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bioRxiv2018

Cost-effectiveness of telephone-based weight loss support for patients with knee osteoarthritis: a pragmatic randomised controlled trial

BackgroundTelephone-based support offers a promising option to provide widely accessible and cost-effective weight loss care to the people with knee osteoarthritis who are overweight. While telephone-based interventions targeting weight loss are used routinely in the general populations, the cost-effectiveness of referring patients with knee osteoarthritis to these is unknown. The aim of this study was to assess the cost-effectiveness of referral to a telephone-based weight management and healthy lifestyle service for patients with knee osteoarthritis, who are overweight or obese, compared to usual care. MethodsWe randomised 120 patients with knee osteoarthritis to an intervention or usual care control group in a 1:1 ratio. Participants in the intervention group received a referral to an existing non-disease specific 6-month telephone-based weight management and healthy lifestyle service. The primary outcome of the study was quality-adjusted life years (QALYs). Secondary outcomes included pain intensity, disability, weight, and body mass index (BMI). Costs included intervention costs, healthcare utilisation costs (healthcare services and medication use) and absenteeism costs due to knee pain. The primary cost-effectiveness analysis was performed from the societal perspective. ResultsMean cost differences between groups (intervention minus control) were, $454 (95%CI: -2735 to 4206) for healthcare costs, $-36, (95%CI: -73 to 2) for medication costs, and $-13 (95%CI: -225 to 235) for absenteeism costs. The total mean difference in societal costs was $1022 (95%CI: -2201 to 4771). For all outcomes, the probability of the intervention being cost-effective compared with usual care was less than 0.33 at all willingness-to-pay values. ConclusionFrom a societal perspective, telephone-based weight loss support, provided using an existing non-disease specific 6-month weight management and healthy lifestyle service was not cost-effective in comparison with usual care for overweight and obese patients with knee osteoarthritis for QALYs, pain intensity, disability, weight, and BMI.

clinical trials↗

bioRxiv2017

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial

Major Depressive Disorder affects about 350 million people worldwide, and about one-third of the patients are considered treatment-resistant. Furthermore, available antidepressants take usually two weeks for the onset of their antidepressant effect. Recent open label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants. Although promising, these studies were not controlled for the placebo effect. To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a parallel arm, double-blind randomised placebo-controlled trial, in patients with treatment-resistant major depression. Thirty-five patients with treatment-resistant major depression received a single dose of ayahuasca or placebo. We measured as primary outcome the change in the Hamilton Depression Rating scale (HAM-D) seven days after the dosing session, and as secondary outcomes the changes in Montgomery-[A]sberg Depression Rating Scale (MADRS), and response rates at one day (D1), two days (D2) and seven days (D7) after dosing, and remission rates at D7. This study is registered with http://clinicaltrials.gov (NCT02914769). We observed robust evidence of rapid antidepressant effects of a single dosing session with ayahuasca when compared to placebo. HAM-D scores at D7 were significantly lower in patients treated with ayahuasca than in those treated with placebo (p=0{middle dot}019; Cohens d=0{middle dot}98). MADRS scores were significantly reduced in the ayahuasca group compared to the placebo group at all endpoints (at D1 and D2, p=0{middle dot}04; at D7, p<0{middle dot}0001). Between-group effect sizes increased from D1 to D7 (D1: Cohens d=0{middle dot}84; D2: Cohens d=0{middle dot}84; D7: Cohens d=1{middle dot}49). Response rates were high for both groups at D1 and D2, and were significantly higher in the ayahuasca group only at D7 (64% vs. 27%; OR = 4{middle dot}95; p = 0{middle dot}04; NNT = 2{middle dot}66). Remission rate was not significantly different between groups. Our study provides new evidence of rapid antidepressant effects of ayahuasca for treatment-resistant major depression.

clinical trials↗

bioRxiv2017

The NSIGHT1 Randomized Controlled Trial: Rapid Whole Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants

ImportanceGenetic disorders, including congenital anomalies, are a leading cause of morbidity and mortality in infants, especially in neonatal and pediatric intensive care units (NICU and PICU). While genomic sequencing is useful for diagnosis of genetic diseases, results are usually reported too late to guide inpatient management.\n\nObjectiveTo test the hypothesis that rapid whole genome sequencing (rWGS) increases the proportion of infants in NICUs and PICUs receiving a genetic diagnosis within 28 days.\n\nDesignAn investigator-initiated, partially blinded, pragmatic, randomized controlled study with enrollment from October 2014 - June 2016, and follow up until December 2016.\n\nSettingA regional neonatal and pediatric intensive care unit in a tertiary referral childrens hospital.\n\nParticipantsSixty five of 129 screened families with infants aged less than four months, in neonatal and pediatric intensive care units, and with illnesses of unknown etiology, completed the study.\n\nInterventionParent and infant trio rWGS.\n\nMain Outcome and MeasureThe hypothesis and end-points were formulated a priori. The primary end-point was rate of genetic diagnosis within 28 days of enrollment or first standard test order.\n\nResultsTwenty six female proband infants, 37 male infants, and two infants of undetermined sex were randomized to receive rWGS plus standard tests (n=32, cases) or standard tests alone (n=33, controls). The study was terminated early due to loss of equipoise: 63% (21) controls received genomic sequencing as standard tests. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days to be higher in cases (31%, ten of 32) than controls (3%, one of 33; difference, 28% [95% CI, 10% to 46%]; p=0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, seven of 22) than controls (0%, zero of 23; difference, 32% [95% CI, 11% to 53%]; p=0.004). Age at diagnosis (median in cases 25 days, range 14-90 days vs median in controls 130 days, range 37-451) and time to diagnosis (median in cases thirteen days, range 1-84 days vs median in controls 107 days, range 21-429 days) were significantly less in cases than controls (p=0.04).\n\nCONCLUSIONSrWGS increased the proportion of infants in a regional NICU and PICU who received a timely diagnosis of a genetic disease. Additional, adequately powered studies are needed to determine whether accelerated diagnosis is associated with improved outcomes in this setting. ClinicalTrials.gov Identifier: NCT02225522.

clinical trials↗

bioRxiv2017

Community-Led Research Discovers Links Between Elusive Symptoms And Clinical Tests

Human breath and body odors have been used for diagnosis of serious and life-threatening conditions since the dawn of medical practice. More recently, it has been recognized that malodors without accompanying physical symptoms could be a sign of psychologically but not physically debilitating disorders such as Trimethylaminuria (TMAU). Self-reported intermittent odors without apparent cause, are, however, still treated with suspicion by medical professionals. Most cases of socially-disabling idiopathic malodor remain undiagnosed and there are no guidelines for diagnostic tests nor treatment options that extend beyond TMAU. Internationally-recruited volunteers with undiagnosed body odor and halitosis enrolled to participate in our study, registered as NCT02692495 at clinicaltrials.gov. Each volunteer underwent several blood and urine tests conducted by Biolab Medical Unit, a medical referral laboratory in London, specializing in nutritional and environmental medicine. Intestinal permeability measurements were strikingly different for subjects that named the nose/mouth as the malodor source(s) versus other, often unidentified, body regions. Furthermore, metabolite levels in blood and urine allowed matching of participants by dietary sensitivities and the type of odor reported, emphasizing the potential of harnessing patients olfactory observations. In discussing the anecdotal \"People are Allergic to Me\" condition (PATM), we show how it fits into the picture.

clinical trials↗

bioRxiv2017

Performance Of Children With Autism In Parent-Administered Cognitive And Language Exercises

There is a broad scientific consensus that early and intensive therapy has the greatest chance of positive impact on an individual with autism spectrum disorder (ASD). However, the availability, quality, and general funding for early intervention programs is often lacking, leaving newly diagnosed children without adequate and sufficient therapy during the most critical early period of their development. Parent-administered iPad-assisted therapy has the potential to reduce the gap between the amount of therapy recommended for children with ASD and the amount they receive. However it is unclear how ASD severity and age influence a childs ability to engage with and learn from computerized cognitive exercises. In this manuscript, we describe data from a tablet-based therapeutic application administered by parents to 1,514 young children with ASD over the course of four to twelve months. We report that older children and children with milder forms of ASD performed better and progressed faster in cognitive and language exercises. However, most children were able to engage with and learn from exercises independent of their age or ASD severity. This data confirm that tablet-based cognitive and language exercises can be successfully administered by parents to children as young as two years of age over the course of many months independent of ASD severity.

