A study to investigate the prevalence of headache disorders and migraine conducted using medical claims data and linked results from online surveys: post-hoc analysis of other headache disorders.

BACKGROUND: Surveys using questionnaires to collect epidemiologic data may be subject to misclassification. Here, we analyzed a headache questionnaire to evaluate which questions led to a classification other than migraine. METHODS: Anonymized surveys coupled with medical claims data from individuals 19-74 years old were obtained from DeSC Healthcare Inc. to examine proportions of patients with primary headache disorders (i.e.; migraine, tension-type headache, cluster headache, and "other headache disorders"). Six criteria that determined migraine were used to explore how people with other headache disorders responded to these questions. RESULTS: Among the 21480 respondents, 7331 (34.0%) reported having headaches. 691 (3.2%) respondents reported migraine, 1441 (6.7%) had tension-type headache, 21 (0.1%) had cluster headache, and 5208 (24.2%) reported other headache disorders. Responses of participants with other headache disorders were analyzed, and the top 3 criteria combined with "Symptoms associated with headache" were "Site of pain" (7.3%), "Headache changes in severity during daily activities" (6.4%), and the 3 criteria combined (8.8%). The symptoms associated with headache were "Stiff shoulders" (13.6%), "Stiff neck" (9.4%), or "Nausea or vomiting" (8.7%), Photophobia" (3.3%) and "Phonophobia" (2.5%). CONCLUSIONS: Prevalence of migraine as diagnosed by questionnaire was much lower than expected while the prevalence of "other headache" was higher than expected. We believe the reason for this observation was due to misclassification, and resulted from the failure of the questionnaire to identify some features of migraine that would have been revealed by clinical history taking. Questionnaires should, therefore, be carefully designed, and doctors should be educated, on how to ask questions and record information when conducting semi-structured interviews with patients, to obtain more precise information about their symptoms, including photophobia and phonophobia.

Formation dynamics of branching structure in the slippery DLCA model.

We numerically investigated the aggregation dynamics and resulting network structures of colloidal gels using the slippery diffusion-limited cluster aggregation (DLCA) model. In this model, bonds are irreversibly formed upon the particle contacts, but the angles among them are not fixed, unlike the conventional DLCA. This allows clusters to be deformed in the process of aggregation. By characterizing the aggregation dynamics and using a reduced network scheme, our simulation revealed two distinct branching structure formation routes depending on the particle volume fraction ϕ. In lower volume fraction systems (ϕ ≤ 8%), the deformations of small-size clusters proceed prior to the percolation. When the Maxwell criterion is satisfied and the clusters become mechanically stable, the formation of the branching structure is nearly completed. After forming the branching structures, they aggregate and form a larger percolating network. Then, the aggregation proceeds through the elongation and straightening of the chain parts of the network. In higher volume fraction systems (ϕ > 8%), on the other hand, the clusters percolate, and a fine and homogeneous branching structure is formed at the early stage of the aggregation. In the aging stage, it collapses into a denser and more heterogeneous structure and becomes more stable. Our quantitative analyses of the branching structure will shed light on a new strategy for describing the network formation and elasticity of colloidal gels.

CGRP-monoclonal antibodies in Japan: insights from an online survey of physician members of the Japanese headache society.

BACKGROUND: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) have greatly changed migraine treatment options. In Japan, although CGRPmAb guidelines (≥ 4 monthly migraine days (MMDs) and ≥ 1 previous preventive failure) are well-acknowledged, the actual use of CGRPmAbs and the circumstances of the related headache care are unknown. METHODS: We conducted an online survey of Japanese Headache Society members, inquiring about the physicians' experience with CGRPmAbs and how they make decisions related to their use. RESULTS: Of the 397 respondents, 320 had prescribed CGRPmAbs. The threshold number of previous preventive failures for recommending a CGRPmAb was two for the majority of the respondents (n = 170, 54.5%), followed by one (n = 64, 20.5%). The MMD threshold was ≥ 4 for 71 respondents (22.8%), ≥ 6 for 68 (21.8%), ≥ 8 for 76 (24.4%), and ≥ 10 for 81 (26.0%). The respondents tended to assess treatment efficacy after 3 months (episodic migraine: n = 217, 69.6%, chronic migraine: n = 188, 60.3%). The cost of CGRPmAbs was described by many respondents in two questions: (i) any request for a CGRPmAb (27.7%), and (ii) the most frequently reported reason for responders to discontinue CGRPmAbs (24.4%). CONCLUSIONS: Most of the respondents recommended CGRPmAbs to patients with ≥ 2 preventive failures, followed by ≥ 1. The MMD threshold ranged mostly from ≥ 4 to ≥ 10. The concern for costs was raised as a major limiting factor for prescribing CGRPmAbs.

