Humanistic Burden Research Articles

Safety and effectiveness of vagus nerve stimulation in patients with drug-resistant epilepsy: a single center experience

BackgroundDrug-resistant epilepsy (DRE) exerts substantial clinical, humanistic and economic burdens on patients, their families and the healthcare system. Vagus nerve stimulation (VNS) has been extensively tested in clinical trial settings to decrease the frequency of seizures in patients with DRE who are not candidates for surgery; the results indicate promising efficacy and a well-tolerated safety profile. However, real-world evidence is still lacking. This retrospective study evaluated the safety and efficacy of VNS in patients with DRE.MethodsThe current study was a retrospective chart review of the medical records of children and adults with DRE treated with VNS between December 2006 and November 2022. The primary outcome of the present study was the percentage of patients who experienced a reduction in seizure frequency of more than 50% compared with the frequency at baseline (the period before VNS device insertion).ResultsA total of 103 patients were included. The percentage of patients who achieved a reduction of more than 50% in seizure frequency was 23% at six months, 36% at 12 months, 65% at 18 months, and 72% at 24 months. Similarly, the percentage of patients with complete resolution of interictal epileptiform discharges (IEDs) increased from 30% at six months to 60% after 24 months. The overall Quality of Life in Epilepsy (QOLIE-31) score at the end of follow-up was 39.46 ± 13.68 points. Two patients (1.9%) reported experiencing side effects at the end of follow-up.ConclusionsVNS implementation led to a significant reduction in the seizure frequency and resolution of IEDs, with a well-tolerated safety profile. The findings highlight the potential role of VNS in managing DRE and warrant its consideration for treating patients with DRE.

Sea Squirt-Derived Peptide WLP Mitigates OKA-Induced Alzheimer’s Disease-like Phenotypes in Human Cerebral Organoid

Alzheimer’s disease (AD), a prevalent neurodegenerative disorder in the elderly, poses significant humanistic and economic burdens worldwide. Previously, we identified Trp-Leu-Pro (WLP), a novel antioxidant peptide derived from the sea squirt (Halocynthia roretzi); however, its effects on AD remained unexplored. In this study, we developed a rapid and efficient method to generate AD cerebral organoids with consistent quality using okadaic acid (OKA) exposure. This study aimed to evaluate the protective effects of WLP on OKA-induced AD pathology in cerebral organoids and elucidate its underlying mechanisms. Our results demonstrated that cerebral organoids exposed to 25 nM OKA successfully recapitulated hallmark AD pathologies, including amyloid-beta (Aβ) plaque deposits, neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau proteins, and neuronal loss. WLP treatment significantly enhanced cell viability, increased the proportion of neuronal progenitor cells, and reduced Aβ plaques and NFTs in OKA-induced cerebral organoids. Furthermore, transcriptomic analysis revealed that the neuroprotective effects of WLP are primarily mediated through the regulation of synapse-related and oxidative stress pathways. These findings highlight the potential of WLP as a promising nutraceutical candidate for AD prevention.

Cost-Effectiveness of Adjuvant Alectinib Versus Chemotherapy for Patients with Resectable, ALK-positive Non-small Cell Lung Cancer in Canada.

For patients with resected non-small cell lung cancer (NSCLC), the risk of disease recurrence and progression is associated with a substantial humanistic, clinical, and economic burden. In the phase III ALINA trial (NCT03456076), adjuvant alectinib significantly improved disease-free survival (DFS) compared with chemotherapy in patients with resected ALK-positive NSCLC. The aim of this study was to assess the cost-effectiveness of adjuvant alectinib versus chemotherapy for patients with resected ALK-positive NSCLC in Canada. A cost-utility model comprising eight health states was developed to estimate lifetime patient outcomes and costs of patients with resected, ALK-positive NSCLC treated with adjuvant alectinib versus platinum-based chemotherapy from a societal perspective. Patterns of disease recurrence and progression were based on ALINA and other trial data; model assumptions were consistent with existing models and validated through consultation with expert Canadian clinicians. Cost-effectiveness was assessed in terms of estimated effect on life-years, quality-adjusted life-years (QALYs), and healthcare costs. In addition, scenario and probabilistic analyses were performed to explore model uncertainty. An annual discount rate of 1.5% was applied to both costs and outcomes (evaluated for 2023). Compared with chemotherapy, alectinib was associated with greater total life-years (19.2 versus 13.1 years) and QALYs (15.0 versus 10.1). Alectinib was dominant over platinum-based chemotherapy as it yielded a lower lifetime cost (CA $480,967.00) versus chemotherapy (CA $592,959.00). Scenario analyses showed model robustness and consistent dominance in cost-effectiveness. Probabilistic analyses results were similar to those from the base case and scenario analyses; alectinib was dominant over chemotherapy in 93.6% of simulations of incremental costs versus incremental QALYs, and remained under a willingness-to-pay threshold of CA$50,000.00 per QALY gained in 99.7% of simulations. Our analysis suggests that adjuvant alectinib is dominant (i.e., more effective and less costly) to platinum-based chemotherapy in Canadian patients with resected ALK-positive NSCLC. Together with the DFS benefit seen in ALINA, this analysis supports adjuvant alectinib as an important new treatment strategy.

