Detransition and Desistance Among Previously Trans-Identified Young Adults.

Persons who have renounced a prior transgender identification, often after some degree of social and medical transition, are increasingly visible. We recruited 78 US individuals ages 18-33 years who previously identified as transgender and had stopped identifying as transgender at least six months prior. On average, participants first identified as transgender at 17.1 years of age and had done so for 5.4 years at the time of their participation. Most (83%) participants had taken several steps toward social transition and 68% had taken at least one medical step. By retrospective reports, fewer than 17% of participants met DSM-5 diagnostic criteria for Gender Dysphoria in Childhood. In contrast, 53% of participants believed that "rapid-onset gender dysphoria" applied to them. Participants reported a high rate of psychiatric diagnoses, with many of these prior to trans-identification. Most participants (N = 71, 91%) were natal females. Females (43%) were more likely than males (0%) to be exclusively homosexual. Participants reported that their psychological health had improved dramatically since detransition/desistance, with marked decreases in self-harm and gender dysphoria and marked increases in flourishing. The most common reason given for initial trans-identification was confusing mental health issues or reactions to trauma for gender dysphoria. Reasons for detransition were more likely to reflect internal changes (e.g., the participants' own thought processes) than external pressures (e.g., pressure from family). Results suggest that, for some transgender individuals, detransition is both possible and beneficial.

Efficacy and safety of fentanyl inhalant for the treatment of breakthrough cancer pain: a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Breakthrough cancer pain (BTcP) has a negative impact on patients' quality of life, general activities, and is related to worse clinical outcomes. Fentanyl inhalant is a hand-held combination drug-device delivery system providing rapid, multi-dose (25µg/dose) administration of fentanyl via inhalation of a thermally generated aerosol. This multicenter, randomized, placebo-controlled, multiple-crossover, double-blind study evaluated the efficacy, safety, and tolerability of fentanyl inhalant in treating BTcP in opioid-tolerant patients. METHODS: The trial was conducted in opioid-tolerant cancer patients with 1 ~ 4 BTcP outbursts per day. Each patient was treated and observed for 6 episodes of BTcP (4 with fentanyl inhalant, 2 with placebo). During each episode of targeted BTcP, patients were allowed up to six inhalations, with an interval of at least 4 min between doses. Primary outcome was the time-weighted sum of PID (pain intensity difference) scores at 30 min (SPID30). RESULTS: A total of 335 BTcP episodes in 59 patients were treated. The mean SPID30 was -97.4 ± 48.43 for fentanyl inhalant-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes (p < 0.001). Significant differences in PID for episodes treated with fentanyl inhalant versus placebo was seen as early as 4 min and maintained for up to 60 min. The percentage of episodes reported PI (pain intensity) scores ≤ 3, a ≥ 33% or ≥ 50% reduction in PI scores at 30 min, PR30 (pain relief scores at 30 min) and SPID60 favored fentanyl inhalant over placebo. Only 4.4% of BTcP episodes required rescue medication in fentanyl inhalant group. Most AEs were of mild or moderate severity and typical of opioid drugs. CONCLUSION: Treatment with fentanyl inhalant was shown to be a promising therapeutic option for BTcP, with significant pain relief starting very soon after dosing. Confirmation of effectiveness requires a larger phase III trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05531422 registered on 6 September 2022 after major amendment, NCT04713189 registered on 14 January 2021.

Effectiveness of fentanyl buccal soluble film in cancer patients with inadequate breakthrough pain control.

