Amygdala-derived-EEG-fMRI-pattern neurofeedback for the treatment of chronic post-traumatic stress disorder. A prospective, multicenter, multinational study evaluating clinical efficacy.

We conducted a prospective, single arm, multisite, multinational, open label trial assessing the safety and efficacy of a novel amygdala derived neurofeedback treatment, designated Amygdala-Derived-EFP, for chronic PTSD. Participants, including veterans and civilians, underwent screening, training, 15 neurofeedback sessions over 8 weeks and; baseline, termination (8 weeks) and 3 month post treatment assessments with validated measures. The primary endpoint was more than 50 % of the participants demonstrating a Minimally Clinically Important Difference (MCID) defined as a 6-point reduction, on the Clinician Administered PTSD Scale (CAPS-5) total score at 3 months. Secondary measures included the PCL-5, ERQ, PHQ-9, and CGI. Statistical analyses were performed using SAS®V9.4. The primary endpoint was met, with a CAPS-5 MCID response rate of 66.7 %. The average reduction in CAPS-5 total scores at 3 month follow up was 13.5 points, more than twice the MCID. Changes from baseline in CAPS-5, PCL-5, PHQ-9 scores at 8 weeks and the 3 month follow-up demonstrated statistically significant improvements in response and; demonstrated effect sizes ranging from 0.46 to 1.07. Adverse events were mild and resolved after treatment. This study builds on prior research demonstrating similar outcomes using amygdala-derived neurofeedback. Positive attributes of this therapy include monitoring by non-physician personnel, affordability, accessibility, and tolerability.

Reliability, validity and normal ranges of the Zur Balance Scale for detecting mild postural control differences: introducing the modified, short version mZBS.

Introduction: Balance is achieved through interactions between the vestibular, somatosensory, and visual systems. There are several clinical tests to measure postural stability. However, most of them do not assess postural stability with head movements, which is the main function of the vestibular system, and those that do, require the use of sizeable, expensive equipment. Therefore, an applicable, easy-to-perform test that challenges the function of the visual, somatosensory and vestibular systems, using head movements, is needed. The Zur Balance Scale (ZBS) contains ten conditions, which are a combination of surfaces (floor or Styrofoam with subject standing on its width in Romberg position or its length in tandem position), stances (Romberg or tandem), tasks (no head movement with eyes open or closed and horizontal or vertical head movements with eyes open). The purpose of this study was to determine the validity, inter- and intra-examiner reliability, and normal performance values of the ZBS among individuals 29-70-years of age and to introduce the modified version: the mZBS, using kinetic measurements. Methods: Healthy participants ages 29-70 years were evaluated for inter- and intra-tester reliability (n = 65), kinetic measurements on a force plate, and validity compared to the modified clinical test of sensory interaction and balance (mCTSIB) (n = 44) and characterization of normal values (n = 251). Results: Zur Balance Scale head movements, duration of each condition (up to 10 s) and the total ZBS score agreed across examiners (ICC > 0.8). Normal ZBS scores were negatively correlated with age (r = -0.34; P < 0.0001). Older subjects (60-70 years) had a median score of 95.5 compared with younger subjects, where medians ranged from 97.6 to 98.9. Kinetic parameters showed positive correlations between ZBS and the mCTSIB scores, with the highest correlation between the five Romberg tasks (modified ZBS). Conclusion: Zur Balance Scale is a valid and reliable test. Its advantages include using head movements and the ability to detect minimal differences in postural control, even in healthy populations. Kinetic evaluation of the ZBS enables the use of a modified, shorter version of the ZBS (mZBS).

Reframing the local-global food systems debate through a resilience lens.

Despite the growing knowledge that food system solutions should account for interactions and drivers across scales, broader societal debate on how to solve food system challenges is often focused on two dichotomous perspectives and associated solutions: either more localized food systems or greater global coordination of food systems. The debate has found problematic expressions in contemporary challenges, prompting us to revisit the role that resilience thinking can play when faced with complex crises that increase uncertainty. Here we identify four 'aching points' facing food systems that are central points of tension in the local-global debate. We apply the seven principles of resilience to these aching points to reframe the solution space to one that embeds resilience into food systems' management and governance at all scales, supporting transformative change towards sustainable food systems.

Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, observational, and non-randomized open-label interventional study.

Background: Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran's Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both alpha and delta variants. Analysis of 3233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930.

Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

Diffusing Alpha-Emitters Radiation Therapy Promotes a Proimmunogenic Tumor Microenvironment and Synergizes With Programmed Cell Death Protein 1 Blockade.

PURPOSE: Diffusing alpha-emitters Radiation Therapy (DaRT) releases alpha-emitting atoms into the tumor microenvironment. The treatment effectively ablates human and mice xenografts and shows 100% response rates in skin or head and neck squamous cell carcinoma patients. DaRT induces specific and systemic antitumor immune activation and synergizes with immune stimulation and modulation in mice. Here, the transcriptional profile activated by DaRT, and its potential to enhance responsiveness to immune checkpoint inhibition by programmed cell death protein 1 (PD-1) blockade were studied. METHODS AND MATERIALS: Squamous cell carcinoma tumor- bearing BALB/C mice were treated with DaRT or inert seeds in combination with anti-PD-1 (aPD-1) or IgG control antibody. Sixteen days after seed insertion, tumors and spleens were subjected to immunophenotyping and immunohistochemical staining. Combination of DaRT and aPD-1 was tested for efficacy. Gene expression analysis was performed on mRNA extracted from tumors 7 days after DaRT or inert insertion using Nanostring PanCancer-IO-360 panel, and tumors and spleens were subjected to flow cytometry analysis. RESULTS: DaRT in combination with aPD-1 delayed tumor development, induced CD3 and CD8 lymphocytes infiltration more efficiently than either monotherapy. The combined treatment reduced splenic polymorphonuclear myeloid derived suppressor cells more than aPD-1 therapy or control. Granzyme B release in the tumor was increased only in the combinational treatment and was correlated with T-lymphocyte infiltration. Gene expression and gene set enrichment analysis of mRNA levels 7 days after DaRT insertion indicated that DaRT upregulated apoptosis, p53 signaling, G1/S-related arrest, interferon signaling and myeloid related transcription, while downregulating DNA repair, cell proliferation, and notch-related transcription. Flow cytometry showed that DaRT increased dendritic cells activation and led to changes in MDSCs distribution. CONCLUSIONS: DaRT promotes a "hot" tumor microenvironment and changes in immune suppression that lead to a potentiation of aPD-1 blockade induced effector T cell function and improved treatment efficacy. This study provides rationale for investigating DaRT and aPD-1 combination in patients with squamous cell carcinoma.

Diffusing alpha-emitters radiation therapy in combination with temozolomide or bevacizumab in human glioblastoma multiforme xenografts.

Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of 224Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients.

External Concurrent Occipital and Trigeminal Neurostimulation Relieves Migraine Headache: A Prospective, Randomized, Double-Blind, Sham-Controlled Trial.

INTRODUCTION: Current external peripheral nerve stimulation devices stimulate only one nerve. This prospective, randomized, double-blind, sham-controlled trial assessed efficacy, safety, and tolerability of a novel external combined occipital and trigeminal neurostimulation (eCOT-NS) device as a self-administered home treatment for migraine (Relivion®MG, Neurolief Ltd; Netanya, Israel). METHODS: Episodic and chronic migraine subjects (N = 55) were randomized to receive active (n = 27) or sham (n = 28) treatment. Subjects received eCOT-NS devices and performed 60 ± 20-min home treatments within 45 min of migraine episode onset. The primary endpoint was relative (percent) change in mean baseline VAS pain scores 1 h after treatment initiation. Treatment outcomes assessed at 1-, 2-, and 24-h post-treatment initiation were pain reduction and proportion of pain-free subjects and treatment responders, defined as ≥ 50% pain reduction. Categorical pain ratings (none, mild, moderate, and severe pain) were also analyzed. RESULTS: Active stimulation was significantly more effective than sham stimulation for decreasing pain intensity at 1 h (53% vs. 10%), 2 h (52% vs. 17%), and 24 h (71% vs. 34%). Pain-free ratings were greater for the active treatment arm at 1 h (29.2% vs. 16%), 2 h (41.7% vs. 20%), and 24 h (65.2% vs. 40%). The number of subjects with baseline moderate or severe migraine pain who were pain-free at 2 h was significantly greater among active treatment subjects (43% vs. 10.5%). The responder rate was significantly higher among the active treatment group at 1 h (67% vs. 20%), 2 h (66.7% vs. 32%,), and 24 h (78.3% vs. 48%). Overall headache relief was significantly higher in the active treatment group at 1 h (67% vs. 26%) and 2 h (76% vs. 31.6%). Mild adverse events, reported by a minority of subjects, resolved spontaneously. CONCLUSIONS: eCOT-NS provides superior clinically meaningful relief and freedom from migraine pain, offering an effective and safe therapy for acute treatment of migraine. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03398668.

