Oxytocin Receptors on Calvarial Periosteal Innervation: Therapeutic Target for Post-Traumatic Headache?

OBJECTIVE: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. METHODS: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. RESULTS: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist. CONCLUSION: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.

The burden of headache and a health-care needs assessment in the adult population of Mali: a cross-sectional population-based study.

BACKGROUND: Our recent studies have shown headache disorders to be very common in the central and western sub-Saharan countries of Benin and Cameroon. Here we report headache in nearby Mali, a strife-torn country that differs topographically, culturally, politically and economically. The purposes were to estimate headache-attributed burden and need for headache care. METHODS: We used cluster-random sampling in seven of Mali's eleven regions to obtain a nationally representative sample. During unannounced household visits by trained interviewers, one randomly selected adult member (18-65 years) from each household was interviewed using the structured HARDSHIP questionnaire, with enquiries into headache in the last year and, additionally, headache yesterday (HY). Headache on ≥ 15 days/month (H15+) was diagnosed as probable medication-overuse headache (pMOH) when associated with acute medication use on ≥ 15 days/month, and as "other H15+" when not. Episodic headache (on < 15 days/month) was recorded as such and not further diagnosed. Burden was assessed as impaired participation (days lost from paid and household work, and from leisure activity). Need for headache care was defined by criteria for expectation of benefit. RESULTS: Data collection coincided with the SARS-CoV-2 pandemic. The participating proportion was nonetheless extremely high (99.4%). The observed 1-year prevalence of any headache was 90.9%. Age- and gender-adjusted estimates were 86.3% for episodic headache, 1.4% for pMOH and 3.1% for other H15+. HY was reported by 16.8% with a mean duration of 8.7 h. Overall mean headache frequency was 3.5 days/month. Participants with pMOH lost more days from paid (8.8 days/3 months) and household work (10.3 days/3 months) than those with other H15+ (3.1 and 2.8 days/3 months) or episodic headache (1.2 and 0.9 days/3 months). At population level, 3.6-5.8% of all time was spent with headache, which led to a 3.6% decrease in all activity (impaired participation). Almost a quarter (23.4%) of Mali's adult population need headache care. CONCLUSION: Headache is very common in Mali, as in its near neighbours, Benin and Cameroon, and associated with substantial losses of health and productivity. Need for headache care is high - a challenge for a low-income country - but lost productivity probably translates into lost gross domestic product.

Diagnosis and Treatment of Spontaneous Intracranial Hypotension: Role of Epidural Blood Patching.

Purpose of Review: This review focuses on the challenges of diagnosing and treating spontaneous intracranial hypotension (SIH), a condition caused by spinal CSF leakage. It emphasizes the need for increased awareness and advocates for early and thoughtful use of empirical epidural blood patches (EBPs) in suspected cases. Recent Findings: SIH diagnosis is hindered by variable symptoms and inconsistent imaging results, including normal brain MRI and unreliable spinal opening pressures. It is crucial to consider SIH in differential diagnoses, especially in patients with connective tissue disorders. Early EBP intervention is shown to improve outcomes. Summary: SIH remains underdiagnosed and undertreated, requiring heightened awareness and understanding. This review promotes proactive EBP use in managing suspected SIH and calls for continued research to advance diagnostic and treatment methods, emphasizing the need for innovative imaging techniques for accurate diagnosis and timely intervention.

Long-Term Epidural Patching Outcomes and Predictors of Benefit in Patients With Suspected CSF Leak Nonconforming to ICHD-3 Criteria.

