Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies.

Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor ß-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN), complementing the antibody previously described by our laboratory with unique TRBC1 specificity (Jovi-1) in targeting broader spectrum of T cell malignancies clonally expressing either of the two chains. This permits generation of paired reagents (chimeric antigen receptor-T cells) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies.

Designer Small-Molecule Control System Based on Minocycline-Induced Disruption of Protein-Protein Interaction.

A versatile, safe, and effective small-molecule control system is highly desirable for clinical cell therapy applications. Therefore, we developed a two-component small-molecule control system based on the disruption of protein-protein interactions using minocycline, an FDA-approved antibiotic with wide availability, excellent biodistribution, and low toxicity. The system comprises an anti-minocycline single-domain antibody (sdAb) and a minocycline-displaceable cyclic peptide. Here, we show how this versatile system can be applied to OFF-switch split CAR systems (MinoCAR) and universal CAR adaptors (MinoUniCAR) with reversible, transient, and dose-dependent suppression; to a tunable T cell activation module based on MyD88/CD40 signaling; to a controllable cellular payload secretion system based on IL12 KDEL retention; and as a cell/cell inducible junction. This work represents an important step forward in the development of a remote-controlled system to precisely control the timing, intensity, and safety of therapeutic interventions.

Survey on the Updated German S3 Guideline for Intensive Care in Cardiac Surgery Patients.

BACKGROUND: The German guideline on intensive care treatment of cardiac surgical patients provides evidence-based recommendations on management and monitoring. It remains unclear if, respectively, to which degree the guidelines are implemented into the daily practice. Therefore, this study aims to characterize the implementation of guideline recommendations in German cardiac surgical intensive care units (ICUs). METHODS: An internet-based online survey (42 questions, 9 topics) was sent to 158 German head physicians of cardiac surgical ICUs. To compare the effect over time, most questions were based on a previously performed survey (2013) after introduction of the last guideline update in 2008. RESULTS: A total of n = 65 (41.1%) questionnaires were included. Monitoring changed to increased provision of available transesophageal echocardiography specialists in 86% (2013: 72.6%), SvO2 measurement in 93.8% (2013: 55.1%), and electroencephalography in 58.5% (2013: 2.6%). The use of hydroxyethyl starch declined (9.4% vs. 2013: 38.7%), gelatin 4% presented the most administered colloid with 23.4% (2013: 17.4%). Low cardiac output syndrome was primarily treated with levosimendan (30.8%) and epinephrine (23.1%), while norepinephrine (44.6%) and dobutamine (16.9%) represented the most favored drug combination. The main way of distribution was web-based (50.9%), with increasing impact on therapy regimens (36.9% vs. 2013: 24%). CONCLUSION: Changes were found in all questioned sectors compared with the preceding survey, with persisting variability between ICUs. Recommendations of the updated guideline have increasingly entered clinical practice, with participants valuing the updated publication as clinically relevant.

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

Limited efficacy of APRIL CAR in patients with multiple myeloma indicate challenges in the use of natural ligands for CAR T-cell therapy.

BACKGROUND: We used a proliferating ligand (APRIL) to construct a ligand-based third generation chimeric antigen receptor (CAR) able to target two myeloma antigens, B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor. METHODS: The APRIL CAR was evaluated in a Phase 1 clinical trial (NCT03287804, AUTO2) in patients with relapsed, refractory multiple myeloma. Eleven patients received 13 doses, the first 15×106 CARs, and subsequent patients received 75,225,600 and 900×106 CARs in a 3+3 escalation design. RESULTS: The APRIL CAR was well tolerated. Five (45.5%) patients developed Grade 1 cytokine release syndrome and there was no neurotoxicity. However, responses were only observed in 45.5% patients (1×very good partial response, 3×partial response, 1×minimal response). Exploring the mechanistic basis for poor responses, we then compared the APRIL CAR to two other BCMA CARs in a series of in vitro assays, observing reduced interleukin-2 secretion and lack of sustained tumor control by APRIL CAR regardless of transduction method or co-stimulatory domain. There was also impaired interferon signaling of APRIL CAR and no evidence of autoactivation. Thus focusing on APRIL itself, we confirmed similar affinity to BCMA and protein stability in comparison to BCMA CAR binders but reduced binding by cell-expressed APRIL to soluble BCMA and reduced avidity to tumor cells. This indicated either suboptimal folding or stability of membrane-bound APRIL attenuating CAR activation. CONCLUSIONS: The APRIL CAR was well tolerated, but the clinical responses observed in AUTO2 were disappointing. Subsequently, when comparing the APRIL CAR to other BCMA CARs, we observed in vitro functional deficiencies due to reduced target binding by cell-expressed ligand.

