A population-health approach to characterizing migraine by comorbidity: Results from the Mindfulness and Migraine Cohort Study.

BACKGROUND: The heterogeneity of migraine has been reported extensively, with identified subgroups usually based on symptoms. Grouping individuals with migraine and similar comorbidity profiles has been suggested, however such segmentation methods have not been tested using real-world clinical data. OBJECTIVE: To gain insights into natural groupings of patients with migraine using latent class analysis based on electronic health record-determined comorbidities. METHODS: Retrospective electronic health record data analysis of primary-care patients at Sutter Health, a large open healthcare system in Northern California, USA. We identified migraine patients over a five-year time period (2015-2019) and extracted 29 comorbidities. We then applied latent class analysis to identify comorbidity-based natural subgroups. RESULTS: We identified 95,563 patients with migraine and found seven latent classes, summarized by their predominant comorbidities and population share: fewest comorbidities (61.8%), psychiatric (18.3%), some comorbidities (10.0%), most comorbidities - no cardiovascular (3.6%), vascular (3.1%), autoimmune/joint/pain (2.2%), and most comorbidities (1.0%). We found minimal demographic differences across classes. CONCLUSION: Our study found groupings of migraine patients based on comorbidity that have the potential to be used to guide targeted treatment strategies and the development of new therapies.

Combining patient reported outcomes and EHR data to understand population level treatment needs: correcting for selection bias in the migraine signature study.

BACKGROUND: Electronic health records (EHR) data can be used to understand population level quality of care especially when supplemented with patient reported data. However, survey non-response can result in biased population estimates. As a case study, we demonstrate that EHR and survey data can be combined to estimate primary care population prescription treatment status for migraine stratified by migraine disability, without and with adjustment for survey non-response bias. We selected disability as it is associated with survey participation and patterns of prescribing for migraine. METHODS: A stratified random sample of Sutter Health adult primary care (PC) patients completed a digital survey about headache, migraine, and migraine related disability. The survey data from respondents with migraine were combined with their EHR data to estimate the proportion who had prescription orders for acute or preventive migraine treatments. Separate proportions were also estimated for those with mild disability (denoted "mild migraine") versus moderate to severe disability (denoted mod-severe migraine) without and with correction, using the inverse propensity weighting method, for non-response bias. We hypothesized that correction for non-response bias would result in smaller differences in proportions who had a treatment order by migraine disability status. RESULTS: The response rate among 28,268 patients was 8.2%. Among survey respondents, 37.2% had an acute treatment order and 16.8% had a preventive treatment order. The response bias corrected proportions were 26.2% and 11.6%, respectively, and these estimates did not differ from the total source population estimates (i.e., 26.4% for acute treatments, 12.0% for preventive treatments), validating the correction method. Acute treatment orders proportions were 32.3% for mild migraine versus 37.3% for mod-severe migraine and preventive treatment order proportions were 12.0% for mild migraine and 17.7% for mod-severe migraine. The response bias corrected proportions for acute treatments were 24.8% for mild migraine and 26.6% for mod-severe migraine and the proportions for preventive treatment were 8.1% for mild migraine and 12.0% for mod-severe migraine. CONCLUSIONS: In this study, we combined survey data with EHR data to better understand treatment needs among patients diagnosed with migraine. Migraine-related disability is directly related to preventive treatment orders but less so for acute treatments. Estimates of treatment status by self-reported disability status were substantially over-estimated among those with moderate to severe migraine-related disability without correction for non-response bias.

New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis.

Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.

Air pollution, methane super-emitters, and oil and gas wells in Northern California: the relationship with migraine headache prevalence and exacerbation.

