Most downloaded biology preprints, all time
in category clinical trials
99 results found. For more information, click each entry to expand.
7,019 downloads bioRxiv clinical trials
OBJECTIVE: Studies on long-term sustainability of low-carbohydrate approaches to treat diabetes are limited. We aim to assess the effects of a continuous care intervention (CCI) on retention, glycemic control, weight, body composition, cardiovascular, liver, kidney, thyroid, inflammatory markers, diabetes medication usage and disease outcomes at 2 years in adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: An open label, non-randomized, controlled study with 262 and 87 participants with T2D were enrolled in the CCI and usual care (UC) groups, respectively. RESULTS: Significant changes from baseline to 2 years in the CCI group included: HbA1c (-12% from 7.7+0.1%); fasting glucose (-18% from 163.67+3.90 mg/dL); fasting insulin (-42% from 27.73+1.26 pmol L-1); weight (-10% from 114.56+0.60 kg); systolic blood pressure (-4% from 131.7+0.9 mmHg); diastolic blood pressure (-4% from 81.8+0.5 mmHg); triglycerides (-22% from 197.2+9.1 mg/dL); HDL-C (+19% from 41.8+0.9 mg/dL), and liver alanine transaminase (-21% from 29.16+0.97 U/L). Spine bone mineral density in the CCI group was unchanged. Glycemic control medication use (excluding metformin) among CCI participants declined (from 56.9% to 26.8%, P=1.3x10-11) including prescribed insulin (-62%) and sulfonylureas (-100%). The UC group had no significant changes in these parameters (except uric acid and anion gap) or diabetes medication use. There was also significant resolution of diabetes (reversal, 53.5%; remission, 17.6%) in the CCI group but not in UC. All the reported improvements had p-values <0.00012. CONCLUSIONS: The CCI sustained long-term beneficial effects on multiple clinical markers of diabetes and cardiometabolic health at 2 years while utilizing less medication. The intervention was also effective in the resolution of diabetes and visceral obesity, with no adverse effect on bone health. Clinical trial registration ID #NCT02519309
5,743 downloads bioRxiv clinical trials
Background: Evaluation of efficacy, safety and feasibility of hyperthermic baths (HTB; head-out-of-water-immersion in 40°C), twice a week, compared to a physical exercise program (PEP; moderate intensity aerobic exercises) in moderate to severe depression. Method: Single-site, open-label randomized controlled 8-week parallel-group pilot study at an university outpatient clinic as part of usual depression care. Medically stable outpatients with depressive disorder (ICD-10: F32/F33) as determined by the 17-item Hamilton Depression Rating Scale (HAM-D) score ≥18 and a score ≥2 on item 1 (Depressed Mood) were randomly assigned to receive either two sessions of HTB or PEP per week (40-45 min) provided by two trained doctoral students. An independent biometric center used computer-generated tables to allocate treatments. Primary outcome measure was the change in HAM-D total score from baseline (T0) to the 2-week time point (T1). Linear regression analyses, adjusted for baseline values, were performed to estimate intervention effects on an intention-to-treat (ITT) principle. Findings: 45 patients (HTB n = 22; PEP n = 23) were randomized and analyzed according to ITT (mean age = 48.4 years, SD = 11.3, mean HAM-D score = 21.7, SD = 3.2). Baseline-adjusted mean difference was 4.3 points in the HAM-D score in favor of HTB (p<0.001). This improvement was achieved after two weeks. Compliance with the intervention and follow-up was far better in the HTB group (2 vs 13 dropouts). There were no treatment-related serious adverse events. Main limitation: the number of dropouts in the PEP group (13 of 23) was far higher than in other trials investigating exercise in depression (18.1 % dropouts). Conclusions: HTB seems to be a fast-acting, safe and easy accessible method leading to clinically relevant improvement in depressive disorder after two weeks; it is also suitable for persons who have problems performing exercise training. Clinical Trial registration ID #DRKS00011013.