BACKGROUND AND OBJECTIVES: Spinal CSF leaks lead to spontaneous intracranial hypotension (SIH). While International Classification of Headache Disorders, Third Edition (ICHD-3) criteria necessitate imaging confirmation or low opening pressure (OP) for SIH diagnosis, their sensitivity may be limited. We offered epidural blood patches (EBPs) to patients with symptoms suggestive of SIH, with and without a documented low OP or confirmed leak on imaging. This study evaluates the efficacy of this strategy. METHODS: We conducted a prospective cohort study with a nested case-control design including all patients who presented to a tertiary headache clinic with clinical symptoms of SIH who completed study measures both before and after receiving an EBP between August 2016 and November 2018. RESULTS: The mean duration of symptoms was 8.7 ± 8.1 years. Of 85 patients assessed, 69 did not meet ICHD-3 criteria for SIH. At an average of 521 days after the initial EBP, this ICHD-3-negative subgroup experienced significant improvements in Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health score of +3.3 (95% CI 1.5-5.1), PROMIS Global Mental Health score of +1.8 (95% CI 0.0-3.5), Headache Impact Test (HIT)-6 head pain score of -3.8 (95% CI -5.7 to -1.8), Neck Disability Index of -4.8 (95% CI -9.0 to -0.6) and PROMIS Fatigue of -2.3 (95% CI -4.1 to -0.6). Fifty-four percent of ICHD-3-negative patients achieved clinically meaningful improvements in PROMIS Global Physical Health and 45% in HIT-6 scores. Pain relief following lying flat prior to treatment was strongly associated with sustained clinically meaningful improvement in global physical health at an average of 521 days (odds ratio 1.39, 95% CI 1.1-1.79; p < 0.003). ICHD-3-positive patients showed high rates of response and previously unreported, treatable levels of fatigue and cognitive deficits. DISCUSSION: Patients who did not conform to the ICHD-3 criteria for SIH showed moderate rates of sustained, clinically meaningful improvements in global physical health, global mental health, neck pain, fatigue, and head pain after EBP therapy. Pre-treatment improvement in head pain when flat was associated with later, sustained improvement after EBP therapy among patients who did not meet the ICHD-3 criteria. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that epidural blood patch is an effective treatment of suspected CSF leak not conforming to ICHD-3 criteria for SIH.

Effect of reducing electrical stimulation rate on hearing performance of Nucleus® cochlear implant recipients.

OBJECTIVE: To evaluate whether a 500 pulses per second per channel (pps/ch) rate would provide non-inferior hearing performance compared to the 900 pps/ch rate in the Advanced Combination Encoder (ACE™) sound coding strategy. DESIGN: A repeated measures single-subject design was employed, wherein each subject served as their own control. All except one subject used 900 pps/ch at enrolment. After three weeks of using the alternative rate program, both programs were loaded into the sound processor for two more weeks of take-home use. Subjective performance, preference, words in quiet, sentences in babble, music quality, and fundamental frequency (F0) discrimination were assessed using a balanced design. STUDY SAMPLE: Data from 18 subjects were analysed, with complete datasets available for 17 subjects. RESULTS: Non-inferior performance on all clinical measures was shown for the lower rate program. Subjects' preference ratings were comparable for the programs, with 53% reporting no difference overall. When a preference was expressed, the 900 pps/ch condition was preferred more often. CONCLUSION: Reducing the stimulation rate from 900 pps/ch to 500 pps/ch did not compromise the hearing outcomes evaluated in this study. A lower pulse rate in future cochlear implants could reduce power consumption, allowing for smaller batteries and processors.

Clinical performance, safety, and patient-reported outcomes of an active osseointegrated bone-conduction hearing implant system at 24-month follow-up.

PURPOSE: To investigate 2-year post-operative hearing performance, safety, and patient-reported outcomes of hearing-impaired adults treated with the Osia® 2 System, an active osseointegrated bone-conduction hearing implant that uses piezoelectric technology. METHODS: A prospective, multicenter, open-label, single-arm, within-subject clinical study conducted at three tertiary referral clinical centers located in Melbourne, Sydney and Hong Kong. Twenty adult recipients of the Osia 2 System were enrolled and followed up between 12 and 24 months post-implantation: 17 with mixed or conductive hearing loss and 3 with single-sided sensorineural deafness. Safety data, audiological thresholds, speech recognition thresholds in noise, and patient-reported outcomes were collected and evaluated. In addition, pre-and 6-month post-implantation data were collected retrospectively for this recipient cohort enrolled into the earlier study (ClinicalTrials.gov NCT04041700). RESULTS: Between 6- and 24-month follow-up, there was no statistically significant change in free-field hearing thresholds or speech reception thresholds in noise (p = > 0.05), indicating that aided improvements were maintained up to 24 months of follow-up. Furthermore, improvements in health-related quality of life and daily hearing ability, as well as clinical and subjective measures of hearing benefit remained stable over the 24-month period. No serious adverse events were reported during extended follow-up. CONCLUSIONS: These study results provide further evidence to support the longer term clinical safety, hearing performance, and patient-related benefits of the Osia 2 System in patients with either a conductive hearing loss, mixed hearing loss, or single-sided sensorineural deafness. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04754477. First posted: February 15, 2021.

