Development and Validation of a Patient-Reported Outcome Measure for Fingernail and Toenail Conditions: The NAIL-Q.

Background: Patient-reported outcome measures (PROMs) are needed to measure outcomes that matter to people with nail conditions, from their perspective. Objective: To design a comprehensive new PROM (NAIL-Q) to measure outcomes important in toenail and fingernail conditions. Methods: A mixed methods iterative approach was used. Phase 1 involved concept elicitation interviews that were audio-recorded, transcribed, and coded line-by-line. Concepts were developed into scales and refined through cognitive debriefing interviews with patients and expert input. Data was then collected from an international sample using a crowdsource platform. Eligible participants were aged ≥18 years with a nail condition for at least 3 months. Rasch Measurement Theory (RMT) analysis was used to examine item and scale performance. Other psychometric tests included test-retest reliability, and convergent and construct validity. Results: Phase 1 interviews involved 23 patients with 10 nail conditions and input from 11 dermatologists. The analysis led to the development of 84 items for field-testing. In Phase 2, 555 participants completed the survey. Toenail conditions (n = 441) were more common than fingernail conditions (n = 186). The RMT analysis reduced the number of items tested to 45 in 7 scales measuring nail appearance, health-related quality of life concerns, and treatment outcomes. All items had ordered thresholds and nonsignificant chi-square p values. Reliability statistics with and without extremes for the Person Separation Index were ≥0.79 and Cronbach's alpha were ≥0.83, and for intraclass correlation coefficients were ≥0.81. Construct validity was further supported in that most participants agreed that the NAIL-Q was easy to understand, asked relevant and important questions in a respectful way, and that it should be used to inform clinical care. Conclusion: The NAIL-Q is a rigorously designed and tested PROM that measures nail appearance, health-related quality of life and treatment outcomes. This PROM can be used in clinical practice to inform patient care and to include the patient perspective in research.

Development and Validation of New BODY-Q Scales Measuring Expectations, Eating Behavior, Distress, Symptoms, and Work Life in 4004 Adults From 4 Countries.

PURPOSE: The BODY-Q is a rigorously developed patient-reported outcome measure (PROM) for patients seeking treatment for obesity and body contouring surgery. A limitation of the uptake of the BODY-Q in weight management treatments is the absence of scales designed to measure eating-specific concerns. We aimed to develop and validate 5 new BODY-Q scales measuring weight loss expectations, eating behaviors, distress, symptoms, and work life. MATERIAL AND METHODS: In phase 1 (qualitative), patient and expert input was used to develop and refine the new BODY-Q scales. In phase 2 (quantitative), the scales were field-tested in bariatric and weight management clinics in the United States (US), The Netherlands, and Denmark between June 2019 and January 2020. Data were also collected in the US and Canada in September 2019 through a crowdworking platform. Rasch measurement theory (RMT) analysis was used for item reduction and to examine reliability and validity. RESULTS: The new BODY-Q scales were refined through qualitative input from 17 patients and 20 experts (phase 1) and field-tested in 4004 participants (phase 2). All items showed ordered thresholds and good fit to the Rasch model. The RMT analysis provided evidence of reliability, with PSI values ≥0.72, Cronbach alpha values ≥0.83, and test-retest values ≥0.79. Better scores on 4 scales (exception expectations scale) correlated with lower BMI, with the strongest correlation between the eating-related distress scale scores and BMI (r= -0.249, P < 0.001). CONCLUSION: The new BODY-Q scales can be used in research and clinical practice to assess weight loss treatments from the patient perspective.

Development and Psychometric Validation of BREAST-Q Scales Measuring Cancer Worry, Fatigue, and Impact on Work.

BACKGROUND: The BREAST-Q is a patient-reported outcome measure for women with breast cancer. The aim of this study was to develop new BREAST-Q scales to measure Cancer Worry, Fatigue and Impact on Work. METHODS: Data were collected between January 2017 and November 2019. Phase 1 (qualitative) included participants from Canada and the USA, pre/post any type of breast cancer treatment (surgery, adjuvant, neoadjuvant). Interviews were audio-recorded, transcribed verbatim and coded line-by-line. New scales were drafted and refined through cognitive interviews and expert input. Phase 2 (field-test study) involved USA members of the Love Research Army (LRA). Rasch measurement theory analysis was used to examine reliability and validity. RESULTS: In phase 1, 57 women were interviewed. Three concepts were identified as important to the breast cancer experience that are not currently covered in the BREAST-Q and developed into scales, i.e., Cancer Worry, Fatigue and Impact on Work. Feedback from nine women and 23 experts was used to establish content validity. The scales were field-tested in the LRA sample (n = 1680), of whom 1006 completed a test-retest. Reliability was > 0.81 for the person separation index, > 0.89 for Cronbach's alpha and > 0.83 for interclass correlation coefficients. Lower scores on all three scales were significantly associated with being closer in time to diagnosis and having a higher cancer stage at diagnosis (p < 0.001 on ANOVA). CONCLUSION: These new scales expand the BREAST-Q measurement system and provide a means to evaluate additional important outcomes for breast cancer patients in clinical care and research.

