See clearer: survey on the subjective and objective information levels as well as perception and information transfer using virtual reality headsets in patients with diabetic macular edema receiving anti-VEGF treatment.

PURPOSE: The purpose of this study is to investigate the use of a VR Headset in routine clinical practice as an additional source of information for patients with diabetic macular edema (DME) and their companions. METHODS: Survey including 121 patients with DME, 22 companions, and 14 healthcare professionals from 8 ophthalmology centers in Germany. Patients' and their companions' health literacy was assessed by questionnaires including knowledge statements before and after watching a VR-based 3-D educational video. HCPs' perspectives on the usability of a VR Headset were also assessed. RESULTS: Patients' mean age was 63.4 ± 12.2 years, 64.5% were men, and 76% (92/121) had previous anti-VEGF (VEGF, vascular endothelial growth factor) injections. After using the VR Headset, over 85% of patients and companions felt better informed about DME and its treatment. Patients' mean (± SD) number of correct answers to knowledge statements increased from 13.2 ± 3.7 before to 15.5 ± 2.3 after using the VR Headset. Over 95% of patients and companions rated content and ease of understanding of the video as "very good" or "good." Most patients and all companions considered the use of a VR Headset as a positive experience, most wishing to obtain information via VR Headset in the future. Most physicians and all medical assistants rated the effect of the VR Headset on patient satisfaction as positive and suggested further VR modules. CONCLUSION: After using the VR Headset, patients with DME and their companions demonstrated knowledge gains that may be meaningful individually and contribute to better adherence. This may offer an additional opportunity for knowledge transfer.

Assessment of Medication Adherence Using a Medical App Among Patients With Multiple Sclerosis Treated With Interferon Beta-1b: Pilot Digital Observational Study (PROmyBETAapp).

BACKGROUND: Accurate measurement of medication adherence using classical observational studies typically depends on patient self-reporting and is often costly and slow. In contrast, digital observational studies that collect data directly from the patient may pose minimal burden to patients while facilitating accurate, timely, and cost-efficient collection of real-world data. In Germany, ~80% of patients with multiple sclerosis (MS) treated with interferon beta 1b (Betaferon) use an electronic autoinjector (BETACONNECT), which automatically records every injection. Patients may also choose to use a medical app (myBETAapp) to document injection data and their well-being (using a "wellness tracker" feature). OBJECTIVE: The goal of this pilot study was to establish a digital study process that allows the collection of medication usage data and to assess medication usage among patients with MS treated with interferon beta-1b who use myBETAapp. METHODS: The PROmyBETAapp digital observational study was a mixed prospective and retrospective, noninterventional, cohort study conducted among users of myBETAapp in Germany (as of December 2017: registered accounts N=1334; actively used accounts N=522). Between September and December 2017, users received two invitations on their app asking them to participate. Interested patients were provided detailed information and completed an electronic consent process. Data from consenting patients' devices were collected retrospectively starting from the first day of usage if historical data were available in the database and collected prospectively following consent attainment. In total, 6 months of data on medication usage behavior were collected along with 3 months of wellness tracker data. Descriptive statistics were used to analyze persistence, compliance, and adherence to therapy. RESULTS: Of the 1334 registered accounts, 96 patients (7.2%) provided informed consent to participate in the study. Of these, one patient withdrew consent later. For another patient, injection data could not be recorded during the study period. Follow-up of the remaining 94 patients ended in May 2018. The mean age of participants was 46.6 years, and 50 (53%) were female. Over the 6-month study period, persistence with myBETAapp usage was 96% (90/94), mean compliance was 94% of injections completed, and adherence (persistence and ≥80% compliance) was 89% (84/94). There was no apparent difference between male and female participants and no trend across age groups. The wellness tracker was used by 21% of participants (20/94), with a mean of 3.1 entries per user. CONCLUSIONS: This study provides important information on medication usage among patients with MS treated with interferon beta-1b and on consenting behavior of patients in digital studies. In future studies, this approach may allow patients' feedback to be rapidly implemented in existing digital solutions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03134573; https://clinicaltrials.gov/ct2/show/NCT03134573.

