Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/637892v1?rss=1

Authors: Stevens, A., Murray, P., De Leonibus, C., Garner, T., Koledova, E., Ambler, G., Hou, J. W., Kapelari, K., Salles, J. P., Binder, G., Maghnie, M., Zucchini, S., Bashnina, E., Skorodok, J., Yeste, D., Belgorosky, A., Lopez Siguero, J. P., Coutant, R., Vangsoy-Hansen, E., Hagenas, L., Dahlgren, J., Deal, C., Chatelain, P., Clayton, P.

Abstract:

Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response can only account for up to 60% of the variance. The aim of this work was to take a novel genomic approach to growth prediction. GHD (n=71) and TS patients (n=43) were recruited in a study on the long term response to r-hGH over five years of therapy. Pharmacogenomic analysis was performed using 1219 genetic markers and baseline blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria required for predictive value. However, we demonstrated that transcriptomic data can be used to predict growth with a high accuracy (AUC > 0.9) for short and long term therapeutic response in GHD and TS. Network models identified an identical core set of genes in both GHD and TS at each year of therapy whose expression can be used to classify therapeutic response to r-hGH. Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. We have characterised the utility of baseline transcriptome for the prediction of growth response including the identification of a set of common genes in GHD and TS. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management.

One Sentence SummaryA blood transcriptome signature predicts response to recombinant human growth hormone in both growth hormone deficient and Turner syndrome children

Trial registration numbers: NCT00256126 & NCT00699855

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/618348v1?rss=1

Authors: Asiedu, M., Agudogo, J. S., Dotson, M. E., Krieger, M. S., Schmitt, J. W., Huchko, M., Suneja, G., Proeschold-Bell, R. J., Smith, J. S., Jenson, D., Hogan, W., Ramanujam, N.

Abstract:

BackgroundInvasive cervical cancer is preventable, yet affects 500,000 women worldwide each year, and over half these women die. Barriers to cervical cancer screening include lack of awareness of cervical cancer and the cervix, fear of the speculum, and lack of women-centric technologies. We developed a low-cost ([~]$50), cervix-imaging device called the Callascope, which comprises an imaging component, camera and inserter that eliminates the need for a speculum and enables self-insertion. We sought to assess the quality of physicians images of the cervix using the Callascope versus the speculum in live patients and study womens willingness to independently use the Callascope to image their cervix.nnMethodsWe conducted two main studies: (1) a clinical study in which a physician imaged the cervix of patients using both the speculum and Callascope in a 2x2 crossover design; and (2) home-based self-cervix imaging with the Callascope.nnResultsParticipants of the clinical study (n=28) and home study (n=12) all indicated greater comfort and an overall preference for the Callascope over the speculum. The clinical study data indicated that the Callascope enabled similar visualization compared to the speculum while significantly improving patient experience. With physician insertion and manipulation, the Callascope enabled cervix visualization for 82% of participants. In the home-study, 83% of participants were able to visualize their cervix with the Callascope on the first try and 100% after multiple attempts.nnConclusionThe Callascope is more comfortable and provides similar visualization to the speculum. The Callascope can be used by medical providers for clinical exams while also enabling home self-screening for cervical cancer and promoting a better understanding of ones cervix to increase awareness of cervical screening needs. The Callascope may increase cervical cancer screening rates through reducing barriers including cost, discomfort, lack of awareness and stigma.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/619999v1?rss=1

Authors: Petrovic Fabijan, A., Lin, R. C., Ho, J., Maddocks, S., Iredell, J. R., Westmead Bacteriophage Therapy Team & AmpliPhi Bio

Abstract:

ImportanceThe 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.nnObjectiveTo assess safety and tolerability of adjunctive bacteriophage therapy in patients with severe S. aureus infections.nnDesign, Setting, ParticipantsObservational, 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.nnInterventionA 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.nnMain Outcome and MeasurementsPhysiological, 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.nnResultsBacteriophage 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.nnConclusions and RelevanceAdjunctive 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.nnTrial RegistrationWestmead 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).nnKey PointsnnQuestionIs intravenous (IV) administration of investigational bacteriophage (phage) therapy safe and well-tolerated in patients with severe Staphylococcus aureus infection?nnFindingsThirteen patients with severe S. aureus infections received AB-SA01, a bacteriophage product prepared according to Good Manufacturing Practices (GMP), as adjunctive therapy to antibiotics. AB-SA01 was well-tolerated with no adverse events identified. Bacterial burden and inflammatory responses were reduced and no phage-resistant staphylococci were isolated during or after therapy.nnMeaningOur results will inform future randomised controlled trials assessing the antibacterial and anti-inflammatory potential of bacteriophages in the treatment of severe S. aureus infection.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/615757v1?rss=1

Authors: Reinecke, A., Nickless, A., Browning, M., Harmer, C.

