Study protocol for a non-inferiority randomised controlled trial of SKY breathing meditation versus cognitive processing therapy for PTSD among veterans

Introduction Post-traumatic stress disorder (PTSD) is a debilitating, highly prevalent condition. Current clinical practice guidelines recommend trauma-focused psychotherapy (eg, cognitive processing therapy; CPT) as the first-line treatment for PTSD. However, while these treatments show clinically meaningful symptom improvement, the majority of those who begin treatment retain a diagnosis of PTSD post-treatment. Perhaps for this reason, many individuals with PTSD have sought more holistic, mind–body, complementary and integrative health (CIH) interventions. However, there remains a paucity of high-quality, active controlled efficacy studies of CIH interventions for PTSD, which precludes their formal recommendation. Methods and analyses We present the protocol for an ongoing non-inferiority parallel group randomised controlled trial (RCT) comparing the efficacy of a breathing meditation intervention (Sudarshan Kriya Yoga [SKY]) to a recommended evidence-based psychotherapy (CPT) for PTSD among veterans. Assessors are blinded to treatment group. The primary outcome measure is the PTSD Checklist-Civilian Version and a combination of clinical, self-report, experimental and physiological outcome measures assess treatment-related changes across each of the four PTSD symptom clusters (re-experiencing, avoidance, negative cognitions or mood and hyperarousal/reactivity). Once the RCT is completed, analyses will use both an intent-to-treat (using the ‘last observation carried forward’ for missing data) and a per-protocol or ‘treatment completers’ procedure, which is the most rigorous approach to non-inferiority designs. Ethics and dissemination To the best of our knowledge, this is this first non-inferiority RCT of SKY versus CPT for PTSD among veterans. The protocol is approved by the Stanford University Institutional Review Board. All participants provided written informed consent prior to participation. Results from this RCT will inform future studies including larger multi-site efficacy RCTs of SKY for PTSD and other mental health conditions, as well as exploration of cost-effectiveness and evaluation of implementation issues. Results will also inform evidence-based formal recommendations regarding CIH interventions for PTSD

Comprehensive translational control of tyrosine kinase expression by upstream open reading frames

Post-transcriptional control has emerged as a major regulatory event in gene expression and often occurs at the level of translation initiation. Although overexpression or constitutive activation of tyrosine kinases (TKs) through gene amplification, translocation or mutation are well-characterized oncogenic events, current knowledge about translational mechanisms of TK activation is scarce. Here, we report the presence of translational cis-regulatory upstream open reading frames (uORFs) in the majority of transcript leader sequences of human TK mRNAs. Genetic ablation of uORF initiation codons in TK transcripts resulted in enhanced translation of the associated downstream main protein-coding sequences (CDSs) in all cases studied. Similarly, experimental removal of uORF start codons in additional non-TK proto-oncogenes, and naturally occurring loss-of-uORF alleles of the c-met proto-oncogene (MET) and the kinase insert domain receptor (KDR), was associated with increased CDS translation. Based on genome-wide sequence analyses we identified polymorphisms in 15.9% of all human genes affecting uORF initiation codons, associated Kozak consensus sequences or uORF-related termination codons. Together, these data suggest a comprehensive role of uORF-mediated translational control and delineate how aberrant induction of proto-oncogenes through loss-of-function mutations at uORF initiation codons may be involved in the etiology of cancer. We provide a detailed map of uORFs across the human genome to stimulate future research on the pathogenic role of uORFs

Role of Umklapp Processes in Conductivity of Doped Two-Leg Ladders

Recent conductivity measurements performed on the hole-doped two-leg ladder material $\mathrm{Sr_{14-x}Ca_xCu_{24}O_{41}}$ reveal an approximately linear power law regime in the c-axis DC resistivity as a function of temperature for $x=11$. In this work, we employ a bosonic model to argue that umklapp processes are responsible for this feature and for the high spectral weight in the optical conductivity which occurs beyond the finite frequency Drude-like peak. Including quenched disorder in our model allows us to reproduce experimental conductivity and resistivity curves over a wide range of energies. We also point out the differences between the effect of umklapp processes in a single chain and in the two-leg ladder.Comment: 10 pages, 2 figure

