Regulation of microRNA biogenesis and turnover by animals and their viruses

Item does not contain fulltextMicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes

Quantitative analysis of MicroRNAs in vaccinia virus infection reveals diversity in their susceptibility to modification and suppression

Vaccinia virus (VACV) is a large cytoplasmic DNA virus that causes dramatic alterations to many cellular pathways including microRNA biogenesis. The virus encodes a poly(A) polymerase which was previously shown to add poly(A) tails to the 3' end of cellular miRNAs, resulting in their degradation by 24 hours post infection (hpi). Here we used small RNA sequencing to quantify the impact of VACV infection on cellular miRNAs in human cells at both early (6 h) and late (24 h) times post infection. A detailed quantitative analysis of individual miRNAs revealed marked diversity in the extent of their modification and relative change in abundance during infection. Some miRNAs became highly modified (e.g. miR-29a-3p, miR-27b-3p) whereas others appeared resistant (e.g. miR-16-5p). Furthermore, miRNAs that were highly tailed at 6 hpi were not necessarily among the most reduced at 24 hpi. These results suggest that intrinsic features of human cellular miRNAs cause them to be differentially polyadenylated and altered in abundance during VACV infection. We also demonstrate that intermediate and late VACV gene expression are required for optimal repression of some miRNAs including miR-27-3p. Overall this work reveals complex and varied consequences of VACV infection on host miRNAs and identifies miRNAs which are largely resistant to VACV-induced polyadenylation and are therefore present at functional levels during the initial stages of infection and replication

Willingness to trade-off: An intermediate factor in patient decision-making regarding escalating care

This study aimed to evaluate treatment necessity, treatment concern, and willingness to engage in decisional trade-offs in the context of treatment escalation decision-making. Participants ( n  = 147) recruited online were randomized to read a vignette about escalating care in psoriasis in a 2 (high treatment concern vs moderate treatment concern) × 2 (high perceived treatment necessity vs moderate perceived treatment necessity) design. High treatment concern was associated with choosing to defer treatment escalation and being unwilling to engage in decisional trade-offs if disease risk changed. Results highlight the importance of treatment concern and willingness trade-off in treatment escalation decision-making

Headache Specialists' Perceptions of the Role of Health Psychologists in Headache Management: A Qualitative Study

Background: Since headache specialists cannot treat all the patients with headache disorders, multidisciplinary teams that include health psychologists are becoming more prevalent. Health psychologists mainly use a form of cognitive-behavioral therapy (CBT), along with biofeedback on occasion, to effectively address patients’ pain and headache disorders. The Veterans Health Administration (VHA) is one setting that routinely includes a health psychologist with advanced training in pain disorders in their pain care to its veterans. The VHA has established Headache Centers of Excellence (HCoE) around the country to provide multidisciplinary treatment for patients with headache disorders, which enables headache specialists to regularly interact with health psychologists. Objective: The study’s objective is to evaluate headache specialists’ views of health psychologists in the treatment of patients with headache disorders. Method: Semi-structured interviews were conducted with headache specialists in academic-based healthcare settings, the community, and VHA HCoE sites. The interviews were audio-recorded and de-identified so they could be transcribed and analyzed using content matrix analysis. Results: Four themes emerged: headache specialists desired to work with health psychologists and included them as members of multidisciplinary teams; valued health psychologists because they provided non-pharmacological treatments, such as CBT and biofeedback; preferred in-person communication with health psychologists; and used multiple titles when referring to health psychologists. Conclusion: Headache specialists valued health psychologists as providers of behavioral and non-pharmacological treatments and considered them essential members of multidisciplinary teams. Headache specialists should strive to work with a headache psychologist, not just a general health psychologist. By committing to this, headache specialists can foster changes in the quality of care, resource allocation, and training experiences related to health psychologists

Frequency, Demographics, Comorbidities, and Health Care Utilization by Veterans With Migraine: A VA Nationwide Cohort Study