BACKGROUND: Migraine-an episodic disorder characterized by severe headache that can lead to disability-affects over 1 billion people worldwide. Prior studies have found that short-term exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone increases risk of migraine-related emergency department (ED) visits. Our objective was to characterize the association between long-term exposure to sources of harmful emissions and common air pollutants with both migraine headache and, among patients with migraine, headache severity. METHODS: From the Sutter Health electronic health record database, we identified 89,575 prevalent migraine cases between 2014 and 2018 using a migraine probability algorithm (MPA) score and 270,564 frequency-matched controls. Sutter Health delivers care to 3.5 million patients annually in Northern California. Exposures included 2015 annual average block group-level PM2.5 and NO2 concentrations, inverse-distance weighted (IDW) methane emissions from 60 super-emitters located within 10 km of participant residence between 2016 and 2018, and IDW active oil and gas wells in 2015 within 10 km of each participant. We used logistic and negative binomial mixed models to evaluate the association between environmental exposures and (1) migraine case status; and (2) migraine severity (i.e., MPA score > 100, triptan prescriptions, neurology visits, urgent care migraine visits, and ED migraine visits per person-year). Models controlled for age, sex, race/ethnicity, Medicaid use, primary care visits, and block group-level population density and poverty. RESULTS: In adjusted analyses, for each 5 ppb increase in NO2, we observed 2% increased odds of migraine case status (95% CI: 1.00, 1.05) and for each 100,000 kg/hour increase in IDW methane emissions, the odds of case status also increased (OR = 1.04, 95% CI: 1.00, 1.08). We found no association between PM2.5 or oil and gas wells and migraine case status. PM2.5 was linearly associated with neurology visits, migraine-specific urgent care visits, and MPA score > 100, but not triptans or ED visits. NO2 was associated with migraine-specific urgent care and ED visits, but not other severity measures. We observed limited or null associations between continuous measures of methane emissions and proximity to oil and gas wells and migraine severity. CONCLUSIONS: Our findings illustrate the potential role of long-term exposure to multiple ambient air pollutants for prevalent migraine and migraine severity.

The migraine signature study: Methods and baseline results.

OBJECTIVE: To characterize patients who utilize services for migraine in a large integrated health care network, and describe patterns of care and utilization. BACKGROUND: Within health care systems, migraine is a common reason for seeking primary and neurology care, but relatively little is documented about who seeks care and the factors that explain variation in utilization. METHODS: We conducted a retrospective cohort study using electronic health record (EHR) data from Sutter Health primary care (PC) patients who had at least one office visit to a PC clinic between 2013 and 2017. Migraine status was ascertained from diagnosis codes and medication orders. Control status was assigned to those with no evidence of care for any type of headache. We divided the primary care migraine cohort into two groups: those who received all their care for migraine from PC (denoted PC-M) and those who had ≥1 encounter with a neurologist for migraine (denoted N-M). Migraine cases were also designated as having preexisting migraine if they had an encounter with a migraine diagnosis within (±) 6 months of their first study period PC visit and, otherwise, designated as first migraine consult. Two levels of contrasts included: patients with migraine and controls; and within the group of patients with migraine, PC-M and N-M groups. Comorbid conditions were determined from EHR encounter diagnosis codes. RESULTS: We identified 94,149 patients with migraine (including 21,525 N-M and 72,624 PC-M) and 1,248,763 controls. Comorbidities: Proportions of psychiatric [29.8% (n = 28,054) vs. 11.8% (n = 147,043)], autoimmune [(4.4% (n = 4162) vs. 2.6% (n = 31,981)], pain [13.2% (n = 12,439) vs. 5.8% (n = 72,049)], respiratory [24.6% (n = 23,186) vs. 12.3% (n = 153,692)], neurologic [2.9% (n = 2688) vs. 0.9% (n = 11,321)], and cerebrovascular [1.0% (n = 945) vs. 0.6% (n = 7500)] conditions were higher in the migraine group compared to controls, all p < 0.001. Among patients with migraine, the N-M group was similar to the PC-M group in sex, age, ethnicity, and marital status, but were more likely to have preexisting migraine (49.9% (n = 10,734) vs. 36.2% (n = 26,317), p < 0.001). Proportions of comorbid conditions were higher among the N-M group than the PC-M group {psychiatric [38.5% (n = 8291) vs. 27.2% (n = 19,763)], autoimmune [6.3% (n = 1365) vs. 3.9% (n = 2797)], pain [19.6% (n = 4218) vs. 11.3% (n = 8211)], respiratory [30.3% (n = 6516) vs. 23.0% (n = 16,670)], neurologic [6.0% (n = 1288) vs. 1.9% (n = 1400)], cardiovascular [9.7% (n = 2091) vs. 7.0% (n = 5076)], and cerebrovascular [2.3% (n = 500) vs. 0.6% (n = 445)], all p < 0.001}. Medications: During the study period, 82.6% (n = 77,762) of patients with migraine received ≥1 prescription order for an acute migraine medication [89.4% (n = 19,250) of N-M vs. 80.6% (n = 58,512) of PC]. Opioids were prescribed to 52.9% (n = 49,837) of patients with migraine [63.5% (n = 13,669) for N-M and 49.8% (n = 36,168) for PC-M patients). During the study period, 61.4% (n = 57,810) of patients received ≥1 prescription for a migraine preventive medication [81.4% (n = 17,521) of N-M and 55.5% (n = 40,289) of PC-M patients]. The most commonly prescribed classes of preventive medications were antidepressants. CONCLUSIONS: Among patients with migraine in a large health system, those who were also cared for in neurology were more likely to receive both acute and preventive medication migraine orders than those patients who did not see a neurologist, with triptans and antidepressants the most commonly prescribed classes of acute and preventive pharmacotherapies, respectively. Opioids were prescribed to approximately half of the total sample and more common in the N-M group. Adjusting for demographics, patients with migraine had higher rates of nearly every comorbidity we assessed and were more likely to utilize services compared to those without migraine. Overall, patients with migraine also cared for in neurology practices used more of all health care resource types under consideration and had more medical issues, which may be due in some part to a more severe, frequent and disabling disease state compared to those who sought care exclusively from PC practices.

