Prevalence of migraine in adults with celiac disease: A case control cross-sectional study.

AIM: Celiac disease (CD) is an immune-mediated disorder with various manifestations. The aim of this study was to evaluate the prevalence of gastrointestinal (GI) and extra-intestinal symptoms of celiac patients, especially migraine, and compare it with healthy individuals.
METHODS: We compared 1000 celiac subjects (CS) registered at our celiac center with the control group for headache-based on International Classification of Headache Disorders, third edition criteria and their GI symptoms. Besides, CS with migraine and non-migrainous headache were compared in terms of GI symptoms and accompanied conditions.
RESULTS: Headache was more common in CS than controls (34% vs 27% respectively, P value<0.001) and more prevalent in females (71.9% in females vs 28% in males, P value = 0.004). Moreover, the prevalence of migraine in CS was higher than controls (20.7 vs 11.9% respectively, P value<0.001). Furthermore, migraine was more prevalent in females with CD (80% in females vs 19% in males, P value = 0.033), and often without aura (76%). Abdominal pain (76.9%, P value = 0.025), diarrhea (54.9%, P value = 0.002), and constipation (42.9%, P value = 0.011) were the most common GI symptoms in CS with headache and more prevalent in CS with migraine. Conversely, type 1 diabetes mellitus was less common in CS with migraine than in CS with non-migrainous headache. (P value = 0.001). On multivariate logistic regression analysis, female sex (OR 1.50, 95%CI 1.22-1.83, P value < 0.001), and CD (OR 1.36, 95%CI 1.12-1.65, P value = 0.002) were independent predictors of headache, whereas age more than 60 years (OR 0.70, 95%CI 0.50-0.97, P value = 0.032) had a protective effect.
CONCLUSION: Headache especially migraine is more prevalent in CS than healthy controls. In addition, abdominal pain, diarrhea, and constipation are more common in CS with migraine than in CS with non-migrainous headaches. Therefore, evaluation of CD in patients with migraine and these simultaneous GI symptoms seems reasonable.

Introduction

Celiac disease (CD) affects about 1% of the population worldwide [1]. It is an immune-mediated disorder occurs in genetically predisposed people after a gluten exposure [2]. This immune response subsequently causes intraepithelial lymphocytic infiltration, villous atrophy and crypt hyperplasia in intestinal mucosa [3]. CD can present with typical gastrointestinal (GI) symptoms such as bloating or diarrhea or with atypical extra-intestinal manifestations such as neurological disorders or it may be silent or asymptomatic [4]. There are reports of numerous CD patients in whom neurologic symptoms are the main complaint even in the absence of GI symptoms at the time of diagnosis [5,6]. Also, many individuals with neurologic disorders of unknown origin and migraine have been positive for anti-gliadin antibodies [7,8]. On the other hand, migraine is a throbbing often disabling unilateral headache generally associated with nausea, vomiting, photophobia and phonophobia [9-12]. About 6% of men and 17% of women have experienced migraine attacks in their lifetime and this severely affects their quality of life [13-15]. Although, the exact pathophysiology of migraine is not fully understood [16,17], the level of pro-inflammatory cytokines like tumor necrosis factor alpha (TNF α) and interleukin 1 Beta (IL 1β) have been increase in serum of patients during migraine attack [18]. Subsequently, these substances cause migraine attack by affecting the trigeminal nerve nociceptors. The relationship between migraine and GI disorders such as CD and Non celiac gluten sensitivity (NCGS) has been discussed in numerous studies [19-24], and there is a pro-inflammatory response in either CD after gluten exposure and migraine [25]. Moreover, some evidence show that migraine are dramatically improved by treatment of the underlying GI disease (i.e. Gluten- free diet in CD) [23,26,27].

