MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Appeared originally in Nat Med 2021; 27:1025-1033.

Prevention of pulmonary complications in sedated patients undergoing interventional procedures in the nonoperating room anesthesia setting.

PURPOSE OF REVIEW: Nonoperating room anesthesia (NORA) procedures have expanded in number, variety, and complexity. NORA involves all age groups, including frail older adults and patients often considered too sick to tolerate traditional surgical interventions. Postoperative pulmonary complications are a significant source of adverse events in the perioperative setting. We present a review focused on preventing pulmonary complications in the interventional NORA setting. RECENT FINDINGS: NORA locations should function as independent, autonomous ambulatory units. We discuss a strategic plan involving a thorough preoperative evaluation of patients, including recognizing high-risk patients and their anesthetic management. Finally, we offer guidance on the challenges of conducting sedation and anesthesia in patients with coronavirus disease 2019 (COVID-19) or a history of COVID-19. SUMMARY: The demands on the interventional NORA anesthesia team are increasing. Strategic planning, checklists, consistent staffing assignments, and scheduled safety drills are valuable tools to improve patient safety. In addition, through quality improvement initiatives and reporting, NORA anesthetists can achieve reductions in periprocedural pulmonary complications.

Non-invasive MR imaging techniques for measuring femoral arterial flow in a pediatric and adolescent cohort.

Magnetic Resonance Imaging (MRI) is well-suited for imaging peripheral blood flow due to its non-invasive nature and excellent spatial resolution. Although MRI is routinely used in adults to assess physiological changes in chronic diseases, there are currently no MRI-based data quantifying arterial flow in pediatric or adolescent populations during exercise. Therefore the current research sought to document femoral arterial blood flow at rest and following exercise in a pediatric-adolescent population using phase contrast MRI, and to present test-retest reliability data for this method. Ten healthy children and adolescents (4 male; mean age 14.8 ± 2.4 years) completed bloodwork and resting and exercise MRI. Baseline images consisted of PC-MRI of the femoral artery at rest and following a 5 × 30 s of in-magnet exercise. To evaluate test-retest reliability, five participants returned for repeat testing. All participants successfully completed exercise testing in the MRI. Baseline flow demonstrated excellent reliability (ICC = 0.93, p = 0.006), and peak exercise and delta rest-peak flow demonstrated good reliability (peak exercise ICC = 0.89, p = 0.002, delta rest-peak ICC = 0.87, p = 0.003) between-visits. All three flow measurements demonstrated excellent reliability when assessed with coefficients of variance (CV's) (rest: CV = 6.2%; peak exercise: CV = 7.3%; delta rest-peak: CV = 7.1%). The mean bias was small for femoral arterial flow. There was no significant mean bias between femoral artery flow visits 1 and 2 at peak exercise. There were no correlations between age or height and any of the flow measurements. There were no significant differences between male and female participants for any of the flow measurements. The current study determined that peripheral arterial blood flow in children and adolescents can be evaluated using non-invasive phase contrast MRI. The MRI-based techniques that were used in the current study for measuring arterial flow in pediatric and adolescent patients demonstrated acceptable test-retest reliability both at rest and immediately post-exercise.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

Limb movement frequency is a significant modulator of the ventilatory response during submaximal cycling exercise in humans.

Human experimentation investigating the contribution of limb movement frequency in determining the fast exercise drive to breathe has produced controversial findings. To evaluate the role of limb movement frequency in determining the fast exercise drive to breathe, endurance runners and recreationally-active controls performed two sinusoidal exercise protocols on a cycle ergometer. One protocol was performed at constant workload with sinusoidal pedaling cadence, and a second with sinusoidal workload at constant cadence. Metabolic rate (VO2) increases and means were matched between these two experiments. The ventilatory response was significantly faster when limb movement speed was varied, compared to when pedal loading was varied (18.49 ± 15.6s vs. 50.5 ± 14.5s, p<0.05). Ventilation response amplitudes were significantly higher during pedal cadence variation versus pedal loading variation (3.99 ± 0.25 vs. 2.58 ± 0.17 L/min, p<0.05). Similar findings were obtained for endurance athletes, with significantly attenuated ventilation responses to exercise versus control subjects. We conclude that fast changes in limb movement frequency are a potent stimulus for ventilation at submaximal workloads, and that this response is susceptible to attenuation through training.

Shame, self-acceptance and disclosure in the lives of gay men living with HIV: an interpretative phenomenological analysis approach.

