Postural orthostatic tachycardia syndrome (POTS) is a chronic, debilitating condition that is characterized by an excessive increase in heart rate upon orthostatic challenge. Before the COVID-19 pandemic, POTS affected 0.5 % to 1 % of the U.S. population. Since the pandemic, the incidence has risen sharply, adding an estimated 6-7 million new cases in the U.S. Despite its importance, there is currently no reliable biomarker for POTS, leading to significant diagnostic delays. A major hurdle in identifying biomarkers is the heterogeneous nature of the syndrome. To address this, we focused on a homogeneous subgroup of post-COVID-19 POTS (PC-POTS) patients. We conducted quantitative proteomics on sera from 9 PC-POTS patients and 9 healthy controls, identifying 31 proteins with significantly different abundances in PC-POTS patients. Most elevated proteins were linked to actin filaments or immune functions/inflammation. Weighted Gene Co-Expression Network Analysis revealed module 7 (M7) correlated strongly with PC-POTS diagnosis and related traits. The key proteins in M7 included MTPN, TAGLN2, ADP-ribosylation factor 1, PDLIM1, PPIA, CNN2, LGALSL, TXN, TLN1, TUBA4A, IL4, TREML1, GP1BA, and, all highly correlated with these traits. Cell-type enrichment analysis revealed that M7 was highly associated with immune and neuronal cells. The main pathways identified in M7 included the integrin signaling pathway, blood coagulation, and glycolysis. These findings suggest that the key proteins in M7 could serve as biomarkers for PC-POTS. This study uses quantitative proteomics to identify potential biomarkers that differentiate PC-POTS patients from healthy controls, establishing a foundation for further research and validation.

Oral rehydration solution (ORS) is predominantly utilized in the management of hypovolemic postural orthostatic tachycardia syndrome (POTS). This study aimed to identify effective indicators and develop models to assess the impact of ORS on pediatric patients diagnosed with POTS. We utilized a retrospective analysis of totally 158 pediatric patients with POTS receiving a 3-month course of ORS treatment. All patients were classified into training set (n = 98) and validation set (n = 60). Within the training set, univariate analysis and binary logistic regression were employed to select candidate predictors. To predict the efficacy of ORS in pediatric patients with POTS, a nomogram model and a scoring model were constructed and demonstrated. Additionally, the predictive ability and calibration performance were evaluated using receiver operating characteristic (ROC) curves, Hosmer-Lemeshow (H-L) goodness of fit test, and calibration plots. Decision curve analysis (DCA) was employed to assess the clinical applicability of the predictive models. Body mass index (BMI) z-score, serum chlorine, and urine specific gravity (USG) before treatment were identified as significant and independent predictors of efficacy of ORS in pediatric patients with POTS. Consequently, these indicators were included in the predictive models. A nomogram model was constructed in the training set (AUC = 0.87, which yields a sensitivity of 84.5% and a specificity of 85.0%) and validated in the validation set (the sensitivity, specificity, and accuracy were 87.5%, 85%, and 86.7%, respectively). A scoring model was advanced in the training set (AUC = 0.88, which yields a sensitivity of 79.3% and a specificity of 82.5%) and validated in the validation set (the sensitivity, specificity, and accuracy were 77.5%, 80.0%, and 78.3%, respectively). The H-L test results indicated a good model fit. The calibration plots and DCA for both models exhibited excellent calibration and satisfactory net benefit. Based on pre-treatment BMI z-score, serum chlorine, and USG, a nomogram model and a scoring model were developed and validated. The models can effectively assess the efficacy of ORS in pediatric patients with POTS, offering an accurate and individualized therapeutic strategy.

This case highlights the intersection of psychiatric symptoms and hypermobility spectrum disorder (HSD) in a woman in her 20s with multiple comorbidities, including postural orthostatic tachycardia syndrome, chronic pain and obstructive sleep apnoea. The patient had been unresponsive to conventional psychiatric treatments for anxiety and panic attacks. On recognition of HSD, a multidisciplinary approach, including propranolol for autonomic dysfunction, pregabalin for pain and anxiety, and lisdexamfetamine for cognitive impairment, significantly improved her condition. Early identification and tailored management of HSD in psychiatric settings can optimise treatment outcomes by addressing both physical and psychiatric symptoms. This case underscores the need for psychiatrists to incorporate physical health assessments into their diagnostic processes when treating complex psychiatric presentations.