Clinical benefits and economic cost-savings of remote electrical neuromodulation (REN) for migraine prevention.

AIMS: Assess the clinical benefits and associated direct and indirect cost-savings from Remote Electrical Neuromodulation (REN) for migraine prevention. METHODS: REN, a prescribed, wearable, FDA-cleared neuromodulation-device for acute and/or preventive treatment of migraine, recently demonstrated efficacy for migraine prevention when used every-other-day, in a prospective, randomized, double-blind, placebo-controlled, multi-center study. Following baseline (4-weeks), subjects underwent treatment with REN or placebo (8-weeks), and electronically reported migraine symptoms and acute treatments daily. Therapeutic-gain was the between-groups difference (REN minus placebo) in change from baseline to the second month of intervention. Health-economics impact was derived as cost-savings associated with REN's clinical benefits. RESULTS: Out of 248 subjects randomized (128 active, 120 placebo), 179 (95:84) qualified for modified intention-to-treat (mITT) analysis. Significant therapeutic gains favoring REN vs. placebo were found (Tepper et al. 2023), including mean (±SD) reduction in number of acute medication days (3.5 ± 0.4 vs. 1.2 ± 0.5; gain = 2.2; p = .001) and presenteeism days (2.7 ± 0.3 vs. 1.1 ± 0.4; gain = 1.6, p = .001). Mean changes of provider visits (reduction of 0.09 ± 0.1 vs. increase of 0.08 ± 0.2; p = .297), and reduction of absenteeism days (0.07 ± 0.1 vs. 0.07 ± 0.2; p = .997) were not significant. Mean annual cost-saving for one patient using REN for migraine prevention estimated $10,000 (±$1,777) from reductions in these four clinical outcomes relative to baseline without REN treatment. Extrapolated to a hypothetical US commercial health-plan of one-million covered lives, assuming the national prevalence of migraine patients on preventive treatment, annual mean (±SE) cost-saving from using REN migraine prevention estimated $560.0 million (±$99.5 million) from reduction in direct (∼$330 millionm) and indirect costs (∼$230 millionm) measured. LIMITATIONS: Clinical and cost-savings benefits presented are conservative, assessed only from endpoints measured in the clinical trial. Moreover, some of the endpoints had only scarce or no occurrences during the study period. CONCLUSIONS: Coverage of the REN-device for migraine prevention may significantly reduce disease-burden and save a one-million-member payer plan at least $560 million per year.

Migraine affects more than 1 billion people worldwide, causing significant disability and substantial clinical economic burden. Remote Electrical Neuromodulation (REN) is a prescribed, wearable, non-pharmacological, non-invasive device (Nerivio), indicated for acute and/or preventive treatment of migraine with or without aura in patients 12 years and older. Efficacy of REN for migraine prevention was recently demonstrated in a randomized, blinded, placebo-controlled clinical-trial. This study further analyzes clinical benefits from endpoints measured in the clinical-trial as well as their associated direct and indirect costs. Out of 248 subjects randomized (128 active, 120 placebo), 179 (95:84) qualified for modified intention-to-treat (mITT) analysis. Significant therapeutic gains favoring REN over placebo were found, including an average reduction of 3.4 acute medication days/month, and an average reduction of 2.7 presenteeism days/month. A reduction in the number of provider visits and absenteeism days was also reported, though not significantly differed from changes in the control group. Mean annual cost-saving from reductions in these four clinical outcomes relative to baseline without REN treatment for a patient using REN for migraine prevention estimated $10,000. Extrapolated to a hypothetical US commercial health-plan of one million covered lives, annual mean cost-saving from using REN for migraine prevention is estimated to be $560.0 million, composed of $327.8 million direct costs and $232.2 million indirect costs. Thus, REN preventive treatment for migraine reduces disease burden and leads to meaningful cost-saving, both direct and indirect, proposing clinical and financial incentives for patients, health insurance systems, and employers to utilize REN for migraine prevention.

Eptinezumab improved patient-reported outcomes in patients with migraine and medication-overuse headache: Subgroup analysis of the randomized PROMISE-2 trial.