On the other hand, some studies have reported an inverse relationship between migraine and type 1 diabetes mellitus [28,29], the pathophysiology of which is not exactly understood. However, vascular stiffness due to intimal thickening as well as a decrease in pain sensation following diabetic neuropathy and subsequent decrease in cerebrovascular reactivity may have protective effects for migraine [30,31]. Limited studies have been performed on the association of migraine with celiac disease in the Iranian population. we investigated the prevalence of migraine in CD patients for early diagnosis and appropriate treatment.

Materials & methods

Study population

In this case-control cross sectional multicentric study, we assessed the data of 1000 celiac patients over 18 years of age (mean 41.16 ± 15.12) from medical centers in different provinces of Iran (medical centers in Tehran, Khorasan Razavi and Mazandaran provinces), who were registered to celiac registry center at Shariati Hospital, Tehran, Iran between 2014 and 2019. Celiac disease was diagnosed based on its positive serologic markers including immunoglobulin A against tissue transglutaminase (Anti tTG IgA) and endomysial antibody (EMA), and confirmed by endoscopy and duodenal biopsy (Marsh classification 3 and 4) in all subjects subsequently [32,33]. Celiac serological titers were assessed according to the ELISA method. We also used International classification of headache disorders 3rd edition (ICHD-3) criteria for headache diagnosis and classification [34]. The control group included 1000 healthy individuals over 18 years of age (mean 40.27±14.95) with negative celiac serologic markers and/or duodenal mucosal biopsy, who were recruited from hospital staff (physicians and nurses), friends, as well as patients family members. Subjects who had a history of inflammatory bowel diseases (IBD), previous head trauma, brain tumor, head and neck surgery or vascular problems were excluded from both groups. Out of 2000 participants, 642 (64.2%) and 557 (55.7%) were female from the celiac group and the control group, respectively (P value = 0.000). Characteristics of these two groups were shown in Table 1.

Table 1

Demographic characteristics in celiac patients and control group.

		Control group (n = 1000)	Celiac group (n = 1000)	P value
Sex	Female	557 (55.7%)	642 (64.2%)	<0.001
	Male	443(44.3%)	358(35.8%)
Age	18–40	597(59.7%)	569(56.9%)	0.412
	41–60	294(29.4%)	309(30.9%)
	>60	109(10.9%)	122(12.2%)

Study protocol

For all participants, a checklist including general information, age, sex, medical conditions, symptoms at the time of diagnosis, which included GI and non-gastrointestinal symptoms, initial diagnostic tests (endoscopic examination, duodenal biopsy report) and treatment plan was filled at the first visit. Subjects who reported a history of headache at initial evaluation were further evaluated with a checklist based on ICHD-3 criteria for different types of primary headache (i.e., migraine without aura, migraine with aura and non-migrainous headaches). Finally, the data of the two groups were compared (Fig 1). Moreover, celiac subjects (CS) with migraine and non-migrainous headache were compared in terms of GI symptoms and accompanied conditions.

Fig 1

Study nomogram.

Ethics statement

The study was performed in accordance with appropriate guidelines and reviewed and approved by the Local Ethics Committee of Tehran University of Medical Sciences (Approval No: IR.TUMS.DDRI.REC.1396.10).

Address: Tehran University of Medical Sciences (TUMS), Poursina St., Qods St., Enqelab St., Tehran, Iran.

Tel No.: 0098–2164053419.

Fax No.: 0098–88962510.

Written consent was obtained from all participants after informing them.

Statistical analysis

In this study, statistical analysis was done using SPSS version 16. The chi-square test and fisher’s exact test were used to compare proportions. P values < 0.05 were considered statistically significant. A multivariate logistic regression analysis was done to evaluate the associations between having celiac disease, gender, age group and having headache.