Effectiveness of three calcitonin gene-related peptide monoclonal antibodies for migraine: A 12-month, single-center, observational real-world study in Japan.

BACKGROUND: Real-world data on the effectiveness of calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) in migraine patients are needed. METHODS: We performed a single-center, real-world study with an observation period of up to 12 months (mean 7.5 ± 3.4 months) after CGRP mAb administration. A total of 228 Japanese patients with episodic or chronic migraine (age, 45.9 ± 13.2 years; 184F; 45 erenumab; 60 galcanezumab; 123 fremanezumab) who were treated with CGRP mAbs for at least three months were ultimately included in this study. RESULTS: In the total cohort, after CGRP mAb treatment, mean monthly migraine days decreased by 7.2 ± 4.8, 8.3 ± 4.7, and 9.5 ± 5.0 at three, six and 12 months, respectively. The ≥50% monthly migraine day reduction rates at three, six and 12 months were 48.2%, 61.0% and 73.7%, respectively. In the logistic regression analysis, the presence of osmophobia and fewer baseline monthly migraine days contributed to ≥50% responders at three, six and 12 months. The ≥50% responders at three or six months were useful in predicting ≥50% responders at 12 months. In subgroups of patients with difficult-to-treat migraine (those with medication overuse headache or psychiatric comorbidities) and previous CGRP mAb users, monthly migraine days were substantially reduced over 12 months. There was no difference in monthly migraine day reduction over 12 months among three different CGRP mAbs. Adverse reactions were observed in 28 (12.3%) patients, with injection site reactions being the most common (n = 22) though generally mild in severity. CONCLUSION: This real-world study confirmed the efficacy and safety of three different CGRP mAbs for prophylactic treatment of patients with migraine.

Clinical characteristics, medication use, and impact of primary headache on daily activities: an observational study using linked online survey and medical claims data in Japan.

BACKGROUND: Limited epidemiological data are available for headache disorders in Japan, and no recent studies have reported the impact of several primary headache disorders in Japan. This study aimed to report the up-to-date epidemiological data and impact of primary headaches on daily activities as well as the use of medical care, clinical features, and pain severity/activity impairment using nationwide data in Japan. METHODS: We used anonymized online survey data coupled with medical claims data, from individuals aged 19-74 years old, that were provided by DeSC Healthcare Inc. The outcomes included the prevalence of migraine, tension-type headache, cluster headache, and other headache types stratified by age and sex, use of medical care, clinical features, medication use, and severity of pain/activity impairment. All outcomes were examined separately for each headache type. This is the second paper reported concurrently with this research. RESULTS: The study population comprised 691/1,441/21/5,208 individuals with migraine/tension-type headache/cluster headache/other headache types, respectively. The prevalence of migraine and tension-type headache was higher in women than in men but was similar for cluster headache (male vs. female, 1.7% vs. 7.4%, 5.3% vs. 10.8%, and 0.1% vs. 0.1%, respectively). The percentage of individuals with migraine, tension-type headache, cluster headache who had not seen a doctor was 81.0%, 92.0%, 57.1%, respectively. The common headache triggers were fatigue in migraine and tension-type headache, and weather-related phenomena and turning of the seasons in migraine. Common activities refrained from or reduced by headaches were "operating a computer or smartphone", "drinking alcohol", and "going to crowded places" in all three headache types and housework-related activities in women. Among individuals taking medicines, 16.8%, 15.8%, 47.6% with migraine, tension-type headache, and cluster headache reported moderate to severe pain, respectively, and 12.6%, 7.7%, 19.0% reported moderate to severe disability, respectively. CONCLUSIONS: This study found various triggers of headache attacks, and daily activities refrained from or reduced by headaches. Additionally, this study suggested that the disease burden in people possibly experiencing tension-type headaches, many of whom had not seen a doctor. The study findings are of clinical value for the diagnosis and treatment of primary headaches.

High-risk patent foramen ovale and elderly in cryptogenic stroke.