OBJECTIVE: To evaluate the effect of eptinezumab on patient-reported outcomes in patients with chronic migraine (CM) and medication-overuse headache (MOH). BACKGROUND: MOH is a secondary headache disorder commonly occurring in patients with CM and associated with functional and psychological impairments. Medication overuse and monthly headache and migraine days were reduced with eptinezumab compared with placebo as published previously; however, these outcomes do not fully capture the burden of migraine and treatment effect. METHODS: PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled trial in adults with CM. Patients were randomized (1:1:1) to receive eptinezumab 100 mg, eptinezumab 300 mg, or placebo (up to 2 doses, 12 weeks apart). Patients completed the following patient-reported outcomes: 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), patient-identified most bothersome symptom (PI-MBS), and 36-item Short-Form Health Survey (SF-36). RESULTS: A total of 431 CM patients (139, 147, and 145 patients in the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups, respectively) had MOH diagnosed at screening (40.2% of the total PROMISE-2 population [n = 1072]). In CM with MOH patients, both doses of eptinezumab were associated with clinically meaningful improvements in mean HIT-6 total scores by week 4 and remained improved throughout the 24-week study. Responder rates for individual HIT-6 items were greater with eptinezumab than with placebo at all time points. At week 12, almost twice as many eptinezumab-treated patients indicated the PGIC was "much" or "very much" improved (58.5% [79/135, 100 mg] and 67.4% [95/147, 300 mg] vs. 35.8% [48/134, placebo]). Patients in the eptinezumab groups showed numerically greater improvements over placebo in the PI-MBS and SF-36 scores. CONCLUSIONS: This subgroup analysis in patients with CM/MOH at baseline suggests that eptinezumab treatment is associated with early, sustained, and clinically meaningful improvements in patient-reported outcomes.

Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial.

OBJECTIVE: To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine. BACKGROUND: Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary. RESULTS: Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval -3.9 to -1.5], p < 0.001). The significance was maintained when analyzing the episodic (-3.2 ± 3.4 vs. -1.0 ± 3.6, p = 0.003) and chronic (-4.7 ± 4.4 vs. -1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group. CONCLUSION: Applied every other day, REN is effective and safe for the prevention of migraine.

Adar1 deletion causes degeneration of the exocrine pancreas via Mavs-dependent interferon signaling.

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing alters post-transcriptional RNA processing, making ADAR1 a crucial regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we conditionally deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth, likely due to malabsorption associated with exocrine pancreatic insufficiency. Analyses of pancreata revealed ductal cell expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway, rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis.

Quantity changes in acute headache medication use among patients with chronic migraine treated with eptinezumab: subanalysis of the PROMISE-2 study.

BACKGROUND: Patients with chronic migraine (CM) treated with eptinezumab in the PROMISE-2 trial achieved greater reductions in migraine and headache frequency, impact, and acute headache medication (AHM) use than did patients who received placebo. This post hoc analysis examines relationships between headache frequency reductions and changes in AHM use in patients in PROMISE-2. METHODS: PROMISE-2 was a double-blind, placebo-controlled trial conducted in adults with CM. Patients were randomized to eptinezumab 100 mg, 300 mg, or placebo, administered intravenously once every 12 weeks for up to two doses. Patients recorded headache/AHM information daily and for each event in an electronic diary; data from all days with daily reports were included. Shifts in headache frequency and AHM use were assessed in the three populations: total CM population, patients with CM and medication-overuse headache (MOH), and patients with CM and MOH who were ≥ 50% responders during treatment (response over weeks 1-24). RESULTS: A total of 1072 adults with CM received treatment (eptinezumab, n = 706; placebo, n = 366). Mean baseline headache frequency was 20.5 days; mean baseline AHM days was 13.4; 431 patients had MOH, of which 225 (52.2%) experienced ≥50% response over weeks 1-24. Relative to baseline, the proportion of days with both headache and AHM use decreased 25.1% (eptinezumab) versus 17.0% (placebo) in the total population (N = 1072), 29.2% versus 18.4% in the MOH subpopulation (n = 431), and 38.3% versus 31.5% in the CM with MOH population with ≥50% response subgroup (n = 225) during weeks 1-24. The proportion of days with headache and triptan use decreased 9.1% (eptinezumab) versus 5.8% (placebo), 11.8% versus 7.2%, and 14.5% versus 12.6%, respectively. Reductions in other AHM types were smaller. CONCLUSIONS: In this post hoc analysis, eptinezumab use in patients with CM was associated with greater decreases in days with headache with AHM overall and with triptans in particular. The magnitude of effect was greater in the subgroup of CM patients with MOH and ≥ 50% response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02974153 . Eptinezumab reduces headache frequency and acute medication use in patients with chronic migraine.

