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Alexander Keenan,1 Hoa H Le,1 Kavita Gandhi,2 Lola Adedokun,3 Eddie Jones,4 Mia Unsworth,4 James Pike,5 Emily Trenholm4 1Scientific Affairs, Janssen Pharmaceuticals Inc., Titusville, NJ, USA; 2Research and Development, Janssen Pharmaceuticals Inc., Titusville, NJ, USA; 3Research and Development, Janssen-Cilag Ltd, High Wycombe, UK; 4Central Nervous System, Adelphi Real World, Bollington, Cheshire, UK; 5Statistics & Data Analytics, Adelphi Real World, Bollington, Cheshire, UKCorrespondence: Mia Unsworth, Adelphi Real World, Adelphi Mill, Grimshaw Lane, Macclesfield, Bollington, Cheshire, SK10 5JB, United Kingdom, Tel +441625578677, Email mia.unsworth@adelphigroup.comIntroduction: Multiple sclerosis (MS) is a neurodegenerative disease characterized by progressive deterioration of cognitive and physical functioning, reducing activities of daily living and quality of life (QoL). Several treatments are available that modify the course of the disease and reduce the frequency of relapses. Although effective, all treatment options are accompanied by adverse events, and this study aimed to assess the extent to which patients were involved in the choice of treatment.Methods: Data were drawn from the Adelphi Multiple Sclerosis Disease Specific Program (DSP)™, a cross-sectional survey of healthcare practitioners (HCP) and their patients with MS in real-world clinical settings in Europe and the United States (US) between December 2020 and July 2021. HCPs reported patient demographics, clinical characteristics, current and previous treatment, and treatment outcomes. Patients voluntarily completed questionnaires reporting the physical and psychological impact of their MS and its treatment. Regression analysis with inverse probability of treatment weighting was used to compare treatment outcomes in patients actively involved in their current treatment choice with those who were not.Results: Of a total of 692 patients, median age 40 years and 64% female, mostly diagnosed with relapsing-remitting MS, those who were involved in shared decision-making tended to choose oral therapies such as dimethyl fumarate more often than HCPs. MS had greater impact on physical and psychological functioning in patients whose HCP made treatment decisions solely. Patients involved in decision-making reported greater satisfaction with their treatment and a better QoL.Discussion: Because no single optimal therapy exists for patients with MS, treatments should be individualized with consideration of patients’ preferences. Our study shows that shared decision-making is under-utilized in the management of MS and supports the benefits of patient involvement.Conclusion: Patients who have an active role in treatment decision-making show improved wellbeing and QoL, and overall treatment satisfaction.Plain Language Summary: Multiple sclerosis (MS) is a disease that affects the brain, causing symptoms such as blurred vision and problems with movements, thoughts, and feelings. MS is a lifelong condition that becomes worse over time and limits the activities that people can do. There are many treatments that can help to reduce relapses (when symptoms become worse), but all have their benefits and drawbacks. It is often the physician who decides which treatment to use, but we wanted to know if patients would feel better if they were involved in the decision.Using our standardized and validated questionnaires, we surveyed physicians and nurses who treat patients with MS in Europe and the United States of America between December 2020 and July 2021, to assess how they felt about the treatment they chose and its effect on the patient. We also asked the patients themselves how they felt about their illness and treatment, whether they were given the chance to choose which treatment to take, and how their treatment affected their symptoms and overall quality of life.The information provided by both the physicians and their patients was used to compare how patients responded when they were involved in the treatment decisions. We found that patients who were involved in choosing their treatment were more satisfied with their treatment and responded better than those whose physicians decided alone. Therefore, it is important for physicians treating patients with MS to consider their patients’ preferences when deciding which treatment is best for them.Keywords: multiple sclerosis, patient preference, decision-making, shared, multinational, survey