Sleep quality, daytime sleepiness, fatigue, and quality of life in patients with multiple sclerosis treated with interferon beta-1b: results from a prospective observational cohort study.

BACKGROUND: Sleep disorders and fatigue are common in multiple sclerosis (MS). The underlying causes are not fully understood, and prospective studies are lacking. Therefore, we conducted a prospective, observational cohort study investigating sleep quality, fatigue, quality of life, and comorbidities in patients with MS. METHODS: Patients with relapsing-remitting MS or clinically isolated syndrome treated with interferon beta-1b were followed over two years. The primary objective was to investigate correlations between sleep quality (PSQI), fatigue (MFIS), and functional health status (SF-36). Secondary objectives were to investigate correlations of sleep quality and daytime sleepiness (ESS), depression (HADS-D), anxiety (HADS-A), pain (HSAL), and restless legs syndrome (RLS). We applied descriptive statistics, correlation and regression analyses. RESULTS: 139 patients were enrolled, 128 were available for full analysis. The proportion of poor sleepers (PSQI≥5) was 55.47% at the beginning and 37.70% by the end of the study (106 and 41 evaluable questionnaires, respectively). Poor sleepers performed worse in MFIS, SF-36, ESS, HADS-D, and HADS-A scores. The prevalence of patients with RLS was low (4.5%) and all were poor sleepers. Poor sleep quality was positively correlated with fatigue and low functional health status. These relationships were corroborated by multivariable-adjusted regression analyses. ESS values and poor sleep quality at baseline seem to predict sleep quality at the one-year follow-up. No variable predicted sleep quality at the two-year follow-up. CONCLUSIONS: Our results confirm the high prevalence of poor sleep quality among patients with MS and its persistent correlation with fatigue and reduced quality of life over time. They highlight the importance of interventions to improve sleep quality. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov: NCT01766063 (registered December 7, 2012). Registered retrospectively (first patient enrolled December 6, 2012).

Adherence, satisfaction and functional health status among patients with multiple sclerosis using the BETACONNECT® autoinjector: a prospective observational cohort study.

BACKGROUND: Maintaining patient adherence to disease modifying drugs in multiple sclerosis is a challenge, which can be improved by autoinjectors. The BETACONNECT® is a fully electronic autoinjector for the injection of interferon beta-1b (IFN beta-1b) automatically recording injections. METHODS: The BETAEVAL study was a prospective, observational, cohort study over 24 weeks among patients with relapsing remitting multiple sclerosis or clinically isolated syndrome treated with IFN beta-1b in Germany using the BETACONNECT®. The primary aim was to investigate treatment adherence, secondary aims included assessing satisfaction and functional health status. Adherence was evaluated from injection data recorded by the device. Patient-related data were obtained from clinical examinations and patient questionnaires. RESULTS: Of the 151 patients enrolled, 143 were available for analysis. Thirty-four patients discontinued the study prematurely. 107/143 (74.8%) patients still used the BETACONNECT® at the end of the study. Injection data from the device at any visit was available for 107 patients. Among those, the percentage of adherent patients injecting ≥80% of doses and still participating in the study was 57.9% at week 24. 29% of patients prematurely stopped the study, 13.1% injected <80%. Among patients with BETACONNECT® data at the respective visit, the proportion of adherent patients was high over the entire study period (week 4: 81.1% [N = 95], week 12: 86.7% [N = 83], week 24: 80.5% [N = 77]). Participants (N = 143) indicated high satisfaction with the BETACONNECT®. At week 24, 98.0% of patients who completed the corresponding questionnaire (strongly) agreed that it was user-friendly, 81.2% felt confident in using it compared to their previous way and 85.5% preferred it to their previous way of injection. Injection-related pain was rated as mild to moderate at all follow-up visits. Whereas 17.2% of patients with corresponding questionnaire indicated using analgesics prior to injection at week 4, only 9.1% did at week 24. Outcomes from questionnaires assessing functional health status, depression, fatigue and cognitive function were very similar throughout the study course. CONCLUSIONS: The majority of patients continued using the BETACONNECT® for IFN beta-1b treatment during the 24-week study period. Adherence was high among participants still using the BETACONNECT® and patients were highly satisfied with the device. Ongoing studies will evaluate long-term adherence and treatment outcomes in patients using the BETACONNECT®. TRIAL REGISTRATION: clinicaltrails.gov NCT02121444 (registered April 22, 2014).