Clinical Performance, Safety, and Patient-Reported Outcomes of an Active Osseointegrated Steady-State Implant System.

OBJECTIVE: To investigate the clinical performance, safety, and patient-reported outcomes of an active osseointegrated steady-state implant system that uses piezoelectric technology. STUDY DESIGN: A prospective, multicenter, open-label, single-arm, within-subject clinical investigation. SETTING: Three tertiary referral clinical centers located in Melbourne, Sydney, and Hong Kong. PATIENTS: Twenty-nine adult subjects, 24 with mixed hearing loss or conductive hearing loss and 5 with single-sided sensorineural deafness. INTERVENTION: Implantation with the Cochlear Osia 2 System. MAIN OUTCOME MEASURES: Audiological threshold evaluation and speech recognition in quiet and in noise. Patient satisfaction and safety. RESULTS: At 6-month follow-up after surgery, a mean improvement in pure-tone average of 26.0 dB hearing level and a mean improvement of 8.8 dB signal-to-noise ratio in speech reception threshold in noise was achieved with the investigational device as compared with the unaided situation. Usability of the investigational device was rated 71.4/100 mm for sound processor retention and 81.4/100 mm for overall comfort using a visual analog scale. CONCLUSION: These outcomes confirm the clinical safety, performance, and benefit of an innovative active transcutaneous bone conduction implant using a piezoelectric transducer design in subjects with conductive hearing loss, mixed hearing loss, or single-sided sensorineural deafness.

Diagnostic accuracy of an artificial intelligence online engine in migraine: A multi-center study.

OBJECTIVE: This study assesses the concordance in migraine diagnosis between an online, self-administered, Computer-based, Diagnostic Engine (CDE) and semi-structured interview (SSI) by a headache specialist, both using International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria. BACKGROUND: Delay in accurate diagnosis is a major barrier to headache care. Accurate computer-based algorithms may help reduce the need for SSI-based encounters to arrive at correct ICHD-3 diagnosis. METHODS: Between March 2018 and August 2019, adult participants were recruited from three academic headache centers and the community via advertising to our cross-sectional study. Participants completed two evaluations: phone interview conducted by headache specialists using the SSI and a web-based expert questionnaire and analytics, CDE. Participants were randomly assigned to either the SSI followed by the web-based questionnaire or the web-based questionnaire followed by the SSI. Participants completed protocols a few minutes apart. The concordance in migraine/probable migraine (M/PM) diagnosis between SSI and CDE was measured using Cohen's kappa statistics. The diagnostic accuracy of CDE was assessed using the SSI as reference standard. RESULTS: Of the 276 participants consented, 212 completed both SSI and CDE (study completion rate = 77%; median age = 32 years [interquartile range: 28-40], female:male ratio = 3:1). Concordance in M/PM diagnosis between SSI and CDE was: κ = 0.83 (95% confidence interval [CI]: 0.75-0.91). CDE diagnostic accuracy: sensitivity = 90.1% (118/131), 95% CI: 83.6%-94.6%; specificity = 95.8% (68/71), 95% CI: 88.1%-99.1%. Positive and negative predictive values = 97.0% (95% CI: 91.3%-99.0%) and 86.6% (95% CI: 79.3%-91.5%), respectively, using identified migraine prevalence of 60%. Assuming a general migraine population prevalence of 10%, positive and negative predictive values were 70.3% (95% CI: 43.9%-87.8%) and 98.9% (95% CI: 98.1%-99.3%), respectively. CONCLUSION: The SSI and CDE have excellent concordance in diagnosing M/PM. Positive CDE helps rule in M/PM, through high specificity and positive likelihood ratio. A negative CDE helps rule out M/PM through high sensitivity and low negative likelihood ratio. CDE that mimics SSI logic is a valid tool for migraine diagnosis.