The vitamin D receptor with its ligand 1,25 dihydroxy vitamin D3 (1,25D3) regulates epidermal stem cell fate, such that VDR removal from Krt14 expressing keratinocytes delays re-epithelialization of epidermis after wound injury in mice. In this study we deleted Vdr from Lrig1 expressing stem cells in the isthmus of the hair follicle then used lineage tracing to evaluate the impact on re-epithelialization following injury. We showed that Vdr deletion from these cells prevents their migration to and regeneration of the interfollicular epidermis without impairing their ability to repopulate the sebaceous gland. To pursue the molecular basis for these effects of VDR, we performed genome wide transcriptional analysis of keratinocytes from Vdr cKO and control littermate mice. Ingenuity Pathway analysis (IPA) pointed us to the TP53 family including p63 as a partner with VDR, a transcriptional factor that is essential for proliferation and differentiation of epidermal keratinocytes. Epigenetic studies on epidermal keratinocytes derived from interfollicular epidermis showed that VDR is colocalized with p63 within the specific regulatory region of MED1 containing super-enhancers of epidermal fate driven transcription factor genes such as Fos and Jun. Gene ontology analysis further implicated that Vdr and p63 associated genomic regions regulate genes involving stem cell fate and epidermal differentiation. To demonstrate the functional interaction between VDR and p63, we evaluated the response to 1,25(OH)2D3 of keratinocytes lacking p63 and noted a reduction in epidermal cell fate determining transcription factors such as Fos, Jun. We conclude that VDR is required for the epidermal stem cell fate orientation towards interfollicular epidermis. We propose that this role of VDR involves cross-talk with the epidermal master regulator p63 through super-enhancer mediated epigenetic dynamics.

Gavin Taylor-Stokes1, James Pike1, Alesia Sadosky2, Arthi Chandran2, Thomas Toelle31Adelphi Real World, Adelphi Mill, Bollington, Macclesfield, Cheshire, UK; 2Pfizer Inc, New York, NY, USA; 3Department of Neurology, Technische Universität München, Munich, GermanyObjective: To evaluate the association of patient-reported severity of painful diabetic peripheral neuropathy (pDPN) with other outcomes in a European population of patients using the Adelphi Disease Specific Programme for pDPN (DSP III, 2008).Methods: The severity of patients' pDPN (mild, moderate, or severe) was rated independently by both patients and physicians. Relationships were evaluated between patient-reported pDPN severity and other patient-reported outcomes including pain, sleep, function, and work productivity. Physicians rated the severity of patients’ pDPN (1 = mild, 2 = moderate, 3 = severe) and sleep interference.Results: Patient-reported data were available from 634 individuals (56.2% male, mean age 63 years) from France, Germany, Italy, and the UK, of whom only 22.2% reported that they were currently employed. pDPN severity was rated as mild, moderate, and severe by 22.2%, 60.9%, and 16.9% of the patients, respectively. There was a significant association between patient-rated and physician-rated pDPN severity (P < 0.0001), although there were discrepancies in agreement (kappa = 0.37, 95% confidence interval [CI] 0.31, 0.43; weighted kappa = 0.43, 95% CI 0.37, 0.48) among physician and patient ratings in a substantial proportion of patients across severity categories. Higher pDPN severity was associated with greater interference of daily function including sleep (P < 0.0001 for all pairwise comparisons). Among employed patients, percent of pDPN-related impairment while at work (presenteeism) and overall work impairment increased with greater pDPN severity, resulting in indirect costs that increased significantly with pDPN severity; $8266, $15,449, and $24,300 for mild, moderate, and severe pDPN, respectively (overall P < 0.001).Conclusion: Severity of patient-rated pDPN was significantly associated with outcomes, including function and productivity; poorer function and lower productivity were reported at higher pDPN severity levels. Moreover, physicians rated pDPN severity different from patients in a substantial proportion of patients.Keywords: diabetic neuropathy, pain, outcomes

Epidermal lineages and injury induced regeneration are controlled by transcriptional programs coordinating cellular signaling and epigenetic regulators, but the mechanism remains unclear. Previous studies showed that conditional deletion of the transcriptional coactivator Mediator 1 (Med1) changes epidermal lineages and accelerates wound re-epithelialization. Here, we studied a molecular mechanism by which Med1 facilitates these processes, in particular, by focusing on TGFβ signaling through genome wide transcriptome analysis. The expression of the TGF ligands (Tgfβ1/β2) and their downstream target genes is decreased in both normal and wounded Med1 null skin. Med1 silencing in cultured keratinocytes likewise reduces the expression of the ligands (TGFβ1/β2) and diminishes activity of TGFβ signaling as shown by decreased p-Smad2/3. Silencing Med1 increases keratinocyte proliferation and migration in vitro. Epigenetic studies using chromatin immuno-precipitation and next generation DNA sequencing reveals that Med1 regulates transcription of TGFβ components by forming large clusters of enhancers called super-enhancers at the regulatory regions of the TGFβ ligand and SMAD3 genes. These results demonstrate that Med1 is required for the maintenance of the TGFβ signaling pathway. Finally, we show that pharmacological inhibition of TGFβ signaling enhances epidermal lineages and accelerates wound re-epithelialization in skin similar to that seen in the Med1 null mice, providing new insights into epidermal regeneration.