Selectivity in genetic association with sub-classified migraine in women.

Migraine can be sub-classified not only according to presence of migraine aura (MA) or absence of migraine aura (MO), but also by additional features accompanying migraine attacks, e.g. photophobia, phonophobia, nausea, etc. all of which are formally recognized by the International Classification of Headache Disorders. It remains unclear how aura status and the other migraine features may be related to underlying migraine pathophysiology. Recent genome-wide association studies (GWAS) have identified 12 independent loci at which single nucleotide polymorphisms (SNPs) are associated with migraine. Using a likelihood framework, we explored the selective association of these SNPs with migraine, sub-classified according to aura status and the other features in a large population-based cohort of women including 3,003 active migraineurs and 18,108 free of migraine. Five loci met stringent significance for association with migraine, among which four were selective for sub-classified migraine, including rs11172113 (LRP1) for MO. The number of loci associated with migraine increased to 11 at suggestive significance thresholds, including five additional selective associations for MO but none for MA. No two SNPs showed similar patterns of selective association with migraine characteristics. At one extreme, SNPs rs6790925 (near TGFBR2) and rs2274316 (MEF2D) were not associated with migraine overall, MA, or MO but were selective for migraine sub-classified by the presence of one or more of the additional migraine features. In contrast, SNP rs7577262 (TRPM8) was associated with migraine overall and showed little or no selectivity for any of the migraine characteristics. The results emphasize the multivalent nature of migraine pathophysiology and suggest that a complete understanding of the genetic influence on migraine may benefit from analyses that stratify migraine according to both aura status and the additional diagnostic features used for clinical characterization of migraine.

Population-based approaches to genetics of migraine.

BACKGROUND: While the most accurate diagnosis of migraine typically requires a clinical interview guided by strict diagnostic criteria, an alternative approach that ascertains migraine by questionnaire in population-based settings has been instrumental in the discovery of common genetic variants influencing migraine risk. This result may be surprising. Population-based approaches are often criticized for limited ability to distinguish migraine from other forms of primary headache. It is thus useful to revisit prevailing ideas about population-based ascertainment of migraine to evaluate the extent to which this approach has potential for additional insights into migraine genetics and therefore pathophysiology. OVERVIEW: We review recent findings suggesting that the success of the population-based approach is derived from the possibility of collecting much larger samples than in the clinic-based setting even at the risk of introducing phenotypic and genetic heterogeneity. The findings are also consistent with new appreciations for the genetic basis of many other common, complex clinical characteristics. However, clinic-based ascertainment and other settings will remain more effective than population-based approaches for investigating certain, often very specific aspects of migraine genetics. CONCLUSION: We argue that the detailed genetic architecture of migraine, various aspects of methodology, and the ultimate sample size achieved by population-based ascertainment will be critical determinants of the future success of this approach to genetic analysis of migraine and its comorbidities.

Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

BACKGROUND AND PURPOSE: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. METHODS: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. RESULTS: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). CONCLUSIONS: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.

Circulating fetuin-A and risk of ischemic stroke in women.