BACKGROUND: High-risk patent foramen ovale (PFO) could be pathological in cryptogenic stroke (CS), but its clinical characteristics have not been fully studied, especially in elderly patients. METHODS: Patients with CS were enrolled in the CHALLENGE ESUS/CS registry, a multicenter registry of CS patients undergoing transesophageal echocardiography. Clinical characteristics were compared among three groups: high-risk PFO group, large shunt PFO (≥25 microbubbles) or PFO with atrial septal aneurysm (ASA); right-to-left shunt (RLS) group, RLS including PFO with <25 microbubbles or without ASA; and no-RLS group. RESULTS: In total, 654 patients were analyzed: 91, 221, and 342 in the high-risk PFO, RLS, and no-RLS groups, respectively. In multinomial logistic regression analysis, the male sex (odds ratio [OR] 1.825 [1.067-3.122]) was independently associated with high-risk PFO, but hypertension (OR, 0.562 [0.327-0.967]), multiple infarctions (OR, 0.601 [0.435-0.830]), and other cardioaortic embologenic risks (OR, 0.514 [0.294-0.897]) were inversely associated with high-risk PFO compared with non-RLS. In 517 patients aged ≥60 years, multiple infarctions (OR, 0.549 [0.382-0.788]) and other cardioaortic embologenic risks (OR, 0.523 [0.286-0.959]) were inversely associated with high-risk PFO. CONCLUSIONS: High-risk PFO had specific clinical characteristics and possible mechanistic associations, and this trend was consistent among CS patients aged ≥60 years. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.umin.ac.jp/ctr/ (UMIN000032957).

Cranial autonomic symptoms in migraine are related to central sensitization: a prospective study of 164 migraine patients at a tertiary headache center.

BACKGROUND: Cranial autonomic symptoms (CASs) during migraine attacks are reported to be quite common regardless of ethnicity. In our previous study investigating 373 migraineurs, we found that 42.4% of them had CASs. The patients with CASs more frequently had cutaneous allodynia than did those without CASs, and we speculated that CASs were associated with central sensitization. The present study searched for substantial evidence on the relationship between CASs and central sensitization in migraine patients. METHODS: This was a prospective cross-sectional study. We studied a new independent cohort of 164 migraineurs who presented to the Tominaga Hospital Headache Center from July 2018 until December 2019. The clinical features of CASs according to the criteria in ICHD-3 (beta) were investigated. We also evaluated central sensitization based on the 25 health-related symptoms utilizing the validated central sensitization inventory (CSI), and each symptom was rated from 0 to 4 resulting a total score of 0-100. RESULTS: The mean age was 41.8 (range: 20 to 77) years old. One hundred and thirty-one patients (78.9%) were women. Eighty-six of the 164 (52.4%) patients had at least 1 cranial autonomic symptom. The CSI score of the patients with ≥3 CASs reflected a moderate severity and was significantly higher than in those without CASs (41.9 vs. 30.7, p = 0.0005). The score of the patients with ≥1 conspicuous CAS also reflected a moderate severity and was significantly higher than in those without CASs (40.7 vs. 33.2, p = 0.013). The patients in the CSI ≥40 group had lacrimation, aural fullness, nasal blockage, and rhinorrhea, which are cranial autonomic parasympathetic symptoms, significantly more frequently than those in the CSI < 40 group. CONCLUSIONS: Migraine patients with CASs showed significantly greater central sensitization than those without such symptoms. In particular, cranial parasympathetic symptoms were more frequent in centrally sensitized patients than in nonsensitized patients, suggesting that cranial parasympathetic activation may contribute to the maintenance of central sensitization. TRIAL REGISTRATION: This study was retrospectively registered with UMIN-CTR on 29 Aug 2020 ( UMIN000041603 ).

A Nationwide Epidemiological Survey of Adolescent Patients With Diverse Symptoms Similar to Those Following Human Papillomavirus Vaccination: Background Prevalence and Incidence for Considering Vaccine Safety in Japan.