The vestibulo-autonomic interaction refers to the neural interplay between the vestibular and autonomic systems. In particular, the vestibular system plays an active role in adjusting blood distribution during movement and changes in posture, thereby complementing the baroreflex. This review summarizes recent clinical evidence highlighting the interaction between the vestibular and autonomic systems, including altered vestibular-evoked myogenic potentials in patients with postural orthostatic tachycardia syndrome, orthostatic hypotension, and neurodegenerative disorders. Additionally, the review introduces a model-based explanation of vestibular modulation of the autonomic system via the velocity storage mechanism. Specifically, the model demonstrates how vertigo attacks influence cardiovascular autonomic outflow by altering the estimation of gravity and inertia under pathological conditions.

Postural orthostatic tachycardia syndrome (PoTS) is a clinically significant condition affecting numerous patients across the UK. This article aims to enhance understanding and management strategies for registered nurses by exploring its pathophysiology, clinical presentations, diagnostic processes and treatment protocols. PoTS, characterised by an excessive increase in heart rate on standing, presents multifaceted symptoms impacting patients' quality of life. Effective management requires a multidisciplinary approach encompassing pharmacological treatments, lifestyle modifications and psychological support. This review seeks to provide nurses with the knowledge to improve patient outcomes and advocate for holistic care.

To report the prevalence and severity of nonpelvic symptoms for patients with venous-origin chronic pelvic pain (VO-CPP) and to describe outcomes after pelvic vein stenting and embolization. We retrospectively reviewed outcomes of 45 women with VO-CPP who underwent treatment with iliac vein stenting and/or embolization. Patients completed symptom-severity questionnaires before and after treatment that assessed for pelvic pain, and multiple other symptoms, including brain fog, anxiety, depression, musculoskeletal pain, fatigue, migraines and more. Patient age ranged from 18 to 65 years. The prevalence of common symptoms was as follows: migraines, 69%; brain fog, 76%; anxiety attacks, 58%; excess sweating, 64%; hip pain, 73%; diarrhea, 62%; constipation, 76%; and abdominal bloating, 82%. After treatment, most symptom scores improved by more than 50%; exceptions were excessive sweating (41% improvement) and bloating (47% improvement). Prevalence of individual symptoms that bundle into POTS ranged from 29% to 76%, where symptom improvement ranged from 23% to 59% after treatment. Overlapping individual symptoms characteristic of fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) were present in 64% to 82% of patients and all improved by 49% to 63% after treatment. Pelvic venous flow abnormality is linked causally to a spectrum of interrelated symptoms, of which many can be bundled into named syndromes of unknown cause. With catheter- based treatment of pelvic venous pooling, nonpelvic symptom and syndrome scores improved.

Inappropriate sinus tachycardia (IST) is a type of cardiovascular autonomic dysfunction (CVAD) that mainly affects young women and has a prevalence of 1%-2%. IST is characterized by a sinus heart rate of >100 bpm at rest with a mean 24-h heart rate of >90 bpm associated with distressing symptoms such as palpitations, dizziness, and syncope. Here, we discuss a case of a 30-year-old woman who presented with complaints of tachycardia and associated symptoms, including dizziness, diaphoresis, and sudden loss of consciousness. The 24-h Holter monitoring was consistent with the diagnosis of IST. The patient had minimal improvement on β-blocker therapy. Due to persistent symptoms consistent with IST, she was started on non-invasive vagal nerve stimulation (n-VNS) therapy. Following 2 months of n-VNS applied twice daily over the carotid artery, the patient noted near-complete relief of her tachycardia and other debilitating symptoms. While n-VNS has recently been reported as a possible treatment for postural orthostatic tachycardia syndrome, another type of CVAD, to the best of our knowledge, this is the first report of low-level n-VNS as a treatment for IST. Our case study highlights the need for further clinical studies on the benefits of n-VNS in treating IST.