Results

342 (34%) celiac subjects (CS) and 271 (27%) controls reported headache, of which 246 (71.9%) of CS and 165 (60.9%) of controls were female. 207 (20%) CS and 119 (11%) subjects in control group had migraine. Also, 166 (80.2%) of celiac group and 83 (69.7%) of controls who reported migraine were female. Headache descriptions in CS and controls based on gender and age group were shown separately in Table 2, Figs 2 and 3. Forty-nine (23%) of CS and 22 (18%) of controls reported migraine with aura. The characteristics of headache and migraine in both groups were shown in Tables 3 and 4. We also found that abdominal pain (76.9%, P value = 0.025), diarrhea (54.9%, P value = 0.002), and constipation (42.9%, P value = 0.011) were the most common GI symptoms in CS with headache and were more prevalent in CS with migraine than those with non- migrainous headache. Conversely, type 1 diabetes mellitus was less common in CS with migraine than in CS with non-migrainous headache. (P value = 0.001). This comparison was shown completely in Table 5. On multivariate logistic regression analysis, female sex (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.22–1.83, P value < 0.001), and celiac disease (OR 1.36, 95%CI 1.12–1.65, P value = 0.002) were independent predictors of headache; On the other hand, age more than 60 years (OR 0.70, 95%CI 0.50–0.97, P value = 0.032) had a protective effect (Table 6).

Table 2

Headache descriptions in celiac subjects and controls based on gender and age group.

		Controls			Celiac subjects			P-value
		No headache (n = 729)	headache (n = 271)	P-value	No headache (n = 658)	headache (n = 342)	P-value
Gender	Male	337 (46.2%)	106 (39.1%)	0.044	262 (39.8%)	96 (28.1%)	<0.001	0.004
	Female	392 (53.8%)	165 (60.9%)		396 (60.2%)	246 (71.9%)
Age	18–40	430 (59%)	167 (61.6%)	0.227	377 (57.3%)	192 (56.1%)	0.097	0.387
	41–60	212 (29.1%)	82 (30.3%)		192 (29.2%)	117 (34.2%)
	>60	87 (11.9%)	22 (8.1%)		89 (13.5%)	33 (9.6%)

Fig 2

Prevalence of different types of headaches in both celiac and control groups.

Fig 3

Comparison of headache prevalence in different age groups between control and celiac subjects.

Table 3

Comparison of different types of headaches in CD group vs controls.

		Controls			Celiac subjects			P-value
		Non-migrainous headaches (n = 152)	Migraine (n = 119)	P-value	Non-migrainous headaches (n = 135)	Migraine (n = 207)	P-value
Gender	Male	70 (46.1%)	36 (30.3%)	0.005	55 (40.7%)	41 (19.8%)	<0.001	0.033
	Female	82 (53.9%)	83 (69.7%)		80 (59.3%)	166 (80.2%)
Age	18–40	77 (50.7%)	90 (75.6%)	<0.001	49 (36.3%)	143 (69.1%)	<0.001	0.449
	41–60	55 (36.2%)	27 (22.7%)		57 (42.2%)	60 (29%)
	>60	20 (13.2%)	2 (1.7%)		29 (21.5%)	4 (1.9%)

Table 4

Characteristics of migraine in CD group vs controls.

Migraine characteristics	Controls (n = 119)	Celiac group (n = 207)	P value
Aura	22 (18.5%)	49 (23.7%)	0.330
Unilateral	80 (67.2%)	135 (65.2%)	0.808
Pulsatile	95 (79.8%)	169 (81.6%)	0.770
Nausea and/or Vomiting	83 (69.7%)	139 (67.1%)	0.711
Photophobia and phonophobia	70 (58.8%)	126 (60.9%)	0.726

Table 5

Evaluation of GI symptoms and accompanied conditions in CD subjects with migraine in comparison with CD subjects with non-migrainous headache.

