The role of avoiding known triggers, embracing protectors, and adhering to healthy lifestyle recommendations in migraine prophylaxis: Insights from a prospective cohort of 1125 people with episodic migraine.

OBJECTIVES/BACKGROUND: Until recently, guidelines for migraine prevention recommended avoiding known migraine headache triggers. Adhering to healthy lifestyle behaviors is also recommended. In a recent cohort study many triggers were found to decrease the probability of migraine attacks in some individuals. The extent to which people with migraine adhere to healthy lifestyle recommendations is unknown. We set out to determine if known migraine trigger factors and daily adherence to healthy lifestyle recommendations are associated with decreased probability of migraine attacks in some individuals. METHODS: This was an observational longitudinal cohort study of individuals with episodic migraine who registered to track their headache symptoms and daily exposure to trigger factors prospectively using a migraine-headache electronic diary during 90 days. We assessed whether triggers increased or decreased migraine attack risk in each individual. In addition, we calculated the proportion of days in which the individual adhered to lifestyle recommendations. RESULTS: We analyzed a total of 1125 individuals contributing 14,080 migraine attacks. Out of 47 triggers, 24 were more often associated with decreased rather than with increased migraine attack risk. Most pronouncedly this was true for caffeine, alcohol, and chocolate; happiness; relaxedness; sleep factors (longer duration, higher quality, and waking up refreshed); and physical activity. People who were more compliant with healthy behaviors, especially keeping good hydration and regular meals, were significantly older and had been diagnosed with migraine disease for a longer period, compared to those who were less compliant. Overall, exercising ≥3 times a week was the least followed recommendation. CONCLUSION: Many triggers behaved as protectors in a non-negligible proportion of individuals with episodic migraine, challenging the recommendation of avoiding known triggers. Low adherence to healthy lifestyle recommendations demonstrates an opportunity to increase awareness among people with migraine.

An observational study of self-reported migraine triggers and prospective evaluation of the relationships with occurrence of attacks enabled by a smartphone application (App).

OBJECTIVE: To investigate the relationship between self-reported triggers and the occurrence of migraine attacks using a smartphone application. BACKGROUND: One of several issues around the study of migraine attack triggers is that limited available evidence supports whether self-reported triggers can induce a headache on a particular subject. METHODS: This is an observational longitudinal cohort study of individuals with migraine registered to track their headaches prospectively using a smartphone application. For 90 days, participants entered daily data about triggers (potential triggers and premonitory symptoms) that may be associated with attack risk, as well as migraine symptoms. The statistical significance of univariate associations between each trigger and migraine recurrent events was determined for each individual. Statistically identified triggers were then compared to self-reported triggers. RESULTS: In 328 individuals (290/328 [88.4%] female; mean [standard deviation] 4.2 [1.5] migraine attacks/month) the mean (standard deviation) number of triggers moderately or highly endorsed per individual was 28.0 (7.7) in individuals presented with up to 38 possible triggers. Of these, an average (standard deviation) of 2.2 (2.1) triggers per individual were statistically associated with increased risk of attacks. Even the most commonly endorsed triggers (sleep quality, stress, tiredness/fatigue, sleep duration, dehydration, neck pain, missed meals, eyestrain, mean barometric pressure, and anxiety) were statistically associated in fewer than one third of individuals suspecting each, with the exception of neck pain (117/302 [38.7%]). CONCLUSIONS: Individuals with episodic migraine believe that many triggers contribute to their attacks; however, few of these withstand statistical testing at the individual level. Improved personal knowledge of potential triggers and premonitory symptoms may help individuals adopt behavioral changes to mitigate attack risk.

Between and within-woman differences in the association between menstruation and migraine days.

OBJECTIVE: To investigate between and within-woman differences in the association between menstruation and migraine days. BACKGROUND: Prior diary studies have shown that at the population level, aggregating across individuals, the odds of migraine increase during the perimenstrual window (from day -2 to day +3, where +1 is the first day of bleeding). These studies have been neither long nor large enough to assess the association between migraine and menses from an individual perspective. Consequently, existing research on menstrual-related migraine has largely overlooked between and within-woman variation that is critical for progressing clinical understanding and practice. METHODS: Intensive longitudinal data for the current study were collected in a digital platform (N1-Headache® ) that tracks individual migraine-related factors daily. Participants for the current study were actively menstruating adult (18+ years old) women who used the platform. Two variables were of primary interest, migraine day (no/yes) and menstrual status (inside or outside the 5-day perimenstrual window). RESULTS: The sample consisted of 203 women with a mean age of 35.6 (SD = 8.7) years. At baseline, the women reported an average of 30.6 (SD = 23.6) headache days over the last 3 months. Analyses were based on a total of 53,302 days (median of 150 per person), 18,520 of which were migraine days (median of 44 per person), and a total of 2,126 menstrual cycles (median of 7 per person). Results showed that the 5-day perimenstrual window was associated with a 34% increase in odds of a migraine day compared to other days (OR = 1.34, 95% CI: 1.23-1.45, p < 0.0001). Importantly, there was between and within-woman variability in the association between menses and migraine days (between-woman variability: p = 0.002; within-woman [between-cycles] variability: p < 0.0001). Exploration of these individual differences demonstrated that relationship between menses and migraine days varied more within-person across cycles than between women. DISCUSSION: This study supports previous research and demonstrates that the odds of migraine days are elevated from day -2 to day +3 of the menstrual cycle. We also show that the effect of menses on migraine days varies more within-woman than between-women. This work provides an initial foundation for better understanding menstrual-related migraine from the perspective of the individual patient.