clinical trials↗

bioRxiv2017

Within-infection diversity of Plasmodium falciparum antigens reflects host-mediated selection

Host immunity exerts strong selection on pathogens, but it does not act in a uniform manner across individual hosts. By providing a direct approach for understanding host-specific selection pressures, patterns of intra-host pathogen diversity complement population genetic analyses performed on broad geographic scales. Here, we perform a combined analysis of inter- and intra-host diversity for the malaria parasite Plasmodium falciparum with haplotype sequences of three antigens sampled from over 4,500 natural infections in sub-Saharan Africa using targeted deep sequencing. We find that multi-strain infections in young children contain non-random combinations of parasite genotypes, and identify individual amino acid positions that may contribute to strain-specific blocking of infections. These results demonstrate for the first time that natural host defenses to Plasmodium detectably impact which infections proceed to the blood stage within a given host. This selection partially explains the extreme amino acid diversity observed at many parasite antigens and suggests that vaccines targeting such proteins should account for the impact of allele-specific immunity.

evolutionary biology↗

bioRxiv2017

Influence of APOA5 locus on the treatment efficacy of three statins: evidence from a randomized pilot study in Chinese subjects

Pharmacogenetics or pharmacogenomics approaches are important for addressing the individual variabilities of drug efficacy especially in the era of precision medicine. One particular interesting gene to investigate is APOA5 which has been repeatedly linked with the inter-individual variations of serum triglycerides. Here, we explored APOA5-statin interactions in 195 Chinese subjects randomized to rosuvastatin (5-10 mg/day), atorvastatin (10-20 mg/day), or simvastatin (40 mg/day) for 12 weeks by performing a targeted genotyping analysis of the APOA5 promoter SNP rs662799 (-1131T>C). There were no significant differences between the treatment arms for any of the statin-induced changes in clinical biomarkers. Reductions in LDL cholesterol were influenced by the APOA5 genotype in all three treatment groups. By contrast, changes in HDL cholesterol and triglycerides were only affected by the APOA5 genotype in the atorvastatin and simvastatin groups and not in the rosuvastatin group. Our results support earlier findings indicating that rosuvastatin is a better treatment option and that future studies should consider stratifying subjects not only by genetic background but also by statin type.\n\nAbbreviations

clinical trials↗

bioRxiv2017

Evaluating a sepsis prediction machine learning algorithm using minimal electronic health record data in the emergency department and intensive care unit

IntroductionSepsis is a major health crisis in US hospitals, and several clinical identification systems have been designed to help care providers with early diagnosis of sepsis. However, many of these systems demonstrate low specificity or sensitivity, which limits their clinical utility. We evaluate the effects of a machine learning algodiagnostic (MLA) sepsis prediction and detection system using a before-and-after clinical study performed at Cabell Huntington Hospital (CHH) in Huntington, West Virginia. Prior to this study, CHH utilized the St. Johns Sepsis Agent (SJSA) as a rules-based sepsis detection system.\n\nMethodsThe Predictive algoRithm for EValuation and Intervention in SEpsis (PREVISE) study was carried out between July 1, 2017 and August 30, 2017. All patients over the age of 18 who were admitted to the emergency department or intensive care units at CHH were monitored during the study. We assessed pre-implementation baseline metrics during the month of July, 2017, when the SJSA was active. During implementation in the month of August, 2017, SJSA and the MLA concurrently monitored patients for sepsis risk. At the conclusion of the study period, the primary outcome of sepsis-related in-hospital mortality and secondary outcome of sepsis-related hospital length of stay were compared between the two groups.\n\nResultsSepsis-related in-hospital mortality decreased from 3.97% to 2.64%, a 33.5% relative decrease (P = 0.038), and sepsis-related length of stay decreased from 2.99 days in the pre-implementation phase to 2.48 days in the post-implementation phase, a 17.1% relative reduction (P < 0.001).\n\nConclusionReductions in patient mortality and length-of-stay were observed with use of a machine learning algorithm for early sepsis detection in the emergency department and intensive care units at Cabell Huntington Hospital, and may present a method for improving patient outcomes.\n\nTrial RegistrationClinicalTrials.gov, NCT03235193, retrospectively registered on July 27th 2017.