The burden of illness in thyroid eye disease: current state of the evidence

IntroductionThyroid eye disease (TED) is a disabling autoimmune condition characterized by proptosis and progressive orbital inflammation involving the extraocular muscles, orbital fat, and connective tissues. Clinical features include facial disfigurement, diplopia, dry eyes, and in severe cases, vision loss. Consequently, individuals with TED suffer significant physical and psychological burdens that impact their quality of life. Currently, there is no standardized definition or International Classification of Diseases code for TED, and the disease landscape remains incompletely understood; moreover, TED diagnostic criteria and treatment recommendations have not been thoroughly assessed across diverse populations. It is necessary to better understand the clinical, humanistic, and economic burden of TED and identify gaps in our knowledge to improve TED management and outcomes.MethodsTo describe the current understanding of TED epidemiology, diagnosis, disease burden, and recent TED treatment guidelines, a targeted literature review was conducted, searching multiple databases using key words of specific search topics (i.e., TED; epidemiology, humanistic, economic, and clinical burden; treatment; and practice guidelines) for articles published between October 2013 and October 2023 in the United States, United Kingdom, and Europe (France, Germany, Italy, and Spain). Articles published between May 2014 and May 2024 describing diverse racial and sociodemographic presentations of TED were included.ResultsTED is a complex disease with an array of risk factors, including thyroid dysfunction, thyroid-stimulating immunoglobin, smoking, and comorbid conditions. The natural history of TED is not clearly defined, and diagnosis is complicated due to the array of phenotypes and orbital symptoms observed. Although novel first-line treatments are available in select countries, there is an unmet need for improved treatments for moderate-to-severe and sight-threatening TED. Individuals with TED continue to experience poor health-related quality of life due to the clinical burden that TED imposes along with large healthcare resource utilization costs and treatment costs, and economic evaluation studies are limited. Importantly, there is still a need for studies that explore diverse populations and the impact of race and ethnicity on the disease landscape.ConclusionTED remains an incompletely characterized disease with major knowledge gaps, particularly among historically underserved populations.

Health-related quality of life and economic impacts in adults with sickle cell disease with recurrent vaso-occlusive crises: findings from a prospective longitudinal real-world survey.

Characterize health-related quality of life (HRQoL) and economic impacts associated with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs). A prospective longitudinal real-world study was performed with adults with SCD with recurrent VOCs in the US and Europe (France, Germany, Italy, and the UK). Evidence of recurrent VOCs was self-reported (≥ 2 VOCs per year in each of the 2 years before enrolment). Study outcomes were reported at baseline, months 3, and 6 and included self-reported demographics, clinical characteristics, patient-reported outcome measures (EQ-5D-5L VAS, FACT-G, FACIT-F, 11-point numerical rating scale [NRS] of pain, ASCQ-Me, WPAI), and bespoke questions on financial burden, stigma/prejudice, and time burden associated with SCD. Participants (N = 142) reported an annual mean (standard deviation) of 5.9 (4.8) VOCs requiring hospitalization and 7.5 (7.7) VOCs requiring home management in the past 24 months. Participants reported fatigue and HRQoL impairment, demonstrated by significantly lower baseline EQ-5D-5L utility and VAS, FACT-G, and FACIT-F scores compared to published information about the US general population. Participants also reported increased pain, stiffness, and emotional impacts compared to a reference sample of adults with SCD on the ASCQ-Me, and most (60%) reported moderate to extreme pain/discomfort on the NRS of pain. Out-of-pocket expenses represented a moderate-to-major burden for 61.9% of participants, with employed participants missing a mean of 9.8h of work in the last 7 days. Participants reported significant impairments to their HRQoL and financial constraints associated with SCD with recurrent VOCs, indicating humanistic and economic burden and unmet needs in this population.