Despite there being a wide variety of symptoms reported in pediatric long COVID, one condition that has become increasingly recognized is orthostatic intolerance (OI), which can cause significant morbidity, limiting activities of daily living. This study examines rates of OI in 92 children with long COVID who underwent a bedside passive standing test in a pediatric post-COVID-19 rehabilitation clinic. Seventy-one percent met criteria for an orthostatic condition, including postural orthostatic tachycardia syndrome (POTS), orthostatic tachycardia (OT), classic orthostatic hypotension (OH), delayed OH, and orthostatic hypertension. Our findings suggest that OI is common in pediatric long COVID, necessitating appropriate clinical screening and treatment.

Postural orthostatic tachycardia syndrome (POTS) is a complex clinical syndrome predominantly affecting females during puberty and early adulthood. The exact cause of POTS is unknown; however, patients often endure a myriad of symptoms including lightheadedness, palpitations, weakness, and fatigue, which significantly impact their quality of life and academic performance. Additional psychological effects include anxiety and depression which is common among POTS patients, further emphasizing the need for comprehensive care and adequate school accommodations. Despite its considerable impact, there remains a paucity of research and standardized guidelines, underscoring the need for increased awareness and collaborative efforts among healthcare providers, educators, and policymakers. Further research and international collaboration are imperative to the successful development of standardized treatment and accommodations for this vulnerable population.

Postural Orthostatic Tachycardia Syndrome (POTS) is a form of cardiovascular autonomic disorders characterized by orthostatic intolerance and a symptomatic increase in heart rate upon standing, which can significantly impair patients' quality of life. Its pathophysiology is complex, multifactorial; thus, a variety of treatment approaches have been investigated. Recent studies have identified three primary POTS phenotypes-hyperadrenergic, neuropathic, and hypovolemic-each requiring tailored management strategies. First-line treatment for all patients focuses on lifestyle modifications, including increased fluid and salt intake, compression garment use, physical reconditioning, and postural training. Currently, there are no medications approved by the United States Food and Drug Administration (FDA)for POTS. Pharmacologic therapies are primarily used to manage specific symptoms, though the evidence supporting their efficacy is limited. In hyperadrenergic POTS, excessive norepinephrine production or impaired reuptake leads to sympathetic overactivity, making beta-blockers an effective option. Neuropathic POTS, resulting from impaired vasoconstriction during orthostatic stress, responds to agents that enhance vascular tone, such as pyridostigmine and midodrine. Hypovolemic POTS, often triggered by dehydration and physical deconditioning, respond primarily to volume expansion and exercise. This review article provides a comprehensive overview of the pathophysiology and management strategies for POTS, with a focus on phenotype-based approaches to guide tailored treatment and improve patient outcomes.

Postural orthostatic tachycardia syndrome (POTS) is characterized by symptoms of orthostatic intolerance and is frequently observed in post-COVID conditions. We conducted controlled, prospective, and randomized clinical trials to explore the potential therapeutic benefits of low-level tragus stimulation (LL-TS) in patients with POTS following COVID-19 infection. This study enrolled 57 participants with confirmed post-acute COVID-19 who had been diagnosed with POTS. The ear clip was attached to the right tragus of the patients for stimulation (20 Hz with a 1-ms duration) or sham stimulation. They were divided into two groups: the sham LL-TS group (sham stimulation, n = 26) and the LL-TS group (stimulation for 1 month, n = 31). LL-TS was performed 1 h twice daily for 1 month. Postural tachycardia was evaluated at baseline, 1-month visit, and 1-year visit. Heart rate variability (HRV) and plasma neuropeptide Y (NPY) were evaluated at respective time points. The mean age of participants was 31.9 ± 7.2 years (61.4% female). LL-TS significantly attenuated the increase in heart rate from supine to a 10-min stand, as well as the average and maximum heart rates after 1 month of treatment. LL-TS also significantly reduced NPY levels. In addition, LL-TS significantly increased the high frequency (HF), but decreased the low frequency (LF) and LF/HF ratio during the postural test (all p < 0.01). These effects persisted during the 1-year follow-up. LL-TS may be a promising therapeutic approach for attenuating autonomic imbalance in patients with POTS following COVID-19 infection.