clinical trials↗

bioRxiv2017

Similar clinical improvement and maintenance after rTMS at 5 Hz using a simple vs. complex protocol in Alzheimer’s disease

BrackgroundCurrent treatments for Alzheimers disease (AD) have a limited clinical response and methods, such as repetitive transcranial magnetic stimulation (rTMS), are being studied as possible treatments for the clinical symptoms with positive results. However, there is still seldom information on the type of rTMS protocols that deliver the best clinical improvement in AD.\n\nObjetiveTo compare the clinical response between a simple stimulation protocol on the left dorsolateral prefrontal cortex (lDLPFC) against a complex protocol using six regions of interest.\n\nMethods19 participants were randomized to receive any of the protocols. The analysis of repeated measures evaluated the change.\n\nResultsBoth protocols were equally proficient at improving cognitive function, behavior and functionality after 3 weeks of treatment, and the effects were maintained for 4 weeks more without treatment.\n\nConclusionWe suggest rTMS on the lDLPFC could be enough to provide a clinical response, and the underlying mechanisms should be studied.

clinical trials↗

bioRxiv2018

Rapid Whole Genome Sequencing Decreases Morbidity and Healthcare Cost of Hospitalized Infants

BACKGROUNDGenetic disorders are a leading cause of morbidity and mortality in infants. Rapid Whole Genome Sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants.\n\nMETHODSRetrospective cohort study of acutely ill inpatient infants in a regional childrens hospital from July 2016-March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points.\n\nFINDINGSThe diagnostic sensitivity was 43% (eighteen of 42 infants) for rWGS and 10% (four of 42 infants) for standard of care (P=.0005). The rate of clinical utility for rWGS (31%, thirteen of 42 infants) was significantly greater than for standard of care (2%, one of 42; P=.0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800, 000 to $2,000,000.\n\nDISCUSSIONThese findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.

clinical trials↗

bioRxiv2018

Cardiovascular Disease Risk Factor Responses to a Type 2 Diabetes Care Model Including Nutritional Ketosis at One Year: An Open Label, Non-Randomized, Controlled Study

Background\n\nCardiovascular disease (CVD) is a leading cause of death among adults with type 2 diabetes mellitus (T2D). We recently reported that glycemic control in patients with T2D can be significantly improved through a continuous care intervention (CCI) including nutritional ketosis. The purpose of this study was to examine CVD risk factors in this cohort.\n\nMethods\n\nWe investigated CVD risk factors in patients with T2D who participated in a one year open label, non-randomized, controlled study. The CCI group (n = 262) received treatment from a health coach and medical provider. A usual care (UC) group (n = 87) was independently recruited to track customary T2D progression. Circulating biomarkers of cholesterol metabolism and inflammation, blood pressure (BP), carotid intima media thickness (cIMT), multi-factorial risk scores and medication use were examined.\n\nResults\n\nThe CCI group consisted of 262 patients (baseline mean(SD): age 54(8) y, BMI 40.4(8.8) kg/m2). Intention-to-treat analysis (% change) revealed the following at 1-year with P values < 0.0019 indicating statistical significance after adjustment for multiple comparisons: total LDL-particles (LDL-P) (-4.9%, P=0.02), small LDL-P (-20.8%, P=1.2x10-12), LDL-P size (+1.1%, P=6.0x10-10), ApoB (-1.6%, P=0.37), ApoA1 (+9.8%, P<10-16), ApoB/ApoA1 ratio (-9.5%, P=1.9x10-7), triglyceride/HDL-C ratio (-29.1%, P<10-16), large VLDL-P (-38.9%, P=4.2x10-15), and LDL-C (+9.9%, P=4.9x10-5). Additional effects were reductions in blood pressure, high sensitivity C-reactive protein, and white blood cell count (all P<1x10-7) while cIMT was unchanged. The 10-year atherosclerotic cardiovascular disease (ASCVD) risk score decreased -11.9% (P=4.9x10-5). Antihypertensive medication use was discontinued in 11.4 % of CCI participants (P=5.3x10-5). The UC group of 87 patients (baseline mean(SD): age 52(10)y, BMI 36.7(7.2) kg/m2) showed no significant changes. After adjusting for baseline differences when comparing CCI and UC groups, significant improvements for the CCI group included small LDL-P, ApoA1, triglyceride/HDL-C ratio, HDL-C, hs-CRP, and ASCVD score. The CCI group showed a greater rise in LDL-C.\n\nConclusions\n\nA continuous care treatment including nutritional ketosis in patients with T2D improved most biomarkers of CVD risk after one year. The increase in LDL-cholesterol appeared limited to the large LDL subfraction. LDL particle size increased, total LDL-P and ApoB were unchanged, and inflammation and blood pressure decreased.\n\nTrial registration\n\nClinicaltrials.gov: NCT02519309. Registered 10 August 2015