Recruitment, retention, and adherence in a randomized feasibility trial of mindfulness-based stress reduction for patients with migraine.

OBJECTIVES: Increasing evidence demonstrates effectiveness of Mindfulness-Based Stress Reduction (MBSR) for pain-related and functional disorders. In order to conduct successful and efficient trials of MBSR, evidence regarding the relative performance of strategies to improve recruitment, retention, and adherence is required, but few studies have examined these issues specifically. DESIGN: In preparation for a fully powered trial, we conducted a 2-arm, parallel comparison randomized controlled feasibility trial of MBSR vs. usual-care for 60 patients with migraine headache. SETTING: Two large U.S. health systems in Northern California. INTERVENTION: MBSR is an 8-week classroom-based intervention that combines mindfulness meditation and yoga, with didactic presentations about stress psychology and group process/experiential education. Participants received the intervention at their choice of one of several existing, vetted community-based classes. MAIN OUTCOME MEASURES: Successful recruitment was defined a priori as 18 participants within any 9-week period or 60 participants enrolled within a 36-week period. We considered participants adherent to the intervention if they attended at least 5 of the 8 weekly classes and the day-long retreat. RESULTS: We successfully enrolled 18 participants within a 7-week period, however, we did not attain our second goal of recruiting 60 participants within a 36-week period. Sixty-eight percent of our participants were adherent to the intervention. CONCLUSIONS: We found that close monitoring of recruitment activities, flexibility in protocol modifications, and integration within the delivery system were crucial factors for successful participant recruitment, retention, and adherence in mindfulness research.

Conducting a pilot randomized controlled trial of community-based mindfulness-based stress reduction versus usual care for moderate-to-severe migraine: protocol for the Mindfulness and Migraine Study (M&M).