BACKGROUND: Since June 2013, Japan has suspended proactive recommendation of human papillomavirus (HPV) vaccination due to self-reported diverse symptoms, including pain and motor dysfunction, as possible serious adverse events following immunization. Although these symptoms may be seen in adolescents without HPV vaccination, their frequency, taking into account disease severity, has not been examined. METHODS: A two-stage, descriptive, nationwide epidemiological survey was conducted in 2016, with a 6-month target period from July 1 to December 31, 2015, to estimate the prevalence and incidence of diverse symptoms among Japanese adolescents without HPV vaccination. Participants were 11,037 medical departments in hospitals selected nationwide by stratified random sampling. Eligible patients had to satisfy four criteria: (1) aged 12-18 years upon visiting hospital; (2) having at least one of four symptoms/disorders (pain or sensory dysfunction, motor dysfunction, autonomic dysfunction, or cognitive impairment); (3) symptoms/disorders persisting for at least 3 months; and (4) both criteria (2) and (3) influence attendance at school or work. We then extracted data of patients with diverse symptoms similar to those after HPV vaccination while considering opinions of doctors in charge. RESULTS: Estimated 6-month period prevalence of diverse symptoms among girls aged 12-18 years without HPV vaccination was 20.2 per 100,000. Annual incidence was estimated to be 7.3 per 100,000. CONCLUSION: Adolescent Japanese girls without HPV vaccination also visited hospitals with diverse symptoms similar to those following HPV vaccination. Our findings predict the medical demands for coincident diverse symptoms, which are temporally associated with but not caused by HPV vaccination of Japanese adolescents.

Nationwide registry for patients with neuroendocrine neoplasm of pancreas, gastrointestinal tract, lungs, bronchi, or thymus in Japan.

BACKGROUND: Neuroendocrine neoplasm (NEN) is a comparatively rare tumor that has been considered indolent. Due to these characteristics, detailed epidemiological data have not been analyzed in Japan. To elucidate the present status of NEN diagnosis and treatment in Japan, we started a registry cohort study in January 2015. METHODS: Patients pathologically diagnosed with NENs of the pancreas, gastrointestinal tract, lungs, bronchi, or thymus after January 2012 were enrolled in this registry after the date of ethics review committee approval in each hospital or institute. Follow-up was continued for enrolled patients. RESULTS: During 5 years of enrollment between January 2015 and December 2019, a total of 1526 participants from 63 departments were enrolled in this registry (mean, 305.2 participants/year), covering approximately 5.8% of the annual incidence of NENs in Japan. For pancreatic NEN, 41.9% of patients had metastasis and the dominant metastatic site was the liver, at twice the rate of lymph node metastasis in the current registry. In contrast, the frequency of lymph node metastasis from gastrointestinal (GI)-NEN was similar to that of the liver. The distribution of WHO 2019-based grades varied according to the primary site. Low-to-intermediate grade (G1-G2) was dominant for duodenal, jejunal/ileal, rectal, and pancreatic NENs, whereas high grade (G3 or NEC) was dominant for esophageal, stomach, and colon NENs. For PanNENs, G3 and NEC accounted only for 1.6% and 2.9%, respectively. CONCLUSIONS: These cohort data provide crucial information for clinical research to clarify the characteristics of NENs in Japan.

A study to investigate the prevalence of headache disorders and migraine among people registered in a health insurance association in Japan.

BACKGROUND: Migraine is a chronic disease characterized by episodic headache attacks. No recent studies have, however been conducted on the epidemiology of migraine or the treatment landscape in Japan. This study was conducted as a fact-finding survey using medical claims data and an online survey on migraine and headaches, conducted among members of health insurance associations with the objective of gaining an understanding of migraine prevalence and the treatment status in Japan. METHODS: The study methodology utilized a unique approach of combined data sources. The data sources used in this study are medical claims data and linked online survey data provided by DeSC Healthcare Inc (DeSC). The primary outcomes (from survey responses) were: the overall number and proportion of migraine patients; and the overall prevalence of migraine, stratified by age and sex. The secondary outcomes (from survey responses) were use of medical care; and clinical features/headache symptoms. The analysis population included all individuals who had response data for surveys conducted by DeSC. The online survey data and medical claims data were summarized. RESULTS: The data population comprised 21,480 individuals. On the basis of the survey results, including probable cases, the overall prevalence of migraine was 3.2%. The highest prevalence of migraine was observed in patients aged 30-39 years. The prevalence of migraine in women was 4.4 times higher than in men. The percentage of migraine patients who had not been seen by a doctor was 81.0%. More than 80% of patients were taking over-the-counter drugs and 4.8% took prescription medicines only. Approximately 52.9% of patients considered that the intensity of pain symptoms was severe. Moreover, the majority of patients (72.9%) considered that the impairment of daily life activities was of moderate or severe degree. CONCLUSIONS: In Japan, the percentage of people with migraine who did not receive medical attention is as high as 80%. Additionally, the majority of patients tend to endure symptoms and continue with everyday activities. With innovative treatment approaches becoming available it is necessary to disseminate information that migraine is not a simple headache but an illness that requires medical treatment and consultation.