The aim of the study was to assess the feasibility of conducting a definitive multicentre randomised controlled trial (RCT) testing an online exercise rehabilitation and behavioural/motivational support intervention for people with postural tachycardia syndrome (PoTS). Feasibility RCT. Two secondary care centres. Adults aged 18 to 60 years with PoTS. Exclusions were serious mental health/cognitive problem preventing safe participation; currently undertaking physical activity equivalent to the Chief Medical Officer guidelines; pregnancy. Participants were randomly assigned (1:1) to best-practice usual care (a single 1:1 session of advice) or the 'postural tachycardia syndrome exercise' (PULSE) intervention: (1) individual online consultation, (2) 12 weeks of supervised online group exercise and behavioural/motivational support, and (3) home exercise programme with recumbent exercise bike. The primary outcome was feasibility: (1) patients screened, eligible, recruited, randomised, withdrawn; (2) adherence; (3) physiological, clinical and patient-reported outcomes (4 and 7 months); and (4) embedded qualitative study to evaluate acceptability. 209 patients screened between 5 May 2021 and 1 December 2022, 44 (female 98%; age 29.9 SD, 7.5) were randomised to usual care (n=21) or PULSE (n=23) (71% of target). Follow-up at 4 months was n=12 and n=17 respectively (66% of target). Median live exercise/support session attendance was 15 (IQR 12 to 17) of 18 sessions. Home exercise bike usage was highly variable. There were two serious adverse events in each treatment arm, both unrelated to the trial. Exercise rehabilitation was considered important by participants, and trial procedures, outcomes and interventions were acceptable. The PULSE trial procedures and interventions were acceptable, and important design considerations were identified. A definitive RCT testing a remotely supervised exercise rehabilitation and behavioural/motivational support intervention for people with PoTS is feasible in the UK National Health Service. ISRCTN45323485.

Adolescents with autonomic disorders who attend Intensive Interdisciplinary Pain Treatment (IIPT) programs report improvements in functioning. However, it is unclear whether they experience corresponding improvements in physiological measures. As such, the aim of this pilot study was to examine changes in physiological measures in youth attending an IIPT program who demonstrated excessive postural tachycardia on an active stand test. The secondary goal was to examine associations between physiological measurements and self-reported measures of chronic orthostatic intolerance (cOI) and functioning. At admission and discharge, eighteen adolescents and young adults (AYAs) attending IIPT ( age = 17.39 years; SD = 2.15 years) completed an active stand test, measures of breathing rate and muscle tension, as well as self-reported measures of cOI symptoms and functioning. AYAs showed significant reduction in active stand test heart rate increase ( < 0.001; = 1.07) and maximum heart rate ( = 0.002, = 0.76) from admission to discharge. Improvements were also observed in resting respiration rate ( = 0.001, = 89) and resting trapezoid tension ( = 0.03, = 0.49). Although patients showed significant improvements on self-report measures of functioning ( < 0.001, = 1.78), changes on subjective report of cOI symptoms did not reach significance. Exploratory analyses that only included patients with a POTS diagnosis were consistent with the overall results. Youth who demonstrated excessive postural tachycardia on active stand test at admission to an IIPT showed significant improvements from admission to discharge in their active stand maximum heart rate and heart rate increase, as well as respiration rate, muscle tension, and reports of their functioning. Future research is necessary to examine the mechanisms of change that contribute to symptom improvement.

Cerebral blood flow (CBF) is vital for delivering oxygen and nutrients to the brain. Many forms of orthostatic intolerance (OI) involve impaired regulation of CBF in the upright posture, which results in disabling symptoms that decrease quality of life. Because CBF is not easy to measure, rises in heart rate or drops in blood pressure are used as proxies for abnormal CBF. These result in diagnoses such as postural orthostatic tachycardia syndrome and orthostatic hypotension. However, in many other OI syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and long COVID, heart rate and blood pressure are frequently normal despite significant drops in CBF. This often leads to the incorrect conclusion that there is nothing hemodynamically abnormal in these patients and thus no explanation or treatment is needed. There is a need to measure CBF, as orthostatic hypoperfusion is the shared pathophysiology for all forms of OI. In this review, we examine the literature studying CBF dysfunction in various syndromes with OI and evaluate methods of measuring CBF including transcranial Doppler ultrasound, extracranial cerebral blood flow ultrasound, near infrared spectroscopy, and wearable devices.