BACKGROUND: Clinical evidence for the rapidity and effectiveness of fentanyl buccal soluble film (FBSF) in reducing pain intensity of breakthrough cancer pain (BTcP) remains inadequate. This study aimed to evaluate the efficacy of FBSF proportional to the around-the-clock (ATC) opioid regimens in rapidly relieving the intensity of BTcP episodes by determining the percentage of patients requiring further dose titration. METHODS: The study procedure included a dose-finding period followed by a 14-day observation period. Pain intensity was recorded with a Numeric Rating Scale (NRS) at onset and 5, 10, 15, and 30 min after FBSF self-administration. Meaningful pain relief was defined as the final NRS score ≤ 3. Satisfaction survey was conducted for each patient after treatment using the Global Satisfaction Scale. RESULTS: A total of 63 BTcP episodes occurred in 30 cancer patients. Only one patient required rescue medication at first BTcP episode and then achieved meaningful pain relief after titrating FBSF by 200 µg. Most BTcP episodes relieved within 10 min. Of 63 BTcP episodes, 30 (47.6%), 46 (73.0%), and 53 (84.1%) relieved within 5, 10, and 15 min after FBSF administration. Only grade 1/2 adverse events were reported, including somnolence, malaise, and dizziness. Of the 63 BTcP episodes, 82.6% were rated as excellent/good satisfaction with FBSF. CONCLUSION: FBSF can be administrated "on demand" by cancer patients at the onset of BTcP, providing rapid analgesia by achieving meaningful pain relief within 10 min. TRIAL REGISTRATION: This study was retrospectively registered 24 December, 2021 at Clinicaltrial.gov (NCT05209906): https://clinicaltrials.gov/study/NCT05209906 .

Anti-ZSCAN1 Autoantibodies Are a Feasible Diagnostic Marker for ROHHAD Syndrome Not Associated with a Tumor.

Recent studies have reported the presence of autoantibodies against zinc finger and SCAN domain-containing protein 1 (ZSCAN1) in the sera of patients with rapid-onset obesity with hypoventilation, hypothalamic and autonomic dysregulation (ROHHAD) syndrome associated with neuroendocrine tumors, suggesting immunologic and paraneoplastic processes as the pathologic underpinnings. Moreover, several hypothalamic regions, including the subfornical organ (SFO), were reported to exhibit antibody reactivity in a patient with ROHHAD syndrome not associated with a tumor. Whether ROHHAD syndrome not associated with a tumor is associated with anti-ZSCAN1 autoantibodies remains unclear. We used a comprehensive protein array analysis to identify candidate molecules in the sera of patients with ROHHAD syndrome and identified ZSCAN1 as a target antigen. We also found that ZSCAN1 was co-expressed at the site of antibody reactivity to the IgG in the patient serum observed in mouse SFOs and an enzyme-linked immunosorbent assay showed that >85% of the patients with ROHHAD syndrome were positive for anti-ZSCAN1 autoantibodies. These results suggest anti-ZSCAN1 autoantibodies as a feasible diagnostic marker in ROHHAD syndrome regardless of the presence of a tumor.

Rapid onset vasodilation during baroreceptor loading and unloading.

The purpose of these experiments was to determine if the increase in vascular conductance following a single muscle contraction (50% of maximal voluntary contraction) (6 male and 6 female subjects) was altered during baroceptor loading and unloading. Rapid onset vasodilation (ROV) was determined by measuring brachial artery blood flow (Doppler ultrasound) and blood pressure (Finapress monitor). Brachial artery vascular conductance was calculated by dividing blood flow by mean arterial pressure. ROV was described by the area under the Δvascular conductance (VC)-time curve during the 30 s following muscle contraction. ROV was determined using chamber pressures of +20, +10, 0, -10, -20, and -40 mmHg (lower body positive and negative pressure, LBPP, and LBNP). We tested the hypothesis that the impact of baroreceptor loading and unloading produces a proportion change in ROV. The level of ROV following each contraction was proportional to the peak force (r2 = 0.393, P = 0.0001). Peak force was therefore used as a covariate in further analysis. ROV during application of -40 mmHg LBNP (0.345 ± 0.229 mL·mmHg-1) was lower than that observed at Control (0.532 ± 0.284 mL·mmHg-1, P = 0.034) and +20 mmHg LBPP (0.658 ± 0.364 mL·mmHg-1, P = 0.0008). ROV was linearly related to chamber pressure from -40 to +20 mmHg chamber pressure (r2 = 0.512, P = 0.022, n = 69) and from -20 to +10 mmHg chamber pressure (r2= 0.973, P < 0.0425, n = 45), Overall, vasoconstrictor tone altered with physiologically relevant baroreceptor loading and unloading resulted in a proportion change in ROV.NEW & NOTEWORTHY Rapid onset vasodilation (ROV) was linearly related to the peak force of each single 1-s muscle contraction. In addition, ROV is reduced by baroreceptor unloading (LBNP: -10, -120, and -40 mmHg) and increased by baroreceptor loading (LBPP: +10 and +20 mmHg). Without accounting for peak force and the level of baroreceptor engagement makes comparison of ROV in subjects of differing muscle size or strength untenable.

