Development and initial validation of the menstrual sensitivity index.

OBJECTIVE: The present study sought to develop and perform the initial validation of a scale assessing sensitivity to menstrual pain and symptoms. METHODS: Data were taken from a larger parent study in which participants were recruited from a nationwide sample of individuals via the UniVox platform (www.univoxcommunity.com). In that study, participants were stratified by age and self-reported menstrual pain. Participants in the parent study completed 2 online surveys, one at baseline and one at a 3-month follow up. Participants who provided complete responses to the potential scale items, as well as a variety of validated questionnaires, were included in the present analyses. Final item selection was determined by factor analyses, and measures of validity and reliability were examined. RESULTS: Factor analyses support an 8-item scale assessing menstrual sensitivity. This scale, the Menstrual Sensitivity Index, demonstrates excellent internal consistency, good item-total correlations, and good total score test-retest reliability. Convergent validity emerged for menstrual- and pain-specific measures, and divergent validity emerged for anxiety sensitivity, anxiety, depression, nonmenstrual bodily pain, and premenstrual symptoms. CONCLUSIONS: Menstrual sensitivity is a unique construct that reflects women's attunement to and fear of menstrual symptoms, and the Menstrual Sensitivity Index is a valid and reliable measure of this construct. This scale could be useful in advancing research and clinical work targeting menstrual pain.

Estrogen and alcohol use in women: a targeted literature review.

PURPOSE: Alcohol is posited to affect sex steroid hormone concentrations, and a growing body of research has demonstrated menstrual cycle effects on women's use of alcohol. The present targeted review synthesizes the literature examining the relationship between alcohol use and estradiol in women and suggests directions for future research. METHODS: Articles were identified using the PubMed database using the following criteria: published in English, presented original findings for women, were peerreviewed, and included measures of estradiol levels in the analyses. Twenty-nine articles were identified for inclusion. RESULTS: Results from this review indicate acute alcohol use temporarily increases estradiol levels in women, and this may be strongest when gonadotropins are high. Regular alcohol use (≥1 drink per day) increases estradiol levels, but estradiol appears to be suppressed in women with alcohol use disorders and physiologic dependence. Alcohol use tends to be highest in women during ovulation, when estradiol is high, and progesterone is low. CONCLUSION: Alcohol use increases estradiol levels in women, particularly in the presence of gonadotropins. More research is needed to assess the effect of estradiol on alcohol use in women. Research on the relationship of estrogen and alcohol use in women is needed to elucidate health outcomes through the lifespan.

Connexin 43 across the Vasculature: Gap Junctions and Beyond.

Connexin 43 (Cx43) is essential to the function of the vasculature. Cx43 proteins form gap junctions that allow for the exchange of ions and molecules between vascular cells to facilitate cell-to-cell signaling and coordinate vasomotor activity. Cx43 also has intracellular signaling functions that influence vascular cell proliferation and migration. Cx43 is expressed in all vascular cell types, although its expression and function vary by vessel size and location. This includes expression in vascular smooth muscle cells (vSMC), endothelial cells (EC), and pericytes. Cx43 is thought to coordinate homocellular signaling within EC and vSMC. Cx43 gap junctions also function as conduits between different cell types (heterocellular signaling), between EC and vSMC at the myoendothelial junction, and between pericyte and EC in capillaries. Alterations in Cx43 expression, localization, and post-translational modification have been identified in vascular disease states, including atherosclerosis, hypertension, and diabetes. In this review, we discuss the current understanding of Cx43 localization and function in healthy and diseased blood vessels across all vascular beds.

Pericyte Progenitor Coupling to the Emerging Endothelium During Vasculogenesis via Connexin 43.