Autonomic dysfunction, including postural orthostatic tachycardia syndrome (POTS), has been reported in individuals with post-acute sequelae of COVID-19 (PASC). However, the degree of dysautonomia in PASC has not been compared to those with POTS and healthy controls. All participants were prospectively enrolled between August 5, 2021 and October 31, 2022. Autonomic testing included beat-to-beat hemodynamic monitoring to assess respiratory sinus arrhythmia, Valsalva ratio, and orthostatic changes during a 10-minute active standing test, as well as sudomotor assessment. The Composite Autonomic Symptom Score (COMPASS-31) was used to assess symptoms and the EuroQuol 5-Dimension survey (EQ-5D-5L) was used to assess health-related quality of life (HrQoL) measures. A total of 99 participants (n = 33 PASC, n = 33 POTS, and n = 33 healthy controls; median age 32 years, 85.9% females) were included. Compared with healthy controls, the PASC and POTS cohorts demonstrated significantly reduced respiratory sinus arrhythmia (P < .001), greater heart rate increase during 10-minute active standing test (P < .001), greater burden of autonomic dysfunction evidenced by higher COMPASS-31 scores across all subdomains (all P < .001), and poor HrQoL across all EQ-5D-5L domains (all P < .001), lower median EuroQol-visual analogue scale (P < .001), and lower utility scores (P < .001). The majority (79%) of those with PASC met the internationally established criteria for POTS. The prevalence of autonomic symptomology for POTS was high in those with PASC, leading to poor HrQoL and high health disutility. Autonomic testing should be routinely undertaken in those with PASC to aid diagnosis and direct appropriate management to improve health outcomes.

Postural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasis via the reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. In this study, we reveal NET is palmitoylated in male Sprague-Dawley rats and Lilly Laboratory Cell Porcine Kidney (LLC-PK) cells. S-palmitoylation, or the addition of a 16-carbon saturated fatty acid, is a reversible post-translational modification responsible for the regulation of numerous biological mechanisms. We found that LLC-PK NET is dynamically palmitoylated, and that inhibition with the palmitoyl acyltransferase (DHHC) inhibitor, 2-bromopalmitate (2BP) results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely by a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co-expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted wild-type (WT) hNET palmitoylation and elevated NET protein levels. The POTS-associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression, we co-expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N-terminal immuno-detectable forms and fragments. Elimination of a potential palmitoylation site at cysteine 44 in the N-terminal tail of hNET resulted in a low expression phenotype mimicking the A457P hNET variant. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of adrenergic disorders like POTS.

Cognitive dysfunction is frequently reported in individuals with postural orthostatic tachycardia syndrome (POTS), possibly resulting from reduced cerebral blood flow (CBF). We used brain SPECT, an accessible imaging modality that has not been systematically evaluated in this patient group. Retrospective review of participants from our registry was undertaken to identify those who had a brain SPECT performed for investigation of cognitive dysfunction. Abnormal CBF was taken as z-score > 2 standard deviations of healthy control reference values. Patient reported outcome measures (PROMs) such as autonomic, gastric and quality of life symptom scores were analyzed. From a total of 56 participants (mean 34.8 ± 10.7 years, 88% females), PROMs indicate: moderate to severe autonomic dysfunction in 75%; at least mild to moderate gastroparesis in 23%; low global health rating and utility scores. Abnormal CBF was seen in 61% but did not differ by POTS triggers. The regions with the lowest mean z-scores were the lateral prefrontal and sensorimotor cortices. Hierarchal regression analyses found number of brain regions with abnormal CBF, autonomic and gastric symptoms to account for 51% of variances in health utility. Cerebral hypoperfusion is prevalent in those with POTS and cognitive dysfunction even whilst supine, contributing to reduced quality of life.