An international mixed methods study to develop a new preference-based measure for women with breast cancer: the BREAST-Q Utility module.

BACKGROUND: Generic preference-based measures (PBM), though commonly used, may not be optimal for use in economic evaluations of breast cancer interventions. No breast cancer-specific PBM currently exists, and the generic PBMs fail to capture the unique concerns of women with breast cancer (e.g., body image, appearance, treatment-specific adverse effects). Hence, the objective of this study was to develop a breast cancer-specific PBM, the BREAST-Q Utility module. METHODS: Women diagnosed with breast cancer (stage 0-4, any treatment) were recruited from two tertiary hospitals in Canada and one in the US. The study followed an exploratory sequential mixed methods approach, whereby semi-structured interviews were conducted and at the end of the interview, participants were asked to list their top five health-related quality of life (HRQOL) concerns and to rate the importance of each item on the BREAST-Q. Interviews were audio-recorded, transcribed verbatim, and coded. Constant comparison was used to refine the codes and develop a conceptual framework. Qualitative and quantitative data were triangulated to develop the content of the Utility module  that was refined through 2 rounds of cognitive debriefing interviews with women diagnosed with breast cancer and feedback from experts. RESULTS: Interviews were conducted with 57 women aged 55 ± 10 years. A conceptual framework was developed from 3948 unique codes specific to breasts, arms, abdomen, and cancer experience. Five top-level domains were HRQOL (i.e., physical, psychological, social, and sexual well-being) and appearance. Data from the interviews, top 5 HRQOL concerns, and BREAST-Q item ratings were used to inform dimensions for inclusion in the Utility module. Feedback from women with breast cancer (N = 9) and a multidisciplinary group of experts (N = 27) was used to refine the module. The field-test version of the HSCS consists of 10 unique dimensions. Each dimension is measured with 1 or 2 candidate items that have 4-5 response levels each. CONCLUSION: The field-test version of the BREAST-Q Utility module was derived from extensive patient and expert input. This comprehensive approach ensured that the content of the Utility module is relevant, comprehensive, and includes concerns that matter the most to women with breast cancer.

The BODY-Q Cellulite Scale: A Development and Validation Study.

BACKGROUND: Cellulite is a localized metabolic disorder of the subcutaneous tissue. To measure the impact of cellulite and its treatment(s) on patients' health-related quality of life, a psychometrically sound patient-reported outcome measure is needed. OBJECTIVES: The authors sought to develop and field test a new BODY-Q cellulite scale to measure the appearance of cellulite. METHODS: Appearance-related codes from the original BODY-Q qualitative interviews were reexamined, and a set of cellulite-specific items was developed and refined through cognitive patient interviews (n = 10) and expert input (n = 17). This scale was field-tested in adults with cellulite through 2 crowdworking platforms. Rasch Measurement Theory analysis was employed to refine the scale and examine its psychometric properties. RESULTS: The field-test sample included 2129 participants. The 15-item scale was reduced in length to 11 items. Data from the sample fit the Rasch model (X2 [99] = 21.32, P = 0.06). All items had ordered thresholds and mapped out a targeted clinical hierarchy. The reliability statistics for the person separation index was 0.94 and for Cronbach's alpha was 0.97. In terms of validity, worse scores on the cellulite scale were associated with being more bothered by how the cellulite looked overall, having more severe cellulite on the Patient-Reported Photo-numeric Cellulite Severity Scale, and having more self-reported cellulite and more areas of the body with cellulite. CONCLUSIONS: The BODY-Q cellulite scale can be utilized to measure appearance of cellulite and provides a solid basis for future studies evaluating the impact of cellulite and its treatment.

Using the BODY-Q to Understand Impact of Weight Loss, Excess Skin, and the Need for Body Contouring following Bariatric Surgery.