A randomized phase 2b efficacy study in patients with seizure episodes with a predictable pattern using Staccato® alprazolam for rapid seizure termination.

OBJECTIVE: Alprazolam administered via the Staccato® breath-actuated device is delivered into the deep lung for rapid systemic exposure and is a potential therapy for rapid epileptic seizure termination (REST). We conducted an inpatient study (ENGAGE-E-001 [NCT03478982]) in patients with stereotypic seizure episodes with prolonged or repetitive seizures to determine whether Staccato alprazolam rapidly terminates seizures in a small observed population after administration under direct supervision. METHODS: Adult patients with established diagnosis of focal and/or generalized epilepsy with a documented history of seizure episodes with a predictable pattern were enrolled. They were randomized 1:1:1 to double-blind treatment of a single seizure event with one dose of Staccato alprazolam 1.0 mg or 2.0 mg, or Staccato placebo in an inpatient unit. The primary end point of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 min after administration of study drug and no recurrence of seizure activity within 2 h. RESULTS: A total of 273 patients were screened, and 116 randomized patients received treatment with the study drug in the double-blind part. The proportion of treated patients who were responders was 65.8% for each of Staccato alprazolam 1.0 mg (n = 38; p = .0392) and 2.0 mg (n = 38; p = .0392), compared with 42.5% for Staccato placebo (n = 40). Staccato alprazolam was well tolerated when administered as a single dose of 1.0 or 2.0 mg: cough and somnolence were the most common adverse events (AEs) (both 14.5%), followed by dysgeusia (13.2%). AEs were mostly mild or moderate in intensity; there were no treatment-related serious AEs. SIGNIFICANCE: Both 1.0 mg and 2.0 mg doses of Staccato alprazolam demonstrated efficacy in rapidly terminating seizures in an inpatient setting and were well tolerated. The next step is a Phase 3 confirmatory study to demonstrate efficacy and safety of Staccato alprazolam for rapid cessation of seizures in an outpatient setting.

Rapid Onset Gender Dysphoria: Parent Reports on 1655 Possible Cases.

During the past decade there has been a dramatic increase in adolescents and young adults (AYA) complaining of gender dysphoria. One influential if controversial explanation is that the increase reflects a socially contagious syndrome: Rapid Onset Gender Dysphoria (ROGD). We report results from a survey of parents who contacted the website ParentsofROGDKids.com because they believed their AYA children had ROGD. Results focused on 1655 AYA children whose gender dysphoria reportedly began between ages 11 and 21 years, inclusive. These youths were disproportionately (75%) natal female. Natal males had later onset (by 1.9 years) than females, and they were much less likely to have taken steps toward social gender transition (65.7% for females versus 28.6% for males). Pre-existing mental health issues were common, and youths with these issues were more likely than those without them to have socially and medically transitioned. Parents reported that they had often felt pressured by clinicians to affirm their AYA child's new gender and support their transition. According to the parents, AYA children's mental health deteriorated considerably after social transition. We discuss potential biases of survey responses from this sample and conclude that there is presently no reason to believe that reports of parents who support gender transition are more accurate than those who oppose transition. To resolve controversies regarding ROGD, it is desirable that future research includes data provided by both pro- and anti-transition parents, as well as their gender dysphoric AYA children.

Neurocognition as a biomarker in the rare autonomic disorders of CCHS and ROHHAD.

PURPOSE: Congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) are rare disorders of autonomic regulation with risk for disrupted neurocognitive development. Our aim is to summarize research on neurocognitive outcomes in these conditions, advance understanding of how to best support these individuals throughout development, and facilitate future research. METHODS: We conducted a narrative review of literature on neurocognitive outcomes in CCHS and ROHHAD, supplemented with previously unpublished data from patients with CCHS and ROHHAD at our Center for Autonomic Medicine in Pediatrics (CAMP). RESULTS: Individuals with CCHS and ROHHAD experience a wide range of neurocognitive functioning ranging from above average to below average, but are at particular risk for difficulties with working memory, processing speed, perceptual reasoning, and visuographic skills. An assessment framework emphasizing fluid cognition seems especially appropriate for these conditions. Owing to small cohorts and varied methods of data collection, it has been difficult to identify associations between disease factors (including CCHS PHOX2B genotypes) and cognitive outcomes. However, results suggest that early childhood is a period of particular vulnerability, perhaps due to the disruptive impact of recurrent intermittent hypoxic episodes on brain and cognitive development. CONCLUSION: Neurocognitive monitoring is recommended as a component of routine clinical care in CCHS and ROHHAD as a marker of disease status and to ensure that educational support and disability accommodations are provided as early as possible. Collaborative efforts will be essential to obtain samples needed to enhance our understanding of neurocognitive outcomes in CCHS and ROHHAD.