BACKGROUND: Migraine is one of the most common neurological disorders in clinical practice and is a substantial cause of disability worldwide. Current approaches to therapy are primarily based on medication but are often limited by inadequate effectiveness and common side effects. Newer, more effective medications are expensive. Mindfulness-based stress reduction (MBSR), an 8-week classroom-based meditation intervention, is inexpensive, has no known side effects, and has demonstrated clinically meaningful effectiveness for several chronic-pain syndromes. In addition, MBSR has shown promising results for migraine therapy in a few small case studies and pilot studies. We present here the protocol for a two-arm randomized controlled pilot trial of MBSR for moderate-to-severe episodic migraine, which, if successful, will form the basis for a fully powered clinical trial. METHODS/DESIGN: This study, set in Northern California, is a two-arm parallel-comparison single-blinded randomized controlled pilot trial with the goal of recruiting approximately 60 participants with moderate-to-severe episodic migraine. The feasibility outcomes include ability and time required to recruit, adherence to the MBSR treatment, and ability to measure outcomes using 31-day headache diaries and patient-reported questionnaire data. The active treatment arm consists of an 8-week community-based MBSR class plus usual care, and the wait-list control group is usual care. Recruitment is underway and expected to be complete by the end of 2018. DISCUSSION: To our knowledge, this is the first pragmatic trial in the U.S. of MBSR for migraine using community-based classes, and if it proves viable, we plan to conduct a fully powered trial to determine the effectiveness of the intervention for reducing headache days for moderate-to-severe episodic migraineurs. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02824250 . Registered on 6 July 2016.

Prepectoral Breast Reconstruction: A Technical Algorithm.

Despite falling out of favor in the 1970s, prepectoral breast reconstruction has resurfaced in the recent years as a safe and effective alternative to subpectoral/partial subpectoral breast reconstruction in carefully selected patients. This article outlines an algorithmic technical approach to prepectoral breast reconstruction for new patients and revision patients.

A Pharmacist-Staffed, Virtual Gout Management Clinic for Achieving Target Serum Uric Acid Levels: A Randomized Clinical Trial.

CONTEXT: Relatively few patients with gout receive appropriate treatment. OBJECTIVE: To determine whether a pharmacist-staffed gout management program is more effective than usual care in achieving target serum uric acid (sUA) levels in gout patients. DESIGN: A parallel-group, randomized controlled trial of a pharmacist-staffed, telephone-based program for managing hyperuricemia vs usual care. Trial duration was 26 weeks. MAIN OUTCOME MEASURES: Primary outcome measure was achieving sUA levels at or below 6 mg/dL at the 26-week visit. Secondary outcome was mean change in sUA levels in the control and intervention groups. Participants were adults with recurrent gout and sUA levels above 6.0 mg/dL. Participants were randomly assigned to management by a clinical pharmacist following protocol or to monitoring of sUA levels but management of their gout by their usual treating physician. RESULTS: Of 102 patients who met eligibility criteria, 77 subjects obtained a baseline sUA measurement and were entered into the trial. Among 37 participants in the intervention group, 13 (35%) had sUA levels at or below 6.0 mg/dL at 26 weeks, compared with 5 (13%) of 40 participants in the control group (risk ratio = 2.8, 95% confidence interval [CI] = 1.1 to 7.1, p = 0.03). The mean change in sUA levels among controls was +0.1 mg/dL compared with -1.5 mg/dL in the intervention group (sUA difference = -1.6, 95% CI = -0.9 to -2.4, p < 0.001). CONCLUSIONS: A structured pharmacist-staffed program was more effective than usual care for achieving target sUA levels. These results suggest a structured program could greatly improve gout management.

Prevalence of migraine in a diverse community--electronic methods for migraine ascertainment in a large integrated health plan.

INTRODUCTION: The growing availability of electronic health data provides an opportunity to ascertain diagnosis-specific cases via systematic methods for sample recruitment for clinical research and health services evaluation. We developed and implemented a migraine probability algorithm (MPA) to identify migraine from electronic health records (EHR) in an integrated health plan. METHODS: We identified all migraine outpatient diagnoses and all migraine-specific prescriptions for a five-year period (April 2008-March 2013) from the Kaiser Permanente, Northern California (KPNC) EHR. We developed and evaluated the MPA in two independent samples, and derived prevalence estimates of medically-ascertained migraine in KPNC by age, sex, and race. RESULTS: The period prevalence of medically-ascertained migraine among KPNC adults during April 2008-March 2013 was 10.3% (women: 15.5%, men: 4.5%). Estimates peaked with age in women but remained flat for men. Prevalence among Asians was half that of whites. CONCLUSIONS: We demonstrate the feasibility of an EHR-based algorithm to identify cases of diagnosed migraine and determine that prevalence patterns by our methods yield results comparable to aggregate estimates of treated migraine based on direct interviews in population-based samples. This inexpensive, easily applied EHR-based algorithm provides a new opportunity for monitoring changes in migraine prevalence and identifying potential participants for research studies.