Patterns of Perceived Stress Throughout the Migraine Cycle: A Longitudinal Cohort Study Using Daily Prospective Diary Data.

OBJECTIVES: To describe patterns of perceived stress across stages of the migraine cycle, within and between individuals and migraine episodes as defined for this study. METHODS: Individuals with migraine aged ≥18 years, who were registered to use the digital health platform N1-HeadacheTM , and completed 90 days of daily data entry regarding migraine, headache symptoms, and lifestyle factors were eligible for inclusion. Perceived stress was rated once a day at the participant's chosen time with a single question, "How stressed have you felt today?" with response options graded on a 0-10 scale. Days were categorized into phases of the migraine cycle: Ppre  = pre-migraine headache (the 2 days prior to the first day with migraine headache), P0  = migraine headache days, Ppost  = post-migraine headache (the 2 days following the last migraine day with migraine headache), and Pi  = interictal days (all other days). Episodes, defined as discrete occurrences of migraine with days in all 4 phases, were eligible if there was at least 1 reported daily perceived stress value in each phase. Individuals with ≥5 valid episodes, and ≥75% compliance (tracking 90 days in 120 calendar days or less) were eligible for inclusion in the analysis. RESULTS: Data from 351 participants and 2115 episodes were included in this analysis. Eighty-six percent of the sample (302/351) were female. The mean number of migraine days per month was 6.1 (range 2-13, standard deviation = 2.3) and the mean number of episodes was 6.0 (range 5-10, standard deviation = 1.0) over the 90-day period. Only 8 (8/351, 2.3%) participants had chronic migraine (defined as 15 or more headache days per month with at least 8 days meeting criteria for migraine). Cluster analysis revealed 3 common patterns of perceived stress variation across the migraine cycle. For cluster 1, the "let down" pattern, perceived stress in the interictal phase (Pi ) falls in the pre-headache phase (Ppre ) and then decreases more in the migraine phase (P0 ) relative to Pi . For cluster 2, the "flat" pattern, perceived stress is relatively unchanging throughout the migraine cycle. For cluster 3, the "stress as a trigger/symptom" pattern, perceived stress in Ppre increases relative to Pi , and increases further in P0 relative to Pi . Episodes were distributed across clusters as follows: cluster 1: 354/2115, 16.7%; cluster 2: 1253/2115, 59.2%, and cluster 3: 508/2115, 24.0%. Twelve participants (12/351, 3.4%) had more than 50% of their episodes fall into cluster 1, 216 participants (216/351, 61.5%) had more than 50% of their episodes fall into cluster 2, and 25 participants (25/351, 7.1%) had more than 50% of their episodes fall into cluster 3. There were 40 participants with ≥90% of their episodes in cluster 2, with no participants having ≥90% of their episodes in cluster 1 or 3. CONCLUSIONS: On an aggregate level, perceived stress peaks during the pain phase of the migraine cycle. However, on an individual and episode basis, there are 3 dominant patterns of perceived stress variation across the migraine cycle. Elucidating how patterns of perceived stress vary across the migraine cycle may contribute insights into disease biology, triggers and protective factors, and provide a framework for targeting individualized treatment plans.

Towards improved migraine management: Determining potential trigger factors in individual patients.

Background Certain chronic diseases such as migraine result in episodic, debilitating attacks for which neither cause nor timing is well understood. Historically, possible triggers were identified through analysis of aggregated data from populations of patients. However, triggers common in populations may not be wholly responsible for an individual's attacks. To explore this hypothesis we developed a method to identify individual 'potential trigger' profiles and analysed the degree of inter-individual variation. Methods We applied N = 1 statistical analysis to a 326-migraine-patient database from a study in which patients used paper-based diaries for 90 days to track 33 factors (potential triggers or premonitory symptoms) associated with their migraine attacks. For each patient, univariate associations between factors and migraine events were analysed using Cox proportional hazards models. Results We generated individual factor-attack association profiles for 87% of the patients. The average number of factors associated with attacks was four per patient: Factor profiles were highly individual and were unique in 85% of patients with at least one identified association. Conclusion Accurate identification of individual factor-attack profiles is a prerequisite for testing which are true triggers and for development of trigger avoidance or desensitisation strategies. Our methodology represents a necessary development toward this goal.