clinical trials↗

bioRxiv2018

Ripple-Mapping for the Detection of Long Duration Action Potential Areas in Patients with Brugada Syndrome

PurposeCatheter ablation has been recently utilised in patients with Brugada syndrome to prevent ventricular arrhythmias. We hypothesized whether a mapping algorithm \"Ripple-mapping\" would be able to rapidly identify the areas of long-duration multicomponent electrograms which constitute the targets for ablation for an automated strategy.\n\nMethodsRipple-Mapping analysis was performed in all patients undergoing catheter ablation of Brugada syndrome in 2 centers. The activity propagation pattern determined by Ripple-Mapping was assessed, and areas of long duration potentials identified by visual inspection. The area of interest with long-duration potentials was correlated with the location of the ablation lesions.\n\nResultsDetection of long duration potentials was possible in all four patients in this analysis. Points marking the ablation area in 2 patients were a perfect match to abnormal areas identified by Ripple-mapping. However, in 2 patients Ripple-mapping identified additional sites of long duration potentials which were not ablated. Acute and mid-term normalization of the ECG pattern was observed in three patients, and all these were free from arrhythmia relapse during a 10.3{+/-}3.2 months follow-up. In one patient, who had no ECG normalization and had arrhythmia relapse, the ablated area corresponded to <25% of the Ripple-map region of interest.\n\nConclusionsThis study shows the potential use of Ripple-mapping for identifying areas of long duration multicomponent electrograms in patients with Brugada syndrome and recurrent ventricular arrhythmias. This technique enables the rapid definition of an area of interest which should then be validated by the operator before performing ablation with an end-point of ECG normalisation.

clinical trials↗

bioRxiv2018

Digitally-Supported Continuous Care Intervention Including Individualized Nutritional Ketosis Significantly Improves Surrogate Markers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Liver Fibrosis in Patients with Type 2 Diabetes: An Open Label, Non-Randomized, Controlled Study