5,691 downloads bioRxiv clinical trials
Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias, Katia C Andrade, Morgana Novaes, Jessica A Pessoa, Sergio A Mota-Rolim, Flavia Osório, Rafael Sanches, Rafael G dos Santos, Luís F Tófoli, Gabriela de Oliveira Silveira, Mauricio Yonamine, Jordi Riba, Francisco RR Santos, Antonio A Silva-Junior, João Alchieri, Nicole L Galvão-Coelho, Bruno Lobão-Soares, Jaime Hallak, Emerson Arcoverde, João P Maia-de-Oliveira, Draulio B Araújo
Recent open label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. In order to further test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. Changes in depression severity were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale (HAM-D). Assessments were made at baseline, and at one (D1), two (D2) and seven (D7) days after dosing. We observed significant antidepressant effects of ayahuasca when compared to placebo at all timepoints. MADRS scores were significantly lower in the ayahuasca group compared to placebo (at D1 and D2: p=0.04; and at D7: p<0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen's d=0.84; D2: Cohen's d=0.84; D7: Cohen's d=1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% vs. 27%; p=0.04), while remission rate was marginally significant at D7 (36% vs. 7%, p=0.054). To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. Clinical trial registration ID #NCT02914769
5,427 downloads bioRxiv clinical trials
Sarah Lebeer, Eline Oerlemans, Ingmar Claes, Sander Wuyts, Tim Henkens, Irina Spacova, Marianne van den Broek, Ines Tuyaerts, Stijn Wittouck, Ilke De Boeck, Camille N. Allonsius, Filip Kiekens, Julien Lambert
The skin is home to an important part of our commensal microbiota, despite it being a cool, acidic and desiccated environment. Tailored microbiome modulation approaches with, for example probiotics, are highly challenging for this body site. Here we show by next-generating sequencing that Lactobacillus taxa -especially those known to be dominant in the human vagina- are underestimated members of the skin microbiota. Specific Lactobacillus strains were selected in the lab and formulated in a viable form in an oil in water-based topical cream. Facial application by patients with mild-to-moderate acne symptoms was able to reduce inflammatory lesions and comedone formation. This was associated with a temporary modulation of the skin microbiome, including a reduction in relative abundance of staphylococci and an increase in lactobacilli. Skin microbiome modulation by addition of carefully formulated lactobacilli seems to be new therapeutic option to reduce antibiotic use for common acne symptoms. Clinical trial registration ID #NCT03469076.
5,141 downloads bioRxiv clinical trials
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 trial registration ID #NCT02692495.
4,416 downloads bioRxiv clinical trials
Introduction Non-publication of clinical trials results is an ongoing issue. In 2016 the US government updated the results reporting requirements to ClinicalTrials.gov for trials covered under the FDA Amendments Act 2007. We set out to develop and deliver an online tool which publicly monitors compliance with these reporting requirements, facilitates open public audit, and promotes accountability. Methods We conducted a review of the relevant legislation to extract the requirements on reporting results. Specific areas of the statutes were operationalized in code based on the results of our policy review, publicly available data from ClinicalTrials.gov, and communications with ClinicalTrials.gov staff. We developed methods to identify trials required to report results, using publicly available registry data; to incorporate additional relevant information such as key dates and trial sponsors; and to determine when each trial became due. This data was then used to construct a live tracking website. Results There were a number of administrative and technical hurdles to successful operationalization of our tracker. Decisions and assumptions related to overcoming these issues are detailed along with clarifications directly from ClinicalTrials.gov. The FDAAA TrialsTracker was successfully launched in February 2018 and provides users with an overview of results reporting compliance. Discussion Clinical trials continue to go unreported despite numerous guidelines, commitments, and legal frameworks intended to address this issue. In the absence of formal sanctions from the FDA and others, we argue tools such as ours - providing live data on trial reporting - can improve accountability and performance. In addition, our service helps sponsors identify their own individual trials that have not yet reported results: we therefore offer positive practical support for sponsors who wish to ensure that all their completed trials have reported.