Histologic Outcomes With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With Ulcerative Colitis (VARSITY).

BACKGROUND AND AIMS: VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis) showed superior clinical remission and endoscopic improvement in ulcerative colitis with vedolizumab vs adalimumab. This analysis compared histologic outcomes. METHODS: Patients in VARSITY were randomized 1:1 to maintenance with vedolizumab IV 300 mg every 8 weeks or adalimumab SC 40 mg every 2 weeks (both following standard induction). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52. RESULTS: In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Mean baseline histologic disease activity was similar between vedolizumab and adalimumab groups. Vedolizumab induced greater histologic remission than adalimumab at week 14 (Geboes: 16.7% vs 7.3%, Δ9.4% [95% confidence interval {CI}, 4.9%-13.9%], P < .0001; RHI: 25.6% vs 16.1%, Δ9.5% [95% CI, 3.8%-15.2%], P = .0011) and week 52 (Geboes: 29.2% vs 8.3%, Δ20.9% [95% CI, 15.6%-26.2%], P < .0001; RHI: 37.6% vs 19.9%, Δ17.6% [95% CI, 11.3%-23.8%], P < .0001) overall and in both anti-tumor necrosis factor (TNF)-naïve and -failure subgroups. Results were similar for minimal histologic disease activity. Histologic outcomes were generally better in anti-TNF-naïve vs -failure patients. At week 52, rates of mucosal healing (composite end point of histologic plus endoscopic improvement) were also higher with vedolizumab than adalimumab (Geboes: 25.6% vs 6.7%; RHI: 30.5% vs 14.5%). CONCLUSIONS: Higher rates of histologic remission, minimal histologic disease activity, and combined histologic plus endoscopic outcomes were observed with vedolizumab than with adalimumab in ulcerative colitis in both anti-TNF-naïve and -failure subgroups. REGISTRATION: ClinicalTrials.gov NCT02497469; EudraCT 2015-000939-33.

Increased quality of life in patients with breakthrough cancer pain after individualized therapy: the CAVIDIOM study.

Aim: To evaluate the quality of life (QoL) in patients with breakthrough cancer pain (BTcP) in Spanish medical oncology departments. Patients & methods: In a prospective, observational, multicenter study, we assessed QoL using the EQ-5D-5L instrument at baseline and after 15 and 30 days of individualized BTcP therapy, as well as BTcP characteristics and treatment. Results: Patients (n = 118) were mainly women, over 64 years old and with advanced cancer. QoL improved at 15 (p = 0.013) and 30 days (p = 0.011) versus baseline. Individualized BTcP therapy consisted mostly of rapid-onset opioids (transmucosal fentanyl at doses of 67-800 µg) according to the physician evaluation. BTcP improved, including statistically significant reductions in intensity, duration, number of episodes in the last 24 h and time to onset of BTcP relief. Conclusion: QoL increased after individualized pain therapy in patients with advanced cancer and BTcP in medical oncology departments.

Cancer patients can experience flares of pain, called breakthrough pain (BTcP), despite treatment with painkillers. Although BTcP can be excruciating, its intensity and other characteristics depend on several factors, including its treatment. However, even if treated, BTcP can impair quality of life for cancer patients. We assessed quality of life in 118 patients with advanced cancer and BTcP treated in 13 medical oncology departments across Spain. We treated BTcP with individualized therapy, taking into account both pain-related and patient-related factors. We also measured quality of life using a specific, widely-used questionnaire at the study visits: at onset of individualized pain therapy and after 3, 15 and 30 days' treatment. At each visit, flare-up pain therapy was adjusted or maintained as necessary. Throughout the study, quality of life and sleep quality improved for all participants. Furthermore, there was a greater reduction in intensity, duration and frequency of BTcP. The most common treatments for flare-ups were low doses of rapid-onset opioids (fentanyl given by sublingual, buccal or nasal administration), which were much better tolerated than high-dose opioids. Overall, the study showed that quality of life in patients with advanced cancer and BTcP increased after individualized pain therapy, mainly with low doses of rapid-onset opioids.