OBJECTIVE: HIV-related stigma is a major driver of poor prognosis for the treatment and reduced spread of HIV. The present article provides a qualitative analysis surrounding various themes related to stigma and shame as a result HIV. DESIGN: Eight gay men recruited from a community HIV clinic contacted the researchers in response to a study involving participation in a structured, eight-week group intervention for HIV-related stigma. Following this group, three men took part in open-ended interviews about their thoughts and experiences. METHODS: Interpretative phenomenological analysis was used to examine the participants' experiences surrounding shame and stigma related to living with HIV. RESULTS: Three superordinate themes were identified: social support and the disclosure of serostatus, stigma associated with serosorting and attempts to negotiate a spoiled identity. CONCLUSION: In San Francisco, a city with a great deal of acceptance surrounding HIV and a large, politically active community of persons living with HIV, gay men continue to struggle with disclosure and stigma. This stigma may be an unexpected result of a high degree of HIV testing and attempts by both HIV-positive and negative gay men to practise serosorting.

A unique alkaline pH-regulated and fatty acid-activated tandem pore domain potassium channel (K2P) from a marine sponge.

A cDNA encoding a potassium channel of the two-pore domain family (K(2P), KCNK) of leak channels was cloned from the marine sponge Amphimedon queenslandica. Phylogenetic analysis indicated that AquK(2P) cannot be placed into any of the established functional groups of mammalian K(2P) channels. We used the Xenopus oocyte expression system, a two-electrode voltage clamp and inside-out patch clamp electrophysiology to determine the physiological properties of AquK(2P). In whole cells, non-inactivating, voltage-independent, outwardly rectifying K(+) currents were generated by external application of micromolar concentrations of arachidonic acid (AA; EC(50) ∼30 µmol l(-1)), when applied in an alkaline solution (≥pH 8.0). Prior activation of channels facilitated the pH-regulated, AA-dependent activation of AquK(2P) but external pH changes alone did not activate the channels. Unlike certain mammalian fatty-acid-activated K(2P) channels, the sponge K(2P) channel was not activated by temperature and was insensitive to osmotically induced membrane distortion. In inside-out patch recordings, alkalinization of the internal pH (pK(a) 8.18) activated the AquK(2P) channels independently of AA and also facilitated activation by internally applied AA. The gating of the sponge K(2P) channel suggests that voltage-independent outward rectification and sensitivity to pH and AA are ancient and fundamental properties of animal K(2P) channels. In addition, the membrane potential of some poriferan cells may be dynamically regulated by pH and AA.

Diagnostic value of routine chest radiography in febrile, neutropenic children for early detection of pneumonia and mould infections.

BACKGROUND: Despite recent studies failing to demonstrate the value of routine chest radiography (CXR) in the initial evaluation of the febrile neutropenic patient with cancer, this screening test is advocated by some experts. We evaluated the benefits of CXR for early diagnosis of pulmonary infection at St. Jude Children's Research Hospital (SJCRH) with emphasis on early recognition of mould infections. PATIENTS AND METHODS: We reviewed the courses of 200 consecutive febrile neutropenic pediatric patients to determine if routine CXR at initial evaluation was useful in the identification of clinically occult pneumonia. We also reviewed all cases of proven or probable mould infections from the opening of SJCRH in 1962 until 1998 when routine CXR was no longer practiced in our institution to identify cases that were first recognized by routine CXR. RESULTS: Of 200 febrile neutropenic patients, pulmonary abnormalities consistent with pneumonia were detected by routine CXR in only five patients without pulmonary signs or symptoms. In only one case was a change in management considered. Of the 70 patients with pulmonary mould infection identified from 1962 to 1998, routine CXR was performed in 45 patients at the onset of a febrile, neutropenic episode in which a mould infection was diagnosed. Routine CXR was pivotal in the recognition of the mould infection in only two cases over this 36-year period. CONCLUSION: CXR is warranted in the evaluation of the newly febrile neutropenic pediatric oncology patient only when respiratory signs or symptoms are present.

Strategies to mitigate the bioactivation of 2-anilino-7-aryl-pyrrolo[2,1-f][1,2,4]triazines: identification of orally bioavailable, efficacious ALK inhibitors.

Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.

2,7-Pyrrolo[2,1-f][1,2,4]triazines as JAK2 inhibitors: modification of target structure to minimize reactive metabolite formation.

The JAK2/STAT pathway has important roles in hematopoiesis. With the discovery of the JAK2 V617F mutation and its presence in many patients with myeloproliferative neoplasms, research in the JAK2 inhibitor arena has dramatically increased. We report a novel series of potent JAK2 inhibitors containing a 2,7-pyrrolotriazine core. To minimize potential drug-induced toxicity, targets were analyzed for the ability to form a glutathione adduct. Glutathione adduct formation was decreased by modification of the aniline substituent at C2.