Three Dimensions of Association Link Migraine Symptoms and Functional Connectivity.

Migraine is a heterogeneous disorder with variable symptoms and responsiveness to therapy. Because of previous analytic shortcomings, variance in migraine symptoms has been inconsistently related to brain function. In the current analysis, we used data from two sites (n = 143, male and female humans), and performed canonical correlation analysis, relating resting-state functional connectivity (RSFC) with a broad range of migraine symptoms, ranging from headache characteristics to sleep abnormalities. This identified three dimensions of covariance between symptoms and RSFC. The first dimension related to headache intensity, headache frequency, pain catastrophizing, affect, sleep disturbances, and somatic abnormalities, and was associated with frontoparietal and dorsal attention network connectivity, both of which are major cognitive networks. Additionally, RSFC scores from this dimension, both the baseline value and the change from baseline to postintervention, were associated with responsiveness to mind-body therapy. The second dimension was related to an inverse association between pain and anxiety, and to default mode network connectivity. The final dimension was related to pain catastrophizing, and salience, sensorimotor, and default mode network connectivity. In addition to performing canonical correlation analysis, we evaluated the current clustering of migraine patients into episodic and chronic subtypes, and found no evidence to support this clustering. However, when using RSFC scores from the three significant dimensions, we identified a novel clustering of migraine patients into four biotypes with unique functional connectivity patterns. These findings provide new insight into individual variability in migraine, and could serve as the foundation for novel therapies that take advantage of migraine heterogeneity.SIGNIFICANCE STATEMENT Using a large multisite dataset of migraine patients, we identified three dimensions of multivariate association between symptoms and functional connectivity. This analysis revealed neural networks that relate to all measured symptoms, but also to specific symptom ensembles, such as patient propensity to catastrophize painful events. Using these three dimensions, we found four biotypes of migraine informed by clinical and neural variation together. Such findings pave the way for precision medicine therapy for migraine.

The Feasibility of the Functional Listening Index-Paediatric (FLI-P®) for Young Children with Hearing Loss.

(1) Background: There is clear evidence supporting the need for individualized early intervention in children with hearing loss. However, relying on hearing thresholds and speech and language test results to guide intervention alone is problematic, particularly in infants and young children. This study aimed to establish the feasibility of a tool to monitor the development of functional listening skills to inform early and ongoing decisions by parents and professionals. (2) Methods: The FLI-P® is a 64-item checklist completed by parents and/or a child's team. The listening development of 543 children with hearing loss enrolled in an early intervention and cochlear implant program was tracked with the FLI-P over a 6-year period. The scores for individual children were grouped according to hearing loss, device, additional needs, and age at device fitting. (3) Results: Results indicate that the FLI-P is a feasible and viable clinical measure that can be used to identify and track a child's developing listening skills. Its use across a wide range of children supports its broad application. Children's individual scores and aggregated group data were consistent with indicated expected differences and variations. Children's individual scores and aggregated group data indicated expected differences and variations. (4) Conclusions: Information provided by children's listening scores on the FLI-P can guide and support discussions and intervention decisions and bridge the gap between information from audiological assessments and language measures.

Evaluation of a Transimpedance Matrix Algorithm to Detect Anomalous Cochlear Implant Electrode Position.