Erenumab treatment for migraine prevention in Japanese patients: Efficacy and safety results from a Phase 3, randomized, double-blind, placebo-controlled study.

OBJECTIVES: Erenumab is a human anti-calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. Global studies have demonstrated its efficacy in chronic and episodic migraine (EM). Here we report the outcomes from a Phase 3 study of erenumab in Japanese patients with chronic migraine (CM) or EM. METHODS: Japanese patients with EM (<15 headache days/month, including ≥4 migraine days/month) or CM (≥15 headache days/month, including ≥8 migraine days/month) were randomized 1:1 to placebo or erenumab 70 mg once monthly for a 24-week double-blind treatment phase (DBTP). The primary endpoint of change from baseline in mean monthly migraine days (MMD) over months 4, 5, and 6 of the DBTP was compared between erenumab and placebo groups. Secondary efficacy and safety endpoints were also assessed. RESULTS: A total of 261 patients were randomized to placebo (n = 131) or erenumab 70 mg (n = 130); all patients were included in the efficacy and safety analyses. The mean (standard deviation) MMD at baseline was 11.84 (5.70) for the placebo group and 12.40 (5.99) for erenumab 70 mg. The mean (standard error) change in MMD was -1.98 (0.38) for the placebo group (n = 131) and -3.60 (0.38) for erenumab 70 mg (n = 130). The difference in MMD reduction between groups was -1.67 (95% CI: -2.56, -0.78, p < 0.001) for EM and -1.57 (95% CI: -3.39, 0.24, p = 0.089) for CM. Adverse events (AEs) were consistent with earlier studies. The most frequent AEs (placebo, erenumab) were nasopharyngitis (28.2% and 26.9%, respectively), back pain (4.6% and 5.4%), and constipation (0.8% and 4.6%). CONCLUSION: Treatment with erenumab 70 mg once monthly demonstrated favorable efficacy and safety findings in Japanese patients with EM or CM.

Long-term efficacy and safety during open-label erenumab treatment in Japanese patients with episodic migraine.

OBJECTIVE: To assess long-term (up to 2 years) efficacy, tolerability, and safety of erenumab for the prevention of episodic migraine (EM) in Japanese patients. BACKGROUND: Previously published results from the double-blind treatment phase (DBTP) of a phase 2 clinical study have demonstrated the efficacy and safety of erenumab in Japanese patients with EM. METHODS: Patients completing the 24-week placebo-controlled DBTP could continue into the 76-week open-label treatment phase (OLTP), receiving erenumab 70 mg or 140 mg subcutaneously once monthly. The initial dose in the OLTP was erenumab 70 mg monthly, which was later changed to 140 mg. After study completion, the following were assessed: change from baseline in monthly migraine days (MMD), change from baseline in monthly acute migraine-specific medication days (MSMD), percentage of patients achieving ≥50% and ≥75% reduction in MMD, change from baseline in the 6-item Headache Impact Test (HIT-6™) score, and safety (exposure-adjusted patient-incidence of adverse events [AEs], calculated as number of patients per 100 patient-years). RESULTS: Of 475 patients enrolled in the DBTP, 459 (96.6%) continued in the OLTP. The mean (SD) MMD was 7.9 (2.3) at baseline with the overall change from baseline at week 100 of -2.9 (4.1) days. The monthly acute MSMD was 5.7 (2.8) at baseline with change from baseline at week 100 of -1.7 (3.7) days. The proportion of patients who achieved ≥50% and ≥75% reduction in MMD from baseline at week 100 was 177/398 (44.5%) and 94/398 (23.6%), respectively. The HIT-6™ score was 58.4 (5.4) at baseline with a change of -6.4 (8.2) at week 100. The exposure-adjusted patient-incidence of AEs during the OLTP was 207.1/100 patient-years for the combined erenumab group, similar to that observed for either erenumab (271.0/100 patient-years) or placebo (257.3/100 patient-years) during the DBTP, and no new safety signals were detected during the OLTP. CONCLUSION: Long-term erenumab treatment in Japanese patients with EM demonstrated sustained efficacy for up to 2 years, with a safety profile similar to previous studies, supporting erenumab as a potential new therapy for EM prevention in Japan.

