1) Do circulating steroids mask sex differences in brain anatomy driven by sex chromosome complement? And 2) What is the contribution of pre- versus post-pubertal hormones to sex-hormone-dependent differences in brain anatomy? We found evidence of both cooperative and compensatory interactions between sex chromosomes and sex hormones in several brain regions, but the interaction effects were of low magnitude. Additionally, most brain regions affected by sex hormones were sensitive to both pre- and post-pubertal hormones. This data provides further insight into the biological origins of sex differences in brain anatomy.

Continuous manganese delivery via osmotic pumps for manganese-enhanced mouse MRI does not impair spatial learning but leads to skin ulceration.

Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique in rodent neuroimaging studies. Traditionally, Mn2+ is delivered to animals via a systemic injection; however, this can lead to toxic effects at high doses. Recent studies have shown that subcutaneously implanted mini-osmotic pumps can be used to continuously deliver manganese chloride (MnCl2), and that they produce satisfactory contrast while circumventing many of the toxic side effects. However, neither the time-course of signal enhancement nor the effect of continuous Mn2+ delivery on behaviour, particularly learning and memory, have been well-characterized. Here, we investigated the effect of MnCl2 dose and route of administration on a) spatial learning in the Morris Water Maze and b) tissue signal enhancement in the mouse brain. Even as early as 3 days after pump implantation, infusion of 25-50 mg/kg/day MnCl2 via osmotic pump produced signal enhancement as good as or better than that achieved 24 h after a single 50 mg/kg intraperitoneal injection. Neither route of delivery nor MnCl2 dose adversely affected spatial learning and memory on the water maze. However, especially at higher doses, mice receiving MnCl2 via osmotic pumps developed skin ulceration which limited the imaging window. With these findings, we provide recommendations for route and dose of MnCl2 to use for different study designs.

Content validity of the PROMIS® pediatric family relationships measure for children with chronic illness.

BACKGROUND: Families play a critical role in supporting the health and well-being of children with chronic illnesses, who face a lifetime of responsibility for self-management of their condition. Our goal was to investigate whether the novel Patient-Reported Outcomes Measurement Information System® (PROMIS®) Pediatric Family Relationships measure, developed primarily within the general pediatric population, reflects the experiences of family relationships for chronically ill children and their parents. METHODS: We conducted semi-structured qualitative interviews with children (aged 8-17) with common chronic conditions: asthma (n = 6), type 1 diabetes (n = 5), or sickle cell disease (n = 5), and separately with one of their parents (n = 16). Interviews were recorded, and two team members independently coded the written transcripts facilitated by Nvivo 10. The systematic content analysis used a combination of: 1) pre-specified themes corresponding to the six facets of the domain identified during measure development and reflected in the content of the items (i.e., Sense of Family; Love and Caring; Value and Acceptance; Trust, Dependability, and Support; Communication; Enjoyment), as well as 2) open-coding, allowing participants to define important concepts (i.e., disease impact). RESULTS: Family relationships were conceptualized in a similar way to the general population, as evidenced by child and parent responses to open-ended questions about family relationships and to specific probes that corresponded with the item content in the Family Relationship 8-item short form. Children spontaneously discussed the impact of their disease on family relationships less often than parents did. Although participants described how living with a chronic illness positively and negatively impacted aspects of family relationships, nearly all participants believed their responses to the PROMIS® Family Relationships items would not change if they (or their child) did not have a chronic illness. CONCLUSIONS: Among a sample of families of children with one of 3 chronic illnesses, participants described family relationships in a way that was consistent with the facets of the PROMIS® Family Relationship domain. This study adds to the content validity of the measure for children with chronic illness.

Testing the feasibility of eliciting preferences for health states from adolescents using direct methods.

BACKGROUND: Measuring adolescents' preferences for health states can play an important role in evaluating the delivery of pediatric healthcare. However, formal evaluation of the common direct preference elicitation methods for health states has not been done with adolescents. Therefore, the purpose of this study is to test how these methods perform in terms of their feasibility, reliability, and validity for measuring health state preferences in adolescents. METHODS: This study used a web-based survey of adolescents, 18 years of age or younger, living in the United States. The survey included four health states, each comprised of six attributes. Preferences for these health states were elicited using the visual analogue scale, time trade-off, and standard gamble. The feasibility, test-retest reliability, and construct validity of each of these preference elicitation methods were tested and compared. RESULTS: A total of 144 participants were included in this study. Using a web-based survey format to elicit preferences for health states from adolescents was feasible. A majority of participants completed all three elicitation methods, ranked those methods as being easy, with very few requiring assistance from someone else. However, all three elicitation methods demonstrated weak test-retest reliability, with Kendall's tau-a values ranging from 0.204 to 0.402. Similarly, all three methods demonstrated poor construct validity, with 9-50% of all rankings aligning with our expectations. There were no significant differences across age groups. CONCLUSIONS: Using a web-based survey format to elicit preferences for health states from adolescents is feasible. However, the reliability and construct validity of the methods used to elicit these preferences when using this survey format are poor. Further research into the effects of a web-based survey approach to eliciting preferences for health states from adolescents is needed before health services researchers or pediatric clinicians widely employ these methods.