Sufficiency and necessity in migraine: how do we figure out if triggers are absolute or partial and, if partial, additive or potentiating?

Migraine is, to a great extent, a genetically determined disorder and once it has manifested itself, it generally continues for years if not for decades. While the migraine is active, headaches can seemingly occur spontaneously but are often reportedly precipitated by events or factors, known as migraine triggers, the interplay of which is the topic of this paper. Among migraine triggers, the menstrual cycle is an important one that probably accounts for much of the excess of migraine in women compared with men. Much has also been written about stress as a trigger of migraine, with headache occurring after rather than during stress, when relaxation occurs. Stress is also 1 of the 4 most often acknowledged headache triggers in general, the others being fatigue, not eating on time, and lack of sleep. Singularly, the triggers are generally necessary but not sufficient, ie, not powerful enough to bring on headache by themselves and, hence, compounding of those triggers is usually required. There is evidence to suggest that the premenstrual phase has a magnifying effect on the stress-headache interaction. The same is true for low-sleep duration with the (predictive) model fitting best when stress and low-sleep duration are considered additive. Menstruation has been identified as possibly the only absolute trigger of headache that is both necessary and sufficient. The scientific study of migraine triggers requires knowledge not just of how often in an individual a trigger is followed by migraine headache but also of how often it is not. Having identified trigger-headache associations, it needs to be determined which triggers are causative in the individual, either singly or in combination with others. This requires running an experiment with the individual that involves behavioral intervention to change exposure to a given trigger and determine whether that improves migraine. The ubiquitous adoption of the smart phone as a personal-data entry device, along with the possibility of bringing the results of sophisticated statistical analysis into the hands of patients and physicians, may well provide us with an important set of tools that will finally allow the unravelling of the age-old migraine-trigger puzzle.

Prevention of medication overuse and medication overuse headache in patients with migraine: a randomized, controlled, parallel, allocation-blinded, multicenter, prospective trial using a mobile software application.

BACKGROUND: Overall, 55% of the German population suffers from primary episodic headaches according to recent studies. Inadequate management of headache disorders is a significant medical problem. The prevalence of medication overuse headache (MOH) is about 1% with an estimated number of 800,000 people in Germany. Medication overuse (MO) and MOH are usually managed through a complex process of medication withdrawal and initiating of prophylaxis. However, patients who were successfully treated for MO or MOH have a high relapse rate in the following 2 years. Previously, continued monitoring of self-reported medication intake demonstrated lower relapse rates. The prevalence and burden of MO and MOH are high, and effective strategies to prevent the development of a relapse into MOH or de novo MOH are still missing. Therefore, the MOH trial was designed to assess the effects of combining self-reported medication intake with daily monitoring of the entered data and a personalized patient-specific medication intake feedback system in an easy-accessible app-based platform in order to prevent the development and relapse of MO(H). METHODS: The MOH trial is a randomized, controlled, parallel, multicenter, prospective trial. A total of 624 migraine patients with frequent migraine attacks and 336 patients who underwent treatment for MO(H) will be randomly allocated to use either a customized app with or without individual feedback regarding their self-reported medication intake for 12 months. The primary outcome will be the proportion of patients developing MO or MOH for at least 3 consecutive months between baseline and end of study visits. DISCUSSION: This trial will assess the effects of providing patients with feedback regarding their self-reported use of migraine medications and migraine days using a mobile software on the development or prevention of MO(H). We hypothesize that the development of MO(H) in patients with frequent episodic migraine (EM) or chronic migraine (CM) and relapse after treatment of MO(H) can be reduced by a feedback system. If this trial proves that using an app with specific and unspecific messaging to the patient is successful, this method, which is now investigated mainly in specialized headache centers, could later be extended to primary care, thus providing benefits for a broader patient group. TRIAL REGISTRATION: German Clinical Trials Register DRKS00025961 . Registered on 04 August 2021.

Impact of fasting on the gastric volume of critically ill patients before extubation: a prospective observational study using gastric ultrasound.