Different phenotypes of neurological diseases, including alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism, caused by de novo ATP1A3 mutation in a family.

BACKGROUND: The spectrum of neurological diseases related to ATP1A3 gene mutations is highly heterogeneous and exhibits different phenotypes. Phenotype overlaps, including alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy, and rapid-onset dystonia-parkinsonism (RDP), can also occur at extremely low incidences. Currently, over 90 types of pathogenic mutations have been identified in ATP1A3. PATIENTS AND METHODS: The family of a 2-year-11-month-old proband with AHC was recruited for this clinical investigation. The proband was screened for candidate mutation gene sites using next-generation sequencing and target-region capture technology. Sanger sequencing was used to identify carriers among family members. RESULTS: The mother of the proband with AHC was diagnosed with dystonia (later diagnosed as RDP). The biochemical and immune indices of the proband and the mother were not abnormal. Moreover, brain imaging of the proband revealed no significant abnormalities. However, the electroencephalogram of the mother was mildly abnormal, with no spike wave discharge. Brain MRI revealed slight cerebellar atrophy. Electromyography revealed neurogenic damage, with a decrease in the conduction velocity of the left ulnar and radial nerves. Based on the sequencing data, both the proband and her mother carried c.823G > C p. (Ala275Pro) heterozygotes; other family members were not identified as carriers. With a PolyPhen-2 score of 0.997 and SIFT score of 0.001, this mutation can be considered damaging. CONCLUSION: Family genotype-phenotype correlation analysis revealed that the phenotype and gene mutation were co-segregated, suggesting that it may be a pathogenic mutation.

Early response to trazodone once-a-day in major depressive disorder: review of the clinical data and putative mechanism for faster onset of action.

BACKGROUND: Most antidepressants have a delayed onset of action and must be administered for several weeks to generate therapeutic effects. Trazodone is a serotonin antagonist and reuptake inhibitor approved for the treatment of major depressive disorder. The once-a-day (OAD) formulation of trazodone has an improved tolerability profile compared to its conventional formulations. In this study, we systematically reviewed the evidence available for the antidepressant efficacy and early improvement in depressive symptoms with trazodone OAD treatment. METHOD: We conducted a PubMed database search for randomized controlled trials published from 2005 to 2020. RESULTS: Two studies, a placebo-controlled and an active-comparator (venlafaxine extended-release or XR) study were found. Both the studies demonstrated that trazodone exhibits antidepressant activity at a starting dose of 150 mg/day and results in statistically significant greater reduction in Hamilton Depression Rating Scale (HAM-D17) scores within 1 week of starting treatment compared to placebo or venlafaxine XR (P < .05). Trazodone also resulted in significant early improvement in the HAM-D17 sleep disturbance factor compared to placebo or venlafaxine XR at day 7 (P < .05). This clinical effect is supported by in vitro proprietary data for the affinity of trazodone for different target receptors. Activity at these receptors may underlie trazodone's fast antidepressant action. CONCLUSIONS: Trazodone, if properly dosed, can be an effective antidepressant with early onset of action and good tolerability. Future studies designed to specifically evaluate onset and timing of improvement of depressive symptoms remain necessary to confirm and extend these results.

Esketamine: a glimmer of hope in treatment-resistant depression.

The motive of this article is to review the pharmacological and clinical aspects of esketamine (ESK), an NMDA-receptor antagonist approved recently by the FDA for treatment-resistant depression (TRD). PubMed/Medline database was searched using keywords 'esketamine' and 'depression', 'S-ketamine' and 'depression', and 'NMDA antagonist' and 'depression'. Individual trials were searched from ClinicalTrials.gov. We included English-language articles evaluating pharmacokinetics and pharmacodynamics of intranasal (IN) esketamine, along with clinical trial data related to its efficacy and safety in patients diagnosed with TRD. Compared to placebo, IN esketamine causes significant and rapid improvement in depression. Dizziness, vertigo, headache, increase in blood pressure are some of its common adverse effects. With the growing number of patients of TRD, additional effective and safe treatment is the need of the hour. Esketamine appears to be an effective therapy when combined with oral antidepressants in patients with TRD. It is of special value due to the rapid onset of its action. Long-term clinical studies are, however, needed to ascertain its safety profile.