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25- vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD., Introduction Vitamin D plays a critical role in bone and mineral metabolism and also controls other physiologic and pathophysiologic processes, including skeletal muscle function, reproductive health, cancer risk and progression, [...]

Epidemiological and observational studies suggest that vitamin D has potential for the chemoprevention of ovarian cancer. The anticancer effect of vitamin D in the fallopian tube epithelium (FTE), which is now thought to harbor the precursor cells for high grade ovarian cancer, is not known. The purpose of this study was to investigate whether vitamin D can inhibit carcinogenesis in the mogp-TAg fallopian tube (FT) ovarian cancer mouse model and examine underlying mechanisms. To test this hypothesis, 3 groups of 40 5-week-old female mogp-TAg mice were divided equally into two cohorts of 20 mice, treated with either vehicle (vitamin D solvent) or the active 1,25(OH)2D3 analogue EB1089, delivered via mini-pump or IP injection or cholecalciferol delivered in the feed. The FTs were characterized histologically and pathologically after 3 and 7 weeks of treatment. The effect of vitamin D on cultured human FTE cells was also examined. After 3 weeks, vitamin D, delivered as either cholecalciferol or EB1089 significantly inhibited FT carcinogenesis. After 7 weeks, cholecalciferol significantly reduced p53 signatures, serous tubal epithelial carcinoma, FT cancer, and plasma CA125 while increasing apoptosis in the FTE. EB1089 had no significant effect on FT carcinogenesis at 7 weeks. Cholecalciferol significantly reduced proliferation and increased apoptosis in vitro in p53-altered FTE cells. In conclusion, vitamin D inhibited FT carcinogenesis by clearing cells with p53 alterations. These data suggest that vitamin D has merit for the chemoprevention of fallopian tube/ovarian cancer. The optimal chemopreventive effect may be dependent on the route of vitamin D administration [ABSTRACT FROM AUTHOR]

Although psoriasis patients often report a negative impact on health-related quality of life (HRQoL) and work productivity, less is known about how disease burden varies between periods of flare and remission. The aim of this study was tocompare HRQoL and work productivity by disease activity level. Data were extracted from Adelphi 2011/2013 Disease Specific Programmes, two real world surveys of US dermatologists and psoriasis patients. HRQoL was measured using the EuroQOL 5-Dimension Health Questionnaire (EQ-5D) and Dermatology Life Quality Index (DLQI). Work productivity was measured using the Work Productivity Activity index (WPAI). Three levels of disease activity were constructed based on physician reports: remission, active not flaring, active, and flaring. Multivariable regression analyses explored the relationship between disease activity, HRQoL and work productivity, controlling for differences in demographics and comorbidities. Out of 681 psoriasis patients 24% were in remission, 62% had active disease without flaring, and 15% experienced active disease and were currently flaring. Greater disease activity was associated with worse HRQoL. EQ-5D scores decreased with more active disease (remission vs. active not flaring vs. active and flaring: 0.93 vs. 0.90 vs. 0.82; p

Psoriasis patients often report dissatisfaction with treatment. However, the extent to which patients and their treating dermatologists are aligned regarding satisfaction with psoriasis therapy is largely unknown. This was explored using data derived from the Adelphi 2011/2013 Psoriasis Disease Specific Programmes, two real world surveys of US dermatologists and their patients. Physicians and patients independently reported their satisfaction with psoriasis control (satisfied, dissatisfied). Two levels of satisfaction alignment between physician and patient responses were constructed: aligned (same responses) and misaligned (different responses). In addition, dermatologists provided patient treatment history and disease/symptom severity whereas patients reported data on health-related quality of life (HRQoL), using the EuroQOL 5-Dimension Health Questionnaire (EQ-5D) and Dermatology Life Quality Index (DLQI), and work productivity using the Work Productivity Activity index (WPAI). Multivariate regressions were employed to examine the relationship between satisfaction alignment, overall disease and symptom severity, HRQoL, and work productivity controlling for differences in patient demographics and comorbidities.From 627 paired dermatologist and psoriasis patient records, 512 (81.7%) and 115 (18.3%) cases fell into the ‘aligned’ and ‘misaligned’ groups, respectively. Compared with patients in the aligned group, those in the misaligned group had more moderate to severe psoriasis (82.3% vs. 43.7%), moderate to severe itching (45.6% vs. 27.8%), pain (23.0% vs. 10.6%), and scaling (54.8% vs. 36.1%), and had lower current biologics use (27.0% vs. 42%) (all p