BACKGROUND: Vascular pericytes stabilize blood vessels and contribute to their maturation, while playing other key roles in microvascular function. Nevertheless, relatively little is known about involvement of their precursors in the earliest stages of vascular development, specifically during vasculogenesis. METHODS: We combined high-power, time-lapse imaging with transcriptional profiling of emerging pericytes and endothelial cells in reporter mouse and cell lines. We also analyzed conditional transgenic animals deficient in Cx43/Gja1 (connexin 43/gap junction alpha-1) expression within Ng2+ cells. RESULTS: A subset of Ng2-DsRed+ cells, likely pericyte/mural cell precursors, arose alongside endothelial cell differentiation and organization and physically engaged vasculogenic endothelium in vivo and in vitro. We found no overlap between this population of differentiating pericyte/mural progenitors and other lineages including hemangiogenic and neuronal/glial cell types. We also observed cell-cell coupling and identified Cx43-based gap junctions contributing to pericyte-endothelial cell precursor communication during vascular assembly. Genetic loss of Cx43/Gja1 in Ng2+ pericyte progenitors compromised embryonic blood vessel formation in a subset of animals, while surviving mutants displayed little-to-no vessel abnormalities, suggesting a resilience to Cx43/Gja1 loss in Ng2+ cells or potential compensation by additional connexin isoforms. CONCLUSIONS: Together, our data suggest that a distinct pericyte lineage emerges alongside vasculogenesis and directly communicates with the nascent endothelium via Cx43 during early vessel formation. Cx43/Gja1 loss in pericyte/mural cell progenitors can induce embryonic vessel dysmorphogenesis, but alternate connexin isoforms may be able to compensate. These data provide insight that may reshape the current framework of vascular development and may also inform tissue revascularization/vascularization strategies.

Pain catastrophizing, but not mental health or social support, is associated with menstrual pain severity in women with dysmenorrhea: A cross-sectional survey.

The aim of this study was to understand the relationship between psychosocial factors, including mental health, pain cognitions and social support associated with menstrual pain severity in women with dysmenorrhea of no identified medical cause (primary dysmenorrhea; PD) and dysmenorrhea related to endometriosis. Participants included 1192 women aged 18-50 years with menstrual pain, recruited to an online cross-sectional survey in 2019. Questionnaires assessed self-reported menstrual pain severity, depression, anxiety, stress, pain catastrophizing, and social support. Women with endometriosis had significantly higher menstrual pain severity (p < 0.001) and pain catastrophizing (p < 0.001) than women with PD. Of the psychosocial factors, only pain catastrophizing (specifically, the helplessness sub-scale) predicted menstrual pain severity in each group. Overall, 36% of women with PD and 58% with endometriosis had clinically relevant levels of pain catastrophizing. Findings suggest a common psychological mechanism in women with menstrual pain, regardless of etiology. Interventions to reduce pain helplessness may be beneficial in supporting women with dysmenorrhea.

Phenotypes of Women with and Without Endometriosis and Relationship with Functional Pain Disability.

OBJECTIVE: Primary dysmenorrhea and secondary dysmenorrhea due to endometriosis share overlapping symptoms and likely demonstrate aspects of central sensitization. The present study aimed to identify distinct phenotypes of women who have dysmenorrhea with and without endometriosis to shed light on the unique mechanisms contributing to the pathogenesis of each condition. METHODS: An online survey was used to investigate the relationship between ratings of menstrual pain severity, menstrual symptoms (abdominal cramps, abdominal discomfort, low back pain, headache, body aches, bloating, nausea, diarrhea, increased bowel movements), widespread pain, and functional pain disability in a community sample of 1,354 women (aged 18-50) with menstrual pain in Australia. RESULTS: Compared with women without endometriosis, those with endometriosis had statistically significant higher menstrual pain severity (P<0.01), symptom severity and fatigue (all symptoms P<0.001, although only cramps and bloating were clinically significant), widespread pain sites (P<0.001), and functional pain disability (P<0.001, although this difference was not clinically significant). When examining symptoms by pain severity, women with severe menstrual pain were more likely to experience symptoms than women with less severe pain, regardless of the presence of endometriosis. Similar predictors of functional pain disability emerged for women with and without endometriosis, such as body aches, nausea, fatigue, and widespread pain, respectively, suggesting the presence of central sensitization in both groups. Logistic regression revealed that after accounting for menstrual pain severity (odds ratio [OR], 1.61) and duration (OR, 1.04), symptoms of bloating (OR, 1.12), nausea (OR, 1.07), and widespread pain sites (OR, 1.06) significantly predicted the presence of endometriosis. CONCLUSIONS: The findings suggest that phenotypes specific to endometriosis can be identified.