Both postural orthostatic tachycardia syndrome (POTS) and Long COVID are currently viewed as heterogeneous disorders with complex, multi-factorial and multi-systemic pathophysiology. POTS, one of the most common autonomic disorders, is a frequent sequela of SARS-CoV-2 infection. Both POTS and autonomic dysfunction, in general, are major pathophysiologic mechanisms of Long COVID. There is emerging evidence that neuroinflammation of the brainstem may be one of the mechanisms of POTS and Long COVID. This commentary argues that neuroinflammation at the dorsolateral inferior medulla is a possible central nervous system localization for POTS and Long COVID based on the limited scientific literature available to date and the neurologic manifestations of both disorders. Further studies involving advanced neuroimaging techniques and animal models with immunohistochemical brainstem tissue assessments are needed to understand how and why possible neuroinflammation at the dorsolateral inferior medulla may occur in patients with Long COVID, POTS and other disorders involving autonomic dysfunction.

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), is increasingly recognized as a condition affecting not only adults but also children and adolescents. While children often experience milder acute COVID-19 symptoms compared to adults, some develop persistent physical, psychological, and neurological symptoms lasting for weeks or months after initial infection. The most commonly reported symptoms include debilitating fatigue, respiratory issues, headaches, muscle pain, gastrointestinal disturbances, and cognitive difficulties, which significantly impact daily activities, schooling, and social interactions. Additionally, many children with long COVID experience psychological symptoms, such as anxiety, depression, mood swings, and irritability, likely exacerbated by prolonged illness and lifestyle disruptions. Risk factors for long COVID in children include pre-existing health conditions such as asthma, obesity, and neurological disorders, with adolescents and females seemingly more affected. Hypothesized mechanisms underlying long COVID include chronic immune dysregulation, persistent viral particles stimulating inflammation, autonomic nervous system dysfunction, and mitochondrial impairment, which may collectively contribute to the variety of observed symptoms. Long-term outcomes remain uncertain; however, long COVID can lead to school absenteeism, social withdrawal, and psychological distress, potentially affecting cognitive development. Severe cases may develop chronic conditions such as postural orthostatic tachycardia syndrome (POTS) and reduced exercise tolerance. This review synthesizes the existing literature on long COVID in children, examining its prevalence, symptomatology, risk factors, and potential mechanisms, with an emphasis on the need for further clinical studies. While existing research largely relies on surveys and self-reported data, clinical assessments are essential to accurately characterize long COVID in pediatric populations and to guide effective management strategies.

Hereditary alpha-tryptasemia (HαT) is associated with postural orthostatic tachycardia syndrome (POTS), hypermobile Ehlers-Danlos syndrome (hEDS), and mast cell activation syndrome (MCAS). While POTS, hEDS, and MCAS have all demonstrated increased prevalence of autoimmunity, this has not been investigated in HαT populations. Our objective was to describe the prevalence of autoantibodies in individuals with HαT. We retrospectively studied a cohort of patients with positive genotyping for HαT at a tertiary-care allergy clinic. Demographic data including previous autoimmune history and autoantibody serologies were extracted on chart review. A literature search was conducted to determine the prevalence of specific autoimmune and autoantibody prevalences in the general population. We compared the proportions of autoantibody positivity and established autoimmune diseases in our cohort of HαT individuals against those in general populations. We identified 101 patients with HαT. Median age was 43 years (range 15-75), and most were female (87/101; 86.1%). Prevalence of self-reported drug hypersensitivity was 52/101 (52.5%) patients. The proportion of individuals with HαT with positive tTG antibody (3/61, 4.9%) was significantly higher than that reported in the general population (133/16,667, 0.8%) (p < 0.001). The prevalence of systemic lupus erythematosus (SLE) (1/101, 1%) and celiac disease (5/101, 5%) in our cohort were found to be significantly higher than the prevalence in the general population (194/96,996, 0.2% [p = 0.035] and 26/2,845, 0.9% [p < 0.001], respectively). Patients with HαT have increased prevalence of celiac disease, SLE, and positive anti-tTG serology, as well as self-reported drug hypersensitivity, relative to general populations.