As current external nerve stimulation devices stimulate only one nerve, this study assessed the effectiveness, safety, and tolerability of a new external nerve stimulation device that stimulates two nerves (occipital and trigeminal) as a self-administered home treatment for migraine (Relivion^®MG, Neurolief Ltd; Netanya, Israel). Fifty-five subjects with episodic and chronic migraine were randomly assigned to active (n = 27) or sham (dummy) treatment (n = 28). Subjects performed a 60-min home treatment within 45 min of migraine onset. The primary endpoint was the change in pain intensity 1 h after treatment initiation. Active treatment was significantly more effective than sham stimulation for decreasing pain intensity at 1 h (53% vs. 10%) and 2 h (52% vs. 17%). Pain-free ratings were also greater for the active treatment arm at 1 h (29.2% vs. 16%) and 2 h (41.7% vs. 20%). Overall headache relief was significantly higher in the active treatment group at 1 h (67% vs. 26%) and 2 h (66.7% vs. 32%). Mild, transient side effects reported by a few subjects resolved without treatment. This new external concurrent occipital and trigeminal neurostimulation (eCOT-NS) device provides superior and meaningful relief and freedom from migraine pain compared to sham treatment.

Migraine treatment with external concurrent occipital and trigeminal neurostimulation-A randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of concurrent non-invasive stimulation of occipital and trigeminal nerves in acute treatment of migraine with or without aura. BACKGROUND: Non-invasive neuromodulation devices stimulating a single peripheral nerve or anatomic distribution are routinely used by patients with migraine refractory to the first-line drugs or those who opt out of pharmaceutical treatment. Concurrent occipital and trigeminal stimulation was described in an invasive setting, and its safety cost outweighed its efficacy gain. This study evaluated the efficacy and safety of an external concurrent occipital and trigeminal device in acute treatment of migraine. DESIGN AND METHODS: This was a randomized, sham-controlled, double-blind, multi-center trial. Patients 18 years of age or older who met the International Classification of Headache Disorders (2018) diagnostic criteria for migraine with or without aura, reported 1-6 migraine attacks per month, and other headaches no more than 6 days per month were enrolled. Of 131 intention-to-treat participants (67 and 64 in the active and sham groups, respectively), 109 (50 and 59 in the active and sham groups, respectively) treated at least one migraine episode. Reduction of migraine headache (pain relief) 2 h after treatment initiation was the primary efficacy endpoint. Pain relief at 1 h, and pain freedom and relief in most bothersome symptom at 2 h after treatment initiation were the secondary endpoints. Freedom from most bothersome symptom at 2 h and sustained pain freedom 24 h after treatment initiation were among the exploratory endpoints. RESULTS: Sixty percent of participants (30/50) in the active arm reported pain relief at 2 h after initiation of the first eligible treatment (primary outcome) compared to 37% (22/59) in the control arm (difference, 23%; 95% confidence interval [CI], 2%-41%; p = 0.018). Pain freedom at 2 h without rescue medication was reported by 46% (23/50) of participants in the active arm and by 12% (7/59) of participants in the sham arm (p < 0.001). Pain freedom 2 h after the treatment and, subsequently, at 24 h, was reported by 4.25 times more participants in the active arm (36%; 18/50) than in the sham arm (8%; 5/59). The 28% difference was statistically significant (95% CI, 1%-43%; p < 0.001). A 4.25-fold difference was also observed comparing the proportion of participants free from pain and most bothersome symptom 2 h after the stimulation (47% [17/36] and 11% [5/45] in the active and sham arms, respectively; 95% CI, 14%-54%; p < 0.001). Adverse events were not serious or severe. All study-related events resolved without treatment. CONCLUSION: External concurrent occipital and trigeminal neurostimulation is a well-tolerated, safe, and effective migraine treatment that provided a fast and durable relief and freedom from migraine pain and associated symptoms in a randomized setting. The observed safety and performance suggest external concurrent occipital and trigeminal neurostimulation is a viable alternative to the currently available acute migraine treatments. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT03631550.

