Home Biofeedback for the Treatment of Dyssynergic Defecation: Does It Improve Quality of Life and Is It Cost-Effective?

OBJECTIVES: Biofeedback therapy, whether administered at home or in office settings, is effective for dyssynergic defecation (DD). Whether home biofeedback improves quality of life (QOL) and is cost-effective when compared with office biofeedback is unknown. METHODS: QOL was assessed in 8 domains (SF-36) at baseline and after treatment (3 months), alongside economic evaluation during a randomized controlled trial (RCT) comparing home and office biofeedback in patients with DD (Rome III). Costs related to both biofeedback programs were estimated from the hospital financial records, study questionnaires, and electronic medical records. A conversion algorithm (Brazier) was used to calculate the patient's quality-adjusted life years (QALYs) from SF-36 responses. Cost-effectiveness was expressed as incremental costs per QALY between the treatment arms. RESULTS: One hundred patients (96 female patients, 50 in each treatment arm) with DD participated. Six of the 8 QOL domains improved (P < 0.05) in office biofeedback, whereas 4 of the 8 domains improved (P < 0.05) in home biofeedback; home biofeedback was noninferior to office biofeedback. The median cost per patient was significantly lower (P < 0.01) for home biofeedback ($1,112.39; interquartile range (IQR), $826-$1,430) than for office biofeedback ($1,943; IQR, $1,622-$2,369), resulting in a cost difference of $830.11 The median QALY gained during the trial was 0.03 for office biofeedback and 0.07 for home biofeedback (P = NS). The incremental cost-effectiveness ratio was $20,752.75 in favor of home biofeedback. DISCUSSION: Biofeedback therapy significantly improves QOL in patients with DD regardless of home or office setting. Home biofeedback is a cost-effective treatment option for DD compared with office biofeedback, and it offers the potential of treating many more patients in the community.

Factors Associated With Response to Biofeedback Therapy for Dyssynergic Defecation.

BACKGROUND & AIMS: Biofeedback therapy is effective for dyssynergic defecation (DD), but it is not widely available or reimbursed, and is labor intensive. It is therefore important to select the appropriate patients for this treatment. We investigated symptoms and demographic, manometric, and other factors associated with outcomes of biofeedback therapy in patients with DD. METHODS: We performed a post hoc analysis of 2 prospective studies of biofeedback therapy in 127 adult outpatients (18-75 years old, 120 female) with chronic constipation who failed to respond to treatment with dietary fiber or laxatives (>1 year) and were diagnosed with DD based on standard criteria. In each study, patients received 1-hour, biweekly office biofeedback therapy (6 sessions) or home biofeedback therapy with a device. A therapist used visual feedback, postural, and diaphragmatic breathing techniques to teach subjects to improve defecation. Treatment success was defined by a composite of normalization of dyssynergia pattern and increase of 20 mm in baseline bowel satisfaction score. Factors were compared between the treatment success and failure groups. Intention-to-treat analysis was performed. RESULTS: Of the 127 patients enrolled, 77 (61%) had treatment success. Dyssynergia was corrected in 78% of patients and bowel satisfaction improved in 64% of patients. Baseline demographic features, constipation symptoms, manometric and sensory parameters, balloon expulsion time, and colonic transit results were similar between treatment failure and success groups. Patients with lower baseline bowel satisfaction score (P = .008) and patients who used digital maneuvers (P = .04) were more likely to have successful biofeedback therapy. CONCLUSIONS: Biofeedback therapy is successful in more than 60% of patients with DD. Patients who used digital maneuvers and patients with lower baseline levels of bowel satisfaction were more likely to have treatment success, whereas other factors were not associated with success. Biofeedback therapy should be offered to all patients with DD, irrespective of baseline symptoms or anorectal physiology findings.

Accuracy and Reproducibility of High-definition Anorectal Manometry and Pressure Topography Analyses in Healthy Subjects.