Symptoms and associated Conditions	CD subjects with Non-migrainous Headaches (n = 135)	CD subjects with migraine (n = 207)	P-value	Total CD group (n = 342)
Hypothyroidism	23 (17.03%)	34 (16.4%)	0.756	57 (16.6%)
Hyperthyroidism	5 (3.7%)	7 (3.3%)	0.829	12 (3.5%)
Type I Diabetes mellitus	12 (8.8%)	3 (1.4%)	0.001	15 (4.3%)
Type II Diabetes mellitus	2 (1.4%)	7 (3.3%)	0.299	9 (2.6%)
Abdominal Pain	97 (71.8%)	166 (80.1%)	0.025	263 (76.9%)
Constipation	48 (35.5%)	99 (47.8%)	0.011	147 (42.9%)
Diarrhea	62 (45.9%)	126 (60.8%)	0.002	188 (54.9%)
Nausea	60 (44.4%)	97 (46.8%)	0.466	157 (45.9%)
Vomiting	28 (20.7%)	54 (26%)	0.158	82 (23.9%)
Flatulence	97 (71.8%)	166 (80.1%)	0.064	263 (76.9%)
GERD	68 (50.3%)	112 (54.1%)	0.252	180 (52.6%)

GERD = Gastro-esophageal reflux disease; GI = Gastro-intestinal; CD = Celiac disease.

Table 6

Univariate and multivariate analysis for headache prediction.

		Odds Ratio (CI95%)
		Univariate Analysis	P-value	Multivariate Analysis	P-value
Celiac	Yes / No	1.40 (1.15–1.69)	0.001	1.36 (1.12–1.65)	0.002
Gender	Female / Male	1.54 (1.26–1.88)	<0.001	1.50 (1.22–1.83)	<0.001
Age	41–60 / 18–40	1.11 (0.89–1.37)	0.343	1.09 (0.88–1.35)	0.430
	>60 / 18–40	0.70 (0.51–0.97)	0.034	0.70 (0.50–0.97)	0.032

Discussion

Our findings suggest that headache is more common in CS than controls (34% vs 27% respectively, P value< 0.001), And is more prevalent in females than males with celiac disease (71.9% in females vs 28% in males, P value = 0.004). In addition, the prevalence of migraine in CS is higher than controls (20.7 vs 11.9% respectively, P value<0.001). Furthermore, migraine was more prevalent in women than men with celiac disease (80% in women vs 19% in men, P value = 0.033), and was often without aura (76%). The migraine was often pulsatile (81.6%), unilateral (65%), and was accompanied by nausea and/or vomiting (67%), photophobia and phonophobia (60.9%). Dimitrova et al. [22] have also reported higher prevalence of headaches and migraine in celiac disease, gluten sensitivity, IBD (ulcerative colitis) than in the controls, in the United states. Gluten-sensitive group had the highest rate of headache (56%), to compare with celiac disease (30%), IBD (22%) and (14%) controls. Although, the prevalence of migraine diagnosed by ID Migraine criteria was 21% in celiac group, 40% in gluten sensitivity and 6% in control group. In our study compared to Dimitrova et al, [22] the celiac and control groups were more matched in age and sex. Furthermore, Dimitrova et al. found that the age more 65 years is a protective factor for migraine, whereas our study suggests the age more than 60 years is protective. Cicarelli et al. [35] and Briani et al. [5], reported a migraine prevalence of 32% and 5.6% in celiac patients in Italy, respectively. Although the sample size of our study was much larger than the studies mentioned, with different percent, they all indicate an increased prevalence of migraine in celiac disease. In addition, we assessed further characteristics of migraine (i.e., aura, pulsatile, nausea, vomiting, photophobia and phonophobia) in CD patients. We revealed abdominal pain (76.9%, P value = 0.025), diarrhea (54.9%, P value = 0.002), and constipation (42.9%, P value = 0.011) were the most common GI symptoms in CD patients with headache and were more prevalent in CD patients with migraine than those with non-migrainous headache. Although, according to ICHD-3 criteria, migraine may be associated with some GI symptoms such as abdominal pain [34], concurrent GI disorders like CD should be ruled out before attributing these symptoms to migraine. Some studies show that the physiopathology of migraine and some functional gastrointestinal diseases are relatively similar [36]. It is important to note that, regardless of celiac disease, migraines can be associated with some GI symptoms that may be helpful in understanding their physiopathology. On the other hand, as Hagen K et al. have revealed the inverse relationship between type 1 diabetes mellitus and migraine in non- celiac individuals [32], we also found that type 1 diabetes mellitus is less common in celiac patients with migraine than in celiac patients with non-migrainous headache. (P value = 0.001). We also performed a multivariate logistic regression analysis to evaluate independent association between celiac disease and presence of headache; and found that female sex (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.22–1.83, P value < 0.001), and celiac disease (OR 1.36, 95%CI 1.12–1.65, P value = 0.002) were independent predictors of headache. On the other hand, age more than 60 years (OR 0.70, 95%CI 0.50–0.97, P value = 0.032) had a protective effect (Table 6).