Objective: To describe the relative frequency, demographics, comorbidities, and healthcare utilization of veterans who receive migraine care at the Veteran's Health Administration (VHA) and to evaluate differences by gender. Methods: This study extracted data from VHA administrative sources. Veterans diagnosed with migraine by a healthcare provider between fiscal year 2008-2019 were included. Demographics and military exposures were extracted at cohort entry. Comorbidities were extracted within 18 months of the first migraine diagnosis. Health care utilization and headache comorbidities were extracted across the study period. Differences between men and women were evaluated using chi-square tests and student t-tests. Results: More than half a million (n = 567,121) veterans were diagnosed with migraine during the 12-year study period, accounting for 5.3% of the 10.8 million veterans served in the VHA; in the most recent year of the study period (2019), the annual incidence and one-year period prevalence of medically diagnosed migraine was 2.7% and 13.0% for women, and 0.7% and 2.5% for men. In the total cohort diagnosed with migraine, 27.8% were women and 72.2% men. Among those with diagnosed migraine, a higher proportion of men vs. women also had a TBI diagnosis (3.9% vs. 1.1%; p < 0.001). A higher proportion of women vs. men reported military sexual trauma (35.5% vs. 3.5%; p < 0.001). Participants with diagnosed migraine had an average of 1.44 (SD 1.73) annual encounters for headache. Primary care was the most common headache care setting (88.1%); almost one-fifth of veterans with diagnosed migraine sought care in the ED at least once during the study period. Common comorbidities were overweight/obesity (80.3%), non-headache pain disorders (61.7%), and mental health disorders (48.8%). Conclusions: Migraine is commonly treated in the VHA setting, but likely under ascertained. Most people treated for migraine in the VHA are men. Pain comorbidities and psychiatric disorders are common. Future research should identify methods to improve diagnosis and treatment and to reduce use of the emergency department

Complementary and integrative medicine perspectives among veteran patients and VHA healthcare providers for the treatment of headache disorders: a qualitative study

Objective To evaluate veteran patient and provider perceptions and preferences on complementary and integrative medicine (CIM) for headache management. Background The Veterans Health Administration (VHA) has spearheaded a Whole Health system of care focusing on CIM-based care for veteran patients. Less is known about patients’ and providers’ CIM perceptions and preferences for chronic headache management. Methods We conducted semi-structured interviews with 20 veteran patients diagnosed with headache and 43 clinical providers, across 12 VHA Headache Centers of Excellence (HCoE), from January 2019 to March 2020. We conducted thematic and case comparative analyses. Results Veteran patients and VHA clinical providers viewed CIM favorably for the treatment of chronic headache. Specific barriers to CIM approaches included: (1) A lack of personnel specialized in specific CIM approaches for timely access, and (2) variation in patient perceptions and responses to CIM treatment efficacy for headache management. Conclusion Veteran patients and VHA clinical providers in this study viewed CIM favorably as a safe addition to mainstream headache treatments. Advantages to CIM include favorable adverse effect profiles and patient autonomy over the treatment. By adding more CIM providers and resources throughout the VHA, CIM modalities may be recommended more routinely in the management of veterans with headache

Interactive CBT for headache and relaxation training (iCHART): Study protocol of a single-arm trial of interactive voice response technology delivery of cognitive-behavioral therapy for Veterans with post-traumatic headache

Background: Post-traumatic headache (PTH) is persistent and highly disabling. Cognitive-behavioral therapy for headache (CBT-HA) reduces headache frequency and severity and improves people’s quality of life, yet it is underutilized and inaccessible to many. Leveraging technology to deliver evidence-based psychological treatments for headache may address barriers to treatment engagement. Methods/design: This single-arm, single-site pilot trial aims to test the feasibility, acceptability, clinical signal, and cost of a five-session CBT-HA intervention delivered via interactive voice response technology (IVR). Participants will include 35 Veterans with PTH receiving care within VA Connecticut Healthcare System. Participants will complete an intake interview and a 9-item, 30-day electronic headache diary during a baseline run-in period. The same diary will be done again by participants immediately after treatment completion. Following the baseline assessment period, eligible participants will receive CBT-HA via IVR for 10 weeks, including an automated daily assessment of patient-reported outcomes and retrieval of biweekly tailored feedback from a study therapist. In addition, participants will access an electronic patient workbook, and study therapists will visualize patient-reported data through a secure provider dashboard. Participants will complete validated and reliable assessment measures at baseline, immediately post-treatment completion (week 10), and 1-month post-treatment completion (week 14). The primary clinical signal outcome is the change in self-reported headache days from the 30-day baseline run-in period before treatment (weeks −4 to 0) to the 30-day post-treatment completion (weeks 10–14). Paired-samples t -tests will explore changes in outcomes from baseline. All cost analyses will be exploratory and will use micro-costing techniques. Trial Registration: Clinical Trials.gov: NCT05093556. Registered October 26, 2021

Does mindfulness-based cognitive therapy for migraine reduce migraine-related disability in people with episodic and chronic migraine? A phase 2b pilot randomized clinical trial