BACKGROUND & AIMS: High-definition anorectal manometry (HDAM-3D) provides a topographic and 3-dimensional profile of anorectal pressure. We assessed anorectal sensorimotor function and the reproducibility of measurements made with HDAM-3D in healthy adults, and the accuracy of data analysis by its software. METHODS: Anal sphincter pressures and rectal sensory thresholds were measured in 78 healthy subjects via placement of a 10-mm rigid probe, with 256 circumferentially arrayed pressure sensors, and a balloon in the rectum. The bearing down maneuver was assessed in a subset of 18 subjects. We compared data analyzed by an expert with findings from automated software analysis. Measurements made in a subset of 16 subjects, 2 weeks apart, were compared to determine reproducibility. RESULTS: Resting, squeezing, and sustained squeezing pressures were significantly higher in men than in women (P < .05); other parameters were similar. Desire and urgency to defecate were similar between men and women, but the maximal tolerable volume was significantly lower in women (P < .05). Older women (>50 years) had significantly lower resting (P < .01) and sustained squeeze pressures (P < .04). Dyssynergic patterns of defecation were observed in 12 of 18 subjects (67%) who attempted to defecate without the 60-mL rectal balloon distention and in 6 of 18 subjects (33%) with the 60-mL rectal balloon distention. Test-retest values correlated (r = 0.81), as did analyses made by an expert vs software analyses of data (r = 0.99). CONCLUSIONS: On the basis of HDAM-3D measurements in healthy adults, anal sphincter pressures are higher in men than in women, but sensory and other parameters are similar; older subjects have weaker sphincters. Many people were found to have dyssynergic patterns of defecation, which could be related to the probe or other technical issues, so this technique may not be suitable for assessing defecation patterns. Measurements made by HDAM-3D are reproducible, and data can be accurately analyzed by its software.

Barostat or syringe-assisted sensory biofeedback training for constipation with rectal hyposensitivity: A randomized controlled trial.

BACKGROUND: Rectal hyposensitivity (RH) is a well-known pathophysiological dysfunction in chronic constipation. Whether biofeedback training improves RH and restores bowel function is unknown. AIM: To investigate the efficacy of barostat-assisted sensory training (BAST) with syringe-assisted sensory training (SAST) in patients with RH in a randomized controlled trial. METHODS: Patients with RH and chronic constipation (Rome III) were randomized to receive 6 biweekly sessions of BAST or SAST. Verbal/visual feedback was provided during repeated rectal distensions to improve defecation desire/urge and first sensations with either 10-cm balloon connected to barostat (BAST) or 4-cm balloon connected to syringe and manometry probe (SAST). Sensory thresholds, bowel symptoms, and therapist and patient's rating of treatments were compared. The primary outcome (responders) was the improvement in ≥2 sensory thresholds. RESULTS: Sixty-six patients were enrolled: 32 received BAST, 34 received SAST, and 56 completed study. There were significantly more responders in BAST group than SAST (78% vs. 53%, p = 0.0320). Rectal sensation normalized in 81% with BAST compared to 56% with SAST (p = 0.0270). When compared to baseline, desire and urge to defecate thresholds and bowel satisfaction improved with BAST (p = 0.0013; p = 0.0002; p = 0.0001) and SAST (p = 0.0012; p = 0.0001; p < 0.0001) and number of complete spontaneous bowel movements with BAST (p = 0.0029) but without inter-group differences. Therapists rated BAST as superior to SAST (p < 0.0001), but patients rated both equally. CONCLUSIONS: Sensory biofeedback training was effective and significantly improved rectal sensation and constipation symptoms. Although both techniques were useful, the novel BAST was more efficacious and easier to administer for treating RH.

Translumbar and transsacral motor-evoked potentials: a novel test for spino-anorectal neuropathy in spinal cord injury.

OBJECTIVES: Spinal cord injury (SCI) causes anorectal problems, whose pathophysiology remains poorly characterized. A comprehensive method of evaluating spino-anorectal function is lacking. The aim of this study was to investigate the neuropathophysiology of bowel dysfunction in SCI by evaluating motor-evoked potentials (MEP) of anus and rectum following transspinal magnetic stimulation and anorectal physiology. METHODS: Translumbar and transsacral magnetic stimulations, anorectal manometry, and pudendal nerve terminal motor latency (PNTML) were performed in 39 subjects with SCI and anorectal problems and in 14 healthy controls, and data were compared. MEPs were recorded with an anorectal probe containing bipolar ring electrodes. RESULTS: The MEPs were significantly prolonged (P<0.05) bilaterally, and at lumbar and sacral levels, as well as at rectal and anal sites in SCI subjects compared with controls. A total of 95% of SCI subjects had abnormal MEPs and 53% had abnormal PNTML. All subjects with abnormal PNTML also demonstrated abnormal MEP, but 16/17 subjects with normal PNTML had abnormal MEP. Overall, SCI patients had weaker anal sphincters (P<0.05), higher prevalence of dyssynergia (85%), and altered rectal sensation (82%). CONCLUSIONS: Translumbar and transsacral MEPs revealed significant and hitherto undetected lumbosacral neuropathy in 90% of SCI subjects. Test was safe and provided neuropathophysiological information that could explain bowel dysfunction in SCI subjects.