Tarsier Anterior Chamber Cell Grading: Improving the SUN Grading Scheme with a Visual Analog Scale.

PURPOSE: To compare an analog visual scale in grading anterior chamber cells (ACC) to a modified Standardization of Uveitis Nomenclature (SUN) ACC scale. METHOD: A graphical representation of anterior chamber cells as a reference and a test set was created and shown to two groups of experienced uveitis experts. Group 1 was given the analog scale in written format, while group two was given the reference images for comparison. Each test subject was asked to provide the best approximation for each grade. RESULTS: Eleven graders participated in phase 1. Correct grading occurred in 87.4% of cases. Discrepancies were seen at all grades. Only 3 of 11 graders were able to achieve a perfect score. Seven graders participated in phase 2. Agreement was 95.2% with 4/7 graders achieving a perfect score. Discrepancies were seen at higher grades only. CONCLUSIONS: ACC grading is improved by a visual grading scale, and interobserver variability is reduced.

Deep Transcranial Magnetic Stimulation Combined With Brief Exposure for Posttraumatic Stress Disorder: A Prospective Multisite Randomized Trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD. METHODS: Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers. RESULTS: Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024). CONCLUSIONS: Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory-mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.

Age, pre-arrest neurological condition, and functional status as outcome predictors in out-of-hospital cardiac arrest: Secondary analysis of the Jerusalem Cohort Study data.

PURPOSE: Investigate the relation between age, baseline neurological and functional status, and survival after out-of-hospital cardiac arrest (OHCA). METHODS: Data analysis from the Jerusalem District Resuscitation Study. Patients >80 years and those 18-80 years with OHCA from 4/2005-12/2010 were compared. PRIMARY OUTCOME: survival at four time points; secondary outcomes: neurological and functional status at hospital discharge, and relationship between survival, age and pre-arrest activities of daily living (ADL) and Cerebral Performance Category (CPC) scores (higher scores indicate worse function in both). RESULTS: 3,211 patients (1,259 >80 years, 1952 aged 18-80) with median follow-up 5.9 years (range 0.1-11.1 years) were included. Survival was better for younger patients at all four time points, including 7.8% versus 2.5% at hospital discharge, 4.6% versus 0.2% at late follow-up. Functional status at discharge was also better, 4.8 ± 5.4 versus 9.0 ± 4.7, p<0.001, and more young patients had CPC1/2, 60.7% versus 32.2%, p = 0.004. Older patients who survived to emergency department admission had increased mortality per year of age (2.6%, hazard ratio [HR] 1.026, 95% confidence interval [CI] 1.006-1.048 versus 1.7%, HR 1.017, 95% CI 1.010-1.025), per point in pre-arrest ADL (3.0%, HR 1.030, 95% CI 1.007-1.054 versus 5.8%, HR 1.058, 95% CI 1.036-1.080), and per point in pre-arrest CPC (24%, HR 1.242, 95% CI 1.097-1.406 versus 37%, HR 1.370 95% CI 1.232-1.524). CONCLUSION: Patient independence before arrest may be a more crucial determinant of resuscitation outcome than older age alone. Discussion of end-of-life preferences is particularly important for older individuals with functional and cognitive decline.