3,398 downloads bioRxiv clinical trials
Jean de Gunzburg, Amine Ghozlane, Annie Ducher, Emmanuelle Le Chatelier, Xavier Duval, Etienne Ruppe, Laurence Armand-Lefevre, Frédérique Sablier-Gallis, Charles Burdet, Loubna Alavoine, Elisabeth Chachaty, Violaine Augustin, Marina Varastet, Florence Levenez, Sean Kennedy, Nicolas Pons, France Mentré, Antoine Andremont
Background: Antibiotics are life-saving drugs but severely affect the gut microbiome with short term consequences including diarrhoea, Clostridium difficile infections and selection of antibiotic-resistant bacteria. Long-term links to allergy and obesity are also suggested. We devised a product, DAV132, and previously showed its ability to deliver a powerful adsorbent, activated charcoal, in the late ileum of human volunteers. Methods: We performed a randomized controlled trial (ClinicalTrials.gov NCT02176005) in 28 human volunteers treated with a 5-day clinical regimen of the fluoroquinolone antibiotic moxifloxacin in two parallel groups, with or without DAV132 co-administration. Two control goups of 8 volunteers each receiving DAV132 alone, or a non-active substitute, were added. Results: The co-administration of DAV132 decreased free moxifloxacin fecal concentrations by 99%, while plasmatic levels were unaffected. Shotgun quantitative metagenomics showed that the richness and composition of the intestinal microbiota were largely preserved in subjects co-treated with DAV132 in addition to moxifloxacin. No adverse effect was observed. In addition, DAV132 efficiently adsorbed a wide range of clinically relevant antibiotics ex-vivo. Conclusions: DAV132 was highly effective to protect the gut microbiome of moxifloxacin-treated healthy volunteers and may constitute a clinical breakthrough by preventing adverse health consequences of a wide range of antibiotic treatments. Clinical trial registration ID #NCT02176005.
3,147 downloads bioRxiv clinical trials
Eleanor J Cole, Katy H Stimpson, Brandon Stephen Bentzley, Merve Gulser, Kirsten Cherian, Claudia Tischler, Romina Nejad, Heather Pankow, Elizabeth Choi, Haley Aaron, Flint M Espil, Jaspreet Pannu, Xiaoqian Xiao, Dalton Duvio, Hugh B Solvason, Jessica Hawkins, Austin Guerra, Booil Jo, Kristin S. Raj, Charles Debattista, Jennifer Keller, Alan Schatzberg, Keith D Sudheimer, Nolan R. Williams
Background Current treatments for depression are limited by suboptimal efficacy, delayed response, and frequent side effects. Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation treatment that is FDA-approved for treatment-resistant depression (TRD). Recent methodological advancements suggest iTBS could be improved through 1) treating with multiple sessions per day at optimally-spaced intervals, 2) applying a higher overall pulse-dose of stimulation and 3) precision targeting of the left dorsolateral prefrontal cortex (L-DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. We examined the feasibility, tolerability, and preliminary efficacy of an accelerated, high-dose, resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for TRD termed ‘Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)’. Methods Twenty-one participants with TRD received open-label SAINT. FcMRI was used to individually target the region of L-DLPFC most anticorrelated with sgACC. Fifty iTBS sessions (1800 pulses per session, 50-minute inter-session interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT. Results Nineteen of 21 participants (90.48%) met criteria for remission (≤10 on the Montgomery-Åsberg Depression Rating Scale) immediately after SAINT. Neuropsychological testing demonstrated no negative cognitive side-effects. There were no seizures or other severe adverse events. Discussion Our accelerated, high-dose, iTBS protocol with fcMRI-guided targeting (SAINT) was well tolerated and safe. Efficacy was strikingly high, especially for this treatment-resistant population. Double-blinded sham-controlled trials are required to confirm the high remission rate found in this initial study. Trial registration ClinicalTrials.gov [NCT03240692] : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03240692&atom=%2Fbiorxiv%2Fearly%2F2019%2F08%2F06%2F581280.atom
2,919 downloads bioRxiv clinical trials
Yasir S Elhassan, Katarina Kluckova, Rachel S Fletcher, Mark Schmidt, Antje Garten, Craig L. Doig, David M Cartwright, Lucy Oakey, Claire V. Burley, Ned Jenkinson, Martin Wilson, Samuel J E Lucas, Ildem Akerman, Alex Seabright, Yu-Chiang Lai, Daniel A. Tennant, Peter Nightingale, Gareth A Wallis, Konstantinos N Manolopoulos, Charles Brenner, Andrew Philp, Gareth G Lavery
NAD+ is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome, and questioned if tissue NAD+ levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31P magnetic resonance spectroscopy-based NAD+ measurement in muscle and brain showed no difference between young and aged individuals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD+ decline is not associated with chronological aging per se in human muscle or brain.