Abstract:

ObjectiveDrugs targeting the N-Methyl-D-aspartic acid (NMDA) system and the ability to learn new associations have been proposed as potential adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment.

MethodsUnmedicated patients with panic disorder were randomised to single-dose d-cycloserine (250mg; N=17) or matching placebo (N=16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces and amygdala response to threat. Clinical symptom severity was measured using self-report and clinician-rated scales the day before and after treatment, and at 1- and 6-months follow-up. Analysis was by intention-to-treat.

ResultsOne day after treatment, threat bias for fearful faces and amygdala threat response were attenuated in the drug compared to the placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. D-cycloserine led to greater clinical recovery at 1-month follow-up (d-cycloserine 71% versus placebo 25%).

DiscussionD-cycloserine-augmented single-session exposure therapy reduces amygdala threat response, and this effect predicts later clinical response. These findings highlight a neurocognitive mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate future development of adjunct treatments with CBT for anxiety disorders. (D-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov; NCT01680107)

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/581280v1?rss=1

Authors: Cole, E. J., Stimpson, K. H., Gulser, M., Cherian, K., Tischler, C., Nejad, R., Bentzley, B. S., Pankow, H., Choi, E., Aaron, H., Espil, F. M., Pannu, J., Xiao, X., Duvio, D., Solvason, H. B., Hawkins, J., Keller, J., Schatzberg, A. F., Sudheimer, K. D., Williams, N. R.

Abstract:

BackgroundCurrent 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).

MethodsTwenty-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.

ResultsNineteen of 21 participants (90.48%) met criteria for remission ([≤]10 on the Montgomery-[A]sberg Depression Rating Scale) immediately after SAINT. Neuropsychological testing demonstrated no negative cognitive side-effects. There were no seizures or other severe adverse events.

DiscussionOur 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 registrationClinicalTrials.gov NCT03240692

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/587980v1?rss=1

Authors: Lagas, A. K., Black, J. M., Russell, B. R., Kydd, R. R., Thompson, B.

Abstract:

Non-human animal models have demonstrated that selective serotonin reuptake inhibitors (SSRIs) can enhance plasticity within the mature visual cortex and enable recovery from amblyopia. The aim of this study was to test the hypothesis that the SSRI citalopram combined with part-time patching of the fellow fixing eye would improve amblyopic eye visual acuity in adult humans. Following a cross-over, randomized, double blind, placebo-controlled design (pre-registration: ACTRN12611000669998), participants completed two 2-week blocks of fellow fixing eye patching. One block combined patching with citalopram (20 mg/day) and the other with a placebo tablet. The blocks were separated by a 2-week washout period. The primary outcome was change in amblyopic eye visual acuity. Secondary outcomes included stereoacuity and electrophysiological measures of retinal and cortical function. Seven participants were randomized, fewer than our pre-specified sample size of 20. There were no statistically significant differences in amblyopic eye visual acuity change between the active (mean {+/-} SD change = 0.08{+/-}0.16 logMAR) and the placebo (mean change = -0.01{+/-}0.03 logMAR) blocks. No treatment effects were observed for any secondary outcomes. However, 3 of 7 participants experienced a 0.1 logMAR or greater improvement in amblyopic eye visual acuity in the active but not the placebo block. These results from a small sample suggest that larger-scale trials of SSRI treatment for adult amblyopia may be warranted. Considerations for future trials include drug dose, treatment duration and recruitment challenges.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/570143v1?rss=1

Authors: Rabipour, S., Morrison, C., Crompton, J., Petrucelli, M., Germano, M. d. O. G., Popescu, A., Davidson, P. S. R.