INTRODUCTION: Transimpedance measurements from cochlear implant electrodes have the potential to identify anomalous electrode array placement, such as tip fold-over (TFO) or fold-back, basal electrode kinking, or buckling. Analysing transimpedance may thus replace intraoperative or post-operative radiological imaging to detect any potential misplacements. A transimpedance algorithm was previously developed to detect deviations from a normal electrode position with the aim of intraoperatively detecting TFO. The algorithm had been calibrated on 35 forced, tip folded electrode arrays in six temporal bones to determine the threshold criterion required to achieve a sensitivity of 100%. Our primary objective here was to estimate the specificity of this TFO algorithm in patients, in a prospective study, for a series of electrode arrays shown to be normally inserted by post-operative imaging. METHODS: Intracochlear voltages were intraoperatively recorded for 157 ears, using Cochlear's Custom Sound™ EP 5 electrophysiological software (Cochlear Ltd., Sydney, NSW, Australia), for both Nucleus® CI512 and CI532 electrode arrays. The algorithm analysed the recorded 22 × 22 transimpedance matrix (TIM) and results were displayed as a heatmap intraoperatively, only visible to the technician in the operating theatre. After all clinical data were collected, the algorithm was evaluated on the bench. The algorithm measures the transimpedance gradients and corresponding phase angles (θ) throughout the TIM and calculates the gradient phase range. If this was greater than the predetermined threshold, the algorithm classified the electrode array insertion as having a TFO. RESULTS: Five ears had no intraoperative TIM and four anomalous matrices were identified from heatmaps and removed from the specificity analysis. Using the 148 remaining data sets (n = 103 CI532 and n = 45 CI512), the algorithm had an average specificity of 98.6% (95.80%-99.75%). CONCLUSION: The algorithm was found to be an effective screening tool for the identification of TFOs. Its specificity was within acceptable levels and resulted in a positive predictive value of 76%, with an estimated incidence of fold-over of 4% in perimodiolar arrays. This would mean 3 out of 4 cases flagged as a fold-over would be correctly identified by the algorithm, with the other being a false positive. The measurements were applied easily in theatre allowing it to be used as a routine clinical tool for confirming correct electrode placement.

Computerized migraine diagnostic tools: a systematic review.

BACKGROUND: Computerized migraine diagnostic tools have been developed and validated since 1960. We conducted a systematic review to summarize and critically appraise the quality of all published studies involving computerized migraine diagnostic tools. METHODS: We performed a systematic literature search using PubMed, Web of Science, Scopus, snowballing, and citation searching. Cutoff date for search was 1 June 2021. Published articles in English that evaluated a computerized/automated migraine diagnostic tool were included. The following summarized each study: publication year, digital tool name, development basis, sample size, sensitivity, specificity, reference diagnosis, strength, and limitations. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was applied to evaluate the quality of included studies in terms of risk of bias and concern of applicability. RESULTS: A total of 41 studies (median sample size: 288 participants, median age = 43 years; 77% women) were included. Most (60%) tools were developed based on International Classification of Headache Disorders criteria, half were self-administered, and 82% were evaluated using face-to-face interviews as reference diagnosis. Some of the automated algorithms and machine learning programs involved case-based reasoning, deep learning, classifier ensemble, ant-colony, artificial immune, random forest, white and black box combinations, and hybrid fuzzy expert systems. The median diagnostic accuracy was concordance = 89% [interquartile range (IQR) = 76-93%; range = 45-100%], sensitivity = 87% (IQR = 80-95%; range = 14-100%), and specificity = 90% (IQR = 77-96%; range = 65-100%). Lack of random patient sampling was observed in 95% of studies. Case-control designs were avoided in all studies. Most (76%) reference tests exhibited low risk of bias and low concern of applicability. Patient flow and timing showed low risk of bias in 83%. CONCLUSION: Different computerized and automated migraine diagnostic tools are available with varying accuracies. Random patient sampling, head-to-head comparison among tools, and generalizability to other headache diagnoses may improve their utility.

Comparison of the In Vitro and In Vivo Electrochemical Performance of Bionic Electrodes.

The electrochemical performance of platinum electrodes was assessed in vitro and in vivo to determine the impact of electrode implantation and the relevance of in vitro testing in predicting in vivo behaviour. A significant change in electrochemical response was seen after electrode polarisation. As a result, initial in vitro measurements were poor predictors of subsequent measurements performed in vitro or in vivo. Charge storage capacity and charge density measurements from initial voltammetric measurements were not correlated with subsequent measurements. Electrode implantation also affected the electrochemical impedance. The typically reported impedance at 1 kHz was a very poor predictor of electrode performance. Lower frequencies were significantly more dependent on electrode properties, while higher frequencies were dependent on solution properties. Stronger correlations in impedance at low frequencies were seen between in vitro and in vivo measurements after electrode activation had occurred. Implanting the electrode increased the resistance of the electrochemical circuit, with bone having a higher resistivity than soft tissue. In contrast, protein fouling and fibrous tissue formation had a minimal impact on electrochemical response. In vivo electrochemical measurements also typically use a quasi-reference electrode, may operate in a 2-electrode system, and suffer from uncompensated resistance. The impact of these experimental conditions on electrochemical performance and the relevance of in vitro electrode assessment is discussed. Recommended in vitro testing protocols for assessing bionic electrodes are presented.