2,414 downloads bioRxiv clinical trials
Our knowledge of the relationship between the gut microbiome and health has rapidly expanded in recent years. Diet has been shown to have causative effects on microbiome composition, which can have subsequent implications on health. Soylent 2.0 is a liquid meal replacement drink that satisfies nearly 20% of all recommended daily intakes per serving. This study aims to characterize the changes in gut microbiota composition resulting from a short-term Soylent diet. Fourteen participants were separated into two groups: 5 in the regular diet group and 9 in the Soylent diet group. The regular diet group maintained a diet closely resembling self-reported regular diets. The Soylent diet group underwent three dietary phases: A) a regular diet for 2 days, B) a Soylent-only diet (five servings of Soylent daily and water as needed) for 4 days, and C) a regular diet for 4 days. Daily logs self-reporting diet, Bristol stool ratings, and any abdominal discomfort were electronically submitted. Eight fecal samples per participant were collected using fecal sampling kits, which were subsequently sent to uBiome, Inc. for sample processing and V4 16S rDNA sequencing. Reads were clustered into operational taxonomic units (OTUs) and taxonomically identified against the GreenGenes 16S database. We find that an individual′s alpha-diversity is not significantly altered during a Soylent-only diet. In addition, principal coordinate analysis using the unweighted UniFrac distance metric shows samples cluster strongly by individual and not by dietary phase. Among Soylent dieters, we find a significant increase in the ratio of Bacteroidetes to Firmicutes abundance, which is associated with several positive health outcomes, including reduced risks of obesity and intestinal inflammation. Clinical trial registration ID #NCT03203044.
2,128 downloads bioRxiv clinical trials
Introduction: Sepsis 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. John's Sepsis Agent (SJSA) as a rules-based sepsis detection system. Methods: The 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. Results: Sepsis-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). Conclusion: Reductions 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. Trial Registration: ClinicalTrials.gov, NCT03235193, retrospectively registered on July 27th 2017.