Background: A period of fasting before tracheal extubation of ventilated patients in the ICU is common practice, aiming to reduce gastric volume and aspiration risk. As the volume of gastric content is unknown at the time of extubation, the efficacy of this practice is uncertain. Methods: A prospective, observational study using gastric ultrasound was undertaken. Images were obtained at four time points: (i) at baseline, with gastric feeds running; (ii) after suctioning of gastric contents through a gastric tube; (iii) after a 4 h period with no gastric feed running; and (iv) after both a 4 h fasting period and gastric tube suctioning. The primary outcome was the proportion of patients classed as low risk of aspiration with each intervention, using qualitative and quantitative gastric ultrasound. Results: Fifty-four patients in the ICU were enrolled. Forty-four (81%) subjects had images that were suitable for analysis. Suctioning of stomach content through a gastric tube and fasting were equivalent with 39/44 (88.6%) and 5/44 (11.4%) subjects classified as low risk and at risk of aspiration, respectively. A period of fasting followed by suction resulted in 41/44 (93.2%) patients being at low risk. Conclusions: Suctioning of stomach contents through the gastric tube and a 4 h fasting period appear equivalent at reducing gastric volume below a safe threshold. A small percentage did not reach the threshold despite all interventions.

Natalizumab for active Crohn's disease.

BACKGROUND: In chronic inflammatory conditions such as Crohn's disease, the migration of leukocytes from the circulation into the parenchyma and their activation within inflammatory sites are mediated in part by alpha4 integrins. METHODS: We conducted a double-blind, placebo-controlled trial of the alpha4 integrin-specific humanized monoclonal antibody natalizumab in 248 patients with moderate-to-severe Crohn's disease. Patients were randomly assigned to receive one of four treatments: two infusions of placebo; one infusion of 3 mg of natalizumab per kilogram of body weight, followed by placebo; two infusions of 3 mg of natalizumab per kilogram; or two infusions of 6 mg of natalizumab per kilogram. Infusions were given four weeks apart. Outcomes included changes in scores for the Crohn's Disease Activity Index (higher scores indicate more severe disease), the health-related quality of life, and C-reactive protein levels. RESULTS: The group given two infusions of 6 mg of natalizumab per kilogram did not have a significantly higher rate of clinical remission (defined by a score of less than 150 on the Crohn's Disease Activity Index) than the placebo group at week 6 (the prospectively defined primary end point in the efficacy analysis). However, both groups that received two infusions of natalizumab had higher remission rates than the placebo group at multiple time points. Natalizumab also produced a significant improvement in response rates (defined by a reduction of at least 70 points in the score on the Crohn's Disease Activity Index). The highest remission rate was 44 percent and the highest response rate was 71 percent (at week 6 in the group given two infusions of 3 mg per kilogram). Overall, the two infusions of 6 mg of natalizumab per kilogram and of 3 mg per kilogram had similar effects. The quality of life improved in all natalizumab groups; C-reactive protein levels improved in groups receiving two infusions of natalizumab. The rates of adverse events were similar in all four groups. CONCLUSIONS: Treatment with the selective adhesion-molecule inhibitor natalizumab increased the rates of clinical remission and response, improved the quality of life and C-reactive protein levels, and was well tolerated in patients with active Crohn's disease.

Abortion for foetal abnormalities in Ireland; the limited scope of the Irish Government's response to the A, B and C judgment.

Abortion has been a controversial topic in Irish law and one which the Government has been forced to address following the decision of the European Court of Human Rights in A, B and C v. Ireland. The Working Group established to make recommendations have specifically been instructed to deal only with the issues raised in the A, B and C judgment and legislate on the basic of the 'X case'. This restricted approach calls for legalisation of abortion only where the life of the mother is at risk, a position unique only to Ireland and Andorra within Europe. The vast majority of member states to the European Convention on Human Rights allow for legal abortion on the basis of foetal abnormality and with this emerging consensus the margin of appreciation hitherto afforded by the European Court to member states is diminishing. The advancement and availability of non-invasive genetic tests that can determine foetal abnormalities together with the ruling in R. R. v. Poland leaves Ireland in a precarious position for omitting any reference to foetal abnormalities in any proposed legislation.

Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis.

Ligand-induced down-regulation controls the signaling potency of the epidermal growth factor receptor (EGFR/ErbB1). Overexpression studies have identified Cbl-mediated ubiquitinylation of EGFR as a mechanism of ligand-induced EGFR down-regulation. However, the role of endogenous Cbl in EGFR down-regulation and the precise step in the endocytic pathway regulated by Cbl remain unclear. Using Cbl-/- mouse embryonic fibroblast cell lines, we demonstrate that endogenous Cbl is essential for ligand-induced ubiquitinylation and efficient degradation of EGFR. Further analyses using Chinese hamster ovary cells with a temperature-sensitive defect in ubiquitinylation confirm a crucial role of the ubiquitin machinery in Cbl-mediated EGFR degradation. However, internalization into early endosomes did not require Cbl function or an intact ubiquitin pathway. Confocal immunolocalization studies indicated that Cbl-dependent ubiquitinylation plays a critical role at the early endosome to late endosome/lysosome sorting step of EGFR down-regulation. These findings establish Cbl as the major endogenous ubiquitin ligase responsible for EGFR degradation, and show that the critical role of Cbl-mediated ubiquitinylation is at the level of endosomal sorting, rather than at the level of internalization.