How Can eHealth Meet the Hearing and Communication Needs of Adults With Hearing Impairment and their Significant Others? A Group Concept Mapping Study.

OBJECTIVES: To seek the perspectives of key stakeholders regarding: (1) how eHealth could help meet the hearing and communication needs of adults with hearing impairment and their significant others; and (2) how helpful each aspect of eHealth would be to key stakeholders personally. DESIGN: Group concept mapping, a mixed-methods participatory research method, was used to seek the perspectives of key stakeholders: adults with hearing impairment (n = 39), significant others (n = 28), and hearing care professionals (n = 56). All participants completed a short online survey before completing one or more of the following activities: brainstorming, sorting, and rating. Brainstorming required participants to generate ideas in response to the focus prompt, "One way I would like to use information and communication technologies to address the hearing and communication needs of adults with hearing loss and their family and friends is to…." The sorting task required participants to sort all statements into groups that made sense to them. Finally, the rating task required participants to rate each of the statements according to "How helpful would this idea be to you?" using a 5-point Likert scale. Hierarchical cluster analysis was applied to the "sorting" data to develop a cluster map using the Concept Systems software. The "rating" data were subsequently analyzed at a cluster level and an individual-item level using descriptive statistics. Differences in cluster ratings between stakeholder groups were examined using Kruskal-Wallis tests. RESULTS: Overall, 123 statements were generated by participants in response to the focus prompt and were included in subsequent analyses. Based on the "sorting" data and hierarchical cluster analysis, a seven-cluster map was deemed to be the best representation of the data. Three key themes emerged from the data, including using eHealth to (1) Educate and Involve Others; (2) Support Aural Rehabilitation; and (3) Educate About and Demonstrate the Impacts of Hearing Impairment and Benefits of Hearing Rehabilitation. Overall median rating scores for each cluster ranged from 3.97 (educate and involve significant others) to 3.44 (empower adults with hearing impairment to manage their hearing impairment from home). CONCLUSIONS: These research findings demonstrate the broad range of clinical applications of eHealth that have the capacity to support the implementation of patient- and family-centered hearing care, with self-directed educational tools and resources typically being rated as most helpful. Therefore, eHealth appears to be a viable option for enabling a more biopsychosocial approach to hearing healthcare and educating and involving significant others in the hearing rehabilitation process without adding more pressure on clinical time. More research is needed to inform the subsequent development of eHealth interventions, and it is recommended that health behavior change theory be adhered to for such interventions.

Pancreatic Cancer-Related Mutational Burden Is Not Increased in a Patient Cohort With Clinically Severe Chronic Pancreatitis.

INTRODUCTION: Chronic pancreatitis is associated with an increased risk of developing pancreatic cancer, and patients with inherited forms of pancreatitis are at greatest risk. We investigated whether clinical severity of pancreatitis could also be an indicator of cancer risk independent of etiology by performing targeted DNA sequencing to assess the mutational burden in 55 cancer-associated genes. METHODS: Using picodroplet digital polymerase chain reaction and next-generation sequencing, we reported the genomic profiles of pancreases from severe clinical cases of chronic pancreatitis that necessitated palliative total pancreatectomy with islet autotransplantation. RESULTS: We assessed 57 tissue samples from 39 patients with genetic and idiopathic etiologies and found that despite the clinical severity of disease, there was no corresponding increase in mutational burden. The average allele frequency of somatic variants was 1.19% (range 1.00%-5.97%), and distinct regions from the same patient displayed genomic heterogeneity, suggesting that these variants are subclonal. Few oncogenic KRAS mutations were discovered (7% of all samples), although we detected evidence of frequent cancer-related variants in other genes such as TP53, CDKN2A, and SMAD4. Of note, tissue samples with oncogenic KRAS mutations and samples from patients with PRSS1 mutations harbored an increased total number of somatic variants, suggesting that these patients may have increased genomic instability and could be at an increased risk of developing pancreatic cancer. DISCUSSION: Overall, we showed that even in those patients with chronic pancreatitis severe enough to warrant total pancreatectomy with islet autotransplantation, pancreatic cancer-related mutational burden is not appreciably increased.