2,081 downloads bioRxiv clinical trials
The sense of touch is critical for skillful hand control, but is largely missing for people who use prosthetic devices. Instead, prosthesis users rely heavily on visual feedback, even though state transitions that are necessary to skillfully interact with objects, such as object contact, are relayed more precisely through tactile feedback. Here we show that restoring tactile sensory feedback, through intracortical microstimulation of the somatosensory cortex, enables a person with a bidirectional intracortical brain-computer interface to improve their performance on functional object transport tasks completed with a neurally-controlled prosthetic limb. The participant had full visual feedback and had practiced the task for approximately two years prior to these experiments. Nevertheless, successful trial times on a commonly used clinical upper limb assessment task were reduced from a median time of 20.9 s (13.1 - 40.5 s interquartile range) to 10.2 s (5.4 - 18.1 s interquartile range) when vision was supplemented with microstimulation-evoked cutaneous percepts that were referred to different fingers and were graded in intensity based on real-time prosthesis contact forces. Faster completion times were primarily due to a reduction in the amount of time spent attempting to grasp objects. These results demonstrate the importance of tactile sensations in upper-limb control and the utility of creating bidirectional brain-computer interfaces to restore this stream of information using intracortical microstimulation. This study was conducted under an Investigational Device Exemption from the U.S. Food and Drug Administration and is registered at ClinicalTrials.gov. Clinical Trial Registration ID #[NCT01894802]. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01894802&atom=%2Fbiorxiv%2Fearly%2F2019%2F05%2F31%2F653428.atom
2,020 downloads bioRxiv clinical trials
Xiaoqian Xiao, Brandon Stephen Bentzley, Eleanor J Cole, Claudia Tischler, Katy H Stimpson, Dalton Duvio, James H. Bishop, Danielle D. DeSouza, Alan Schatzberg, Corey Keller, Keith D Sudheimer, Nolan R. Williams
Major depressive disorder (MDD) is prevalent and debilitating, and development of improved treatments is limited by insufficient understanding of the neurological changes associated with disease remission. In turn, efforts to elucidate these changes have been challenging due to disease heterogeneity as well as limited effectiveness, delayed onset, and significant off-target effects of treatments. We recently developed a form of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex (lDLPFC) that induces remission from MDD in 90% of individuals in 1-5 days (Stanford Accelerated Intelligent Neuromodulation Therapy, SAINT). This provides a new tool to begin exploring the functional connectivity (FC) changes associated with MDD remission. Herein, we report our investigation of the FC changes that occur following SAINT. Resting-state fMRI scans were performed before and after SAINT in 18 participants with severe, treatment-resistant MDD. FC was determined between regions of interest defined a priori by well-described roles in emotion regulation. Following SAINT, FC was significantly decreased between subgenual cingulate cortex (sgACC) and 3 of 4 default mode network (DMN) nodes. Significant reductions in FC were also observed between the following: DLPFC-striatum, DLPFC-amygdala, DMN-amygdala, DMN-striatum, and amygdala-striatum. Greater clinical improvements were correlated with larger decreases in FC between DLPFC-amygdala and DLPFC-insula, as well as smaller decreases in FC between sgACC-DMN. Greater clinical improvements were correlated with lower baseline FC between DMN-DLPFC, DMN-striatum, and DMN-ventrolateral prefrontal cortex. The multiple, significant reductions in FC we observed following SAINT and remission from depression support the hypothesis that MDD is a state of hyper-connectivity within these networks, and rapid decoupling of network nodes may lead to rapid remission from depression. ### Competing Interest Statement Dr. Bentzley receives consulting payments from Owl Insights.
1,871 downloads bioRxiv clinical trials
Alexander V. Lebedev, Jonna Nilsson, Joanna Lindström, William Fredborg, Ulrika Akenine, Carolina Hillilä, Pia Andersen, Gabriela Spulber, Elizabeth CM de Lange, Dirk-Jan van den Berg, Miia Kivipelto, Martin Lövdén
Cognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signaling in plasticity. We investigated whether transient enhancement of dopaminergic neurotransmission via administration of L-dopa improves effects of cognitive training on performance. Sixty-three participants for this randomised, parallel-group, double-blind, placebo-controlled trial were recruited via newspaper advertisements. Inclusion criteria were: age of 65-75 years, Mini-Mental State Examination score >25, absence of serious medical conditions. Eligible subjects were randomly allocated to either receive 100/25mg L-dopa/benserazide (n=32) or placebo (n=31) prior to each of twenty cognitive training sessions administered during a four-week period. Participants and staff were blinded to group assignment. Primary outcomes were latent variables of spatial and verbal fluid intelligence. Compared to the placebo group, subjects receiving L-dopa improved less in spatial intelligence (-0.267 SDs; 95%CI [-0.498, -0.036]; p=0.024). Change in verbal intelligence did not significantly differ between the groups (-0.081 SDs, 95%CI [-0.242, 0.080]; p=0.323). Subjects receiving L-dopa also progressed slower through the training and the groups displayed differential volumetric changes in the substantia nigra. Adverse events occurred for 10 (31%) and 7 (23%) participants in the active and control groups, correspondingly. The results speak against early pharmacological interventions in older healthy adults to improve cognitive functions by targeting the dopaminergic system and provide no support for learning-enhancing properties of L-dopa supplements. The findings warrant closer investigation about the cognitive effects of early dopamine-replacement therapy in neurological disorders.