Efficacy and safety of fremanezumab for chronic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

OBJECTIVE: To determine the efficacy and safety of fremanezumab administration in Japanese and Korean patients with chronic migraine (CM). BACKGROUND: Available preventive treatments for CM are limited by various efficacy and safety issues. Fremanezumab, a monoclonal antibody that targets the calcitonin gene-related peptide pathway involved in migraine pathogenesis, has been shown to be effective and well tolerated in large-scale, international Phase 3 trials. METHODS: Randomized, placebo-controlled trial of patients with CM who received subcutaneous fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. Primary endpoint was the mean change from baseline in the monthly (28-day) average number of headache days of at least moderate severity during the 12 weeks after the first dose. RESULTS: Among 571 patients randomized (safety set, n = 569; full analysis set, n = 566), the least-squares mean (±standard error [SE]) reduction in the average number of headache days of at least moderate severity per month during 12 weeks was significantly greater with fremanezumab monthly (-4.1 ± 0.4) and fremanezumab quarterly (-4.1 ± 0.4) than with placebo (-2.4 ± 0.4). The difference from the placebo group in the mean change (95% confidence interval [CI]) was -1.7 days (-2.54, -0.80) for the fremanezumab monthly group and -1.7 days (-2.55, -0.82) for the fremanezumab quarterly group (p < 0.001 vs. placebo for both fremanezumab groups). The percentage of patients with a ≥50% reduction in the average number of headache days of at least moderate severity per month (response rate) was higher with fremanezumab monthly (29.0%) and fremanezumab quarterly (29.1%) than with placebo (13.2%) in addition to other improvements in secondary endpoints, including reduction of acute medication use (mean change from baseline during 12-week period ± SE: fremanezumab monthly, -3.7 ± 0.4; fremanezumab quarterly, -3.9 ± 0.4; placebo, -2.4 ± 0.4) and improvements in disability scores (mean change from baseline in six-item Headache Impact Test score at 4 weeks after third injection ± SE: fremanezumab monthly, -8.1 ± 0.7; fremanezumab quarterly, -8.0 ± 0.7; placebo, -6.5 ± 0.7). Fremanezumab was well tolerated with a similar incidence of adverse events including injection-site reactions as placebo (patients with at least one treatment-emergent adverse event: fremanezumab total, n = 232 [61.4%]; placebo, n = 118 [61.8%]). CONCLUSION: Fremanezumab effectively prevents CM in Japanese and Korean patients and was well tolerated. No safety signal was detected.

The Japan Society for Surgical Infection: guidelines for the prevention, detection, and management of gastroenterological surgical site infection, 2018.

BACKGROUND: The guidelines for the prevention, detection, and management of gastroenterological surgical site infections (SSIs) were published in Japanese by the Japan Society for Surgical Infection in 2018. This is a summary of these guidelines for medical professionals worldwide. METHODS: We conducted a systematic review and comprehensive evaluation of the evidence for diagnosis and treatment of gastroenterological SSIs, based on the concepts of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The strength of recommendations was graded and voted using the Delphi method and the nominal group technique. Modifications were made to the guidelines in response to feedback from the general public and relevant medical societies. RESULTS: There were 44 questions prepared in seven subject areas, for which 51 recommendations were made. The seven subject areas were: definition and etiology, diagnosis, preoperative management, prophylactic antibiotics, intraoperative management, perioperative management, and wound management. According to the GRADE system, we evaluated the body of evidence for each clinical question. Based on the results of the meta-analysis, recommendations were graded using the Delphi method to generate useful information. The final version of the recommendations was published in 2018, in Japanese. CONCLUSIONS: The Japanese Guidelines for the prevention, detection, and management of gastroenterological SSI were published in 2018 to provide useful information for clinicians and improve the clinical outcome of patients.

Association between preoperative tumor necrosis factor alpha inhibitor and surgical site infection after surgery for inflammatory bowel disease: a systematic review and meta-analysis.

Tumor necrosis factor-alpha inhibitor (TNFi) treatment is effective for ulcerative colitis (UC) and Crohn's disease (CD). Although several meta-analyses have been performed to evaluate the association between TNFi treatment and surgical morbidity, the results are controversial. We conducted a systematic review and meta-analysis of the prevention of surgical site infection (SSI) after surgery for UC and CD in patients on TNFis, based on literature published between January 2000 and May 2019 (registered on PROSPERO, No. CRD42019134156). Overall, 2175 UC patients in 13 observational studies (OBSs) and 7084 CD patients in 16 OBSs were included. The incidences of incisional (INC) SSI and organ/space (O/S) SSI after surgery for UC were 179/1985 (9.0%) and 176/2175 (8.1%), respectively. TNFi use was not associated with the incidences of INC SSI (odds ratio (OR) 1.04, 95% confidence interval (CI) (0.47-2.32) or O/S SSI (OR 1.85, 95% CI (0.82-4.20)) after surgery for UC. The INC SSI and O/S SSI incidences after surgery for CD were 289/3089 (9.4%) and 526/7,084 (7.4%), respectively. Preoperative TNFi use was not associated with INC SSI (OR 0.98, 95% CI (0.52-1.83)) or O/S SSI incidence (OR 1.09, 95% CI (0.78-1.52)) after surgery for CD. We did not find a significant association between preoperative TNFi use and SSI in surgery for UC or CD.

Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale.

OBJECTIVE: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score. MATERIALS AND METHODS: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis. RESULTS: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores. CONCLUSIONS: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.

Investigating the relationships between the burden of multiple sensory hypersensitivity symptoms and headache-related disability in patents with migraine.

OBJECTIVE: Sensory hypersensitivities such as photophobia, phonophobia, and osmophobia are common in patients with migraine. We investigated the burden of these multiple sensory hypersensitivities in migraine. METHODS: In this cross-sectional study, 187 consecutive patients with migraine (26 men/161 women; age, 45.9 ± 13.2 years) were included. Sensory hypersensitivity symptoms such as photo-/phono-/osmophobia and accompanying symptoms were determined by neurologists in interviews. The Migraine Disability Assessment (MIDAS) was used to assess headache-related disability. The Kessler Psychological Distress Scale (K6) was also administered. RESULTS: Photophobia, phonophobia and osmophobia were observed in 75.4%, 76.5% and 55.1% of the patients with migraine, respectively. A significant overlap in sensory hypersensitivities (photo-/phono-/osmophobia) was found; the proportions of patients with 2 and 3 coexisting sensory hypersensitivities were 33.2% and 41.7%, respectively. The MIDAS score was higher in those with 3 sensory hypersensitivity symptoms than in those with 0 to 2 sensory hypersensitivity symptoms. A generalized linear model with ordinal logistic regression analysis revealed that multiple sensory hypersensitivities, younger age, more migraine days per month, and a higher K6 score were significantly related to the higher MIDAS score. CONCLUSION: Our study showed that sensory hypersensitivities commonly occur and overlap in patients with migraine and that multiple sensory hypersensitivity symptoms have a significant impact on headache-related disability.

Efficacy and safety of erenumab in Japanese migraine patients with prior preventive treatment failure or concomitant preventive treatment: subgroup analyses of a phase 3, randomized trial.

BACKGROUND: These subgroup analyses of a Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of erenumab 70 mg in Japanese migraine patients with/without prior preventive treatment failure(s) ("failed-yes" and "failed-no" subgroups) and with/without concomitant preventive treatment ("concomitant preventive-yes" and "concomitant preventive-no" subgroups). METHODS: Overall, 261 patients were randomized; 130 and 131 patients to erenumab 70 mg and placebo, respectively. Subgroup analyses evaluated the change from baseline to Months 4-6 in mean monthly migraine days (MMD) (primary endpoint), achievement of a ≥50% reduction in mean MMD, and change from baseline in mean monthly acute migraine-specific medication (MSM) treatment days. Treatment-emergent adverse events were also evaluated. RESULTS: Of the 261 patients randomized, 117 (44.8%) and 92 (35.3%) patients were in the failed-yes and concomitant preventive-yes subgroups, respectively. Erenumab 70 mg demonstrated consistent efficacy across all subgroups, with greater reductions from baseline in mean MMD versus placebo at Months 4-6 (treatment difference versus placebo [95% CI], failed-yes: - 1.9 [- 3.3, - 0.4]; failed-no: - 1.4 [- 2.6, - 0.3]; concomitant preventive-yes: - 1.7 [- 3.3, 0.0]; concomitant preventive-no: - 1.6 [- 2.6, - 0.5]). Similar results were seen for achievement of ≥50% reduction in mean MMD and change from baseline in mean monthly acute MSM treatment days. The safety profile of erenumab 70 mg was similar across subgroups, and similar to placebo in each subgroup. CONCLUSION: Erenumab was associated with clinically relevant improvements in all efficacy endpoints and was well tolerated across all subgroups of Japanese migraine patients with/without prior preventive treatment failure(s) and with/without concomitant preventive treatment. TRIAL REGISTRATION: Clinicaltrials.gov . NCT03812224. Registered January 23, 2019.