Health-related quality of life and economic impacts in adults with transfusion-dependent β-thalassemia: findings from a prospective longitudinal real-world study.

To characterize the health-related quality of life (HRQoL) and economic impacts of transfusion-dependent β-thalassemia (TDT). A prospective longitudinal real-world study was conducted in adults with TDT in the US and Europe (France, Germany, Italy, UK) over 6 months. Eligibility criteria included receiving ≥ 8 blood transfusions/year in each of the 2 years before enrollment. Study outcomes assessed at months 0, 3, and 6, included demographics, clinical characteristics, patient-reported outcome measures (EQ-VAS, FACT-G, FACIT-F, 11-point Numerical Rating Scale (NRS) of pain, TranQoL, and WPAI), and responses to bespoke questions on financial burden/distress. Overall, 155 adults with TDT participated (mean age [standard deviation (SD)]: 38.5 [10.8] years; 65.8% female). Most participants resided in the US (53.5%) or UK (22.6%). EQ-VAS, FACT-G, and FACIT-F mean (SD) scores at month 0 were lower among participants than the US general population (67.1 [20.4] versus 80.4 [15.6], 70.1 [19.0] versus 77.0 [16.1], and 27.9 [13.7] versus 43.6 [9.4], respectively; all p < 0.001). Mean (SD) TranQoL total score was 53.9 (18.5) and overall level of pain was "moderate" (NRS mean [SD]: 3.5 [2.8]). Part- or full-time employed participants missed a mean of 5.9h of work in the preceding 7 days with out-of-pocket expenses being a moderate-to-major burden for 55% of participants. The findings were consistent over time. Participants reported substantial humanistic and economic burdens associated with living with TDT. Our findings highlight the need for alternative treatment options that contribute to improvements in HRQoL and reduce economic burden in this patient population.

The humanistic burden of focal segmental glomerulosclerosis on patients and care-partners in the United States.

This study cross-sectionally surveyed patients with primary focal segmental glomerulosclerosis (FSGS) and their caregivers/care-partners, in terms of physical and mental health-related quality of life (HRQoL) and work productivity. HRQoL instruments, including the KDQoL-36 (with SF-12 v2), PedsQL (v4.0, parent proxy for children/adolescents), GAD-7 (anxiety), PHQ-9 (depression), and WPAI: SHP (work productivity), were used in the study. Participant characteristics and scores were summarized and compared to an external, kidney disease-free cohort. 78 adults and 29 children/adolescents with FSGS, with their care-partners/caregivers, were included. The median ages of adults and children/adolescents with FSGS were 44.5 and 12.0years, respectively; 74.4% and 58.6% were female. Mean physical and mental SF-12 scores for adult patients were 41.9 (SD: 12.1) and 44.8 (10.2), respectively. Both SF-12 components for adult patients, the SF-12 mental component for care-partners, and all PedsQL item scores were worse compared to US general population estimates. Among adult patients, 28.2% reported at least moderate anxiety; 37.3% reported at least moderate depression. Compared to external controls, patients experienced significantly higher severity of anxiety (6.1 vs. 5.0) and depression (7.6 vs. 5.9; both p < 0.0001). Additionally, 14-20% of care-partners and caregivers reported moderate to severe anxiety or depression. All employed groups reported high overall work impairment (15.0-30.6%), with adult patients and their care-partners reporting high FSGS-related activity impairment (37.8%; 17.3%, respectively), absenteeism (10.4%; 6.1%) and presenteeism (21.8%; 11.6%). Patients with FSGS and their care-partners experience impairments to mental/physical HRQoL and work productivity, underscoring the need for effective FSGS therapies and care-partner support.

The humanistic burden of atopic dermatitis in Greece: a cross-sectional study.