1,870 downloads bioRxiv clinical trials
Background. Mobile health and digital medicine technologies are becoming increasingly used by individuals with common, chronic diseases to monitor their health. Numerous devices, sensors, and apps are available to patients and consumers -- some of which have been shown to lead to improved health management and health outcomes. However, no randomized controlled trials have been conducted which examine health care costs, and most have failed to provide study participants with a truly comprehensive monitoring system. Methods. We conducted a prospective randomized controlled trial of adults who had submitted a 2012 health insurance claim associated with hypertension, diabetes, and/or cardiac arrhythmia. The intervention involved receipt of one or more mobile devices that corresponded to their condition(s) and an iPhone with linked tracking applications for a period of 6 months; the control group received a standard disease management program. Moreover, intervention study participants received access to an online health management system which provided participants detailed device tracking information over the course of the study. This was a monitoring system designed by leveraging collaborations with device manufacturers, a connected health leader, health care provider, and employee wellness program -- making it both unique and inclusive. We hypothesized that health resource utilization with respect to health insurance claims may be influenced by the monitoring intervention. We also examined health-self management. Results & Conclusions. There was little evidence of differences in health care costs or utilization as a result of the intervention. Furthermore, we found evidence that the control and intervention groups were equivalent with respect to most health care utilization outcomes. This result suggests there are not large short-term increases or decreases in health care costs or utilization associated with monitoring chronic health conditions using mobile health or digital medicine technologies. Among secondary outcomes there was some evidence of improvement in health self-management which was characterized by a decrease in the propensity to view health status as due to chance factors in the intervention group. Clinical trial registration ID # NCT01975428
1,749 downloads bioRxiv clinical trials
Importance: The effect of IV administration of a bacteriophage cocktail produced under GMP conditions on patients with severe S. aureus infection, including complicated bacteraemia, endocarditis and septic shock, is unknown. Objective: To assess safety and tolerability of adjunctive bacteriophage therapy in patients with severe S. aureus infections. Design, Setting, Participants: Observational, open-label clinical trial of thirteen critically-ill patients admitted to a tertiary-referral hospital with S. aureus bacteraemia (including infective endocarditis, n=6) were assessed by the treating clinician and two consulting infectious diseases physicians to independently verify that routine medical and surgical therapy was optimal and that a poor outcome remained likely. Compassionate access to therapy was approved by both US and Australian regulators and by the Westmead Hospital Human Research Ethics Committee. Intervention: A GMP-quality preparation of three combined Myoviridae bacteriophages with specific activity against S. aureus (AB-SA01), was administered intravenously in conjunction with optimal antibiotic therapy. Main Outcome and Measurements: Physiological, haematological and biochemical markers of infection, bacterial and bacteriophage kinetics in blood, development of resistance to bacteriophages, and mortality at 28 (D28) and 90 (D90) days were measured. Main outcomes were safety and tolerability. Results: Bacteriophage therapy was initiated 4-10 days after antibiotic commencement, at 109 plaque-forming units (PFU) twice daily. Infecting staphylococci were typical of common local subtypes. Initial input ratio of phages to bacteria in the bloodstream (MOIinput) was >100. Five of the thirteen patients died by D28 and a sixth patient suffered sudden cardiac death on D90. Bacteriophage therapy coincided with a marked reduction in staphylococcal bacterial DNA in the blood and in sepsis-associated inflammatory responses in almost all cases. No bacteriophage-attributable adverse events were identified. Development of bacteriophage resistance was not observed. Population analysis revealed no significant effect of bacteriophage therapy on the gut microflora. Conclusions and Relevance: Adjunctive bacteriophage therapy appears to be safe and well-tolerated in critically ill patients with severe S. aureus infection. Two weeks of twice daily intravenous administration may be a suitable protocol. Controlled trials are needed. Trial Registration: Westmead Hospital Human Research Ethics Committee approval July 11, 2017; ClinicalTrials.gov Identifier: NCT03395769, AB-SA01-EAP01 (January 10, 2018); Clinical Trials Notification (Australian Therapeutic Goods Association): CT-2018-CTN-02372-1 (July 23, 2018).