Exploration of T cell immune responses by expression of a dominant-negative SHP1 and SHP2.

SHP1 and SHP2 are SH2 domain-containing proteins which have inhibitory phosphatase activity when recruited to phosphorylated ITIMs and ITSMs on inhibitory immune receptors. Consequently, SHP1 and SHP2 are key proteins in the transmission of inhibitory signals within T cells, constituting an important point of convergence for diverse inhibitory receptors. Therefore, SHP1 and SHP2 inhibition may represent a strategy for preventing immunosuppression of T cells mediated by cancers hence improving immunotherapies directed against these malignancies. Both SHP1 and SHP2 contain dual SH2 domains responsible for localization to the endodomain of inhibitory receptors and a protein tyrosine phosphatase domain which dephosphorylates and thus inhibits key mediators of T cell activation. We explored the interaction of the isolated SH2 domains of SHP1 and SHP2 to inhibitory motifs from PD1 and identified strong binding of both SH2 domains from SHP2 and more moderate binding in the case of SHP1. We next explored whether a truncated form of SHP1/2 comprising only of SH2 domains (dSHP1/2) could act in a dominant negative fashion by preventing docking of the wild type proteins. When co-expressed with CARs we found that dSHP2 but not dSHP1 could alleviate immunosuppression mediated by PD1. We next explored the capacity of dSHP2 to bind with other inhibitory receptors and observed several potential interactions. In vivo we observed that the expression of PDL1 on tumor cells impaired the ability of CAR T cells to mediate tumor rejection and this effect was partially reversed by the co-expression of dSHP2 albeit at the cost of reduced CAR T cell proliferation. Modulation of SHP1 and SHP2 activity in engineered T cells through the expression of these truncated variants may enhance T cell activity and hence efficacy in the context of cancer immunotherapy.

Synthesis and Structural Characterization of Copper Complexes Containing "R-Substituted" Bis-7-Azaindolyl Borate Ligands.

The coordination chemistry of scorpionate ligands based on borates containing the 7-azaindole heterocycle is relatively unexplored. Thus, there is a requirement to further understand their coordination chemistry. This article outlines the synthesis and characterization of a family of complexes containing anionic flexible scorpionate ligands of the type [(R)(bis-7-azaindolyl)borohydride]- ([RBai]-), where R = Me, Ph or naphthyl. The three ligands were coordinated to a series of copper(I) complexes containing a phosphine co-ligand to form the complexes, [Cu(MeBai)(PPh3)] (1), [Cu(PhBai)(PPh3)] (2), [Cu(NaphthBai)(PPh3)] (3), [Cu(MeBai)(PCy3)] (4), [Cu(PhBai)(PCy3)] (5) and [Cu(NaphthBai)(PCy3)] (6). Additional copper(II) complexes, namely, [Cu(MeBai)2] (7) and [Cu(PhBai)2] (8), were obtained during attempts to obtain single crystals from complexes 4 and 2, respectively. Complexes 7 and 8 were also prepared independently from CuCl2 and two equivalents of the corresponding Li[RBai] salt alongside an additional complex, namely, [Cu(NaphthBai)2] (9). The copper(I) and copper(II) complexes were characterized using spectroscopic and analytical methods. Furthermore, a crystal structure was obtained for eight of the nine complexes. In all cases, the boron-based ligand was found to bind to the metal centers via a κ3-N,N,H coordination mode.

Enhancing CAR T-cell Therapy Using Fab-Based Constitutively Heterodimeric Cytokine Receptors.