BACKGROUND: Fetuin-A, a protein secreted primarily by the liver, has been associated with nonalcoholic fatty liver disease and insulin resistance. In a recent study, higher circulating fetuin-A was associated with cardiovascular events, particularly ischemic stroke. However, these data have not been replicated. METHODS: A nested case control design was used to examine the relationship between fetuin-A and ischemic stroke among female participants of the Nurses' Health Study. Fetuin-A was measured in blood samples collected and stored between 1989 and 1990. A total of 459 incident cases of ischemic stroke were identified and confirmed by medical records according to the National Survey of Stroke criteria between 1990 and 2006 and matched to 459 controls by age, race/ethnicity, date of sample collection, menopausal status, postmenopausal hormone use, and smoking status. The association between fetuin-A and ischemic stroke was modeled using conditional logistic regression. RESULTS: Circulating fetuin-A was higher in women (P < 0.01) who reported increased body mass index (BMI) of ≥25 kg/m(2), total cholesterol ≥200 mg/dL, high-sensitivity C-reactive protein ≥3 mg/L, and current hormone use at baseline. Significant partial Spearman correlations (P < 0.001), adjusted for matching factors, were found between measured concentrations of fetuin-A and triglycerides (r = 0.20), C-reactive protein (r = 0.14), and BMI (r = 0.15). Fetuin-A quartiles were not significantly associated with increased risk of incident ischemic stroke when adjusted for matching factors (relative risk, 1.03; 95% CI, 0.69-1.54, extreme quartiles); additional adjustment for lifestyle factors or cardiovascular disease risk factors and biomarkers did not alter results. CONCLUSIONS: In this sample of women, fetuin-A was not significantly associated with risk of ischemic stroke. Further research is needed to explore this association.

Migraine and restless legs syndrome: a systematic review.

BACKGROUND: Restless legs syndrome (RLS) is increasingly being reported as a comorbidity of migraine. METHODS: We conducted a systematic review and meta-analysis of studies investigating RLS in headache/migraine and vice versa. We calculated the prevalence and 95% confidence intervals (CI) of RLS in headache/migraine, of headache/migraine in RLS and controls, and odds ratios (ORs) of the association between the conditions. We then determined pooled effect estimates for the associations. RESULTS: We identified 24 studies. RLS prevalence in migraine ranged from 8.7% to 39.0% with no apparent differences based on gender and aura status. Prevalence among controls was compatible with the literature. Migraine prevalence in RLS ranged from 15.1% to 62.6%. We did not pool prevalence data because of high unexplained heterogeneity. High heterogeneity with respect to the association between any migraine and RLS could be explained by study design. Pooled analyses showed substantially higher effect estimates in case-control studies (pooled OR = 4.19, 95% CI 3.07-5.71; I (2) = 0.0%) than in cohort studies (pooled OR = 1.22, 95% CI 1.14-1.30; I (2) = 0.0%). CONCLUSION: Our results support the concept of RLS as an important comorbidity of migraine. However, the degree of association appears to be strongly determined by study design. Potential effects by gender and aura status and the role of RLS in other headache disorders remain unclear.

Bi-allelic and tri-allelic 5-HTTLPR polymorphisms and triptan non-response in cluster headache.

BACKGROUND: Triptans are only effective in terminating cluster headache (CH) attacks in 70-80% of patients. Pharmacogenetic aspects of the serotonin metabolism, specifically variation in the 5-HTTLPR may be involved. METHODS: Genetic association study in a well-defined cohort of 148 CH patients with information on drug response to triptans. CH was diagnosed according to the criteria of the International Headache Society. Genotypes of the 43-bp insdel (rs4795541) and A > G (rs25531) polymorphisms in the 5-HTTLPR promoter region were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between bi-allelic and tri-allelic genotypes and triptan non-response with genotype models. RESULTS: Mean age at study entry among patients was 44.6 ± 10.5 years, 77.7% were men. The genotype distribution both for the bi-allelic and the tri-allelic polymorphism was in Hardy-Weinberg equilibrium. We did not find an association of the bi-allelic polymorphism with triptan non-response. While the effect estimates for the S variant of the tri-allelic polymorphisms suggested increased odds of triptan non-response in CH patients (multivariable-adjusted odds ratio [95% confidence interval]: L*L* genotype-reference; L*S* genotype-1.33 [0.53-3.32]; S*S* genotype-1.46 [0.54-3.98]), the results were not statistically significant. CONCLUSIONS: Data from our study do not indicate a role of bi-allelic and tri-allelic genotypes of the 5-HTTLPR polymorphism in triptan non-response in CH.