1,710 downloads bioRxiv clinical trials
Susanne Kossatz, Giacomo Pirovano, Paula Demétrio De Souza França, Arianna L Strome, Sumsum P. Sunny, Daniella Karassawa Zanoni, Audrey Mauguen, Brandon Carney, Christian Brand, Veer Shah, Ravindra D Ramanajinappa, Naveen Hedne, Praveen Birur, Smita Sihag, Ronald A Ghossein, Mithat Gönen, Marshall Strome, Amritha Suresh, Daniela Molena, Moni A Kuriakose, Snehal G Patel, Thomas Reiner
Major determining factors for survival of patients with oral, oropharyngeal, and esophageal cancer are early detection, the quality of surgical margins, and the contemporaneous detection of residual tumor. Intuitively, the exposed location at the epithelial surface qualifies these tumor types for utilization of visual aids to assist in discriminating tumor from healthy surrounding tissue. Here, we explored the DNA repair enzyme PARP1 as imaging biomarker and conducted optical imaging in animal models, human tissues and as part of a first-in-human clinical trial. Our data suggests that PARP1 is a quantitative biomarker for oral, oropharyngeal, and esophageal cancer and can be visualized with PARPi-FL, a fluorescently labeled small molecule contrast agent for topical or intravenous delivery. We show feasibility of PARPi-FL-assisted tumor detection in esophageal cancer, oropharyngeal and oral cancer. We developed a contemporaneous PARPi-FL topical staining protocol for human biospecimens. Using fresh oral cancer tissues within 25 min of biopsy, tumor and margin samples were correctly identified with >95% sensitivity and specificity without terminal processing. PARPi-FL imaging can be integrated into clinical workflows, potentially providing instantaneous assessment of the presence or absence of microscopic disease at the surgical margin. Additionally, we showed first-in-human PARPi-FL imaging in oral cancer. In aggregate, our preclinical and clinical studies have the unifying goal of verifying the clinical value of PARPi-FL-based optical imaging for early detection and intraoperative margin assignment. Clinical Trial Registration ID #[NCT03085147]. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03085147&atom=%2Fbiorxiv%2Fearly%2F2019%2F06%2F14%2F663385.atom
1,594 downloads bioRxiv clinical trials
Recent evidence for a significant interference of microcrystalline hydroxapatite (HAP) particles with re- and demineralisation processes at the tooth-biofilm interface suggested, that they may be promising candidates for efficacious caries prevention. This multicenter randomized controlled non-inferiority trial evaluated the impact of the 2 x daily use of a HAP dentifrice without fluoride on the progression of enamel caries in adolescent caries-risk patients subjected to orthodontic therapy, with a fluoridated AmF/SnF dentifrice serving as a positive control. Primary study outcome was the occurrence of enamel caries lesions ≥ ICDAS (International Caries Detection and Assessment System) code 1 around orthodontic brackets on the vestibular surfaces of teeth 15-25 within the 168 days observation period. Secondary study outcomes were the occurrence of enamel caries lesion ≥ ICDAS code 2, Plaque Index (PlI) and Gingival Index (GI). Out of 150 recruited patients, 147 were included in the intent to treat analysis (ITT); 133 finished the study per protocol (PP). PP data analysis revealed the occurrence of enamel caries ≥ ICDAS code 1 in 54.7% of the HAP group patients compared to 60.9% of the fluoride control. In the ITT analysis the corresponding numbers were 56.8% (HAP) and 61.6% (control). Non-inferiority testing of the ITT as well as the PP data set proved that the caries preventive efficacy of the HAP dentifrice was not inferior to the protection provided by the fluoridated AmF/SnF control. Regarding all assessed secondary outcomes (enamel caries ≥ ICDAS code 2, GI, PlI) no significant differences between both experimental groups were observed. Within the restraints set by design and study population of this trial microcrystalline HAP as ingredient of toothpaste may thus be regarded a promising supplement to fluorides in clinical caries prevention. Clinical Trial registration ID #NCT02705456.