Adoptive T-cell therapy aims to achieve lasting tumor clearance, requiring enhanced engraftment and survival of the immune cells. Cytokines are paramount modulators of T-cell survival and proliferation. Cytokine receptors signal via ligand-induced dimerization, and this principle has been hijacked utilizing nonnative dimerization domains. A major limitation of current technologies resides in the absence of a module that recapitulates the natural cytokine receptor heterodimeric pairing. To circumvent this, we created a new engineered cytokine receptor able to constitutively recreate receptor-heterodimer utilizing the heterodimerization domain derived from the IgG1 antibody (dFab_CCR). We found that the signal delivered by the dFab_CCR-IL2 proficiently mimicked the cytokine receptor heterodimerization, with transcriptomic signatures like those obtained by activation of the native IL2 receptor. Moreover, we found that this dimerization structure was agnostic, efficiently activating signaling through four cytokine receptor families. Using a combination of in vivo and in vitro screening approaches, we characterized a library of 18 dFab_CCRs coexpressed with a clinically relevant solid tumor-specific GD2-specific chimeric antigen receptor (CAR). Based on this characterization, we suggest that the coexpression of either the common ß-chain GMCSF or the IL18 dFab_CCRs is optimal to improve CAR T-cell expansion, engraftment, and efficacy. Our results demonstrate how Fab dimerization is efficient and versatile in recapitulating a cytokine receptor heterodimerization signal. This module could be applied for the enhancement of adoptive T-cell therapies, as well as therapies based on other immune cell types. Furthermore, these results provide a choice of cytokine signal to incorporate with adoptive T-cell therapies.

Novel Fas-TNFR chimeras that prevent Fas ligand-mediated kill and signal synergistically to enhance CAR T cell efficacy.

The hostile tumor microenvironment limits the efficacy of adoptive cell therapies. Activation of the Fas death receptor initiates apoptosis and disrupting these receptors could be key to increasing CAR T cell efficacy. We screened a library of Fas-TNFR proteins identifying several novel chimeras that not only prevented Fas ligand-mediated kill, but also enhanced CAR T cell efficacy by signaling synergistically with the CAR. Upon binding Fas ligand, Fas-CD40 activated the NF-κB pathway, inducing greatest proliferation and IFN-γ release out of all Fas-TNFRs tested. Fas-CD40 induced profound transcriptional modifications, particularly genes relating to the cell cycle, metabolism, and chemokine signaling. Co-expression of Fas-CD40 with either 4-1BB- or CD28-containing CARs increased in vitro efficacy by augmenting CAR T cell proliferation and cancer target cytotoxicity, and enhanced tumor killing and overall mouse survival in vivo. Functional activity of the Fas-TNFRs were dependent on the co-stimulatory domain within the CAR, highlighting crosstalk between signaling pathways. Furthermore, we show that a major source for Fas-TNFR activation derives from CAR T cells themselves via activation-induced Fas ligand upregulation, highlighting a universal role of Fas-TNFRs in augmenting CAR T cell responses. We have identified Fas-CD40 as the optimal chimera for overcoming Fas ligand-mediated kill and enhancing CAR T cell efficacy.

Feasibility of dynamic chest radiography to calculate lung volumes in adult people with cystic fibrosis: a pilot study.

INTRODUCTION: Dynamic chest radiography (DCR) is a novel, low-dose, real-time digital imaging system where software identifies moving thoracic structures and can automatically calculate lung areas. In an observational, prospective, non-controlled, single-centre pilot study, we compared it with whole-body plethysmography (WBP) in the measurement of lung volume subdivisions in people with cystic fibrosis (pwCF). METHODS: Lung volume subdivisions were estimated by DCR using projected lung area (PLA) during deep inspiration, tidal breathing and full expiration, and compared with same-day WBP in 20 adult pwCF attending routine review. Linear regression models to predict lung volumes from PLA were developed. RESULTS: Total lung area (PLA at maximum inspiration) correlated with total lung capacity (TLC) (r=0.78, p<0.001), functional residual lung area with functional residual capacity (FRC) (r=0.91, p<0.001), residual lung area with residual volume (RV) (r=0.82, p=0.001) and inspiratory lung area with inspiratory capacity (r=0.72, p=0.001). Despite the small sample size, accurate models were developed for predicting TLC, RV and FRC. CONCLUSION: DCR is a promising new technology that can be used to estimate lung volume subdivisions. Plausible correlations between plethysmographic lung volumes and DCR lung areas were identified. Further studies are needed to build on this exploratory work in both pwCF and individuals without CF. TRIAL REGISTRATION NUMBER: ISRCTN64994816.

Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR.

CAR T cells recognizing CD19 effectively treat relapsed and refractory B-ALL and DLBCL. However, CD19 loss is a frequent cause of relapse. Simultaneously targeting a second antigen, CD22, may decrease antigen escape, but is challenging: its density is approximately 10-fold less than CD19, and its large structure may hamper immune synapse formation. The characteristics of the optimal CD22 CAR are underexplored. We generated 12 distinct CD22 antibodies and tested CARs derived from them to identify a CAR based on the novel 9A8 antibody, which was sensitive to low CD22 density and lacked tonic signaling. We found no correlation between affinity or membrane proximity of recognition epitope within Ig domains 3-6 of CD22 with CART function. The optimal strategy for CD19/CD22 CART co-targeting is undetermined. Co-administration of CD19 and CD22 CARs is costly; single CARs targeting CD19 and CD22 are challenging to construct. The co-expression of two CARs has previously been achieved using bicistronic vectors. Here, we generated a dual CART product by co-transduction with 9A8-41BBζ and CAT-41BBζ (obe-cel), the previously described CD19 CAR. CAT/9A8 CART eliminated single- and double-positive target cells in vitro and eliminated CD19- tumors in vivo. CAT/9A8 CART is being tested in a phase I clinical study (NCT02443831).

Sub-regional analysis of the parotid glands: model development for predicting late xerostomia with radiomics features in head and neck cancer patients.

BACKGROUND: The irradiation of sub-regions of the parotid has been linked to xerostomia development in patients with head and neck cancer (HNC). In this study, we compared the xerostomia classification performance of radiomics features calculated on clinically relevant and de novo sub-regions of the parotid glands of HNC patients. MATERIAL AND METHODS: All patients (N = 117) were treated with TomoTherapy in 30-35 fractions of 2-2.167 Gy per fraction with daily mega-voltage-CT (MVCT) acquisition for image-guidance purposes. Radiomics features (N = 123) were extracted from daily MVCTs for the whole parotid gland and nine sub-regions. The changes in feature values after each complete week of treatment were considered as predictors of xerostomia (CTCAEv4.03, grade ≥ 2) at 6 and 12 months. Combinations of predictors were generated following the removal of statistically redundant information and stepwise selection. The classification performance of the logistic regression models was evaluated on train and test sets of patients using the Area Under the Curve (AUC) associated with the different sub-regions at each week of treatment and benchmarked with the performance of models solely using dose and toxicity at baseline. RESULTS: In this study, radiomics-based models predicted xerostomia better than standard clinical predictors. Models combining dose to the parotid and xerostomia scores at baseline yielded an AUCtest of 0.63 and 0.61 for xerostomia prediction at 6 and 12 months after radiotherapy while models based on radiomics features extracted from the whole parotid yielded a maximum AUCtest of 0.67 and 0.75, respectively. Overall, across sub-regions, maximum AUCtest was 0.76 and 0.80 for xerostomia prediction at 6 and 12 months. Within the first two weeks of treatment, the cranial part of the parotid systematically yielded the highest AUCtest. CONCLUSION: Our results indicate that variations of radiomics features calculated on sub-regions of the parotid glands can lead to earlier and improved prediction of xerostomia in HNC patients.

Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders.

TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal and non-neuronal cells. Recently, rare de novo variants in TRPM3 were identified in individuals with developmental and epileptic encephalopathy, but the link between TRPM3 activity and neuronal disease remains poorly understood. We previously reported that two disease-associated variants in TRPM3 lead to a gain of channel function . Here, we report a further 10 patients carrying one of seven additional heterozygous TRPM3 missense variants. These patients present with a broad spectrum of neurodevelopmental symptoms, including global developmental delay, intellectual disability, epilepsy, musculo-skeletal anomalies, and altered pain perception. We describe a cerebellar phenotype with ataxia or severe hypotonia, nystagmus, and cerebellar atrophy in more than half of the patients. All disease-associated variants exhibited a robust gain-of-function phenotype, characterized by increased basal activity leading to cellular calcium overload and by enhanced responses to the neurosteroid ligand pregnenolone sulfate when co-expressed with wild-type TRPM3 in mammalian cells. The antiseizure medication primidone, a known TRPM3 antagonist, reduced the increased basal activity of all mutant channels. These findings establish gain-of-function of TRPM3 as the cause of a spectrum of autosomal dominant neurodevelopmental disorders with frequent cerebellar involvement in humans and provide support for the evaluation of TRPM3 antagonists as a potential therapy.

Assessing the generalisability of radiomics features previously identified as predictive of radiation-induced sticky saliva and xerostomia.

Background and purpose: While core to the scientific approach, reproducibility of experimental results is challenging in radiomics studies. A recent publication identified radiomics features that are predictive of late irradiation-induced toxicity in head and neck cancer (HNC) patients. In this study, we assessed the generalisability of these findings. Materials and Methods: The procedure described in the publication in question was applied to a cohort of 109 HNC patients treated with 50-70 Gy in 20-35 fractions using helical radiotherapy although there were inherent differences between the two patient populations and methodologies. On each slice of the planning CT with delineated parotid and submandibular glands, the imaging features that were previously identified as predictive of moderate-to-severe xerostomia and sticky saliva 12 months post radiotherapy (Xer12m and SS12m) were calculated. Specifically, Short Run Emphasis (SRE) and maximum CT intensity (maxHU) were evaluated for improvement in prediction of Xer12m and SS12m respectively, compared to models solely using baseline toxicity and mean dose to the salivary glands. Results: None of the associations previously identified as statistically significant and involving radiomics features in univariate or multivariate models could be reproduced on our cohort. Conclusion: The discrepancies observed between the results of the two studies delineate limits to the generalisability of the previously reported findings. This may be explained by the differences in the approaches, in particular the imaging characteristics and subsequent methodological implementation. This highlights the importance of external validation, high quality reporting guidelines and standardisation protocols to ensure generalisability, replication and ultimately clinical implementation.

Accuracy of substance exposure history in patients attending emergency departments after substance misuse; a comparison with biological sample analysis.

CONTEXT: Acute toxicity caused by illicit substance use is a common reason for emergency department (ED) presentation. Knowledge of the substances involved is helpful for predicting and managing potential toxicity, but limited information is available about the accuracy of patient-reported substance exposure. This study assessed the accuracy of the history of exposure in those reporting use of a single substance by comparison with those identified by detailed toxicological analysis, focusing on synthetic cannabinoid receptor agonists (SCRA). METHODS: Adults (≥16 years) presenting between March 2015 and July 2021 to participating UK hospitals with toxicity after reporting use of a single illicit substance were included. Exposure details were documented from medical records and blood and/or urine samples analysed using high-resolution accurate mass liquid chromatography-mass spectrometry (HRAM LCMS). Sensitivity, specificity, and positive and negative predictive values of the exposure history were calculated by comparison with biological sample analysis ("gold standard"). RESULTS: Single substance exposure was reported for 474 (median age 33 years, IQR: 18 range 16-75, 80% males) patients. Analysis commonly identified multiple substances (Median 3, IQR 2-5). A history of exposure was documented for 121 of 151 patients where a SCRA or metabolite was detected on analysis (sensitivity 80.1%, 95% CI 72.9, 86.2%). Corresponding proportions were lower for 3,4-methylenedioxymethamphetamine (MDMA, 44/70, 62.9%., 95% CI 50.5%, 74.1%), heroin 41/108 (38.0% 95% CI 28.8-47.8%) and cocaine (22/56, 31.3%, 95% CI 20.9, 43.6%). CONCLUSIONS: Multiple undeclared substances were detected analytically in most patients reporting single substance use. Clinicians should be alert to the potential presence and toxicity of unreported substances when managing patients presenting after substance misuse.

Real-world outcomes of an innovative digital therapeutic for treatment of panic disorder and PTSD: A 1,500 patient effectiveness study.