Compared to Ruggieri et al. [37] we found that the prevalence of headache was higher in adults with celiac disease than in children. On the other hand, Shahbazkhani et al. have described the headache as one of the most common extra-intestinal symptoms in NCGS patients [20]. Perhaps we can conclude that some factors other than genetic susceptibility and gluten exposure are involved in the occurrence of headache in celiac patients.

The different sex distribution between the two groups (P = 0.000) and the lack of measurement of other serologic markers such as anti-neuronal antibodies [33] in subjects with migraine were the limitations of our study. As Croall et al. [38] said, some changes in brain imaging before and after exposure to gluten are seen in celiac patients. Therefore, performing a brain imaging study in celiac patients with migraine before and after the start of a gluten-free diet can be useful in better understanding the physiopathology of migraine in these patients.

Conclusion

Our study suggests that the prevalence of headache, especially migraine, in celiac patients is higher than healthy controls. In addition, abdominal pain, diarrhea, and constipation are more common in celiac patients with migraines than in celiac patients with non-migrainous headaches. Therefore, evaluation of celiac disease in patients with migraine and these simultaneous GI symptoms seems reasonable. Further interventional studies should also be performed on the role of a gluten-free diet in relieving headaches in celiac disease and other gluten-sensitive disorders.

Checklist for data collection.

(PDF)

Click here for additional data file.

Diagnostic criteria for migraine without aura.

(PDF)

Click here for additional data file.

Diagnostic criteria for migraine with typical aura.

(PDF)

Click here for additional data file.

18 Mar 2021

PONE-D-21-03892

Prevalence of Migraine in Adults with Celiac Disease: A Case Control Cross-Sectional Study

PLOS ONE

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Reviewer #1: 1)

Gluten-related disorders is the term for the diseases triggered by gluten, including celiac disease (CD), non-celiac gluten sensitivity (NCGS), gluten ataxia, dermatitis herpetiformis (DH) and wheat allergy.

Celiac diseae (CD) is one of the most common chronic, immune-mediated disorders, triggered by the eating of gluten.

The classic symptoms of untreated coeliac disease include pale, loose, or greasy stools (steatorrhoea), and weight loss or failure to gain weight. Other common symptoms may be subtle or primarily occur in organs other than the bowel itself.

Coeliac disease has been linked with a number of conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.

Headache is not a highly reported symptoms among the patients with this disease.

People of African, Japanese and Chinese descent are rarely diagnosed this disease.

That reflects a much lower prevalence of the genetic risk factors, such as HLA-B8.

Q1

Dose authors happen to have any data of ethnic background of this study?

Q2

I could not find this paper at Reference of this paper.

Could you please consider adding this paper to Reference of this study?

Headache. 2013 Feb;53(2):344-55.