Diagnostic utility of wireless motility capsule in gastrointestinal dysmotility.

GOALS: To examine the diagnostic utility of wireless motility capsule (WMC) in patients with suspected gastrointestinal (GI) dysmotility. BACKGROUND: Subjects with suspected GI motility disorders undergo invasive and expensive diagnostic tests. In these patients, whether WMC provides clinically useful information is unknown. STUDY: Patients with symptoms of dysmotility and normal endoscopic/radiologic evaluations were assessed with WMC test and conventional motility tests (CMT). Diagnostic utility of WMC was assessed retrospectively by examining device agreement and new information compared with CMT. RESULTS: On the basis of predominant symptom(s), 86 patients were classified into 2 subgroups: lower GI (LGI=50) and upper GI (UGI=36). Clinical suspicion was confirmed in 52% and 66% of patients, respectively, and there was good device agreement between WMC and CMT in 76% and 81% in the LGI and UGI groups, respectively. There was new diagnostic information with the WMC test in 53% of the LGI (P=0.006) and 47% of the UGI group (P=0.001). WMC detected generalized motility disorder in 44 (51%) patients and influenced management in 30% of LGI and 50% of UGI subjects. CONCLUSIONS: WMC confirmed clinical suspicion, provided new diagnostic information, influenced clinical management, and detected many patients with generalized motility disorder. It had good device agreement with conventional tests.

Sensory Adaptation Training or Escitalopram for IBS With Constipation and Rectal Hypersensitivity: A Randomized Controlled Trial.

INTRODUCTION: Rectal hypersensitivity is an important pathophysiological dysfunction in irritable bowel syndrome with predominant constipation (IBS-C), whose treatment remains challenging. In a randomized controlled trial, we compared the efficacy and safety of a novel sensori-behavioral treatment, sensory adaptation training (SAT) with escitalopram. METHODS: Patients with IBS-C (Rome III) with rectal hypersensitivity received 6 biweekly sessions of SAT or escitalopram 10 mg daily for 3 months. SAT was performed by repetitive gradual distension of 10-cm long highly compliant rectal balloon above tolerability thresholds using barostat. Treatment effects on sensory thresholds and symptoms were compared. Coprimary outcome measures were those achieving improvements in rectal hypersensitivity (≥20% increase in ≥2/3 sensory thresholds) and pain (≥30% decrease). RESULTS: We randomized 49 patients; 26 received SAT and 23 escitalopram. SAT significantly improved desire to defecate (Δ 13.5 ± 2.3 vs 2.2 ± 1.1 mm Hg, P = 0.0006) and maximum tolerability (Δ 14.8 ± 1.9 vs 1.6 ± 0.9 mm Hg, P < 0.0001) thresholds compared with escitalopram. There were significantly greater percentage of hypersensitivity responders with SAT than escitalopram (69% vs 17%, P < 0.001), but not pain responders (58% vs 44%, P = 0.4). Daily pain scores did not differ between groups (P = 0.8) or escitalopram (P = 0.06) but decreased with SAT (P = 0.0046) compared with baseline. SAT significantly increased rectal compliance (P < 0.019) and complete spontaneous bowel movements per week than escitalopram (P = 0.04). Five withdrew from adverse events with escitalopram and none with SAT. DISCUSSION: SAT was significantly more efficacious in improving hypersensitivity and bowel symptoms in IBS-C than escitalopram. SAT is a promising novel treatment for IBS with rectal hypersensitivity.

Methanogenic flora is associated with altered colonic transit but not stool characteristics in constipation without IBS.