Objective: Prior clinical trials have shown consistent clinical benefit for Capnometry Guided Respiratory Intervention (CGRI), a prescription digital therapeutic for the treatment of panic disorder (PD) and post-traumatic stress disorder (PTSD). The purpose of this study is to report real-world outcomes in a series of patients treated with the intervention in clinical practice. Design: This paper reports pre- and post-treatment self-reported symptom reduction, measures of respiratory rate and end-tidal carbon dioxide levels, drop-out and adherence rates drawn from an automatic data repository in a large real-world series of patients receiving CGRI for panic disorder and PTSD. Setting: Patients used the intervention in their homes, supported by telehealth coaching. Participants: Patients meeting symptom criteria for panic disorder (n = 1,395) or posttraumatic stress disorder (n = 174) were treated following assessment by a healthcare professional. Intervention: Capnometry Guided Respiratory Intervention is a 28-day home-based treatment that provides breath-to-breath feedback of respiratory rate and exhaled carbon dioxide levels, aimed at normalizing respiratory style and increasing patients' mastery for coping with symptoms of stress, anxiety, and panic. Health coaches provide initial training with weekly follow up during the treatment episode. Remote data upload and monitoring facilitates individualized coaching and aggregate outcomes analysis. Main outcome measures: Self-reported Panic Disorder Severity Scale (PDSS) and the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) scores were obtained at pre-treatment and post-treatment. Results: Panic disorder (PD) patients showed a mean pre-to-post-treatment reduction in total PDSS scores of 50.2% (P < 0.001, d = 1.31). Treatment response rates for PD (defined as a 40% or greater reduction in PDSS total scores) were observed in 65.3% of the PD patients. PTSD patients showed a pre-to-post-treatment reduction in total PCL-5 scores of 41.1% (P < 0.001, d = 1.16). The treatment response rate for PTSD (defined as a ≥10-point reduction in PCL-5 scores) was 72.4%. In an additional analysis of response at the individual level, 55.7% of panic disorder patients and 53.5% of PTSD patients were classified as treatment responders using the Reliable Change Index. Patients with both normal and below-normal baseline exhaled CO2 levels experienced comparable benefit. Across the 28-day treatment period, mean adherence rates of 74.8% (PD) and 74.9% (PTSD) were recorded during the 28-day treatment. Dropout rates were 10% (PD) and 11% (PTSD) respectively. Conclusions: The results from this cohort of 1,569 patients treated with the CGRI intervention demonstrate significant rates of symptom reduction and adherence consistent with prior published clinical trials. The brief duration of treatment, high adherence rates, and clinical benefit suggests that CGRI provides an important addition to treatment options for panic disorder and PTSD.

Predicting radiotherapy-induced xerostomia in head and neck cancer patients using day-to-day kinetics of radiomics features.

Background and purpose: The images acquired during radiotherapy for image-guidance purposes could be used to monitor patient-specific response to irradiation and improve treatment personalisation. We investigated whether the kinetics of radiomics features from daily mega-voltage CT image-guidance scans (MVCT) improve prediction of moderate-to-severe xerostomia compared to dose/volume parameters in radiotherapy of head-and-neck cancer (HNC). Materials and Methods: All included HNC patients (N = 117) received 30 or more fractions of radiotherapy with daily MVCTs. Radiomics features were calculated on the contra-lateral parotid glands of daily MVCTs. Their variations over time after each complete week of treatment were used to predict moderate-to-severe xerostomia (CTCAEv4.03 grade ≥ 2) at 6, 12 and 24 months post-radiotherapy. After dimensionality reduction, backward/forward selection was used to generate combinations of predictors.Three types of logistic regression model were generated for each follow-up time: 1) a pre-treatment reference model using dose/volume parameters, 2) a combination of dose/volume and radiomics-based predictors, and 3) radiomics-based predictors. The models were internally validated by cross-validation and bootstrapping and their performance evaluated using Area Under the Curve (AUC) on separate training and testing sets. Results: Moderate-to-severe xerostomia was reported by 46 %, 33 % and 26 % of the patients at 6, 12 and 24 months respectively. The selected models using radiomics-based features extracted at or before mid-treatment outperformed the dose-based models with an AUCtrain/AUCtest of 0.70/0.69, 0.76/0.74, 0.86/0.86 at 6, 12 and 24 months, respectively. Conclusion: Our results suggest that radiomics features calculated on MVCTs from the first half of the radiotherapy course improve prediction of moderate-to-severe xerostomia in HNC patients compared to a dose-based pre-treatment model.