Caregiver-Child Discrepancies in Reports of Child Emotional Symptoms in Pediatric Chronic Pain.

OBJECTIVE: Pediatric chronic pain evaluation includes self-reports and/or caregiver proxy-reports across biopsychosocial domains. Limited data exist on the effects of caregiver-child discrepancies in pediatric pain assessment. In children with chronic pain, we examined associations among discrepancies in caregiver-child reports of child anxiety and depressive symptoms and child functional impairment. METHODS: Participants were 202 children (Mage=14.49 ± 2.38 years; 68.8% female) with chronic pain and their caregivers (95.5% female). Children and caregivers completed the Revised Child Anxiety and Depression Scale (RCADS) and RCADS-Parent, respectively. Children also completed the Functional Disability Inventory. Mean difference tests examined caregiver-child discrepancies. Moderation analyses examined whether associations between child self-reported anxiety and depressive symptoms and functional impairment varied as a function of caregiver proxy-report. RESULTS: Children reported more anxiety and depressive symptoms compared with their caregivers' proxy-reports (Z = -4.83, p < .001). Both informants' reports of child anxiety and depressive symptoms were associated with child functional impairment (rs = .44, rs = .30, p < .001). Caregiver proxy-report moderated associations between child-reported anxiety and depressive symptoms and functional impairment (B = -0.007, p = .003). When caregiver proxy-report was low, child self-reported anxiety and depressive symptoms were positively related to functional impairment (B = 0.28, SE = 0.07, 95% CI [0.15, 0.41], p < .001). CONCLUSIONS: Discrepant caregiver-child perceptions of child anxiety and depressive symptoms may be associated with functioning in children with chronic pain, especially when caregivers report less child internalizing symptoms. These findings highlight the need for further examination of the effects of caregiver-child discrepancies on pediatric chronic pain outcomes and may indicate targets for intervention.

An Open Trial of a Mind-Body Intervention for Young Women with Moderate to Severe Primary Dysmenorrhea.

OBJECTIVE: To evaluate the feasibility, acceptability, and preliminary efficacy of a mind-body intervention for moderate to severe primary dysmenorrhea (PD). DESIGN: Open trial (single arm). SETTING: Academic medical school. SUBJECTS: A total of 20 young adult women with moderate to severe primary dysmenorrhea were included across four separate intervention groups. METHODS: All participants received five 90-minute sessions of a mind-body intervention and completed self-report measures of menstrual pain, depression, anxiety, somatization, and pain catastrophizing at baseline, post-treatment, and at one-, two-, three-, and 12-month follow-up. Self-report of medication use and use of skills learned during the intervention were also collected at all follow-up points. RESULTS: Participants reported significantly lower menstrual pain over time compared with baseline. No changes in anxiety, depression, or somatization were observed, although pain catastrophizing improved over time. Changes in menstrual pain were not associated with changes in medication use or reported use of skills. CONCLUSIONS: A mind-body intervention is a promising nondrug intervention for primary dysmenorrhea, and future research should focus on testing the intervention further as part of a randomized clinical trial.

"Tomorrow, I'll Be Fine": Impacts and coping mechanisms in adolescents and young adults with primary dysmenorrhoea.