Using machine learning algorithms to review computed tomography scans and assess risk for cardiovascular disease: Retrospective analysis from the National Lung Screening Trial (NLST).

BACKGROUND: The National Lung Screening Trial (NLST) demonstrated that annual screening with low dose CT in high-risk population was associated with reduction in lung cancer mortality. Nonetheless, the leading cause of mortality in the study was from cardiovascular diseases. PURPOSE: To determine whether the used machine learning automatic algorithms assessing coronary calcium score (CCS), level of liver steatosis and emphysema percentage in the lungs are good predictors of cardiovascular disease (CVD) mortality and incidence when applied on low dose CT scans. MATERIALS AND METHODS: Three fully automated machine learning algorithms were used to assess CCS, level of liver steatosis and emphysema percentage in the lung. The algorithms were used on low-dose computed tomography scans acquired from 12,332 participants in NLST. RESULTS: In a multivariate analysis, association between the three algorithm scores and CVD mortality have shown an OR of 1.72 (p = 0.003), 2.62 (p < 0.0001) for CCS scores of 101-400 and above 400 respectively, and an OR of 1.12 (p = 0.044) for level of liver steatosis. Similar results were shown for the incidence of CVD, OR of 1.96 (p < 0.0001), 4.94 (p < 0.0001) for CCS scores of 101-400 and above 400 respectively. Also, emphysema percentage demonstrated an OR of 0.89 (p < 0.0001). Similar results are shown for univariate analyses of the algorithms. CONCLUSION: The three automated machine learning algorithms could help physicians to assess the incidence and risk of CVD mortality in this specific population. Application of these algorithms to existing LDCT scans can provide valuable health care information and assist in future research.

Biomarkers for Autism Spectrum Disorders (ASD): A Meta-analysis.

OBJECTIVE: To compare the reported accuracy and sensitivity of the various modalities used to diagnose autism spectrum disorders (ASD) in efforts to help focus further biomarker research on the most promising methods for early diagnosis. METHODS: The Medline scientific literature database was searched to identify publications assessing potential clinical ASD biomarkers. Reports were categorized by the modality used to assess the putative markers, including protein, genetic, metabolic, or objective imaging methods. The reported sensitivity, specificity, area under the curve, and overall agreement were summarized and analyzed to determine weighted averages for each diagnostic modality. Heterogeneity was measured using the I2 test. RESULTS: Of the 71 papers included in this analysis, each belonging to one of five modalities, protein-based followed by metabolite-based markers provided the highest diagnostic accuracy, each with a pooled overall agreement of 83.3% and respective weighted area under the curve (AUC) of 89.5% and 88.3%. Sensitivity provided by protein markers was highest (85.5%), while metabolic (85.9%) and protein markers (84.7%) had the highest specificity. Other modalities showed degrees of sensitivity, specificity, and overall agreements in the range of 73%-80%. CONCLUSIONS: Each modality provided for diagnostic accuracy and specificity similar or slightly higher than those reported for the gold-standard Autism Diagnostic Observation Schedule (ADOS) instrument. Further studies are required to identify the most predictive markers within each modality and to evaluate biological pathways or clustering with possible etiological relevance. Analyses will also be necessary to determine the potential of these novel biomarkers in diagnosing pediatric patients, thereby enabling early intervention.

The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center study.

INTRODUCTION: Several works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time. METHODS: This phase II, prospective study was open to pediatric patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced ≥4 seizures within four weeks of enrolment and with a history of ≥4 AEDs failing to provide seizure control. Following a 4-week observation period, patients began a 2-week dose-titration phase (up to ≤25mg/kg or 450mg, the lower of the two), followed by a 10-week maintenance treatment period. Caregivers recorded seizure frequency, type, and severity and ranked their global impressions after 7 and 12weeks of treatment. Responders were those showing a ≥50% reduction from baseline monthly seizure frequency. Safety assessments monitored vital signs, adverse effects, physical and neurological exams, and laboratory tests. RESULTS: Sixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p<0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders' rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved. CONCLUSIONS: PTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE.