The purpose of this study was to evaluate the quality of life (QoL) and psychosocial burden in adult Greek patients with atopic dermatitis (AD) using validated tools and to investigate factors that influence AD's humanistic burden. This observational, cross-sectional study was conducted in Greece (January-September 2023) with 150 adult members of the patient association "EPIDERMIA", all diagnosed with AD. Data was collected via a structured questionnaire, including socio-demographic details, clinical history, AD severity (using the Patient-Oriented Eczema Measure [POEM]), QoL, sleep disorders, and psychological health. Based on POEM scores, 11% of participants had clear/almost clear skin, 27% had mild eczema, 51% had moderate eczema, and 12% had severe/very severe eczema. AD had a moderate or very/extremely large impact on QoL for 29% and 42% of participants, respectively. Insomnia affected 55%, while 31% had mild anxiety, 23% had moderate/severe anxiety, 10% had moderate depression, and 8% had moderately severe/severe depression. AD severity was associated with reduced QoL and higher rates of insomnia, anxiety, and depression. Our study highlights significant associations between AD severity, QoL, and psychosocial factors, emphasizing the need for comprehensive management strategies.

A literature review of the healthcare resource use and productivity burden of X-linked hypophosphataemia.

X-linked hypophosphataemia (XLH) is a rare, genetic, renal phosphate wasting disorder that causes a lifelong rapid progression of morbidities, which are associated with substantial humanistic and economic burden. A structured literature review was carried out to identify publications reporting healthcare resource use and productivity impact of XLH to provide a comprehensive description of the burden. Literature searches of the Embase®, Medline®, and EconLit electronic databases were carried out in August 2022 using free-text and subject heading search terms regarding XLH-related clinical morbidities and associated healthcare resource use, limited to English language records from 1992 onwards. After screening by pre-specified inclusion/exclusion criteria, 22 publications were selected for inclusion in the review. Use of conventional pharmacological therapy with oral phosphate and/or active vitamin D was reported in 15 publications, in up to 100% of paediatric patients and 75% of adults. Findings indicated that a high proportion of patients with XLH undergo orthopaedic procedures/surgeries, including a history of osteotomy in up to 25% of paediatric patients and 61% of adults, and a history of growth plate stapling in up to 63% of paediatric patients and 20% of adults. A high prevalence of fractures (in up to 61% of adults) and use of assistive mobility devices was also reported. The findings highlighted a substantial prevalence of morbidities, either due to persistently low phosphate levels or complications of conventional therapy, that had directly associated healthcare resource use, including dental problems, hearing problems, hyperparathyroidism, and nephrocalcinosis. Healthcare resource use and associated clinical events were generally found to be higher in adults compared with paediatric patients, which is consistent with the natural history of XLH as a progressive lifelong condition. Studies also highlighted the negative impact of XLH on school attendance and the ability to work. The results of this structured literature review emphasise the lifelong impact of XLH, showing that it is associated with a substantial economic burden, across many healthcare resource use categories including pharmacological therapy, management of pain and mobility, orthopaedic procedures, morbidities due to XLH or conventional therapy, and work/school productivity.

Humanistic and Economic Burden of Atopic Dermatitis in Pediatric Patients in Spain: A Systematic Review.

Humanistic and Economic Burden of Atopic Dermatitis in Pediatric Patients in Spain: A Systematic Review.

Epidemiology, disease burden of pulmonary arterial hypertension in China: A systematic literature review.

Epidemiology, disease burden of pulmonary arterial hypertension in China: A systematic literature review.

HSR25-174: Impact of Adverse Events on Quality of Life in Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors - Results From the Survey on Humanistic Burden of Intolerance to First or Second TKIs (SHIFT) Study.

HSR25-174: Impact of Adverse Events on Quality of Life in Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors - Results From the Survey on Humanistic Burden of Intolerance to First or Second TKIs (SHIFT) Study.

A US Survey Across Seven Early-Stage Cancers Assessing the Humanistic Burden of Recurrence on Patients and Caregivers.