AIMS: To understand the experiences of adolescents and young adults with primary dysmenorrhoea through the lens of structured frameworks extant in contemporary pain literature. DESIGN: Descriptive qualitative study. METHODS: Thirty-nine adolescents and young adults (ages 16-24 years) with primary dysmenorrhoea participated in semi-structured in-person interviews. Transcripts of the interviews were analysed using deductive thematic analysis from November 2018 to April 2019. RESULTS: Two overarching themes, each with subthemes, were identified. The first theme, primary dysmenorrhoea impacts the whole person, contained the following subthemes: biological, social, and psychological. The second theme, coping mechanisms of women with primary dysmenorrhoea, contained the following subthemes: primary, secondary, and passive coping. CONCLUSION: Women experience several primary dysmenorrhoea-related impacts on their biological, social, and psychological functioning. Women employ a variety of coping mechanisms to manage their primary dysmenorrhoea pain. IMPACT: This study emphasizes the significant effects of primary dysmenorrhoea on nearly every aspect of women's lives and contributes to an understanding of the ways women cope with this pain. The findings of this study underscore the need for continued consideration of primary dysmenorrhoea as a debilitating pain process as well as the need for additional interventions to help women manage this condition.

Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation.

Pericyte investment into new blood vessels is essential for vascular development such that mis-regulation within this phase of vessel formation can contribute to numerous pathologies including arteriovenous and cerebrovascular malformations. It is critical therefore to illuminate how angiogenic signaling pathways intersect to regulate pericyte migration and investment. Here, we disrupted vascular endothelial growth factor-A (VEGF-A) signaling in ex vivo and in vitro models of sprouting angiogenesis, and found pericyte coverage to be compromised during VEGF-A perturbations. Pericytes had little to no expression of VEGF receptors, suggesting VEGF-A signaling defects affect endothelial cells directly but pericytes indirectly. Live imaging of ex vivo angiogenesis in mouse embryonic skin revealed limited pericyte migration during exposure to exogenous VEGF-A. During VEGF-A gain-of-function conditions, pericytes and endothelial cells displayed abnormal transcriptional changes within the platelet-derived growth factor-B (PDGF-B) and Notch pathways. To further test potential crosstalk between these pathways in pericytes, we stimulated embryonic pericytes with Notch ligands Delta-like 4 (Dll4) and Jagged-1 (Jag1) and found induction of Notch pathway activity but no changes in PDGF Receptor-ß (Pdgfrß) expression. In contrast, PDGFRß protein levels decreased with mis-regulated VEGF-A activity, observed in the effects on full-length PDGFRß and a truncated PDGFRß isoform generated by proteolytic cleavage or potentially by mRNA splicing. Overall, these observations support a model in which, during the initial stages of vascular development, pericyte distribution and coverage are indirectly affected by endothelial cell VEGF-A signaling and the downstream regulation of PDGF-B-PDGFRß dynamics, without substantial involvement of pericyte Notch signaling during these early stages.

The pericyte microenvironment during vascular development.

Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.

Feasibility and Acceptance Testing of a Mobile Application Providing Psychosocial Support for Parents of Children and Adolescents With Chronic Pain: Results of a Nonrandomized Trial.

Objective To conduct a single-arm pilot study assessing the feasibility and acceptability of a 30-day parent-focused mindfulness and psychosocial support mobile app intervention for parents of children with chronic pain. Methods Thirty parents completed the intervention, which included a mindfulness curriculum, peer support videos, and written psychoeducational content. Twelve healthcare providers also assessed the app and provided feedback. Feasibility was assessed by server-side documented usage on ≥50% of the days in the intervention period and completion of ≥70% of the mindfulness content. Parent and provider acceptance were assessed by ≥70% of participants rating each acceptance test question as ≥5 on a 7-point Likert scale. Parents completed measures of solicitousness, stress, mindful parenting, and resilience prior to and following the intervention. Results Feasibility results were mixed: parents completed mindfulness content on an average of 11.2 days during the intervention period, slightly under the pre-established criterion. However, parents completed an average of 72.1% of the content, which met feasibility criterion. Acceptance criteria were met for the majority of parent acceptance test questions and all of the provider acceptance test questions. Exploratory analyses of the psychosocial measures revealed significant decreases in parental solicitous behavior and perceived stress, and a significant increase in mindful parenting. Conclusions The current study extends the emerging body of research on mindfulness-based interventions for parents of children with chronic illness and suggests that it may be acceptable to deliver this content through a mobile device. Future research is needed to assess the intervention's efficacy compared to standard of care.