Temperature dependence of the Casimir effect between metallic mirrors

We calculate the Casimir force and free energy for plane metallic mirrors at non-zero temperature. Numerical evaluations are given with temperature and conductivity effects treated simultaneously. The results are compared with the approximation where both effects are treated independently and the corrections simply multiplied. The deviation between the exact and approximated results takes the form of a temperature dependent function for which an analytical expression is given. The knowledge of this function allows simple and accurate estimations at the % level.Comment: 8 pages, 4 figures, uses RevTe

All-electron GW calculation based on the LAPW method: application to wurtzite ZnO

We present a new, all-electron implementation of the GW approximation and apply it to wurtzite ZnO. Eigenfunctions computed in the local-density approximation (LDA) by the full-potential linearized augmented-plane-wave (LAPW) or the linearized muffin-tin-orbital (LMTO) method supply the input for generating the Green function G and the screened Coulomb interaction W. A mixed basis is used for the expansion of W, consisting of plane waves in the interstitial region and augmented-wavefunction products in the augmentation-sphere regions. The frequency-dependence of the dielectric function is computed within the random-phase approximation (RPA), without a plasmon-pole approximation. The Zn 3d orbitals are treated as valence states within the LDA; both core and valence states are included in the self-energy calculation. The calculated bandgap is smaller than experiment by about 1eV, in contrast to previously reported GW results. Self-energy corrections are orbital-dependent, and push down the deep O 2s and Zn 3d levels by about 1eV relative to the LDA. The d level shifts closer to experiment but the size of shift is underestimated, suggesting that the RPA overscreens localized states.Comment: 10 pages, 3 figures, submitted to Phys. Rev.

Randomised clinical non-inferiority trial of breathing-based meditation and cognitive processing therapy for symptoms of post-traumatic stress disorder in military veterans

Objective Test whether Sudarshan Kriya Yoga (SKY) was non-inferior to cognitive processing therapy (CPT) for treating symptoms of post-traumatic stress disorder (PTSD) among veterans via a parallel randomised controlled non-inferiority trial. Setting Outpatient Veterans Affairs healthcare centre. Participants 85 veterans (75 men, 61% white, mean age 56.9) with symptoms of PTSD participated between October 2015 and March 2020: 59 participants completed the study. Interventions SKY emphasises breathing routines and was delivered in group format in a 15-hour workshop followed by two 1-hour sessions per week for 5 weeks. CPT is an individual psychotherapy which emphasises shifting cognitive appraisals and was delivered in two 1-hour sessions per week for 6 weeks. Measures The primary outcome measure was the PTSD Checklist-Civilian Version (PCL-C). The secondary measures were the Beck Depression Inventory-II (BDI-II) and Positive and Negative Affect Scale (PANAS). Results Mean PCL-C at baseline was 56.5 (±12.6). Intent-to-treat analyses showed that PCL-C scores were reduced at 6 weeks (end of treatment) relative to baseline (SKY, −5.6, d=0.41, n=41: CPT, −6.8, d=0.58, n=44). The between-treatment difference in change scores was within the non-inferiority margin of 10 points (−1.2, 95% CI −5.7 to 3.3), suggesting SKY was not inferior to CPT. SKY was also non-inferior at 1-month (CPT–SKY: −2.1, 95% CI −6.9 to 2.8) and 1-year (CPT–SKY: −1.8, 95% CI −6.6 to 2.9) assessments. SKY was also non-inferior to CPT on the BDI-II and PANAS at end of treatment and 1 month, but SKY was inferior to CPT on both BDI-II and PANAS at 1 year. Dropout rates were similar (SKY, 27%, CPT, 34%: OR=1.36, 95% CI 0.51 to 3.62, p=0.54). Conclusions SKY may be non-inferior to CPT for treating symptoms of PTSD and merits further consideration as a treatment for PTSD

A microparticle platform for STING-targeted immunotherapy enhances natural killer cell- and CD8 + T cell-mediated anti-tumor immunity