Magnetic resonance imaging in the evaluation of suspected hip sepsis in children.

Background: Rapid and accurate diagnosis of musculoskeletal infection in children is critical to enable appropriate, targeted surgical interventions. Distinguishing between septic arthritis, myositis, and osteomyelitis around the hip can be difficult using clinical criteria and ultrasound scan alone. Materials and methods: We performed a retrospective 5-year observational review of selective magnetic resonance imaging scanning for hip sepsis in a pediatric tertiary referral center. Included were children with atraumatic hip pain with symptom duration <2 weeks, minimum of two positive modified Kocher's criteria, and a hip effusion on ultrasound. All cases were followed up to discharge. We evaluated hip ultrasound and magnetic resonance imaging findings, operative procedures, microbiology results, duration of treatment, outcomes, and complications. Results: Fifty-one patients, 55% male, with a mean age 6.4 (0-16) years were included. Thirty-nine underwent magnetic resonance imaging scan for suspected septic arthritis of the hip; 24 prior to surgical washout (pre-emptive), and 15 afterwards (postoperative). In the pre-emptive group, 1/24 had septic arthritis, 7/24 had osteomyelitis, 6/24 had myositis, 5/24 had osteomyelitis and myositis, and 5/24 had no evidence of infective pathology. In the postoperative group, 3/15 had myositis, 3/15 had osteomyelitis, 3/15 had re-accumulation of the hip effusion requiring repeat washout, 3/15 had myositis and osteomyelitis, and 1/15 had septic arthritis of a contiguous joint. Conclusion: Pre-emptive magnetic resonance imaging scanning avoided unnecessary hip washout in 23 cases and enabled targeted drainage of an alternative focus in four of those. Magnetic resonance imaging scanning after hip washout indicated that four cases required further surgery to drain a different focus of infection.

Trends in hospital presentations following analytically confirmed synthetic cannabinoid receptor agonist exposure before and after implementation of the 2016 UK Psychoactive Substances Act.

BACKGROUND AND AIMS: The United Kingdom (UK) Psychoactive Substances Act (PSA), implemented on the 26th  May 2016, made the production, supply and sale of all non-exempted psychoactive substances illegal. The aim of this study was to measure trends in hospital presentations for severe toxicity following analytically confirmed synthetic cannabinoid receptor agonist (SCRA) exposure before and after implementation of the PSA. DESIGN: Observational study. SETTING: Thirty-four hospitals across the UK participating in the Identification of Novel Psychoactive Substances (IONA) study. PARTICIPANTS: A total of 627 (79.9% male) consenting individuals who presented to participating hospitals between July 2015 and December 2019 with severe acute toxicity and suspected novel psychoactive substances exposure. MEASUREMENTS: Toxicological analyses of patient samples were conducted using liquid-chromatography tandem mass-spectrometry. Time-series analysis was conducted on the monthly number of patients with and without analytically confirmed SCRA exposure using Poisson segmented regression. FINDINGS: SCRAs were detected in 35.7% (n = 224) of patients. After adjusting for seasonality and the number of active sites, models showed no clear evidence of an upward or downward trend in the number of SCRA exposure cases in the period before (incidence rate ratio [IRR], 1.12; 95% CI, 0.99-1.26; P = 0.068) or after (IRR, 0.97; 95% CI, 0.94-1.01; P = 0.202) the implementation of the PSA. There was also no clear evidence of an upward or downward trend in non-SCRA exposure cases before (IRR, 1.12; 95% CI, 0.98-1.27; P = 0.105) or after (IRR, 1.01; 95% CI, 0.98-1.04; P = 0.478) implementation of the PSA. CONCLUSIONS: There is no clear evidence of an upward or downward trend in the number of patients presenting to UK hospitals with severe acute toxicity following analytically confirmed synthetic cannabinoid receptor agonist exposure since the implementation of the Psychoactive Substances Act.