OBJECTIVES: About 35% of humans have methane-producing gut flora. Methane-producing irritable bowel syndrome (IBS) subjects are generally constipated. In animal models, methane infusion slows intestinal transit. Whether methanogenic flora alters colonic transit or stool characteristics and its relationship to constipation is unclear. The aim of this study was to examine the prevalence and association of methanogenic flora in patients with slow transit (ST) constipation and normal transit (NT) constipation and non-constipated controls. METHODS: Ninety-six consecutive subjects with chronic constipation (CC) (Rome III) were evaluated with radio-opaque marker (ROM) transit studies and were classified as ST (>20% ROM retention) or NT. All constipated subjects and 106 non-constipated controls underwent breath tests to assess methane production. Baseline CH4 of >or=3 p.p.m. was used to define presence of methanogenic flora. Stool frequency and consistency were assessed using a prospective stool diary. Correlation analyses were performed. RESULTS: Forty-eight subjects had ST and 48 had NT. Prevalence of methanogenic flora was higher (P<0.05) in ST (75%) compared to NT (44%) or controls (28%). ST patients had higher methane production compared to NT and controls (P<0.05). NT patients also produced more methane compared to controls (P<0.05). There was moderate(P<0.05) correlation among baseline, peak, and area under the curve (AUC) of methane response with colonic transit but not with stool characteristics. CONCLUSIONS: Presence of methanogenic flora is associated with CC. Methane production after carbohydrate challenge and its prevalence were higher in ST than NT, although stool characteristics were similar in both groups. Methane production correlated with colonic transit, suggesting an association with stool transport but not with stool characteristics.

Long-term efficacy of biofeedback therapy for dyssynergic defecation: randomized controlled trial.

OBJECTIVES: Although biofeedback therapy is effective in the short-term management of dyssynergic defecation, its long-term efficacy is unknown. Our aim was to compare the 1-year outcome of biofeedback (manometric-assisted pelvic relaxation and simulated defecation training) with standard therapy (diet, exercise, laxatives) in patients who completed 3 months of either therapy. METHODS: Stool diaries, visual analog scales (VASs), colonic transit, anorectal manometry, and balloon expulsion time were assessed at baseline, and at 1 year after each treatment. All subjects were seen at 3-month intervals and received reinforcement. Primary outcome measure (intention-to-treat analysis) was a change in the number of complete spontaneous bowel movements (CSBMs) per week. Secondary outcome measures included bowel symptoms, changes in dyssynergia, and anorectal function. RESULTS: Of 44 eligible patients with dyssynergic defecation, 26 agreed to participate in the long-term study. All 13 subjects who received biofeedback, and 7 of 13 who received standard therapy, completed 1 year; 6 failed standard therapy. The number of CSBMs per week increased significantly (P<0.001) in the biofeedback group but not in the standard group. Dyssynergia pattern normalized (P<0.001), balloon expulsion time improved (P=0.0009), defecation index increased (P<0.001), and colonic transit time normalized (P=0.01) only in the biofeedback group. CONCLUSIONS: Biofeedback therapy provided sustained improvement of bowel symptoms and anorectal function in constipated subjects with dyssynergic defecation, whereas standard therapy was largely ineffective.

Rectoanal reflexes and sensorimotor response in rectal hyposensitivity.

PURPOSE: Rectal hyposensitivity commonly causes anorectal disorders, but its underlying mechanism is unknown. We hypothesized that subjects with rectal hyposensitivity have altered rectoanal reflexes and/or sensorimotor response. METHODS: We performed stepwise graded balloon distensions of the rectum in 30 subjects with constipation and rectal hyposensitivity and in 23 healthy controls. Thresholds for first sensation, desire, and urgency to defecate were assessed. The lowest balloon volume that evoked rectoanal inhibitory reflex, rectoanal contractile reflex, and sensorimotor response and manometric characteristics and rectal compliance were examined. RESULTS: Reflex responses were present in all subjects. The balloon volumes were higher in subjects with rectal hyposensitivity for inducing rectoanal inhibitory reflex (P = .008) and contractile reflex (P = .001) compared with controls. All controls showed a sensorimotor response, but in 13 hyposensitive subjects (43%) the onset of sensorimotor response was associated with absent sensation and in 17 (57%), with a transient rectal sensation. Thresholds for eliciting sensorimotor response were similar between patients and controls, but the amplitude, duration, and magnitude of response were higher (P < .05) in patients. Rectal compliance was similar between controls and hyposensitive subjects with transient sensation but higher (P = .001) in subjects with absent sensation. CONCLUSIONS: Constipated subjects with rectal hyposensitivity demonstrate higher thresholds for inducing rectoanal reflexes and abnormal characteristics of sensorimotor response. These findings suggest either disruption of afferent gut-brain pathways or rectal wall dysfunction. These altered features may play a role in the pathogenesis of bowel dysfunction in rectal hyposensitivity.