Psoriasis patients often report dissatisfaction with treatment. However, it is less clear how the severity of key psoriasis symptoms (painful skin, itching, and scaling) as well as overall disease severity influence patient dissatisfaction levels. Using the Adelphi 2011/2013 Psoriasis Disease Specific Programmes, two “real world” surveys of US dermatologists and their patients, patient satisfaction was evaluated. Dermatologists provided data on disease characteristics, while patients indicated their satisfaction with existing treatment. Physician-reported severity (none, mild, moderate/severe) of psoriasis-related itching, pain, and scaling, overall disease severity (mild, moderate and severe) and therapy type were compared by patient satisfaction levels (satisfied vs. dissatisfied). Multivariate regressions examined the relationship between patient satisfaction, clinical symptoms, and psoriasis overall disease severity, controlling for differences in patient demographics and comorbidities. The sample comprised 633 psoriasis patients (56% male) with a mean age of 45. Overall, 18% of patients reported dissatisfaction with their psoriasis treatment. Dissatisfied patients were more likely to have moderate (65% vs. 40%) or severe (21% vs 3%) psoriasis compared to patients who were satisfied (both p

Background: Psoriasis patients report that this disease can impact on their health-related quality of life (HR-QoL) and work productivity. It is important to understand how this is influenced by the clinical characteristics of psoriasis such as symptom severity. Common symptoms include itching, pain, and scaling but the psychosocial impact these features have on patients is not well understood.Objective: To explore the impact of psoriasis symptoms (itching, pain, and scaling) on HR-QoL and work productivity.Method: Data were extracted from the Adelphi 2011 and 2013 Psoriasis Disease Specific Programmes – two real world surveys of US dermatologists and their psoriasis patients.  HR-QoL was measured using the Dermatology Life Quality Index (DLQI) and EuroQOL 5-Dimension Health Questionnaire (EQ-5D). Work productivity loss was measured by the Work Productivity and Activity Impairment (WPAI) questionnaire. The impact of symptom severity (none, mild, moderate/severe) for itching, pain, and scaling on DLQI, EQ-5D, and WPAI scores were examined, controlling for differences in demographics and co-morbidities.Results: Patient mean age was 44 years and 55% were male. Moderate/severe itching, pain, and scaling were experienced by 33%, 13%, and 41% of patients, respectively. Controlling for differences in demographics and co-morbidities, increased symptom severity was associated with reduced HR-QoL. Accordingly, EQ-5D scores decreased with itching severity (moderate/severe vs. none: -0.07; 95% confidence interval [CI] =-0.09, -0.04), whereas DLQI scores increased (moderate/severe versus none: 4.9; CI = 3.9, 5.9) (both p

The primary function of vitamin D in higher vertebrates is to regulate mineral homeostasis through direct actions on intestinal calcium (Ca) and phosphate (P) absorption, bone mineral resorption, and renal [...]

The vitamin D receptor (VDR) is the single known regulatory mediator of hormonal 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]] in higher vertebrates. It acts in the nucleus of vitamin D target cells to regulate the expression of genes whose products control diverse, cell type-specific biological functions that include mineral homeostasis. In this Review we describe progress that has been made in defining new cellular sites of action of this receptor, the mechanisms through which this mediator controls the expression of genes, the biology that ensues, and the translational impact of this receptor on human health and disease. We conclude with a brief discussion of what comes next in understanding vitamin D biology and the mechanisms that underlie its actions., Introduction In the early 1970s, 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]] was identified as both the exclusive, metabolically active form of vitamin D and a key component of what proved to be an [...]