Impact of the COVID-19 pandemic on migraine in Japan: a multicentre cross-sectional study.

OBJECTIVES: To assess the impacts of social situation changes due to the coronavirus disease 2019 (COVID-19) pandemic on headache-related disability and other symptoms in patients with migraine in Japan. METHODS: We conducted a multicentre, cross-sectional study including 659 outpatients with migraine diagnosed by headache specialists. The participants were asked about the impacts of the first wave of the COVID-19 pandemic on headache-related disability, headache days, headache intensity, stress, physical activity, hospital access and their work and home lives. For headache-related disability, the total Migraine Disability Assessment (MIDAS) score and part A and B scores were analysed. Multivariate stepwise linear regression analysis was performed to identify the clinical predictors of changes in the total MIDAS score before and during the COVID-19 pandemic. Logistic regression analysis was performed to determine the factors related to new-onset headache during the COVID-19 pandemic. RESULTS: Finally, 606 migraine patients (73 M/533 F; age, 45.2 ± 12.0 years) were included in the study, excluding those with incomplete data. Increased stress, substantial concern about COVID-19 and negative impacts of the first wave of the COVID-19 pandemic on daily life were reported in 56.8 %, 55.1 and 45.0 % of the participants, respectively. The total MIDAS and A and B scores did not significantly change after the first wave of the COVID-19 pandemic. New-onset headache, which was observed in 95 patients (15.7 %), was associated with younger age and worsened mood and sleep in the logistic regression analysis. The multivariate stepwise linear regression analysis of changes in the total MIDAS score before and during the first wave of COVID-19 pandemic identified worsened sleep, increased acute medication use, increased stress, medication shortages, comorbidities, the absence of an aura and new-onset headache were determinants of an increased total MIDAS score during the first wave of the COVID-19 pandemic. CONCLUSIONS: In this multicentre study, clinical factors relevant to headache-related disability, such as new-onset headache, stress and sleep disturbances, were identified, highlighting the importance of symptom management in migraine patients during the first wave of the COVID-19 pandemic.

Factors associated with insufficient response to acute treatment of migraine in Japan: analysis of real-world data from the Adelphi Migraine Disease Specific Programme.

BACKGROUND: Real-world data on sufficient/insufficient response, and predictors of insufficient response, to acute treatments for migraine are limited in Japan. This study aimed to identify factors associated with insufficient response to acute treatment of migraine by exploring significant differences between people with migraine who sufficiently/insufficiently respond to prescribed acute treatment in Japan. METHODS: This was a retrospective analysis of 2014 Adelphi Migraine Disease Specific Programme cross-sectional survey data collected from physicians and their consulting adult patients with migraine in Japan. Insufficient responders to prescribed acute treatment were patients who achieved headache pain freedom within 2 h of acute treatment in no more than three of their last five migraine attacks. Factors associated with insufficient response to prescribed acute migraine treatment were identified using backward logistic regression. RESULTS: Overall, 227/538 (42.2%) patients were classified as insufficient responders to prescribed acute migraine treatment. Significantly more insufficient responders than sufficient responders had consulted a neurologist or a migraine/headache specialist, and had chronic migraine or medication-overuse or tension-type headaches (p < 0.05). More insufficient responders than sufficient responders reported taking acute treatment when/after the pain started (77.0 vs. 68.9%) than at first sign of migraine (p < 0.05). Compared with sufficient responders, insufficient responders reported a significantly higher mean ± standard deviation (SD) Migraine Disability Assessment total score (12.7 ± 23.3 vs. 5.8 ± 10.4, p < 0.001) and lower quality of life (EuroQol-5 Dimensions utility score 0.847 ± 0.19 vs. 0.883 ± 0.16, p = 0.024). Factors significantly associated with insufficient response to acute treatment included seeing a neurologist versus an internist (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.29-2.88; p = 0.002), taking acute medication when/after pain started versus at first sign of migraine (OR 1.65; 95% CI 1.05-2.60; p = 0.030), a higher MIDAS total score (OR 1.04; 95% CI 1.02-1.06; p < 0.001), and presence of comorbid cardiovascular disease (OR 0.53; 95% CI 0.28-0.98; p = 0.044). CONCLUSIONS: Many people with migraine in Japan struggle to adequately treat migraine attacks with prescribed acute medication and exhibit high levels of unmet need for acute treatment. Optimized management strategies utilizing existing therapeutic options as well as additional effective therapeutic options for migraine are required to improve symptoms and quality of life.