Objective The current Phase 2b study aimed to evaluate the efficacy of mindfulness-based cognitive therapy for migraine (MBCT-M) to reduce migraine-related disability in people with migraine. Background Mindfulness-based interventions represent a promising avenue to investigate effects in people with migraine. MBCT teaches mindfulness meditation and cognitive-behavioral skills and directly applies these skills to address disease-related cognitions. Methods Participants with migraine (6-30 headache days/month) were recruited from neurology office referrals and local and online advertisements in the broader New York City area. During the 30-day baseline period, all participants completed a daily headache diary. Participants who met inclusion and exclusion criteria were randomized in a parallel design, stratified by chronic migraine status, to receive either 8 weekly individual MBCT-M sessions or 8 weeks of waitlist/treatment as usual (WL/TAU). All participants completed surveys including primary outcome evaluations at Months 0, 1, 2, and 4. All participants completed a headache diary during the 30-day posttreatment evaluation period. Primary outcomes were the change from Month 0 to Month 4 in the headache disability inventory (HDI) and the Migraine Disability Assessment (MIDAS) (total score >= 21 indicating severe disability); secondary outcomes (headache days/30 days, average headache attack pain intensity, and attack-level migraine-related disability [Migraine Disability Index (MIDI)]) were derived from the daily headache diary. Results Sixty participants were randomized to receive MBCT-M (n = 31) or WL/TAU (n = 29). Participants (M age = 40.1, SD = 11.7) were predominantly White (n = 49/60; 81.7%) and Non-Hispanic (N = 50/60; 83.3%) women (n = 55/60; 91.7%) with a graduate degree (n = 35/60; 55.0%) who were working full-time (n = 38/60; 63.3%). At baseline, the average HDI score (51.4, SD = 19.0) indicated a moderate level of disability and the majority of participants (50/60, 83.3%) fell in the "Severe Disability" range in the MIDAS. Participants recorded an average of 16.0 (SD = 5.9) headache days/30 days, with an average headache attack pain intensity of 1.7 on a 4-point scale (SD = 0.3), indicating moderate intensity. Average levels of daily disability reported on the MIDI were 3.1/10 (SD = 1.8). For the HDI, mean scores decreased more from Month 0 to Month 4 in the MBCT-M group (-14.3) than the waitlist/treatment as an usual group (-0.2; P < .001). For the MIDAS, the group*month interaction was not significant when accounting for the divided alpha, P = .027; across all participants in both groups, the estimated proportion of participants falling in the "Severe Disability" category fell significantly from 88.3% at Month 0 to 66.7% at Month 4, P < .001. For diary-reported headache days/30 days an average headache attack pain intensity, neither the group*month interaction (Ps = .773 and .888, respectively) nor the time effect (Ps = .059 and .428, respectively) was significant. Mean MIDI scores decreased in the MBCT-M group (-0.6/10), whereas they increased in the waitlist/treatment as an usual group (+0.3/10), P = .007.Conclusions MBCT-M demonstrated efficacy to reduce headache-related disability and attack-level migraine-related disability. MBCT-M is a promising emerging treatment for addressing migraine-related disability

Telehealth perceptions and utilization for the delivery of headache care before and during the COVID-19 pandemic: A mixed-methods study

Objective: The objective of this study was to evaluate the utilization of telehealth for headache services within the Veterans Health Administration's facilities housing a Headache Centers of Excellence and multiple stakeholder's perspectives to inform future telehealth delivery. Background: Telehealth delivery of headache treatment may enhance patient access to headache care, yet little is known about the utilization or patient and provider perceptions of telehealth for veterans with headache. Methods: This mixed-methods study analyzed multiple data sources: (1) administrative data, which included 58,798 patients with medically diagnosed headache disorders, documented in at least one outpatient visit, from August 2019 through September 2020 from the 12 Veterans Health Administration's facilities with a Headache Center of Excellence and (2) qualitative semistructured interviews with 20 patients and 43 providers 6 months before the coronavirus disease 2019 (COVID-19) pandemic, and 10 patients and 20 providers 6 months during the beginning of the pandemic. Results: During the pandemic, in-person visits declined from 12,794 to 6099 (52.0%), whereas video (incidence rate ratio [IRR] = 2.05, 95% confidence interval [CI] = 1.66, 2.52), and telephone visits (IRR = 15.2, 95% CI = 10.7, 21.6) significantly increased. Utilization differed based on patient age, race/ethnicity, and rurality. Patients and providers perceived value in using telehealth, yet had limited experience with this modality pre-pandemic. Providers preferred in-person appointments for initial encounters and telehealth for follow-up visits. Providers and patients identified benefits and challenges of telehealth delivery, often relying on multiple delivery methods for telehealth to enhance patient engagement. Conclusions: The uptake of telehealth delivery of headache-related care rapidly expanded in response to the pandemic. Patients and providers were amenable to utilizing telehealth, yet also experienced technological barriers. To encourage equitable access to telehealth and direct resources to those in need, it is crucial to understand patient preferences regarding in-person versus telehealth visits and identify patient groups who face barriers to access