Patients diagnosed with an early-stage cancer are at risk of recurrence. Although the economic burden of a cancer recurrence is described in the literature, little is known about the humanistic burden of an early-stage cancer recurrence. Therefore, we surveyed patients and caregivers to understand the impact of a first cancer recurrence on patient and caregiver quality of life (QoL). Patients with early-stage bladder, gastric, head and neck (HN), melanoma, non-small cell lung, renal cell, and triple-negative breast cancers (TNBC) that recurred and caregivers of such patients completed a self-administered, online survey exploring QoL impacts. QoL was evaluated using de novo questions and the following instruments: EQ-5D-5L (patients and caregivers), European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (patients only), and CareGiver Oncology Quality of Life questionnaire (caregivers only). Patient and caregiver responses and scores were stratified by type of cancer and type of recurrence (locoregional or distant/metastatic). Among patients (N = 202), QoL was found to differ significantly across tumor types at time of survey, with lower scores seen in patients with renal cell carcinoma, gastric cancer, and HN cancer and higher scores seen in patients with melanoma and TNBC. Among caregivers (N = 100), QoL did not differ across tumor types. In both patients and caregivers, decreases in QoL were observed from pre-recurrence to post-recurrence, with greater worsening in QoL seen with distant/metastatic versus locoregional recurrences. Most patients reported worrying and feeling anxious and stressed about their condition. Most caregivers reported worrying about the cared-for person's cancer getting worse or coming back and that caring for the person was challenging post-recurrence. Our findings demonstrate the importance of preventing recurrences and their negative impact on patients' and caregivers' QoL. Early-stage cancer treatments that prevent recurrences can provide better QoL.

A systematic literature review on the burden of diabetic ketoacidosis in type 2 diabetes mellitus.

To understand the existing literature on the epidemiology and clinical, humanistic, and economic burden of diabetic ketoacidosis (DKA) in people living with type 2 diabetes mellitus (T2DM). MEDLINE, Embase and the Cochrane library were systematically searched for studies published between 1 January 2014 and 14 December 2023. Clinical trials and observational studies, conducted in people living with T2DM, were included if they provided data on DKA epidemiology, morbidity, mortality, hospitalizations or patient-reported outcomes. Studies of DKA-associated costs in T2DM were also included. Data were summarized descriptively. Overall, 197 publications were included. We found wide variations in DKA prevalence (0.0%-50.0%; 5th-95th percentile: 0.02%-26%; 126 publications) and incidence (0.0-24.5 events per 1000 patient years; 5th-95th percentile: 0.004-7.6 events per 1000 patient years; 37 publications). Populations at increased risk of DKA included patients using sodium-glucose cotransporter-2 inhibitors, those using insulin and those with poor glycaemic control. The most common precipitating factors were infection and non-adherence to treatment. There was limited evidence on the humanistic burden of DKA, but the results highlighted a high burden of complications including acute kidney injury or failure. The length of hospital stay ranged from days to several weeks. DKA is associated with a high clinical burden in people living with T2DM. Resources to screen for and potentially prevent DKA may reduce the burden of DKA for patients with T2DM and the healthcare system.

Epidemiological, economic and humanistic burden of cervical intraepithelial neoplasia in Europe: A systematic literature review.

Epidemiological, economic and humanistic burden of cervical intraepithelial neoplasia in Europe: A systematic literature review.

Marginal health care expenditures and health-related quality of life burden in patients with osteoporosis in the United States.

Marginal health care expenditures and health-related quality of life burden in patients with osteoporosis in the United States.

Patient-Reported Burden of Illness and Unmet Needs in Demodex blepharitis.

Demodex blepharitis is an ocular disorder caused by the infestation of Demodex mites that reside on the eyelash follicles. This study assessed the clinical, humanistic, and economic burden of Demodex blepharitis from a patient perspective. This cross-sectional, observational study used a web-enabled survey to collect data from US adults with Demodex blepharitis in 2022. Patients with unique burdens, including those receiving dry eye disease medications, wearing contact lenses, or experiencing cataracts or glaucoma were also examined. Among 113 patients, mean age was 48.5 years (standard deviation [SD] ± 13.6). Half had private/commercial insurance, and 55% had Medicare and/or Medicaid. Patients had Demodex blepharitis for an average of 4.3 years (SD ± 6.7 years) before the study, and 1.2 years (SD ± 3.0 years) elapsed between the appearance of symptoms and diagnosis. Common symptoms, including redness, dryness, itchiness of the eyelids, and itchiness of the eyes, persisted or returned shortly after diagnosis and disease management in most patients, and they were associated with a negative impact on quality of life. Patients visited their healthcare practitioner for Demodex blepharitis a mean of 3.9 times (SD ± 4.8) in the preceding year. Patients were often managed with off-label prescription medications, such as medications indicated for dry eye disease, in-office procedures, or over-the-counter management options. Patients with Demodex blepharitis reported symptoms impacting their quality of life and activities of daily living, which persisted after diagnosis and disease management. This suggested that the effectiveness of the reported symptom management options was temporary and highlighted an unmet need in treating the root cause of the disease. Patients with Demodex blepharitis were symptomatic, and the commonly used management options for Demodex blepharitis lacked long-term symptom relief or mite eradication, demonstrating a high unmet need in treating patients with Demodex blepharitis.