Since its first description more than a decade ago, our understanding of the clinical impact of hereditary alpha-tryptasemia has continued to evolve. First considered to be a genetic disorder with a subset of patients having a syndromic presentation composed of connective tissue abnormalities, symptoms of autonomic dysfunction, and findings of mast cell activation, we now know that hereditary alpha-tryptasemia is a common genetic trait and modifier of mast cell-mediated reactions. More recent studies have shown some previously held associations with congenital hypermobility and postural orthostatic tachycardia syndrome (POTS) to be lacking, and illuminated previously unappreciated associations with clonal and nonclonal mast cell disorders. With the discovery of heterotetrameric tryptases and demonstration of their unique functional activities, the importance of tryptase gene composition in general has begun to take focus. Hereditary alpha-tryptasemia exists at the end of a spectrum of alpha-tryptase expression and as a natural overexpression model of this protein, brought to the fore the potential of tryptase genotyping as a genetic biomarker for anaphylaxis severity. These data and future studies hold the promise of enhancing our understanding of the role that tryptases play in health and disease.

This study utilized a sample of trangender, nonbinary, and gender-diverse (TGD) patients to build on emerging literature that suggests that hypermobile Ehlers-Danlos syndrome may be overrepresented in TGD populations. The objective of this retrospective chart review was to determine the prevalence of hypermobile Ehlers-Danlos syndrome syndrome at a gender-affirming primary care clinic. A retrospective chart review of medical records was conducted with records between May 2021 and June 2024. Eligible participants were active patients at the gender-affirming primary care clinic, who were over the age of 16, were TGD, and had a diagnosis of hypermobile Ehlers-Danlos syndrome. Of 2180 patients over the age of 16, 59 patients met the criteria. The primary outcome was the prevalence of hypermobile Ehlers-Danlos syndrome in the sample, summarized by frequency and percentage. Secondary outcomes were the prevalence of associated clinical features within the sample of TGD patients with hypermobile Ehlers-Danlos syndrome. The prevalence of hypermobile Ehlers-Danlos syndrome syndrome was 2.7%. Within the sample of patients with hypermobile Ehlers-Danlos syndrome, 81.4% were found to have diagnoses of anxiety, depression, or attention deficit hyperactivity disorder, 50.8% had a history of migraines or dysautonomia, 39.0% had a history of gastroesophageal reflux disease, irritable bowel syndrome, nausea, diarrhea, or gastroparesis, 16.9% had history of mast cell activation disorder, 32.2% had postural orthostatic tachycardia syndrome, 30.5% had dysmenorrhea, 83.1% reported chronic pain, and 44.1% reported chronic fatigue. We found that 2.7% of the 2180 patients had a diagnosis of hypermobile Ehlers-Danlos syndrome syndrome. The sample had notably high rates of medical comorbidities as well as anxiety, depression, or attention deficit hyperactivity disorder, consistent with emerging research. The results support the intersecting psychological and healthcare vulnerabilities of TGD patients with hypermobile Ehlers-Danlos syndrome. Further research in this intersection could support mitigation of health care disparities that affect TGD patients with hypermobile Ehlers-Danlos syndrome syndrome.

Hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (h-EDS) are connective tissue disorders associated with joint hypermobility, pain, fatigue and autonomic dysfunction. We sought to assess sexual function in women with h-EDS/HSD. In this cross-sectional community-based case-control study, women with h-EDS/HSD completed the following online questionnaires: Female Sexual Function Index (FSFI), 31-item Composite Autonomic Symptom Score (COMPASS-31), Beck Depression Inventory-II (BDI-II) and an additional short form with questions pertaining to comorbidities and sexual activity. Scores were compared with those of healthy female controls. A total of 84 women with h-EDS/HSD [mean age 37.1 years (s.d. 8.4)] and 75 healthy women [mean age 29.79 years (s.d. 5.38)] completed the questionnaires. Of these, 75% were diagnosed with h-EDS, 25% with HSD and 58% had concurrent postural orthostatic tachycardia syndrome. A majority of women with h-EDS/HSD (52%) did not engage in any sexual activity, and only 25% reported having sexual intercourse with a partner in the past 6 months. The mean COMPASS-31 score was 51.5 (s.d. 13.8), mean BDI-II score was 24.6 (s.d. 11.4) and mean FSFI score was 15.3 (s.d. 7.9) in the patient group. Compared with healthy controls, women with h-EDS/HSD had decreased FSFI scores in the subdomains of desire, arousal, lubrication, orgasm and sexual satisfaction. Neither BDI-II nor COMPASS-31 scores were predictive of the FSFI score. Compared with healthy women, we found significant sexual dysfunction in women with h-EDS/HSD, which did not correlate with depressive or autonomic symptoms in this cohort. Given its health implications, sexual dysfunction represents a significant unmet need that calls for development of targeted diagnostic and therapeutic approaches in the care of women with h-EDS/HSD.