Geographic and Social Factors Associated With Chronic Disease Self-Management Program Participation: Going the "Extra-Mile" for Disease Prevention.

INTRODUCTION: We examined geographic and social factors associated with participation in the Chronic Disease Self-Management Program (CDSMP) and the Diabetes Self-Management Program (DSMP) implemented at 144 sites in Illinois. METHODS: Programs were delivered by trained facilitators, once per week, during 6 weeks to 1,638 participants aged 50 or older. Of the 1,638 participants, we included in our analysis 1,295 participants with complete geographic information and baseline data on demographic characteristics, health history, and health behaviors. We assessed the following program data: program type (CDSMP or DSMP), workshop location, class size, and number of sessions attended by participants. We geocoded each participant's home address, classified the home address as rural or urban, and calculated the distance traveled from the home address to a workshop. We used linear and logistic regression analyses to examine the associations between participant and program factors with number of sessions attended and odds of program completion by whether participants lived in an urban or rural county. RESULTS: Average program attendance was 4.2 sessions; 71.1% (1,106 of 1,556) completed 4 or more sessions. Most participants enrolled in CDSMP (59.6% [954 of 1,600]), but DSMP had greater completion rates. Less than 7% (85 of 1,295) of our sample lived in a rural county; these participants had better completion rates than those living in urban counties (89.4% [76 of 85] vs 75.6% [890 of 1,178]). Traveling shorter distances to attend a workshop was significantly associated with better attendance and program completion rates among urban but not rural participants. The number of sessions attended was significantly higher when class size exceeded 16 participants. Not having a high school diploma was significantly associated with lower levels of attendance and program completion. CONCLUSION: Participation in CDSMP and DSMP was associated with distance traveled, program type, class size, and education. Increasing participation in self-management programs is critical to ensure participants' goals are met.

SECOND-STAGE TREATMENTS FOR RELATIVE NONRESPONDERS TO COGNITIVE BEHAVIORAL THERAPY (CBT) FOR PANIC DISORDER WITH OR WITHOUT AGORAPHOBIA-CONTINUED CBT VERSUS SSRI: A RANDOMIZED CONTROLLED TRIAL.

BACKGROUND: Cognitive behavioral therapy (CBT) and pharmacotherapy are efficacious for the short-term treatment of panic disorder. Less is known about the efficacy of these therapies for individuals who do not respond fully to short-term CBT. METHOD: The current trial is a second-step stratified randomized design comparing two treatment conditions-selective serotonin reuptake inhibitor (SSRI; paroxetine or citalopram; n = 34) and continued CBT (n = 24)-in a sample of individuals classified as treatment nonresponders to an initial course of CBT for panic disorder. Participants were randomized to 3 months of treatment and then followed for an additional 9 months. Only treatment responders after 3 months were maintained on the treatment until 12-month follow-up. Data analysis focused on panic disorder symptoms and achievement of response status across the first 3 months of treatment. Final follow-up data are presented descriptively. RESULTS: Participants in the SSRI condition showed significantly lower panic disorder symptoms as compared to continued CBT at 3 months. Results were similar when excluding individuals with comorbid major depression or analyzing the entire intent-to-treat sample. Group differences disappeared during 9-month naturalistic follow-up, although there was significant attrition and use of nonstudy therapies in both arms. CONCLUSIONS: These data suggest greater improvement in panic disorder symptoms when switching to SSRI after failure to fully respond to an initial course of CBT. Future studies should further investigate relapse following treatment discontinuation for nonresponders who became responders. Clinicaltrials.gov Identifier: NCT00000368; https://clinicaltrials.gov/show/NCT00000368.