Is migraine a risk factor for pediatric stroke?

IMPORTANCE: Our understanding of risk factors for childhood stroke is incomplete. In adults, migraine with aura is associated with a two-fold increase in ischemic stroke risk. OBJECTIVE: In this cohort study we examine the association between migraine and stroke among children in Kaiser Permanente Northern California (KPNC). DESIGN, SETTING, AND PARTICIPANTS: Children ages 2-17 years who were members of KPNC for ≥6 months between 1997 and 2007 were included. Migraine cohort members had one or more of: an ICD-9 code for migraine, migraine listed as a significant health problem, or a prescription for a migraine-specific medication. The comparison group was children with no evidence of headache. MAIN OUTCOME MEASURES: Main outcome measures included stroke incidence rates and incidence rate ratios (IR). RESULTS: Among the 1,566,952 children within KPNC during the study period, 88,164 had migraine, and 1,323,142 had no evidence of headache. Eight migraineurs had a stroke (three (38%) hemorrhagic; five (63%) ischemic). Eighty strokes occurred in children without headache (53 (66%) hemorrhagic; 27 (34%) ischemic). The ischemic stroke incidence rate was 0.9/100,000 person-years in migraineurs vs. 0.4/100,000 person-years in those without headache; IR 2.0 (95% CI 0.8-5.2). A post-hoc analysis of adolescents (12-17 years) showed an increased risk of ischemic stroke among those with migraine; IR 3.4 (95% CI 1.2-9.5). The hemorrhagic stroke incidence rate was 0.5/100,000 person-years in migraineurs and 0.9/100,000 person-years in those without headache; IR 0.6 (95% CI 0.2-2.0). CONCLUSIONS: There was no statistically significant increase in hemorrhagic or ischemic stroke risk in pediatric migraineurs in this cohort study. A post-hoc analysis found that ischemic stroke risk was significantly elevated in adolescents with migraine. Future studies should focus on identifying risk factors for ischemic stroke among adolescent migraineurs. Based on adult data, we recommend that migraine aura status should be studied as a possible risk factor for ischemic stroke among adolescent migraineurs.

Effectiveness of a pharmacist-based gout care management programme in a large integrated health plan: results from a pilot study.

OBJECTIVES: The study objective was to determine the feasibility of using a pharmacist-staffed, protocol-based structured approach to improving the management of chronic, recurrent gout. SETTING: The study was carried out in the outpatient clinic of a single Kaiser Permanente medical centre. This is a community-based clinic. PARTICIPANTS: We report on 100 consecutive patients between the ages of 21 and 94 (75% men) with chronic or recurrent gout, referred by their primary physicians for the purpose of management of urate-lowering therapy. Patients with stage 5 chronic kidney disease or end-stage kidney disease were excluded. INTERVENTIONS: The programme consisted of a trained clinical pharmacist and a rheumatologist. The pharmacist contacted each patient by phone, provided educational and dietary materials, and used a protocol that employs standard gout medications to achieve and maintain a serum uric acid (sUA) level of 6 mg/dL or less. Incident gout flares or adverse reactions to medications were managed in consultation with the rheumatologist. PRIMARY OUTCOME MEASURE: The primary outcome measure was the achievement and maintenance of an sUA of 6 or less for a period of at least 3 months. RESULTS: In 95 evaluable patients enrolled in our pilot programme, an sUA of 6 mg/dL or less was achieved and maintained in 78 patients with 4 still in the programme to date. Five patients declined to participate after referral, and another 13 patients did not complete the programme. (The majority of these were due to non-adherence.) CONCLUSIONS: A structured pharmacist-staffed programme can effectively and safely lower and maintain uric acid levels in a high percentage of patients with recurrent gout in a primary care setting. This care model is simple to implement, efficient and warrants further validation in a clinical trial.