[Aflibercept in a real-world setting: the AURIGA study : 24-month results of the German cohort of treatment-naïve patients with macular edema following retinal vein occlusion receiving intravitreal aflibercept]. / Aflibercept im klinischen Alltag: die AURIGA-Studie : 24-Monats-Ergebnisse der deutschen Kohorte behandlungsnaiver Patienten mit Makulaödem bei retinalem Venenverschluss unter Therapie mit intravitrealem Aflibercept.

BACKGROUND: AURIGA is the largest prospective real-world study to evaluate intravitreal aflibercept 2 mg (IVT-AFL) treatment of macular edema (ME) secondary to retinal vein occlusion (RVO) and diabetic macular edema. Here we present the 24-month data from the German cohort of treatment-naïve patients with ME due to RVO. METHODS: Treatment-naïve patients with ME secondary to RVO were treated with IVT-AFL 2 mg in the routine clinical practice. The primary endpoint was mean change in visual acuity (VA, early treatment diabetic retinopathy, ETDRS, letters) at month 12 compared to baseline. Analyses were descriptive. RESULTS: Analysis included 130 patients with RVO (n = 61, 46.9% with central RVO, n = 69, 53.1% with branch RVO). The mean (± SD) time the RVO patients remained in the study was 18.4 ± 7.4 months. The mean VA gain (95% confidence interval) in the overall cohort was +10.9 (7.5-14.2) letters at month 12 and +9.7 (6.1-13.3) at month 24 (baseline VA 56.5 ± 18.9 letters). At 24 months, 67% of RVO patients gained ≥5 letters and 40% gained ≥15 letters. The mean number of injections was 4.4 ± 1.3 up to month 6, 6.2 ± 2.7 up to month 12 and 8.2 ± 4.5 up to month 24. The mean central retinal thickness (CRT) reduction was -206µm (-252 to -160µm) at 12 months and -219µm (-263 to -175µm) at 24 months (baseline CRT 507 ± 177 µm). The safety profile was consistent with that of previous studies. DISCUSSION: In the German AURIGA cohort of treatment-naïve patients with ME secondary to RVO, IVT-AFL 2 mg treatment in clinical practice resulted in rapid and clinically relevant VA gains and a reduction in CRT. These results were largely maintained over 24 months despite the low injection frequency from month 6.

Low dehydroepiandrosterone sulfate is associated with increased risk of ischemic stroke among women.

BACKGROUND AND PURPOSE: Previous research suggests greater risk of coronary heart disease with lower levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). No studies have examined the association between DHEAS and risk of ischemic stroke. DHEAS may influence ischemic stroke risk through atherosclerotic-related mechanisms (endothelial function and smooth muscle cell proliferation) or insulin resistance. METHODS: Between 1989 and 1990, 32 826 women without prior stroke in the Nurses' Health Study, an observational cohort, provided blood samples and were followed up for cardiovascular events. Among this sample, using a nested case-control design, 461 ischemic strokes were confirmed by medical records by 2006. Cases were matched to controls free of stroke at the time of the index case and by age, race, menopausal status, postmenopausal hormone use, smoking status, and date of sample collection. Multivariable conditional logistic regression was used. RESULTS: Median DHEAS levels did not differ between cases (median=58.7) and controls (median=66.0; P=0.10). Conditional on matching factors, the lowest DHEAS quartile exhibited a relative risk of 1.30 for ischemic stroke (95% confidence interval, 0.88-1.94), compared with the highest quartile and marginally unchanged when adjusted for confounders (relative risk=1.33; 95% confidence interval, 0.87-2.02). When modeled as a binary variable dichotomized at the lowest quartile, women with low DHEAS (≤the lowest quartile) had a significantly increased multivariable adjusted risk of ischemic stroke compared with those with higher levels (relative risk=1.41; 95% confidence interval, 1.03-1.92). CONCLUSIONS: Lower DHEAS levels were associated with a greater risk of ischemic stroke, even after adjustment for potential confounders. These novel observations warrant confirmation in other populations.