Pain Catastrophizing Predicts Menstrual Pain Ratings in Adolescent Girls with Chronic Pain.

OBJECTIVES: The current study aimed to explore relationships among self-reported menstrual pain ratings, acute laboratory pain, pain catastrophizing, and anxiety sensitivity in a sample of girls without pain (No Pain group) and girls with a chronic pain condition (Chronic Pain group). SETTING: A laboratory at an off-campus Medical School office building. SUBJECTS: Eighty-four postmenarchal girls (43 No Pain, 41 Chronic Pain) ages 10-17 participated in the study. METHODS: All participants completed self-report questionnaires assessing menstrual pain, pain catastrophizing, and anxiety sensitivity and completed a cold pressor task. Pain intensity during the task was rated on a 0 (no pain) to 10 (worst pain possible) numeric rating scale. RESULTS: After controlling for age, average menstrual pain ratings (without medication) were significantly correlated with cold pressor pain intensity for the No Pain group only. In the Chronic Pain group, menstrual pain ratings were significantly correlated with pain catastrophizing and anxiety sensitivity. In a multiple linear regression analysis, after controlling for age, only pain catastrophizing emerged as a significant predictor of menstrual pain ratings in the Chronic Pain group. CONCLUSION: Results demonstrate differences in relationships among menstrual pain, acute laboratory pain, and psychological variables in girls with no pain compared with girls with chronic pain. In addition, pain catastrophizing may be a particularly salient factor associated with menstrual pain in girls with chronic pain that warrants further investigation.

Community College Students' Health Insurance Enrollment, Maintenance, and Talking With Parents Intentions: An Application of the Reasoned Action Approach.

A primary objective of health care reform is to provide affordable and quality health insurance to individuals. Currently, promotional efforts have been moderately successful in registering older, more mature adults yet comparatively less successful in registering younger adults. With this challenge in mind, we conducted extensive formative research to better understand the attitudes, subjective norms, and perceived behavioral control of community college students. More specifically, we examined how each relates to their intentions to enroll in a health insurance plan, maintain their current health insurance plan, and talk with their parents about their parents having health insurance. In doing so, we relied on the revised reasoned action approach advanced by Fishbein and his associates (Fishbein & Ajzen, 2010; Yzer, 2012, 2013). Results showed that the constructs predicted intentions to enroll in health insurance for those with no insurance and for those with government-sponsored insurance and intentions to maintain insurance for those currently insured. Our study demonstrates the applicability of the revised reasoned action framework within this context and is discussed with an emphasis on the practical and theoretical contributions.

VCAM-1/α4ß1 integrin interaction is crucial for prompt recruitment of immune T cells into the brain during the early stage of reactivation of chronic infection with Toxoplasma gondii to prevent toxoplasmic encephalitis.

Reactivation of chronic infection with Toxoplasma gondii can cause life-threatening toxoplasmic encephalitis in immunocompromised individuals. We examined the role of VCAM-1/α4ß1 integrin interaction in T cell recruitment to prevent reactivation of the infection in the brain. SCID mice were infected and treated with sulfadiazine to establish a chronic infection. VCAM-1 and ICAM-1 were the endothelial adhesion molecules detected on cerebral vessels of the infected SCID and wild-type animals. Immune T cells from infected wild-type mice were treated with anti-α4 integrin or control antibodies and transferred into infected SCID or nude mice, and the animals received the same antibody every other day. Three days later, sulfadiazine was discontinued to initiate reactivation of infection. Expression of mRNAs for CD3δ, CD4, CD8ß, gamma interferon (IFN-γ), and inducible nitric oxide synthase (NOS2) (an effector molecule to inhibit T. gondii growth) and the numbers of CD4(+) and CD8(+) T cells in the brain were significantly less in mice treated with anti-α4 integrin antibody than in those treated with control antibody at 3 days after sulfadiazine discontinuation. At 6 days after sulfadiazine discontinuation, cerebral tachyzoite-specific SAG1 mRNA levels and numbers of inflammatory foci associated with tachyzoites were markedly greater in anti-α4 integrin antibody-treated than in control antibody-treated animals, even though IFN-γ and NOS2 mRNA levels were higher in the former than in the latter. These results indicate that VCAM-1/α4ß1 integrin interaction is crucial for prompt recruitment of immune T cells and induction of IFN-γ-mediated protective immune responses during the early stage of reactivation of chronic T. gondii infection to control tachyzoite growth.