ObjectiveOne-year of comprehensive continuous care intervention (CCI) through nutritional ketosis improves HbA1c, body weight and liver enzymes among type 2 diabetes (T2D) patients. Here, we report the effect of the CCI on surrogate scores of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis. MethodsThis was a non-randomized longitudinal study, including adults with T2D who were self-enrolled to the CCI (n=262) or to receive usual care (UC, n=87) during one year. A NAFLD liver fat score [N-LFS] > -0.640 defined the presence of fatty liver. A NAFLD fibrosis score [NFS] of > 0.675 identified subjects with advanced fibrosis. Changes in N-LFS and NFS at one year were the main endpoints. ResultsAt baseline, NAFLD was present in 95% of patients in the CCI and 90% of patients in the UC. At one year, weight loss of > 5% was achieved in 79% of patients in the CCI vs. 19% of patients in UC (P<0.001). N-LFS mean score was reduced in the CCI group (-1.95{+/-}0.22, P<0.001) whereas it was not changed in the UC (0.47{+/-}0.41, P=0.26) (CCI vs. UC, P<0.001). NFS was reduced in the CCI group (-0.65{+/-}0.06, P<0.001) compared with UC (0.26{+/-}0.11, P=0.02) (P<0.001 between two groups). In the CCI group, the percentage of individuals with a low probability of advanced fibrosis increased from 18% at baseline to 33% at 1 year (P<0.001). ConclusionsOne year of a digitally-supported CCI significantly improved surrogates of NAFLD and advanced fibrosis in patients with type 2 diabetes. DATA SHARINGData sets and statistical code used for the current study are available from the corresponding author on reasonable request. Article Summary Strengths and limitations of this studyO_LIThis study highlights the beneficial effect of the CCI on NAFLD in high risk patients with T2D C_LIO_LIThis study also identifies positive associations between glycemic improvements and improvements in ALT levels C_LIO_LIThe assessment of resolution of steatosis and fibrosis is limited by the sensitivity and specificity of the non-invasive markers used in the study C_LIO_LIThe patients were restricted in their carbohydrate intake and monitored for their nutritional ketosis state, but dietary energy, macronutrient and micronutrient intakes were not assessed. C_LI

clinical trials↗

bioRxiv2018

A randomised exploratory investigation of the effects of Attention vs Working Memory Training on cognitive performance and everyday functioning following stroke.

Difficulties with attention are common following stroke and are associated with poor outcome. Home-based online cognitive training may have to the potential to provide an efficient and effective way to improve attentional functions in such patients. Little work has been carried out to assess the efficacy of this approach in stroke patients, and the lack of studies with active control conditions and rigorous evaluations of cognitive functioning pre and post training means understanding is limited as to whether and how such interventions may be effective. Here we compare the effects of 20 days of active cognitive training using either novel Selective Attention Training (SAT) or commercial Working Memory Training (WMT) programme, versus a waitlist control group, on a wide range of attentional and working memory tasks, as well as on self-reported everyday functioning. We demonstrate separable effects of each of the active training conditions, with SAT leading to improvements in both spatial and non-spatial aspects of attention and WMT leading to improvements only on very closely related working memory tasks. Both training groups reported improvements in everyday functioning, which were associated with improvements in attentional functions, suggesting that improving attention may be of particular importance in maximising functional recovery in this patient group.

clinical trials↗

bioRxiv2018

Placental-expanded, mesenchymal cells improve muscle function following hip arthroplasty

BackgroundNo regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite high frequency and associated functional deficits. We sought to address surgical trauma related muscle injuries using local intraoperative application of allogeneic placenta-derived, mesenchymal-like adherent cells (PLX-PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type.\n\nMethodsOur pilot phase I/IIa study was prospective, randomized, double blind and placebo-controlled. Twenty patients undergoing hip arthroplasty via a direct lateral approach were injected with 3.0x108 or 1.5x108 PLX-PAD or a placebo into the gluteus medius muscle.\n\nResultsWe did not observe any relevant PLX-PAD-related adverse events at the 2-year follow-up. Improved gluteus medius strength was noted as early as week 6 in the treatment-groups. Surprisingly, until week 26 the low-dose outperformed the high-dose group and reached significantly improved strength compared to placebo, mirrored by an increase in muscle volume. Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that low-dose treatment reduced the surgery-related immunological stress reaction more than high-dose. Signs of late-onset immune reactivity after high-dose treatment corresponded to reduced functional improvement.\n\nConclusionAllogeneic PLX-PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress-related immunological reactions.\n\nTrial RegistrationClinicalTrials.gov (number NCT01525667) and EudraCT (number 2011-003934-16)\n\nFundingThe study was funded by the Sponsor, Pluristem Therapeutics, the Israeli innovation authority and the German Federal Ministry of Education and Research.\n\nConflict of interestT. Winkler, C. Perka and G.N. Duda are members of a clinical advisory board of Pluristem Ltd for future indications. T. Winkler, C. Perka, G.N. Duda, P. von Roth filed a patent together with Pluristem Ltd. E. Lukasiewicz Hagai, R. Ofir, L. Pinzur and E. Eyal are current or former employees of Pluristem Ltd. T. Winkler, P. Reinke and H.-D. Volk received in the past consulting fees from Pluristem Ltd. but not for this project.