Orthostatic intolerance, with or without postural orthostatic tachycardia syndrome (POTS), is collectively referred to as orthostatic intolerance dysautonomia syndromes (OIDS). This condition often presents with daytime hyperventilation, which is considered to be secondary to sympathetic hyperactivity. This hyperventilation appears to be a key characteristic in a newly described subset of patients with OIDS who also exhibit craniocervical instability, mast cell activation syndrome (MCAS), hypermobility spectrum disorder (HSD), and the phenomenon of alternating intracranial hypertension with hypotension due to cerebrospinal fluid (CSF) leaks, collectively termed Spiky-Leaky Syndrome (SLS). We performed a retrospective review of clinical metabolic exercise data in young patients with SLS, comparing them to matched patients with OIDS and healthy controls (CTL). We assessed metabolic parameters at rest, at the anaerobic threshold (AT), and at maximal oxygen consumption (VOmax). The parameters included end-tidal CO (ETCO), end-tidal O (ETO), peak oxygen pulse, total work performed, and peak oxygen uptake efficiency slope (OUESp). Of 323 reviewed exercise stress tests, 44 were conducted on patients with SLS, 210 on those with OIDS, and 53 on healthy controls. VOmax, AT, peak oxygen pulse, total work performed, and OUESp were all significantly reduced in patients with OIDS and were further reduced in those with SLS. ETCO levels were notably lower at rest, at the time of the anaerobic threshold, and at the time of maximal oxygen uptake in the OIDS group, and even more so in the SLS group. These lower levels of ETCO persisted throughout exercise. In contrast, ETO demonstrated a similarly strong but opposite trend. Compared to the control group, patients with OIDS-and especially those with SLS-exhibited reduced metabolic parameters, particularly a decrease in peak oxygen pulse and ETCO levels during both rest and exercise. These findings suggest a reduction in ventricular preload and chronic daytime hyperventilation. These exercise parameters may serve as markers for POTS physiology and sympathetic hyperactivity, both of which could play a role in the pathophysiology of SLS.

The close association of syndromes of orthostatic intolerance with and without postural orthostatic tachycardia syndrome (POTS) with Joint Hypermobility Disorders (JHD) including Hypermobility Spectrum Disorder (HSD) and hypermobile Ehlers Danlos Syndrome (hEDS) and with Mast Cell Activation Syndrome (MCAS) is now firmly established. However, the prevalence of each entity relative to the other is not well established and is affected greatly by the various definitions used for each syndrome. Use of restricting definitions for each syndrome can be problematic in the clinical setting as it under-estimates the presence of disease, thereby preventing clinicians from considering potentially helpful therapeutic options. A retrospective review of the clinical records of 100 young patients meeting POTS criteria was undertaken to determine the frequency of HSD, near-hEDS, and hEDS as well as the frequency of MCAS using consensus-1, conservative consensus-2, and clinical criteria regardless of lab support. Effectiveness of MCAS therapies was assessed in relation to the method of MCAS diagnosis. From records of 392 patients with orthostatic intolerance syndromes, 100 patients met POTS criteria. The frequency of JHD ranged from 13% using strict criteria of hEDS to 34% using HSD Criteria. The frequency of MCAS ranged from 2% using consensus-1 criteria, to 37% using conservative consensus-2 criteria, to 87% using clinical criteria. Patients diagnosed by clinical criteria with or without the aid of labs responded to therapy similarly to those diagnosed with stricter criteria. Using overly strict criteria to diagnose conditions which have a high prevalence of co-occurrence misses opportunities for potential therapeutic strategies.