Immunotherapies have significantly improved cancer patient survival, but response rates are still limited. Thus, novel formulations are needed to expand the breadth of immunotherapies. Pathogen associated molecular patterns (PAMPs) can be used to stimulate an immune response, but several pathogen recognition receptors are located within the cell, making delivery challenging. We have employed the biodegradable polymer acetalated dextran (Ace-DEX) to formulate PAMP microparticles (MPs) in order to enhance intracellular delivery. While treatment with four different PAMP MPs resulted in tumor growth inhibition, cyclic GMP-AMP (cGAMP) MPs were most effective. cGAMP MPs showed anti-tumor efficacy at doses 100-1000 fold lower than published doses of soluble cGAMP in two murine tumor models. Treatment with cGAMP MPs resulted in increased natural killer cell numbers in the tumor environment. Immune cell depletion studies confirmed that NK cells were responsible for the anti-tumor efficacy in an aggressive mouse melanoma model. NK cells and CD8 + T cells were both required for early anti-tumor function in a triple negative breast cancer model. In summary, cGAMP MP treatment results in NK and T cell-dependent anti-tumor immune response

The QCD Phase Structure at High Baryon Density

We consider the possibility that color deconfinement and chiral symmetry restoration do not coincide in dense baryonic matter at low temperature. As a consequence, a state of massive "constituent" quarks would exist as an intermediate phase between confined nuclear matter and the plasma of deconfined massless quarks and gluons. We discuss the properties of this state and its relation to the recently proposed quarkyonic matter.Comment: 17 pages, 9 figure

CD56 as a marker of an ILC1-like population with NK cell properties that is functionally impaired in AML.

An understanding of natural killer (NK) cell physiology in acute myeloid leukemia (AML) has led to the use of NK cell transfer in patients, demonstrating promising clinical results. However, AML is still characterized by a high relapse rate and poor overall survival. In addition to conventional NKs that can be considered the innate counterparts of CD8 T cells, another family of innate lymphocytes has been recently described with phenotypes and functions mirroring those of helper CD4 T cells. Here, in blood and tissues, we identified a CD56+ innate cell population harboring mixed transcriptional and phenotypic attributes of conventional helper innate lymphoid cells (ILCs) and lytic NK cells. These CD56+ ILC1-like cells possess strong cytotoxic capacities that are impaired in AML patients at diagnosis but are restored upon remission. Their cytotoxicity is KIR independent and relies on the expression of TRAIL, NKp30, NKp80, and NKG2A. However, the presence of leukemic blasts, HLA-E-positive cells, and/or transforming growth factor-β1 (TGF-β1) strongly affect their cytotoxic potential, at least partially by reducing the expression of cytotoxic-related molecules. Notably, CD56+ ILC1-like cells are also present in the NK cell preparations used in NK transfer-based clinical trials. Overall, we identified an NK cell-related CD56+ ILC population involved in tumor immunosurveillance in humans, and we propose that restoring their functions with anti-NKG2A antibodies and/or small molecules inhibiting TGF-β1 might represent a novel strategy for improving current immunotherapies

A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination

Most FDA-approved adjuvants for infectious agents boost humoral but not cellular immunity, and have poorly-understood mechanisms. Stimulator of interferon genes (STING, also known as MITA, MPYS, or ERIS) is an exciting adjuvant target due to its role in cyclic dinucleotide (CDN)-driven anti-viral immunity; however, a major hindrance is STING's cytosolic localization which requires intracellular delivery of its agonists. As a result, STING agonists administered in a soluble form have elicited suboptimal immune responses. Delivery of STING agonists via particle platforms has proven a more successful strategy, but the opportunity for improved formulations and bioactivity remains. In this study we evaluated the adjuvant activity of the potent STING agonist, CDN 3′3′-cGAMP (cGAMP), encapsulated in acid-sensitive acetalated dextran (Ace-DEX) polymeric microparticles (MPs) which passively target antigen-presenting cells for intracellular release. This formulation was superior to all particle delivery systems evaluated and maintained its bioactivity following a sterilizing dose of gamma irradiation. Compared to soluble cGAMP, the Ace-DEX cGAMP MPs enhanced type-I interferon responses nearly 1000-fold in vitro and 50-fold in vivo, caused up to a 104-fold boost in antibody titers, increased Th1-associated responses, and expanded germinal center B cells and memory T cells. Furthermore, the encapsulated cGAMP elicited no observable toxicity in animals and achieved protective immunity against a lethal influenza challenge seven months post-immunization when using CDN adjuvant doses up to 100-fold lower than previous reports. For these reasons, Ace-DEX MP-encapsulated cGAMP represents a potent vaccine adjuvant of humoral and cellular immunity