clinical trials↗

bioRxiv2018

Real-time functional connectivity-based neurofeedback of amygdala-frontal pathways reduces anxiety

Deficient emotion regulation and exaggerated anxiety represent a major transdiagnostic psychopathological marker. On the neural level these deficits have been closely linked to impaired, yet treatment-sensitive, prefrontal regulatory control over the amygdala. Gaining direct control over these pathways could therefore provide an innovative and promising strategy to regulate exaggerated anxiety. To this end the current proof-of-concept study evaluated the feasibility, functional relevance and maintenance of a novel connectivity-informed real-time fMRI neurofeedback training. In a randomized within-subject sham-controlled design high anxious subjects (n = 26) underwent real-time fMRI-guided training to enhance connectivity between the ventrolateral prefrontal cortex (vlPFC) and the amygdala (target pathway) during threat exposure. Maintenance of regulatory control was assessed after three days and in the absence of feedback. Training-induced changes in functional connectivity of the target pathway and anxiety ratings served as primary outcomes. Training of the target, yet not the sham-control, pathway significantly increased amygdala-vlPFC connectivity and decreased subjective anxiety levels. On the individual level stronger connectivity increases were significantly associated with anxiety reduction. At follow-up, volitional control over the target pathway and decreased anxiety level were maintained in the absence of feedback. The present results demonstrate for the first time that successful self-regulation of amygdala-prefrontal top-down regulatory circuits may represent a novel strategy to control anxiety. As such, the present findings underscore both the critical contribution of amygdala-prefrontal circuits to emotion regulation and the therapeutic potential of connectivity-informed real-time neurofeedback.

clinical trials↗

bioRxiv2018

Attentional Bias Modification Alters fMRI Response towards Negative Stimuli in Residual Depression

BackgroundModification of attentional biases (ABM) may lead to more adaptive emotion perception and emotion regulation. Understanding the neural basis of these effects may lead to greater precision for future treatment development. Task-related fMRI following ABM training has so far not been investigated in depression. The main aim of the RCT was to explore differences in brain activity after ABM training in response to emotional stimuli.\n\nMethodsA total of 134 previously depressed individuals were randomized into 14 days of ABM- or a placebo training followed by an fMRI emotion regulation task. Depression symptoms and subjective ratings of perceived negativity during fMRI was examined between the training groups. Brain activation was explored within predefined areas (SVC) and across the whole brain. Activation in areas associated with changes in attentional biases (AB) and degree of depression was explored.\n\nResultsThe ABM group showed reduced activation within the amygdala and within the anterior cingulate cortex (ACC) when passively viewing negative images compared to the placebo group. No group differences were found within predefined SVCs associated with emotion regulation strategies. Response within the temporal cortices was associated with degree of change in AB and with degree of depressive symptoms in ABM versus placebo.\n\nLimitationsThe findings should be replicated in other samples of depressed patients and in studies using designs that allow analyses of within-group variability from baseline to follow-up.\n\nConclusionsABM training has an effect on brain function within circuitry associated with emotional appraisal and the generation of affective states.\n\nClinicaltrials.gov identifier: NCT02931487

clinical trials↗

bioRxiv2018

Dose Escalation for Locally Advanced Pancreatic Cancer: How High Can We Go?

Introduction Introduction Methods Results Discussion References Locally advanced pancreatic cancer (LAPC) is particularly difficult to treat given that it exhibits a poor response to chemotherapy and is by definition unresectable. A large proportion of patients experience significant morbidity and mortality due to local progression. As systemic therapy improves with the advent of gemcitabine/ abraxane1 and FOLFIRINOX2, the burden of local disease will only increase. Standard radiation therapy doses have failed to improve survival, which is not unexpected given anatomical and technical limitations. Although the LAP-07 trial3 failed to show an overall survival benefit to radiation at standard doses, it did show benefits in terms of local control and t ...

clinical trials↗