Migraine, headache, and the risk of depression: Prospective cohort study.

BACKGROUND: While cross-sectional studies have shown associations between migraine and depression, few studies have been able to evaluate the association between migraine and incident depression. METHODS: A prospective cohort study among 36,016 women without a history of depression enrolled in the Women's Health Study who provided information about migraine and headache at baseline. Women were classified as either having nonmigraine headache, migraine with aura, migraine without aura, past history of migraine or no history of headache. Cox proportional hazards models were used to evaluate the association between migraine and headache status and incident depression. RESULTS: At baseline, 5115 women reported a history of nonmigraine headache, 1805 reported migraine with aura, 2723 reported migraine without aura, and 1896 reported a past history of migraine. During 13.8 mean years of follow-up, 3833 new cases of depression occurred. The adjusted relative risks of incident depression were 1.44 (95% CI: 1.32, 1.56) for nonmigraine headache, 1.53 (95% CI: 1.35, 1.74) for migraine with aura, 1.40 (95% CI: 1.25, 1.56) for migraine without aura, and 1.56 (95% CI: 1.37, 1.77) for past history of migraine compared to no history of headache. CONCLUSIONS: Middle-aged women with migraine or nonmigraine headache are at increased risk of incident depression. Frequent migraine attacks (weekly or daily) were associated with the highest risk for developing depression.

Migraine and restless legs syndrome in men.

BACKGROUND: Previous studies suggest an association between migraine and restless legs syndrome (RLS). Population-based data, however, have been limited to women. The aim of this study is to evaluate the association between migraine and RLS in a male cohort. METHODS: We conducted a cross-sectional study among 22,926 participants in the Physicians' Health Study. Migraine and RLS information was self-reported. RLS was classified according to four minimal diagnostic criteria. Age- and multivariable-adjusted logistic regression models were calculated. RESULTS: Of the 22,926 participants (mean age 67.8), 2816 (12.3%) reported migraine and 1717 (7.5%) RLS. Migraine was associated with an increased multivariable-adjusted odds ratio (OR) (95% confidence interval (CI)) of 1.20 (1.04-1.38) for having RLS. The association remained stable after excluding men with potential mimics of RLS and was not modified by age. CONCLUSIONS: Results of our study indicate an association between migraine and RLS in men. The magnitude of effect is similar to what has been reported in women.

Identification of Patients With Elevated Urine Albumin-to-Creatinine Ratio Levels in a Type 2 Diabetes Mellitus Cohort Based on Data Submitted by Patients via a Smartphone App (SMART-Finder): Protocol for an Observational Study.

BACKGROUND: Despite effective treatment options, chronic kidney disease (CKD) has become a major cause of mortality worldwide due to the ever-increasing number of patients with type 2 diabetes mellitus (T2DM). Guideline-compliant, at least, annual screening of patients with T2DM is crucial to prevent renal disease progression. However, data on the prevalence of CKD in patients with T2DM and on screening frequency are limited. SMART-Finder is the first study to exclusively use data provided directly by patients via an adherence app to collect information on the prevalence of CKD, risk factors, disease management, and quality of life of patients with T2DM in Germany. OBJECTIVE: The primary objective of this study is to determine the proportion of patients with T2DM and an elevated urine albumin-to-creatinine ratio (UACR; albumin-to-creatinine ratio stage A2 and A3) at baseline and after 12 (±3) months. Secondary objectives include the proportion of patients who remain in or switch to another albumin-to-creatinine ratio classification category after 12 months, information on quality of life, disease awareness, and adherence rates, as well as the proportion of patients without any UACR-screening data. Recruitment occurs via push notification among MyTherapy app users with T2DM. METHODS: This is a single-arm, retrospective/prospective, observational, digital, patient-centered cohort study, with recruitment and data documentation via a health app. Required routine laboratory data are provided by treating physicians to their patients for data entry. The study population includes adult patients with T2DM documenting their data in the MyTherapy app using their own smartphone or tablet. Study participants are provided with a specifically developed electronic case report form containing questions on demographic and general data, quality of life, disease awareness, and laboratory values including estimated glomerular filtration rate, UACR, hemoglobin 1Ac, and blood pressure. Apart from demographic and general data, all data are collected at baseline and 12 months after the last UACR assessment. An automatically generated push notification reminds participants of the second data entry. The extracted and pseudonymized data are analyzed descriptively. RESULTS: The enrollment period for this study started in February 2023 and shall end after 12 months or after the enrollment of 5000 patients. An interim analysis is planned 3 months after the inclusion of the first patient and the final analysis after 12 months of follow-up. CONCLUSIONS: Overall, the study will contribute to minimizing the existing data gap on the prevalence of CKD in patients with T2DM in Germany, provide important insights into the current disease management of patients with T2DM in everyday clinical practice in Germany, and support guideline-based care for the participating patients. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/44996.