Home-based versus office-based biofeedback therapy for constipation with dyssynergic defecation: a randomised controlled trial.

BACKGROUND: Office-based biofeedback therapy is effective for constipation with dyssynergic defecation, but must be performed by skilled staff, is only available in selected centres, and requires multiple visits. The efficacy of home-based biofeedback therapy is unknown. We compared clinical and subjective outcomes with home-based and office-based approaches. METHODS: In this randomised controlled trial, eligible patients were adult outpatients (age 18-80 years) who met the Rome III criteria for functional constipation and who had been referred to a tertiary-care centre after non-response to routine management, and who had dyssynergic defecation. Patients were randomly assigned according to a schedule generated in advance by the study biostatistician, in permuted blocks of four, to receive office-based or home-based biofeedback therapy. Office-based biofeedback comprised therapist-guided pelvic floor training for six sessions over 3 months (visits every 2 weeks). Home-based biofeedback comprised 20 min self-training sessions twice per day, in which a self-inserted probe was used to provide visual feedback via a handheld monitoring device of anal sphincter pressure and push effort. Patients recorded in diaries the time of each defecation attempt, stool consistency, straining effort, feeling of incomplete evacuation, need for digital assistance with stooling, and satisfaction with bowel function, from 1 week before enrolment to the end of follow-up. Treatment responders were defined post hoc as those with normalisation of dyssynergic defecation and an increase in the number of complete spontaneous bowel movements per week by 3 months. Cost outcomes calculated from health-care costs and loss of salary were assessed from hospital billing and medical records and questionnaires. Primary outcome measures were the presence of a dyssynergic pattern during attempted defecation, balloon expulsion time, the number of complete spontaneous bowel movements per week, and satisfaction with bowel function, assessed by intention to treat (non-inferiority) and per protocol. This trial is registered with ClinicalTrials.gov, number NCT03202771. FINDINGS: Of 300 patients screened we enrolled 100, from Jan 7, 2005, to Jan 31, 2010. 83 patients completed training (38 [76%] of 50 in the home-based biofeedback group and 45 [90%] of 50 in the office-based biofeedback group). 34 (68%) patients in the home-based group and 35 (70%) in the office-based group were classified as responders. All primary outcomes improved significantly from baseline in the two treatment groups (all p<0·0001). Home-based biofeedback therapy was non-inferior to office-based therapy for number of complete spontaneous bowel movements per week, satisfaction with bowel function, and balloon expulsion time in the intention-to-treat and per-protocol analyses, and for dyssynergia in the per-protocol analysis. No adverse events were reported. The median cost of home-based biofeedback therapy was significantly lower than that for office-based treatment (US$1081·70, IQR 794·90-1399·30 vs $1942·50, 1621·70-2369·00, p=0·009). INTERPRETATION: Home-based and office-based biofeedback therapy for dyssynergic defecation improved bowel symptoms and physiology with similar efficacy. A home-based programme could substantially broaden the availability and use of this treatment. FUNDING: National Institutes of Health.

Large cell neuroendocrine carcinoma of the lung presenting as pseudoachalasia: a case report.

INTRODUCTION: Pseudoachalasia is a rare disease that accounts for only a small percentage of patients with dysphagia. Neuroendocrine tumors are rare malignancies that most commonly originate within the gastrointestinal tract, with the next most common site being the lungs. Esophageal neuroendocrine tumors are the least common site within the gastrointestinal tract. Pseudoachalasia can be secondary to a malignant process within the body. Its typical characteristic in elderly patients is a short duration of symptoms with substantial weight loss. CASE PRESENTATION: A 68-year-old woman presented with worsening dysphagia that had started six months after the resection of a large cell neuroendocrine carcinoma of the lung in 2011. An extensive work-up in 2012, including esophagogastroduodenoscopy, chest computed tomography and positron emission tomography, was unremarkable. Esophageal manometries revealed findings characteristic of achalasia. A repeat esophagogastroduodenoscopy in January of 2014 revealed a nearly circumferential ulcerated, fungating mass in her distal esophagus. Biopsy results confirming a recurrence of her large cell neuroendocrine carcinoma. CONCLUSION: We report a case of pseudoachalasia due to metastatic large cell neuroendocrine carcinoma of the lung. Our patient had an exceptionally prolonged duration of symptoms preceding the local esophageal recurrence, which was eventually revealed via endoscopy.