Prevalence of migraine in patients with celiac disease and inflammatory bowel disease

Alexandra K Dimitrova 1, Ryan C Ungaro, Benjamin Lebwohl, Suzanne K Lewis, Christina A Tennyson, Mark W Green, Mark W Babyatsky, Peter H Green

Reviewer #2: This is a typical study to assess the prevalence of other comorbid disorders in headache and migraine patients. The authors compared Iranian celiac disease(CD) subjects with the control group to evaluate the prevalence of headache and migraine as well as the prevalence of some specific migrainous symptoms. The results are meaningful but not enough to support the conclusion. There are some points I concern about.

Line 35-36 the sentence should be revised. Headache prevalence is higher in CD patients but that does not mean the presence of headache could be a predictor of CD. You do not have a study to prove that the prevalence of celiac disease is higher in headache or migraine patients. Since CD itself is not a highly prevalent disease, we seldom take it into consideration when dealing with headache patients.

Line 40 change “disorder” to “disorders.”

Line 55-56 this statement seems not fully supported by this study. You do not have data to show a higher prevalence of CD in migraine patients. It may be possibly yes to migraine with concomitant GI symptoms.

Line 71-72 you’d better add “disabling” to describe the migraine symptoms which is also a characteristic of migraine.

Line 75 “but” is not necessary here.

Line 84-86 similar to Line 35-36, this description should be revised as it implies that migraine is a part of CD. Migraine itself is another disease entity, not a symptom. CD is just comorbidity.

Line 100 change “disorder” to “disorders.”

Line 103 “whom” should be “who”; “staffs” should be “staff.”

Line 106 “(P value =0.000)” means that the sex ratios of the study and control groups are not similar, right? It seems no need to emphasize.

Line 118 you just used a self-reported checklist to make the diagnosis of headache disorders. Why didn’t you use some validated screener such as the ID Migraine test?

Line 142 “Diabetes” should be “diabetes”. No need to capitalize.

Line 171-172 “headache” should be removed. “Bilateral” and “pulsatile” are characteristics of headache whereas aura, nausea, vomiting, photo- and phonophobia are associated symptoms. Also, about two-thirds of migraine headaches are unilateral which is one of the diagnostic criteria of migraine. “Bilateral” is not a characteristic of migraine.

Line 176 “;” should be “.” The following is another sentence.

Line 178 “Table 5” should be “Table 6.”

Line 179-180 Ruggieri et al. did the study of gluten sensitivity in children rather than CD in adults. Can you just compare the figures from different studies and make this conclusion?

Line 182 “be concluded” should be “conclude.”

Line 184-186 unclear to me. Please reword.

Line 193-194 as in Line 82-84 please reword. At least “refractory migraine” should be removed.

Table 4. please change “bilateral” to “unilateral” and correct the figures because the former is not a characteristic of migraine.

Line 228 please remove “headache” as some of them in the left column of table 4 are not characteristics of the headache but associated symptoms.

I suggest an English-editing service to correct some grammar mistakes.

Reviewer #3: Comment 1: The sex distribution were differed ( p= 0.000) between celiac and control groups (Table 1), this should be one of the limitations of this study.

Comment 2: Line 117 " Patients who reported a history of headaches..."; Line 132 " reported chronic headache..." . These two descriptions were inconsistent and should be clarified. "Headache " should be clearly defined, do you mean primary headache only, or secondary headache also included? "Chronic headache" is an ambiguous term, I am not able to know the meaning ( chronic primary headache history? or chronic daily headache? or others?) .

Comment 3: The authors didn't let us known how to perform the ICHD-3 based checklist (line 118) during questioning the patients, is it single-blinded or double-blinded?

Comment 4: According to Table 3, the both groups with more bilateral characters ( 67.2% and 65.2%) , this finding is different from the characters of general migraine patients, which "unilateral" were much more than "bilateral". This point should be clearly explained.

Comment 5: Table 5 revealed the two groups were differed in type I DM, abdominal pain, constipation and diarrhea, the possible causes of these differences needs to be explained.