Patient-centred outcomes research: brave new world meets old institutional policies.

Background: Engaging patients across the research trajectory supports research that is generalizable, high quality, timely and actionable. However, this approach comes with challenges and opportunities as investigators and engaged patient stakeholders encounter institutional policies around patient engagement, privacy and research participant protection. Objective: To describe the resolution and impact of quandaries arising when patient stakeholders' values and preferences conflicted with institutional policies. Methods: Case study from a Patient-Centered Outcomes Research Institute-funded trial. Results: The first example focuses on the tension between the health care organization's requirements for background checks for all patient advisors and the funders' requirement to engage hard-to-reach populations. To create an environment of mutual trust and respect with patient stakeholders, the research team decided against imposing background checks. All 53 patient and parent advisors have served continuously for 2 years and meeting attendance exceeds 95%. The second example describes parent stakeholders' role in revising a letter informing patients about a privacy violation. Among 49 families affected by and informed about this violation, 35 (71%) agreed to participate. The third example focuses on how patient stakeholder preferences about study reminders conflict with the 1996 Health Insurance Portability and Accountability Act rules. While patient stakeholders strongly endorsed text message reminders, regulations and technology do not permit reminders with enough detail to ensure clarity. Although retention rates exceeded 90%, attendance at study appointments was below 75% and below 60% for minority and low socio-economic status families. Conclusion: Patient engagement positively impacts research. Resolving conflicts between patient-engaged research and existing institutional policies and regulations would allow this impact to become fully realized.

Family Engagement in Pediatric Sickle Cell Disease Visits.

Adults with sickle cell disease (SCD) report problems in relationship building and information exchange during clinic visits. To explore the origin of these communication challenges, we compare communication in pediatric SCD, diabetes, and asthma visits. We collected visit videos and parent surveys from 78 children ages 9-16 years with SCD, asthma, or diabetes. Coders assessed child, parent, and physician utterances reflecting relationship building, information giving, and information gathering. Associations of engagement with type of chronic disease visit were performed with negative binomial regression. Compared to SCD visits, children in diabetes visits spoke 53% more relationship-building utterances (p < .05) and physicians in asthma visits spoke 48% fewer relationship building utterances to the child (p < .01). In diabetes visits, physicians gave almost twice as much information to children and gave 48% less information to parents (both p < .01) compared to SCD visits. Compared to SCD visits, physicians spoke fewer information-gathering utterances to parents in diabetes and asthma visits (85% and 72% respectively, both p < .001). SCD visits reflect less engagement of the children and greater physician effort to gather information from parents. These differences highlight opportunities to enhance engagement as a mechanism for ultimately improving SCD care.

Lysylated phospholipids stabilize models of bacterial lipid bilayers and protect against antimicrobial peptides.

Aminoacylated phosphatidylglycerols are common lipids in bacterial cytoplasmic membranes. Their presence in Staphylococcus aureus has been linked to increased resistance to a number of antibacterial agents, including antimicrobial peptides. Most commonly, the phosphatidylglycerol headgroup is esterified to lysine, which converts anionic phosphatidylglycerol into a cationic lipid with a considerably increased headgroup size. In the present work, we investigated the interactions of two well-studied antimicrobial peptides, cecropin A and mastoparan X, with lipid vesicles composed of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), containing varying fractions of an aminoacylated phosphatidylethanolamine, a stable analog of the corresponding phosphatidylglycerol-derivative. To differentiate between the effects of headgroup size and charge on peptide-lipid interactions, we synthesized two different derivatives. In one, the headgroup was modified by the addition of lysine, and in the other, by glutamine. The modification by glutamine results in a phospholipid with a headgroup size comparable to that of the lysylated version. However, whereas lysyl-phosphatidylethanolamine (Lys-PE) is cationic, glutaminyl-phosphatidylethanolamine (Gln-PE) is zwitterionic. We found that binding of mastoparan X and cecropin A was not significantly altered if the content of aminoacylated phosphatidylethanolamines did not exceed 20mol.%, which is the concentration found in bacterial membranes. However, a lysyl-phosphatidylethanolamine content of 20mol% significantly inhibits dye release from lipid vesicles, to a degree that depends on the peptide. In the case of mastoparan X, dye release is essentially abolished at 20mol.% lysyl-phosphatidylethanolamine, whereas cecropin A is less sensitive to the presence of lysyl-phosphatidylethanolamine. These observations are understood through the complex interplay between peptide binding and membrane stabilization as a function of the aminoacylated lipid content. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.