A 4-week pilot study with the cannabinoid receptor agonist dronabinol and its effect on metabolic parameters in a randomized trial.

PURPOSE: Dronabinol (synthetic Δ(9)- tetrahydrocannabinol) is used in patients with nausea and vomiting from chemotherapy and in AIDS patients for appetite stimulation. Recently, dronabinol was used to successfully treat visceral hypersensitivity causing noncardiac chest pain. With widening uses of this medication, we aim to explore its effects on metabolic parameters in long-term dosing and hypothesize that it will not affect major metabolic parameters. METHODS: A double-blind, placebo-controlled, 28-day trial was performed with patients 18 to 75 years old without cardiac disease. Patients had at least 2 weekly episodes of chest pain for the last 3 months and evidence of esophageal hypersensitivity after balloon distention testing. Prior use of pain medication, psychiatric diagnosis, or significant medical comorbidities precluded inclusion in the study. Patients were randomized to receive 5 mg dronabinol or placebo twice daily with metabolic parameters examined before and after the use of medication. FINDINGS: Thirteen patients completed the study (7 with dronabinol [6 women and 1 man] and 6 with placebo [5 women and 1 man]). None of the measured values, including body mass index, HDL, triglycerides, calculated LDL, high-sensitivity C-reactive protein, glucose, insulin, leptin, aspartate aminotransferase, alanine aminotransferase, LDH, or non-HDL, differed significantly in either group before or after treatment. In general, treatment with dronabinol coincided with favorable trends in some parameters, although these trends were not statistically significant. IMPLICATIONS: Dronabinol administration does not significantly affect basic metabolic components after a period of 28 days. The implications of these findings are important because dronabinol may be able to be used in patients with metabolic disorders. The favorable trends observed here warrant further exploration into its long-term effects. ClinicalTrials.gov identifier: NCT01598207.

Lack of seasonal variation in the incidence of eosinophilic oesophagitis in adolescent and adult non-PPI-responsive oesophageal eosinophilia midwestern US populations.

BACKGROUND: Eosinophilic oesophagitis (EoO) has been associated with allergic disorders as well as aeroallergens. The current literature has shown a possible association between seasonal variation, mainly in the spring, and the incidence of EoO. However, this data was based on small population studies that did not exclude proton-pump inhibitor (PPI)-responsive oesophageal eosinophilia (PPI-ROE) in their cohort. AIM: The aim of this study was to determine if there is a seasonal variation associated with the diagnosis of EoO in patients that had been treated with high-dose PPI prior to diagnosis. METHODS: Oesophageal biopsies were obtained from a cohort of patients who presented with symptoms of dysphagia, odynophagia, and heartburn during a 10-year period. Symptomatic patients who had biopsies from the mid and distal oesophagus with ≥20 eosinophils per high-power field (hpf) while on high-dose PPI treatment for at least 5 weeks were diagnosed as having EoO. The monthly and seasonal incidences were determined (winter, January-March; spring, April-June; summer, July-September; Autumn, October-December). RESULTS: A total of 20,718 patients were identified and their records evaluated. From this cohort, 193 (0.93%) symptomatic patients had biopsy-proven oesophageal eosinophilia (≥20 eosinophils/hpf) and no seasonal variation was seen in this group. However, only 57 (0.28%) had been adequately treated with PPI prior to diagnosis (i.e. non-PPI-ROE biopsy-proven EoO; ≥20 eosinophils/hpf: 39 males, 18 females; age 29.5 years). The most common medical history components included asthma (12.3%) and food allergies (3.5%), and the most common presenting symptoms included dysphagia (50.9%) and heartburn (26.3%). The monthly and seasonal incidences in our cohort were with no apparent trend (p = 0.713 and 0.703, respectively). CONCLUSIONS: The incidence of EoO was consistent across all 12 months as well as during the four seasons. Our data does not support a seasonal variation in relation to the incidence of EoO in the US midwestern non-PPI-ROE population.