Post-translational modifications of myofilament proteins involved in length-dependent prolongation of relaxation in rabbit right ventricular myocardium.

The phosphorylation state of several cardiac myofilament proteins changes with the level of stretch in intact, twitch-contracting cardiac muscles. It remains unclear which kinases are involved in the length-dependent phosphorylation of these proteins. We set out to investigate which kinases are involved after a step-wise change in cardiac muscle length. We hypothesize that myofilament protein phosphorylation by PKCßII and PKA alters contractile kinetics during length-dependent activation. Right ventricular intact trabeculae were isolated from New Zealand White rabbit hearts and stimulated to contract at 1Hz. Twitch force recordings where taken at taut and optimal muscle lengths before and after administration of kinase inhibitors at 37°C. PKCßII inhibition significantly decreased time from stimulation to peak force (TTP), time from peak force to 50% relaxation (RT50), and 90% relaxation (RT90) at optimal muscle length. This led to a loss in the length-dependent increase of RT50 and RT90 in the presence of the PKCßII inhibitor, whereas the length-dependent increase in RT50 and RT90 was seen in the controls. PKA inhibition using H-89 significantly decreased TTP at both taut and optimal muscle lengths. Detection of Ser/Thr phosphorylation with ProQ-diamond staining indicates a role for PKCßII in the phosphorylation of tropomyosin and myosin light chain-2 (MLC2) and PKA for tropomyosin, troponin-I, MLC2, myosin binding protein-C, troponin-T (TnT) 3 and TnT4. Our data provide evidence for two signaling kinases acting upon myofilament proteins during length-dependent activation, and provide further insight for length-dependent myofilament function.

Current use of unopposed estrogen and estrogen plus progestin and the risk of acute myocardial infarction among women with diabetes: the Northern California Kaiser Permanente Diabetes Registry, 1995-1998.

BACKGROUND: Little is known about hormone replacement therapy (HRT) and risk for myocardial infarction (MI) in diabetic women. We examined associations of current HRT, estrogen dosage, and time since HRT initiation with risk of acute MI in diabetic women. METHODS AND RESULTS: Cox proportional hazards models, with current HRT modeled as a time-dependent covariate, were used to assess the 3-year risk of MI. Among 24 420 women without a recent MI (mean age 64.9 years), 1110 incident MIs were identified. After adjustment for cardiovascular risk factors, current HRT was associated with reduced MI risk (relative hazard [RH] 0.84, 95% CI 0.72 to 0.98). The RH for MI associated with current estrogen plus progestin use was 0.77 (95% CI 0.61 to 0.97), and the RH for MI associated with current unopposed estrogen use was 0.88 (95% CI 0.73 to 1.05). Women were at reduced MI risk if they were taking a low or medium dose of estrogen (equivalent to <0.625 or 0.625 mg of conjugated estrogen, respectively) but not a high dose (>0.625 mg of conjugated estrogen or its equivalent). Among those whose current use of HRT was <1 year, the RH for MI was 1.03 (95% CI 0.74 to 1.44), whereas among users for > or =1 year, the RH was 0.81 (95% CI 0.66 to 1.00). Among 580 women with a recent MI (mean age 69.2 years), 89 recurrent MIs were identified. An increased risk of recurrent MI was observed among current HRT users (RH 1.78, 95% CI 1.06 to 2.98), which was higher among those with current use for <1 year (RH 3.84, 95% CI 1.60 to 9.20). CONCLUSIONS: In women without a recent MI, use of estrogen plus progestin was associated with decreased risk of MI. However, HRT was associated with increased risk of MI in women with history of a recent MI. Data from clinical trials in diabetic women are needed.