2,7-Disubstituted-pyrrolotriazine kinase inhibitors with an unusually high degree of reactive metabolite formation.

There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.

2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazines: new variant of an old template and application to the discovery of anaplastic lymphoma kinase (ALK) inhibitors with in vivo antitumor activity.

A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.

The ventilatory response to sine wave variation in exercise loads and limb movement frequency.

The current study's experiments tested the hypothesis that limb movement frequency is a significant determinant of exercise hyperpnoea. To this end, 19 healthy participants walked on a treadmill, where work was varied sinusiodally by alterations in either treadmill speed or grade. Measured responses were fitted with sine waves to determine their amplitudes and phase angles. Walking pace amplitude was greater during speed tests than grade tests, and phase lag relative to the treadmill smaller, as expected. Ventilation, carbon dioxide production, and oxygen uptake amplitudes were higher during speed tests than grade tests. Further, phase angle lags relative to the treadmill for these measures were shorter during speed tests than grade tests. We concluded that these findings demonstrate the presence of changes in breathing during exercise that can be attributed to changes in limb movement frequency.

Tacrolimus ointment 0.1% for the treatment of peristomal skin disease: 3 case reports.

Patients with stomas face a variety of problems, such as skin breakdown or ulceration at the peristomal site, that can complicate care. Topical steroids are frequently used to treat various inflammatory conditions that affect peristomal skin with good results, but chronic use can lead to undesirable side effects. Tacrolimus ointment 0.1%, a nonsteroidal immunosuppressant, could offer a more favorable alternative to topical steroids. We present 3 cases of peristomal skin disease that were successfully treated with tacrolimus ointment 0.1%.

Synthesis and structure-activity relationships of novel pyrrolocarbazole lactam analogs as potent and cell-permeable inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).

A series of novel pyrrolocarbazole lactams was identified as potent PARP-1 inhibitors in vitro and in a PC12 cellular NAD(+) depletion assay. The SAR trends of substituents at the 3-position, as well as the effect of blocking the indole or lactam NH-groups of the template by methylation or formylation, are discussed in relation to molecular modeling studies.

Synthesis and structure-activity relationships of novel poly(ADP-ribose) polymerase-1 inhibitors.

A series of novel pyrrolocarbazoles was synthesized as potential PARP-1 inhibitors. Pyrrolocarbazole 1 was identified as a potent PARP-1 inhibitor (IC50 = 36 nM) from our internal database. Synthesis of analogs around this template with the aid of modeling studies led to the identification of the truncated imide 14. Compound 14 (IC50 = 40 nM), with deleted B-ring, was found to be an equipotent PARP-1 inhibitor.

Effects of concurrent inspiratory and expiratory muscle training on respiratory and exercise performance in competitive swimmers.

The efficiency of the respiratory system presents significant limitations on the body's ability to perform exercise due to the effects of the increased work of breathing, respiratory muscle fatigue, and dyspnoea. Respiratory muscle training is an intervention that may be able to address these limitations, but the impact of respiratory muscle training on exercise performance remains controversial. Therefore, in this study we evaluated the effects of a 12-week (10 sessions week(-1)) concurrent inspiratory and expiratory muscle training (CRMT) program in 34 adolescent competitive swimmers. The CRMT program consisted of 6 weeks during which the experimental group (E, n = 17) performed CRMT and the sham group (S, n = 17) performed sham CRMT, followed by 6 weeks when the E and S groups performed CRMT of differing intensities. CRMT training resulted in a significant improvement in forced inspiratory volume in 1 s (FIV1.0) (P = 0.050) and forced expiratory volume in 1 s (FEV1.0) (P = 0.045) in the E group, which exceeded the S group's results. Significant improvements in pulmonary function, breathing power, and chemoreflex ventilation threshold were observed in both groups, and there was a trend toward an improvement in swimming critical speed after 12 weeks of training (P = 0.08). We concluded that although swim training results in attenuation of the ventilatory response to hypercapnia and in improvements in pulmonary function and sustainable breathing power, supplemental respiratory muscle training has no additional effect except on dynamic pulmonary function variables.

1,2-Benzothiazine 1,1-dioxide alpha-ketoamide analogues as potent calpain I inhibitors.

A series of potent 1,2-benzothiazine 1,1-dioxide alpha-ketoamide inhibitors of calpain I is described.