Health Care Resource Use and Medical Costs Among Patients With Major Depressive Disorder and Acute Suicidal Ideation or Behavior Initiated on Esketamine Nasal Spray or Traditional Treatments in the United States.

Health Care Resource Use and Medical Costs Among Patients With Major Depressive Disorder and Acute Suicidal Ideation or Behavior Initiated on Esketamine Nasal Spray or Traditional Treatments in the United States.

Burden of illness among patients with asthma prescribed inhaled corticosteroids/long-acting β2-agonists

Inhaled corticosteroids (ICS) plus long-acting β2-agonists (LABA) are recommended for maintenance-only or maintenance and reliever therapy (MART) in patients with asthma. However, real-world data on ICS/LABA as maintenance-only or MART are limited. This study characterized clinical, economic, and humanistic burdens of asthma in Canada, China, Europe, Japan, and the US, using data collected from patients and physicians via a cross-sectional survey (Asthma Disease Specific Programme). Patients were ≥18 years of age with physician-confirmed asthma and receiving fixed-dose ICS/LABA for ≥3 months. Mean physician-reported symptom-free days over the past 30 days ranged from 10.1–20.6 days, and 31.5–34.6% of ICS/LABA users self-reported not well-controlled asthma. SABA co-prescription was reported in 8.8–67.8% of patients. These findings highlight the continued disease burden among ICS/LABA users, with the high level of SABA co-prescription indicating potentially inappropriate prescribing of ICS/LABA as MART or detrimental reliance on SABA medication in addition to MART.

The unmet needs in management, the treatment gap and the burden of migraine in Greece: a Delphi consensus and focus group study from patients' perspective.

Migraine is a chronic, debilitating neurological disease affecting more than 1 billion patients, worldwide. Even though migraines are not life-threatening, they have profound effects on individuals, families, and society. The aim of this study was to describe patients' perspectives on socioeconomic and humanistic burden of migraine, as well as the unmet medical needs in the clinical management of migraine, in Greece. A mixed study design of a Delphi panel and a focus group was conducted, in which 16 and 9 episodic migraine patients from the two Greek migraine patient associations participated, respectively. A structured questionnaire of 45 statements regarding burden of disease diagnosis, treatment and unmet needs was used to collect data at Delphi consensus panel. An open and balanced discussion with all participants took place, under the co-ordination of one moderator during the focus group. At each round of the Delphi panel, the percentage of participants who responded "Agree/Strongly Agree," "Disagree/Strongly disagree" and "Neither Agree nor Disagree" was calculated. The consensus threshold was set at 70% of responses. A thematic analysis was performed for the focus group. Consensus was achieved on 34 out of 45 statements. Thematic analysis revealed that patients face severe problems at work due to a lack of understanding and awareness of migraine burden from colleagues and employees, they are forced to modify their daily activities to avoid migraine attacks, and they experience prolonged diagnostic and treatment journey since they visit different medical specialties until they find the one who will be able to effectively help them manage their migraine. Additionally, they expressed concerns regarding the management of their disease due to patient-physician communication gap, dissatisfaction with traditional oral preventive therapies and lack of therapeutic options for older ages and in case of existence of specific comorbidities. Participants agreed that Migraine has a multifaceted impact on several aspects of patients' lives. Patient-centered care, better training for healthcare providers, targeted therapies, and improved communication tools emerged as key factors in addressing the unmet medical needs of migraine sufferers.