A genome-wide analysis of 'Bounty' descendants implicates several novel variants in migraine susceptibility.

Migraine is a common neurological disease with a complex genetic aetiology. The disease affects ~12% of the Caucasian population and females are three times more likely than males to be diagnosed. In an effort to identify loci involved in migraine susceptibility, we performed a pedigree-based genome-wide association study of the isolated population of Norfolk Island, which has a high prevalence of migraine. This unique population originates from a small number of British and Polynesian founders who are descendents of the Bounty mutiny and forms a very large multigenerational pedigree (Bellis et al.; Human Genetics, 124(5):543-5542, 2008). These population genetic features may facilitate disease gene mapping strategies (Peltonen et al.; Nat Rev Genet, 1(3):182-90, 2000. In this study, we identified a high heritability of migraine in the Norfolk Island population (h (2) = 0.53, P = 0.016). We performed a pedigree-based GWAS and utilised a statistical and pathological prioritisation approach to implicate a number of variants in migraine. An SNP located in the zinc finger protein 555 (ZNF555) gene (rs4807347) showed evidence of statistical association in our Norfolk Island pedigree (P = 9.6 × 10(-6)) as well as replication in a large independent and unrelated cohort with >500 migraineurs. In addition, we utilised a biological prioritisation to implicate four SNPs, in within the ADARB2 gene, two SNPs within the GRM7 gene and a single SNP in close proximity to a HTR7 gene. Association of SNPs within these neurotransmitter-related genes suggests a disrupted serotoninergic system that is perhaps specific to the Norfolk Island pedigree, but that might provide clues to understanding migraine more generally.

Migraine and restless legs syndrome in women.

BACKGROUND: Few clinic-based studies report an association between migraine and restless legs syndrome (RLS); however, population-based data are unavailable. METHODS: Cohort study among 31,370 women participating in the Women's Health Study. We had detailed self-reported information on migraine, including aura status, and RLS. RLS was ascertained at the 9-year follow-up. We calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between migraine and RLS. We investigated any indication of migraine until RLS ascertainment as well as migraine with and without aura at baseline, prior migraine before baseline, and new reports of migraine during follow-up. RESULTS: At baseline or during follow-up 6857 (21.9%) women reported any migraine. These women had an increased risk for RLS (multivariable-adjusted OR = 1.22; 95%CI 1.13-1.32). Further analyses indicated a similar association for migraine with aura (multivariable-adjusted OR = 1.27; 95%CI 1.10-1.48) and migraine without aura (multivariable-adjusted OR = 1.24; 95%CI 1.09-1.40) as well as for new reports of migraine during follow-up (multivariable-adjusted OR = 1.30; 95%CI 1.10-1.54). Prior migraine did not appear to be associated with RLS. CONCLUSIONS: Our data suggest an association between migraine and RLS at the population level. The association is similar for migraine with and without aura and for new reports of migraine during follow-up.

Genetics of migraine in the age of genome-wide association studies.