Comment 6:Table 5 only compared CD subjects with migraine and non-migraine headache, however, it would be more interesting to compare the "symptoms and associated conditions" between CD with migraine headache and controls with migraine headache. If the authors have the data, please analyze and show in results and discussing them.

Comment 7: Based on comment 6, and the other results in this study, it's better to address the different characters between CD with migraine and migraine without CD (controls with migraine), and then provide possible explanations for them, in this way, this article may be more valuable.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Hikoaki Fukaura

Reviewer #2: No

Reviewer #3: Yes: Chi-Hsiang Chou

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: renamed_fa79c.docx

Click here for additional data file.

27 Jun 2021

Responses to the reviewers:

Reviewr1:

Q1: Dose authors happen to have any data of ethnic background of this study?

A1: No

Q2: Q2

I could not find this paper at Reference of this paper.

Could you please consider adding this paper to Reference of this study?

Headache. 2013 Feb;53(2):344-55.

Prevalence of migraine in patients with celiac disease and inflammatory bowel disease

Alexandra K Dimitrova 1, Ryan C Ungaro, Benjamin Lebwohl, Suzanne K Lewis, Christina A Tennyson, Mark W Green, Mark W Babyatsky, Peter H Green

A2: This reference No. is 22.

Reviewer 2:

All items mentioned by the 2nd reviewer were considered.

Reviewer 3:

Most items mentioned by the 3rd reviewer were considered.

Table 4 was corrected; figures and percent are related to unilateral headaches.

For some unknown reasons the prevalence of some diseases and symptoms are different in CD with and without migraine.

Submitted filename: Response to reviewer.docx

Click here for additional data file.

11 Jul 2021

PONE-D-21-03892R1

Prevalence of Migraine in Adults with Celiac Disease: A Case Control Cross-Sectional Study

PLOS ONE

Dear Dr. Alibeik,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The article is much better after revising. But the authors used the terms ‘migraine headache’, and ‘migraine’ interchangeably. 'Migraine headache' is not a good term as it may confuse the readers. Migraine is a specific headache disorder, no need to add 'headache' after it. If you want to describe the symptom ‘headache’, please use 'migrainous headache'. The 'migrainous headache' is a specific headache that presents unilateral, pulsating and disabling characteristics. Please recheck the whole article for this problem.

Line 39 As mentioned above, if you mean the symptom ‘headache’, you should use 'migrainous headache'. If you mean the disease ‘migraine’, you may say 'to evaluate … the comorbidity of migraine in CD…'.

Line 57 The conclusion should be revised again. The migraine itself would be associated with some GI symptoms by ICHD definition. If following this conclusion, every migraine patient should be evaluated for CD. You have to specify what GI symptoms could be related to CD.

Line 217 I don’t mean ‘ be conclude’, but just ‘conclude’. If you want to keep ‘be concluded’, it is okay.

Line 229 As mentioned above, please revise the conclusion.

Reviewer #3: The authors didn't reply my comments in a formal type. Due to the problem, I can't realize my comments were adequately answered or not.The authors have to answer my previous comments one by one.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Tzu-Chou Huang

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

2 Aug 2021

Responses to the Reviewers:

Reviewr1:

Q1: Dose authors happen to have any data of ethnic background of this study?

A1: No

Q2: I could not find this paper at Reference of this paper.

Could you please consider adding this paper to Reference of this study?

Headache. 2013 Feb;53(2):344-55.

Prevalence of migraine in patients with celiac disease and inflammatory bowel disease

Alexandra K Dimitrova 1, Ryan C Ungaro, Benjamin Lebwohl, Suzanne K Lewis, Christina A Tennyson, Mark W Green, Mark W Babyatsky, Peter H Green

A2: This reference No. is 22.

Reviewer 2:

As you mentioned, the terms “migraine headache” and “non-migraine headache” were replaced by the “migraine” and “non- migrainous headache” throughout the manuscript.