Prospective Observational Investigation of Capnography and Pulse Oximetry Monitoring After Cesarean Delivery With Intrathecal Morphine.

BACKGROUND: Intrathecal morphine provides excellent analgesia after cesarean delivery; however, respiratory events such as apnea, bradypnea, and hypoxemia have been reported. The primary study aim was to estimate the number of apneas per subject, termed "apnea alert events" (AAEs) defined by no breath for 30-120 seconds, using continuous capnography in women who underwent cesarean delivery. METHODS: We performed a prospective, observational study with institutional review board approval of women who underwent cesarean delivery with spinal anesthesia containing 150-µg intrathecal morphine. A STOP-Bang obstructive sleep apnea assessment was administered to all women. Women were requested to use continuous capnography and pulse oximetry for 24 hours after cesarean delivery. Nasal sampling cannula measured end-tidal carbon dioxide (EtCO2) and respiratory rate (RR), and oxygen saturation (SpO2) as measured by pulse oximetry. Capnography data were defined as "valid" when EtCO2 >10 mm Hg, RR >5 breaths per minute (bpm), SpO2 >70%, or during apnea (AAE) defined as "no breath" (EtCO2, <5 mm Hg) for 30-120 seconds. Individual respiratory variable alerts were 10-second means of EtCO2 <10 mm Hg, RR <8 bpm, and SpO2 <94%. Nurse observations of RR (hourly and blinded to capnography) are reported. RESULTS: We recruited 80 women, mean (standard deviation [SD]) 35 (5) years, 47% body mass index >30 kg/m2/weight >90 kg, and 11% with suspected obstructive sleep apnea (known or STOP-Bang score >3). The duration of normal capnography and pulse oximetry data was mean (SD) (range) 8:28 (7:51) (0:00-22:32) and 15:08 (6:42) (1:31-23:07) hours:minutes, respectively; 6 women did not use the capnography. There were 198 AAEs, mean (SD) duration 57 (27) seconds experienced by 39/74 (53%) women, median (95% confidence interval for median) (range) 1 (0-1) (0-29) per subject. Observation of RR by nurses was ≥14 bpm at all time-points for all women, r = 0.05 between capnography and nurse RR (95% confidence interval, -0.04 to 0.14). There were no clinically relevant adverse events for any woman. Sixty-five women (82%) had complaints with the capnography device, including itchy nose, nausea, interference with nursing baby, and overall inconvenience. CONCLUSIONS: We report 198 AAEs detected by capnography among women who underwent cesarean delivery after receiving intrathecal morphine. These apneas were not confirmed by the intermittent hourly nursing observations. Absence of observer verification precludes distinction between real, albeit nonclinically significant alerts with capnography versus false apneas. Discomfort with the nasal sampling cannula and frequent alerts may impact capnography application after cesarean delivery. No clinically relevant adverse events occurred.

Sensory modulation dysfunction is associated with Complex Regional Pain Syndrome.

OBJECTIVE: Complex Regional Pain Syndrome (CRPS), a chronic pain condition, develops mainly after limb trauma and severely inhibits function. While early diagnosis is essential, factors for CRPS onset are elusive. Therefore, identifying those at risk is crucial. Sensory modulation dysfunction (SMD), affects the capacity to regulate responses to sensory input in a graded and adaptive manner and was found associated with hyperalgesia in otherwise healthy individuals, suggestive of altered pain processing. AIM: To test SMD as a potential risk factor for CRPS. METHODS: In this cross-sectional study, forty-four individuals with CRPS (29.9±11 years, 27 men) and 204 healthy controls (27.4±3.7 years, 105 men) completed the Sensory Responsiveness Questionnaire-Intensity Scale (SRQ-IS). A physician conducted the CRPS Severity Score (CSS), testing individuals with CRPS. RESULTS: Thirty-four percent of the individuals with CRPS and twelve percent of the healthy individuals were identified to have SMD (χ2 (1) = 11.95; p<0.001). Logistic regression modeling revealed that the risk of CRPS is 2.68 and 8.21 times higher in individuals with sensory over- and sensory under-responsiveness, respectively, compared to non-SMD individuals (p = 0.03 and p = 0.01, respectively). CONCLUSIONS: SMD, particularly sensory under-responsiveness, might serve as a potential risk factor for CRPS and therefore screening for SMD is recommended. This study provides the risk index probability clinical tool a simple evaluation to be applied by clinicians in order to identify those at risk for CRPS immediately after injury. Further research is needed.