Preparation, characterization and in-Vitro/in-Vivo evaluation of meloxicam extruded pellets with enhanced bioavailability and stability.

OBJECTIVE: The present study involved enhancement of Meloxicam (MX) oral absorption for rapid onset of therapeutic action. A challenging approach using hot-melt-extrusion technique (HME) for production of stable novel preparation of MX pellets was successfully proposed. METHODS: Manipulating HME processing parameters (barrel-temperatures and screw-speed) and proper polymer(s) selection (Soluplus, a combination of Soluplus/Poloxamar and Polyethylene Glycol 6000) were the main strategies involved for productive extrusion of MX. Evaluation of MX solid-state (TGA, DSC and PLM), absolute percent crystallinity, in-vitro dissolution (in acidic/aqueous pHs), and stability testing in accelerated conditions up to 6-months as well as a long-term shelf for 36-months were performed. A comparative bioavailability study of selected MX-Pellets was carried-out against the innovator product (Mobic®) in 6 healthy volunteers under fed-conditions. RESULTS: TGA, DSC and PLM analyses proved the dispersion of MX in amorphous-state within polymeric matrix by HME. MX/Soluplus pellets exhibited the lowest crystallinity % and best dissolution performance among other polymers in both pHs. In addition, presence of Soluplus safeguards final pellets stability under different storage conditions. MX rate of absorption (Tmax) from Soluplus-based pellets attained a value of 45 min, which was 6-times faster than Mobic® (4.5 hr). CONCLUSION: A promising oral MX formula prepared by HME was successfully developed with a rapid onset of analgesic action (Tmax of 45 mins; almost 2-times faster than reported intramuscular injection), hence appropriate in the early relief of pain associated with rheumatoid arthritis and osteoarthritis. Moreover, the proposed formula was physico-chemically stable up to 36 months of shelf-life storage.

Greater post-contraction hyperaemia below vs. above heart level: the role of active vasodilatation vs. passive mechanical distension of arterioles.

KEY POINTS: The immediate increase in skeletal muscle blood flow following contraction is greater when the contracting muscle is below vs. above heart level. This has been attributed to muscle pump-mediated venous emptying and subsequent widening of the arterial to venous pressure gradient, which can occur below but not above heart level. However, alternative explanations could include greater rapid onset vasodilatation and/or transmural pressure-mediated mechanical distension of resistance vessels, but these remain unexplored. We demonstrate that active vasodilatation is not responsible for greater post-contraction hyperaemia below the heart. Instead, an increased transmural pressure-mediated mechanical distension of resistance vessels is a key mechanism responsible for this phenomenon. Our findings establish the importance of considering/accounting for local mechanical arteriolar distension effects when investigating exercise hyperaemia. They also inform the application of exercise for rehabilitative purposes and prompt investigation into whether arteriolar distension accompanying vasodilatation is reduced with diseases or ageing, thereby compromising exercising muscle perfusion. ABSTRACT: We tested the hypotheses that increased post-contraction hyperaemia in higher (H; below heart) vs. lower (L; above heart) transmural pressure conditions is due to (1) greater active vasodilatation or (2) greater transmural pressure-mediated arteriolar distension. Participants (n = 20, 12 male, 8 female; combined mean age 24.5 ± 2 years) performed a 2 s isometric handgrip contraction, where arm position was maintained within or changed between H and L during contraction, resulting in four starting-finishing arm position conditions (LL, HL, LH, HH). Post-contraction forearm blood flow (echo and Doppler ultrasound) was higher with contraction release in H vs. L environments (P < 0.05). However, contraction initiated in H did not result in greater vasodilatation (forearm vascular conductance; FVC) than contraction initiated in L, regardless of contraction release condition (peak FVC: LL 217 ± 104 vs. HL 204 ± 92 ml min-1 (100 mmHg)-1 , P = 0.313, LH 229 ± 8 vs. HH 225 ± 85 ml min-1 (100 mmHg)-1 , P = 0.391; first post-contraction cardiac cycle FVC: same comparisons, both P = 0.317). However, FVC of the first post-contraction cardiac cycle was greater for contractions released in H vs. L regardless of pre-contraction condition (LL 106 ± 67 vs. LH 152 ± 76 ml min-1 (100 mmHg)-1 , P < 0.05; HL 80 ± 51 vs. HH 119 ± 58 ml min-1 (100 mmHg)-1 , P < 0.05). These findings refute the hypothesis that greater hyperaemia following a single contraction in higher transmural pressure conditions is due to greater active vasodilatation. Instead, our findings reveal a key role for increased transmural pressure-mediated mechanical distension of arterioles in creating a greater increase in vascular conductance for a given active vasodilatation following skeletal muscle contraction.

Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity.

Heterozygous mutations in the ATP1A3 gene, coding for an alpha subunit isoform (α3) of Na+/K+-ATPase, are the primary genetic cause for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), early infantile epileptic encephalopathy (EIEE), childhood rapid onset ataxia (CROA) and relapsing encephalopathy with rapid onset ataxia (RECA) extend the clinical spectrum of ATP1A3 related disorders. AHC and RDP demonstrate distinct clinical features, with AHC symptoms being generally more severe compared to RDP. Currently, it is largely unknown what determines the disease severity, and whether severity is linked to the degree of functional impairment of the α3 subunit. Here we compared the effect of twelve different RDP and AHC specific mutations on the expression and function of the α3 Na+/K+-ATPase in transfected HEK cells and oocytes. All studied mutations led to functional impairment of the pump, as reflected by lower survival rate and reduced pump current. No difference in the extent of impairment, nor in the expression level, was found between the two phenotypes, suggesting that these measures of pump dysfunction do not exclusively determine the disease severity.

The Expanding Phenotypic Spectrums Associated with ATP1A3 Mutation in a Family with Rapid-Onset Dystonia Parkinsonism.

INTRODUCTION: Rapid-onset dystonia parkinsonism (RDP), also referred to as Dystonia 12, is a rare autosomal dominant genetic disease characterized by abrupt onset of a rostrocaudal gradient of dystonia with prominent bulbar symptoms, and parkinsonian features, primarily bradykinesia and postural instability without tremor. The purpose of this study was to identify the genetic defect in a Chinese pedigree with familial RDP and to explore genotype-phenotype correlation. METHODS: A 3-generation Chinese Han pedigree consisting of 9 members and 3 patients with RDP, and 200 unrelated ethnically matched normal subjects were recruited in this study. Exome sequencing was performed in the proband, and Sanger sequencing was then conducted in other family members and 200 normal controls. RESULTS: In addition to the typical clinical manifestations of RDP, the proband and her sister presented tongue tremor which developed at the onset, and intriguingly the proband showed a "re-emergent" tongue tremor. Both the proband and her sister had a medical history of hyperthyroidism, and at the psychiatric interview they both received diagnoses of depression and anxiety. Excessive grammar errors existed in most sentences written by the proband, and this written-expression disorder occurred years before the onset of RDP. The mother of the proband presented tongue enlargement, oromandibular dystonia, and limb dystonia, which were not observed in her 2 daughters at the time of study. A missense variant, c.1838C>T (p.T613M), in the ATP1A3 gene, was identified in the 3 patients in the family and in 2 young children but was absent in family members without RDP and in the 200 normal controls. CONCLUSION: These findings may broaden the phenotypic spectrums of RDP with mutations in the ATP1A3 gene, provide new insights into the diagnosis of RDP, and have implications for genetic counseling.

Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants.

OBJECTIVE: Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. METHODS: Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. RESULTS: Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. SIGNIFICANCE: This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.

Adolescents with Gender Dysphoria: Reflections on Some Contemporary Clinical and Research Issues.

This article provides an overview of five contemporary clinical and research issues pertaining to adolescents with a diagnosis of gender dysphoria: (1) increased referrals to specialized gender identity clinics; (2) alteration in the sex ratio; (3) suicidality; (4) "rapid-onset gender dysphoria" (ROGD) as a new developmental pathway; (5) and best practice clinical care for adolescents who may have ROGD.

Childhood Rapid-Onset Ataxia: Expanding the Phenotypic Spectrum of ATP1A3 Mutations.

ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in ATP1A3-related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different ATP1A3 variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of ATP1A3 mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of ATP1A3-related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model.