New focus on cardiac voltage-gated sodium channel ß1 and ß1B: Novel targets for treating and understanding arrhythmias?

Voltage-gated sodium channels (VGSCs) are transmembrane protein complexes that are vital to the generation and propagation of action potentials in nerve and muscle fibers. The canonical VGSC is generally conceived as a heterotrimeric complex formed by two classes of membrane-spanning subunit-an α-subunit (pore forming) and two ß-subunits (non-pore forming). NaV1.5 is the main sodium channel α-subunit of mammalian ventricle, with lower amounts of other α-subunits, including NaV1.6, being present. There are four ß-subunits, ß1-ß4, encoded by four genes, SCN1B-SCN4B, each of which are expressed in cardiac tissues. Recent studies suggest that in addition to assignments in channel gating and trafficking, products of Scn1b may have novel roles in conduction of action potential in the heart and intracellular signaling. This includes evidence that the ß-subunit extracellular Amino-terminal domain facilitates adhesive interactions in intercalated discs and that its Carboxyl-terminal region is a substrate for a regulated intramembrane proteolysis (RIP) signaling pathway-with a Carboxyl-terminal peptide generated by ß1 RIP trafficked to the nucleus and altering transcription of various genes, including NaV1.5. In addition to ß1, the Scn1b gene encodes for an alternative splice variant, ß1B, which contains an identical extracellular adhesion domain to ß1, but has a unique Carboxyl-terminus. Whilst ß1B is generally understood to be a secreted variant, evidence indicates that when co-expressed with NaV1.5, it is maintained at the cell membrane, suggesting potential unique roles for this understudied protein. In this review, we focus on what is known on the two ß-subunit variants encoded by Scn1b in heart, with particular focus on recent findings and the questions raised by this new information. We also explore data that indicate ß1 and ß1B may be attractive targets for novel anti-arrhythmic therapeutics.

Association between COVID-19 vaccination and menstruation: a state of the science review.

INTRODUCTION: Menstrual health is a key patient-reported outcome beyond its importance as a general indicator of health and fertility. However, menstrual function was not measured in the clinical trials of COVID-19 vaccines. The purpose of this review was to synthesise the existing literature on the relationship between COVID-19 vaccination and menstrual health outcomes. METHODS: A PubMed search to 31 October 2023 identified a total of 53 publications: 11 prospective cohort studies, 11 retrospective cohort studies or registry-based cohort studies, and 31 cross-sectional or retrospective case-control studies. RESULTS: Identified studies were generally at moderate-to-high risk of bias due to retrospective design, interviewer bias, and failure to include a non-vaccinated control group. Nonetheless, the bulk of the literature demonstrates that COVID-19 vaccine is associated with temporary changes in menstrual characteristics (cycle length and flow) and menstrual pain. Follicular phase (at the time of vaccination) is associated with greater increases in cycle length. Evidence suggests temporary post-vaccine menstrual changes in adolescents, abnormal vaginal bleeding in postmenopausal individuals, and a potential protective effect of using hormonal contraception. CONCLUSIONS: In this review we found evidence supporting an association between the COVID-19 vaccine and menstrual health outcomes. Given the importance of menstrual function to overall health, we recommend that all future vaccine trials include menstruation as a study outcome. Future vaccine studies should include rigorous assessment of the menstrual cycle as an outcome variable to limit sources of bias, identify biological mechanisms, and elucidate the impact of stress.