1,547 downloads bioRxiv clinical trials
Objectives: The Stopping Cavities Trial investigated effectiveness and safety of 38% silver diamine fluoride in arresting caries lesions. Materials and Methods: Double-blind randomized placebo-controlled superiority trial with 2 parallel groups. Oregon preschools. 66 preschool children with ≥1 lesion. 38% silver diamine fluoride or placebo (blue-tinted water), applied topically to the lesion. The primary endpoint was caries arrest (lesion inactivity, Nyvad criteria) 14-21 days post intervention. Dental plaque was collected from all children, and microbial composition was assessed by RNA sequencing from 2 lesions and 1 unaffected surface before treatment and at follow-up for 3 children from each group. Results and Conclusion: Mean fraction of arrested caries lesions in the silver diamine fluoride group was higher (0.72; 95% CI; 0.55, 0.84) than in the placebo group (0.05; 95% CI; 0.00, 0.16). Confirmatory analysis using generalized estimating equation log-linear regression, accounting for the number of treated surfaces and length of follow-up, indicated the fraction of arrested caries was significantly higher in the treatment group (relative risk, 17.3; 95% CI: 4.3 to 69.4). No harms were observed. RNA sequencing analysis identified no consistent changes in relative abundance of caries-associated microbes, nor emergence of antibiotic or metal resistance gene expression. Topical 38% silver diamine fluoride was effective and safe in arresting cavities in preschool children. The treatment is applicable to primary care practice and may reduce the burden of untreated tooth decay in the population. Trial Registration: ClinicalTrials.gov NCT02536040. Clinical Significance In this clinical trial, 72% of caries lesions were arrested by silver diamine fluoride, with no harms. Contrary to the presumed antibacterial mechanism, lesion bacterial composition changed negligibly. This simple topical treatment is applicable to primary care practice and may reduce the burden of untreated tooth decay in the population.
1,479 downloads bioRxiv clinical trials
Extinction is considered a core mechanism underlying exposure-based therapy in anxiety-related disorders. However, marked impairments in threat extinction learning coupled with impaired neuroplasticity in patients strongly impede the efficacy of exposure-based interventions. Recent translational research suggests a role of the renin-angiotensin (RA) system in both these processes. However, the efficacy of pharmacological modulation of the RA system to enhance threat extinction in humans and the underlying neural mechanisms remain unclear. The present pre-registered, randomized placebo-controlled pharmacological neuroimaging trial demonstrates that pre-extinction administration of the angiotensin II type 1 receptor antagonist losartan accelerated attenuation of the psychophysiological threat response during extinction. On the neural level the acceleration of extinction was accompanied by threat-signal specific enhanced ventromedial prefrontal cortex (vmPFC) activation and its coupling with the basolateral amygdala. Multivoxel pattern analysis and voxel-wise mediation analysis further revealed that that losartan reduced the neural threat expression, particularly in the vmPFC, and confirmed that acceleration of extinction critically involved treatment-induced modulation of vmPFC activation. Overall the results provide the first evidence for a pivotal role of the RA system in extinction learning in humans and suggest that adjunct losartan administration can be leveraged to facilitate the efficacy of extinction-based therapies.
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