Changes in Adenoma Detection Rate With Implementation of Full-spectrum Endoscopy: A Report of 3998 Screening Colonoscopies.

GOALS: To investigate the effect of implementing full-spectrum endoscopy (Fuse) on adenoma detection rate (ADR) at an ambulatory surgical center (ASC). BACKGROUND: Traditional forward viewing (TFV) endoscopes have 1 camera and provide an angle of view of 140 to 170 degrees, whereas Fuse provides a 330 degrees view through the addition of 2 side cameras. Although randomized studies have shown that Fuse decreases adenoma miss rates, its impact on ADR in a screening population is currently unknown. STUDY: We conducted a retrospective analysis of data from average risk screening colonoscopies at a 5-room ASC. This ASC transitioned from TFV to Fuse in April 2014. The primary outcome was ADR defined as the percentage of patients who underwent screening colonoscopy and were found to have at least 1 adenomatous polyp. RESULTS: A total of 1696 screening colonoscopies were performed with TFV and 2302 with Fuse. Overall ADR was 23.7% with TFV and 29.0% with Fuse (P<0.01), an absolute increase of 5.3%. ADR for the proximal colon increased from 13.0% with TFV to 16.7% with Fuse (3.8% increase, P<0.01). ADR for advanced adenomas improved from 3.8% with TFV to 6.0% with Fuse (2.2% increase; P<0.01). The mean number of adenomas detected per colonoscopy increased from 0.32 to 0.41 (P<0.01). In multivariate analysis, the adjusted odds ratio for detecting an adenoma with Fuse versus TFV was 1.30 (P<0.01; 95% confidence interval, 1.11-1.51). CONCLUSIONS: ADR significantly increased after adopting Fuse endoscopes at an ASC. Further studies are warranted to further understand the effects of Fuse on ADR in real-world settings.

PTL401, a New Formulation Based on Pro-Nano Dispersion Technology, Improves Oral Cannabinoids Bioavailability in Healthy Volunteers.

There is a growing clinical interest in developing and commercializing pharmaceutical-grade cannabinoid products, containing primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metabolism. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed reference oromucosal spray (Sativex®). Fourteen healthy male volunteers received, on separate treatment days, either a single dose of PTL401 or an equivalent dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma Cmax than the equivalent dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, respectively). Values of Tmax were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clinical studies with this formulation.

Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology.

Cannabidiol (CBD) is the main nonpsychoactive component of the cannabis plant. It has been associated with antiseizure, antioxidant, neuroprotective, anxiolytic, anti-inflammatory, antidepressant, and antipsychotic effects. PTL101 is an oral gelatin matrix pellets technology-based formulation containing highly purified CBD embedded in seamless gelatin matrix beadlets. Study objectives were to evaluate the safety and tolerability of PTL101 containing 10 and 100 mg CBD, following single administrations to healthy volunteers and to compare the pharmacokinetic profiles and relative bioavailability of CBD with Sativex oromucosal spray (the reference product) in a randomized, crossover study design. Administration of PTL101 containing 10 CBD, led to a 1.7-fold higher Cmax and 1.3-fold higher AUC compared with the oromucosal spray. Tmax following both modes of delivery was 3-3.5 hours postdosing. CBD exhibited about a 1-hour lag in absorption when delivered via PTL101. A 10-fold increase in the dose resulted in an ∼15-fold increase in Cmax and AUC. Bioavailability of CBD in the 10-mg PTL101 dose was 134% relative to the reference spray. PTL101 is a pharmaceutical-grade, user-friendly oral formulation that demonstrated safe and efficient delivery of CBD and therefore could be an attractive candidate for therapeutic indications.