Genetic factors importantly contribute to migraine. However, unlike for rare monogenic forms of migraine, approaches to identify genes for common forms of migraine have been of limited success. Candidate gene association studies were often negative and positive results were often not replicated or replication failed. Further, the significance of positive results from linkage studies remains unclear owing to the inability to pinpoint the genes under the peaks that may be involved in migraine. Problems hampering these studies include limited sample sizes, methods of migraine ascertainment, and the heterogeneous clinical phenotype. Three genome-wide association studies are available now and have successfully identified four new genetic variants associated with migraine. One new variant (rs1835740) modulates glutamate homeostasis, thus integrates well with current concepts of neurotransmitter disturbances. This variant may be more specific for severe forms of migraine such as migraine with aura than migraine without aura. Another variant (rs11172113) implicates the lipoprotein receptor LRP1, which may interact with neuronal glutamate receptors, thus also providing a link to the glutamate pathway. In contrast, rs10166942 is in close proximity to TRPM8, which codes for a cold and pain sensor. For the first time this links a gene explicitly implicated in pain related pathways to migraine. The potential function of the fourth variant rs2651899 (PRDM16) in migraine is unclear. All these variants only confer a small to moderate change in risk for migraine, which concurs with migraine being a heterogeneous disorder. Ongoing large international collaborations will likely identify additional gene variants for migraine.

Ascertaining Medication Use and Patient-Reported Outcomes via an App and Exploring Gamification in Patients With Multiple Sclerosis Treated With Interferon ß-1b: Observational Study.

BACKGROUND: The BETACONNECT autoinjector and myBETAapp app were designed to support patients with multiple sclerosis receiving interferon ß-1b and are an ideal platform for digital observational studies. A recent pilot study in Germany demonstrated the feasibility of using the app to recruit patients, obtain informed consent, and evaluate medication-taking behavior over 6 months. OBJECTIVE: This study aims to describe medication-taking behavior for 1 year in patients with multiple sclerosis receiving interferon ß-1b based on data collected from the app and to provide information on patient-reported outcomes (PROs). The optional use of the cognitive training tool PEAK (Peak, formerly Brainbow Ltd) is included to test the feasibility of gamification in this setting. METHODS: A prospective and retrospective, exploratory, digital, observational cohort study was conducted among users of the app in Germany. Invitations to participate were sent to patients' apps between February and May 2019. Participants provided electronic informed consent. Injection-related data from consenting patients' devices were collected prospectively for 1 year following the consent date and retrospectively for ≤1 year from the first day of use (if historical data were available). Participants also completed three electronic PRO instruments every 3 months: the EuroQol 5-Dimension, 5-Level questionnaire (EQ-5D-5L); the Treatment Satisfaction Questionnaire for Medication (TSQM; version II); and a questionnaire on satisfaction with treatment support (on a server accessed via an emailed hyperlink). All patients were offered optional access to the professional version of PEAK. RESULTS: Of 1778 registered app accounts (May 2019), 79 patients (4.44%) provided informed consent; 62 (3.49%) were eligible for inclusion in the prospective analysis, of whom, 60 (97%) also had retrospective data. The mean age of the 62 participants was 43.2 (SD 11.5) years and 41 (66%) were women. Compliance over the 1-year prospective observational period (primary end point) was high (median 98.9%, IQR 94.3%-100%) and similar among men and women. Persistence and adherence (coprimary end points) decreased from 85% (53/62) and 74% (46/62), respectively, at 6 months to 76% (47/62) and 65% (40/62), respectively, at 12 months; both were higher in men than in women. A retrospective analysis showed similar patterns. The PRO questionnaires were answered by 79% (49/62) of the participants at baseline and 50% (31/62) of them at month 12. Women had more severe problems in some EQ-5D-5L dimensions (mobility, usual activities, and pain/discomfort) and lower median convenience scores on the TSQM (version II) than men. At month 12, 84% (26/31) of the patients were satisfied or very satisfied with the app. PEAK was used by 67% (14/21) of men and 49% (20/41) of women. CONCLUSIONS: This study showed high compliance and decreasing persistence and adherence over 1 year and demonstrated the feasibility of including remotely completed electronic PRO instruments in digital observational studies.