BACKGROUND: A consequence of bariatric surgery is redundant skin for most patients. The authors measured health-related quality of life and appearance following bariatric surgery in relation to weight loss, excess skin, and need for body contouring. METHODS: The sample included Canadian participants from the BODY-Q field-test study recruited between November of 2013 and July of 2014. Participants were invited to complete BODY-Q scales and questions to assess weight loss, amount of excess skin, and need for body contouring between June 7, 2016, and November 29, 2016. RESULTS: Two hundred fourteen participants responded (75 percent response rate). Of the 210 who underwent bariatric surgery, most were left with excess skin [n = 196 (93 percent)] and needed body contouring [n = 168 (80 percent)]. Higher percentage total weight loss correlated with more excess skin (r = 0.24, p = 0.001), the need for more body contouring procedures (r = 0.29, p < 0.001), and (worse) scores on seven of 13 BODY-Q scales. Having redundant skin correlated with more physical symptoms (r = 0.31, p < 0.001), the need for more body contouring procedures (r = 0.62, p < 0.001), and lower scores on 12 BODY-Q scales. The need for more body contouring procedures correlated with more physical symptoms (r = 0.23, p = 0.001) and lower scores on 12 BODY-Q scales. CONCLUSIONS: Excess skin after bariatric surgery is a disabling problem. Additional research using the BODY-Q is needed to determine improvements that can be achieved following body contouring.

Further psychometric validation of the BODY-Q: ability to detect change following bariatric surgery weight gain and loss.

BACKGROUND: Recent systematic reviews have identified that current patient-reported outcome instruments have content limitations when used to measure change following bariatric surgery. The aim of this study was to measure change after bariatric surgery using the BODY-Q, a PRO instrument designed for weight loss and body contouring. METHODS: The BODY-Q is composed of 18 independently functioning scales and an obesity-specific symptom checklist that measure appearance, health-related quality of life (HR-QOL) and experience of health-care. The sample for this study included patients who were exploring or seeking bariatric surgery in Hamilton (Canada) at the time of the BODY-Q field-test study and who agreed to further contact from the research team. These patients were invited to complete 12 BODY-Q scales and the symptom checklist between 7 June 2016 and 29 November 2016. Data were collected online (REDCap) and via postal surveys. Clinical change was measured using paired t-tests with effect sizes and standardized response means. RESULTS: The survey was completed by 58 of 89 (65%) pre-bariatric participants from the original BODY-Q field-test sample. The non-participants did not differ from participants in terms of age, gender, ethnicity, BMI or initial BODY-Q scale scores. Participants who had undergone bariatric surgery had a mean BMI of 49 (SD = 7) at time 1 and 35 (SD = 7) at time 2. Time since bariatric surgery was on average 2 years (SD = 0.5) (range 0.4 to 3 years). Percentage total weight loss ranged from 12 to 51 (mean 31, SD = 9). The difference in the proportion of patients to report an obesity-specific symptom on the BODY-Q checklist was significantly lower at follow-up for 5 of 10 symptoms. Participants improved on BODY-Q scales measuring appearance (of abdomen, back, body, buttocks, hips/outer thighs, inner thigh), body image and physical function (p < 0.001 on paired t-tests) and social function (p = 0.002 on paired t-test). These changes were associated with moderate to large effect sizes (0.60 to 2.29) and standardized response means (0.47 to 1.35). CONCLUSIONS: The BODY-Q provides a set of independently functioning scales that measure issues important to patients who undergo weight loss. BODY-Q scales were responsive to measuring clinical change associated with weight loss 2 years after bariatric surgery.

Identification of Autoantigen Epitopes in Alopecia Areata.

Alopecia areata (AA) is believed to be a cell-mediated autoimmune hair loss disease. Both CD4 and cytotoxic CD8 T cells (CTLs) are important for the onset and progression of AA. Hair follicle (HF) keratinocyte and/or melanocyte antigen epitopes are suspected potential targets of autoreactive CTLs, but the specific epitopes have not yet been identified. We investigated the potential for a panel of known epitopes, expressed by HF keratinocytes and melanocytes, to induce activation of CTL populations in peripheral blood mononuclear cells. Specific synthetic epitopes derived from HF antigens trichohyalin and tyrosinase-related protein-2 induced significantly higher frequencies of response in AA CTLs compared with healthy controls (IFN-gamma secretion). Apoptosis assays revealed conditioned media from AA peripheral blood mononuclear cells stimulated with trichohyalin peptides elevated the expression of apoptosis markers in primary HF keratinocytes. A cytokine array revealed higher expression of IL-13 and chemokine ligand 5 (CCL5, RANTES) from AA peripheral blood mononuclear cells stimulated with trichohyalin peptides compared with controls. The data indicate that AA affected subjects present with an increased frequency of CTLs responsive to epitopes originating from keratinocytes and melanocytes; the activated CTLs secreted soluble factors that induced apoptosis in HF keratinocytes. Potentially, CTL response to self-antigen epitopes, particularly trichohyalin epitopes, could be a prognostic marker for human AA.

Hair follicle dermal sheath derived cells improve islet allograft survival without systemic immunosuppression.

Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1) or fibroblasts (FB, group 2) under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days, P < 0.001) without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation.

CCAAT-enhancer binding protein-ß expression and elevation in Alzheimer's disease and microglial cell cultures.

CCAAT-enhancer binding proteins are transcription factors that help to regulate a wide range of inflammatory mediators, as well as several key elements of energy metabolism. Because C/EBPs are expressed by rodent astrocytes and microglia, and because they are induced by pro-inflammatory cytokines that are chronically upregulated in the Alzheimer's disease (AD) cortex, we have investigated whether C/EBPs are expressed and upregulated in the AD cortex. Here, we demonstrate for the first time that C/EBPß can be detected by Western blots in AD and nondemented elderly (ND) cortex, and that it is significantly increased in AD cortical samples. In situ, C/EBPß localizes immunohistochemically to microglia. In microglia cultured from rapid autopsies of elderly patient's brains and in the BV-2 murine microglia cell line, we have shown that C/EBPß can be upregulated by C/EBP-inducing cytokines or lipopolysaccharide and exhibits nuclear translocation possibly indicating functional activity. Given the known co-regulatory role of C/EBPs in pivotal inflammatory mechanisms, many of which are present in AD, we propose that upregulation of C/EBPs in the AD brain could be an important orchestrator of pathogenic changes.

Hair follicle mesenchyme-associated PD-L1 regulates T-cell activation induced apoptosis: a potential mechanism of immune privilege.

The immune privilege (IP) of hair follicles (HFs) has been well established in previous studies. However, whether cultured HF cells still exhibit IP properties, the individual factors involved in this process, and the detailed mechanisms that drive and maintain IP, are largely unidentified. We found preferential expression of IP-associated genes in cultured HF dermal papilla and dermal sheath cup cells (DSCCs) compared with non-follicular fibroblasts (FBs) at passage 4, suggesting a potential for functional IP. Notably, programmed cell death 1 ligand 1 (PD-L1) was significantly upregulated in DSCCs and dermal papilla cells relative to FBs. IFNγ secretion from peripheral blood mononuclear cells (PBMCs) co-cultured with histoincompatible DSCCs was significantly lower than with FB and higher percentages of early apoptotic, Annexin V+ cells were observed in PBMC co-cultured with DSCCs. Knockdown of PD-L1 translation by silencing interfering RNA in DSCCs enabled increased IFNγ secretion by PBMCs, whereas transfection of pCMV6-XL4/hPD-L1 in FB significantly reduced IFNγ secretion and increased apoptosis in co-cultured PBMCs. We also found that apoptosis in allogeneic T cells induced by DSCCs was largely dependent on the mitochondrial pathway. Our study suggests IP properties are exhibited in cultured DSCCs in part through expression of negative co-signaling molecule PD-L1.

Somatostatin expression in human hair follicles and its potential role in immune privilege.

Immune privilege (IP) is believed to exist in the anagen hair follicle (HF). Studies have shown that downregulation of major histocompatibility complex Class I occurs and immunosuppressive factors are expressed in the HF bulb and bulge. However, demonstration and quantification of functional IP in HF cells are required. We examined the middle (sheath) and lower (bulb) portions of the human HF using quantitative real-time RT-PCR (qPCR), immunohistology, ELISA, in vitro coculture with peripheral blood mononuclear cells (PBMCs), and flow cytometry. We found that HF cells, relative to non-follicular epidermal cells, failed to promote allogeneic PBMC proliferation and CD4(+) and CD8(+) IFNγ production. By qPCR, we found significant downregulation of Class I and Class II HLA alleles in both the bulb and sheath, and upregulation of multiple immunoregulatory genes. It is noteworthy that somatostatin (SST) was significantly upregulated relative to epidermis. By immunohistochemistry, SST was most strongly expressed in the HF outer root sheath, and, by ELISA, cultured sheath cells secreted SST. PBMCs, cultured with stimulatory allogeneic epidermal cells and SST, secreted significantly less IFNγ than controls. Addition of SST antagonists to PBMCs cocultured with allogeneic HF cells increased IFNγ secretion. The data identify SST as a secretory factor potentially contributing to the HF IP repertoire.

The basic science of hair biology: what are the causal mechanisms for the disordered hair follicle?

A hair disorder can be difficult to define, but patients are typically motivated to seek treatment when their hair growth patterns are significantly different from their cultural group or when growth patterns change significantly. The causes of hair disorders are many and varied, but fundamentally the disorder is a consequence of aberrant alterations of normal hair biology. The potential trigger factors for hair disorders can be attributed to inflammation, genetics, the environment, or hormones, of which the relative contributions vary for different diagnoses, between individuals, and over time. This article discusses the causal mechanisms for the disordered hair follicle.