Conclusion was revised in “abstract” and “conclusion” sections (Lines 58-60 and Lines 268-271)

Reviewer 3:

Comment 1: As you mentioned, the sex distribution was differed (P= 0.000) between celiac and control groups, and that was one of the limitations of this study and we mentioned that in discussion (line 258)

Comment 2: As you said, the term “chronic headache” was replaced. We mentioned in the method section. (Line 122-125)

Comment 3: The ICHD-3 based checklist was written in Supporting information caption and it was filled single-blinded.

Comment 4: Table 4 was revised; figures and percent are related to unilateral headaches.

Comment 5: GI symptoms and migraine were explained (lines 238-243, discussion section). Migraine and type 1 were explained. (Lines 86-90, Introduction section/ lines 244-247, discussion section)

Comment 6 & 7: Thanks for your good comment. Unfortunately, this data is not available in the control group.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

11 Aug 2021

PONE-D-21-03892R2

Prevalence of Migraine in Adults with Celiac Disease: A Case Control Cross-Sectional Study

PLOS ONE

Dear Dr. Alibeik,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Much better. But there are still two points.

Line 159. The term ‘primary headache’ is a specific term that includes migraine, tension-type headache, trigeminal autonomic cephalalgia, and others only. I believe you mean just a complaint of headache here. Maybe you can remove the word ‘primary’.

Line 240. Common GI symptom of migraine is nausea/vomiting, not abdominal pain. According to ICHD-3 (your reference 34), there is no abdominal pain in the description of migraine. You’d better change it to ‘nausea/vomiting’.

Reviewer #3: About my previous comment 4, I think the table 4 should divide nausea, vomiting, photophobia, phonophobia into four different lines and calculate the individual percentages and P-values. In this way, the data would be more clarified and more easily to be realized.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Tzuchou Huang

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

5 Sep 2021

Responses to the Reviewers:

Reviewer 2:

As you mentioned, the term “primary headache” was replaced by the “headache” in manuscript.

According to ICHD-3, abdominal pain can be one of the episodic syndromes associated with migraine. (The International Classification of Headache Disorders, 3rd edition page 653)

Reviewer 3:

In data collection, nausea and vomiting were both considered as a single manifestation and were not considered individually.

In data collection, photophobia and phonophobia were both considered as a single manifestation and were not considered individually.

Submitted filename: Responses to the Reviewers.docx

Click here for additional data file.

22 Sep 2021

PONE-D-21-03892R3Prevalence of Migraine in Adults with Celiac Disease: A Case Control Cross-Sectional StudyPLOS ONE

Dear Dr. Alibeik,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Nov 06 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: About my comment 4, and ICHD 3, (the diagnostic criteria of migraine without aura, the criteria D: During headache at least one of the following: 1. nausea and/or vomiting; 2.photophobia and phonophobia ) I think in the table 4, the row " photophobia and/or phonophobia " should be corrected into "photophobia and phonophobia". Due to the change, I consider the data in this part needs to be calculated again.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

6 Oct 2021

Responses to the Reviewers:

Reviewer 3:

Thanks for your comment, as you mentioned, based on the ICHD 3, (the diagnostic criteria of migraine without aura, the criteria D) in data collection, photophobia and phonophobia were both considered as a single manifestation and were not considered individually.

In Table 4, the term "photophobia and phonophobia" is correct and the word "or" was incorrectly mentioned, which was corrected.

Submitted filename: Responses to the Reviewers.docx

Click here for additional data file.

21 Oct 2021

Prevalence of Migraine in Adults with Celiac Disease: A Case Control Cross-Sectional Study

PONE-D-21-03892R4

Dear Dr. Alibeik,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

25 Oct 2021

PONE-D-21-03892R4

Prevalence of Migraine in Adults with Celiac Disease: A Case Control Cross-Sectional Study

Dear Dr. Alibeik:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Tai-Heng Chen

Academic Editor

PLOS ONE