Abstract:

Computerized cognitive training programs are becoming increasingly popular and practical for cognitive aging. Nevertheless, basic questions remain about the benefits of such programs, and about the degree to which participant expectations might influence training and transfer. Here we examined a commercial cognitive training program (Activate) in a 5-week double-blind, pseudo-randomized placebo-controlled trial. Based on a priori power analysis, we recruited 99 healthy older adults 59-91 years of age (M = 68.87, SD = 6.31; 69 women), assigning them to either the intervention or an active control program (Sudoku and n-back working memory exercises). We subdivided both groups into high and low expectation priming conditions, to probe for effects of participants expectations on training and transfer. We assessed transfer using a battery of standard neuropsychological and psychosocial measures that had been agreed to by the training program developers. We planned and pre-registered our analyses (on osf.io). The majority (88%) of participants progressed through the training, and most provided positive feedback about it. Similarly, the majority (80%) of participants believed they were truly training their brains. Yet, transfer of training was minimal. Also minimal were any effects of expectations on training and transfer, although participants who received high expectation priming tended to engage more with their assigned program overall. Our findings suggest limited benefits of Activate training on cognition and psychosocial wellbeing in healthy older adults, at least under the conditions we used.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/548826v1?rss=1

Authors: Venetucci Gouveia, F., Germann, J., Campelo Borba de Morais, R. M., Talamoni Fonoff, E., Hamani, C., Alho, E. J., Brentani, H., Martins, A. P., Devenyi, G. A., Patel, R., Steele, C. J., Gramer, R., Chakravarty, M. M., Chacon Ruiz Martinez, R.

Abstract:

Intractable aggressive behaviour is a devastating behavioural disorder that reach 30% of psychiatric aggressive patients. Neuromodulatory surgeries may be treatment alternatives to reduce suffering. We investigated the outcomes of bilateral amygdala radiofrequency ablation in four patients with intractable aggressive behaviour (life-threatening-self-injury and social aggression) by studying whole brain magnetic resonance imaging and clinical data. Post-surgery assessments revealed decreases in aggression and agitation and improvements in quality of life. Aggressive behaviour was positively correlated with serum testosterone levels and the testosterone/cortisol ratio in males. No clinically significant side effects were observed. Imaging analyses revealed preoperative amygdala volumes within normal range and confirmed appropriate lesion locations. Reduction in aggressiveness were accompanied by volumetric reduction in brain areas associated with aggressive behaviour (express genes related to aggressive behaviour), and increases in regions related to somatosensation. These findings further elucidates the neurocircuitry of aggression and suggests novel neuromodulation targets.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/547505v1?rss=1

Authors: Kou, J., Le, J., Fu, M., Lan, C., Chen, Z., Li, Q., Zhao, W., Xu, L., Becker, B., Kendrick, K.

Abstract:

Altered patterns of visual social attention preference detected using eye-tracking and a variety of different paradigms are increasingly proposed as sensitive biomarkers for autism spectrum disorder. However, few eye tracking studies have compared the relative efficacy of different paradigms to discriminate between autistic compared with typically developing children and their sensitivity to specific symptoms. To target this issue, the current study used three common eye tracking protocols contrasting social versus non-social stimuli in young (2-7 years old) Chinese autistic (n = 35) and typically developing (n = 34) children matched for age and gender. Protocols included dancing people vs. dynamic geometrical images, biological motion (dynamic light point walking human or cat) vs. non-biological motion (scrambled controls) and child playing with toy vs. toy alone. Although all three paradigms differentiated autistic and typically developing children, the dancing people versus dynamic geometry pattern paradigm was the most effective, with autistic children showing marked reductions in visual preference for dancing people and correspondingly increased one for geometric patterns. Furthermore, this altered visual preference in autistic children was correlated with the ADOS social affect score and had the highest discrimination accuracy. Our results therefore indicate that decreased visual preference for dynamic social stimuli may be the most effective visual attention-based paradigm for use as a biomarker for autism in Chinese children. Clinical trial ID: NCT03286621 (clinicaltrials.gov); Clinical trial name: Development of Eye-tracking Based Markers for Autism in Young Children.

Lay summaryEye-tracking measures may be useful in aiding diagnosis and treatment of autism, although it is unclear which specific tasks are optimal. Here we compare the ability of three different social eye-gaze tasks to discriminate between autistic and typically developing young Chinese children and their sensitivity to specific autistic symptoms. Our results show that a dynamic task comparing visual preference for social (individuals dancing) versus geometric patterns is the most effective both for diagnosing autism and sensitivity to its social affect symptoms.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/553081v1?rss=1

Authors: Yoshihara, T., Zaitsu, M., Kubota, S., Arima, H., Sasaguri, T.

Abstract:

BackgroundThis study aimed to examine the effect of pool walking on renal function in pregnant women.

MethodsFifteen pregnant women (mean gestational age, 37.8 weeks) walked in a pool (depth 1.3 m) for 1 h. A few days later, they walked on a street for 1 h. Within each activity, the starting and ending levels of plasma renin activity (PRA) and serum aldosterone (SA) were compared using paired t-test. Total urine volume, creatinine clearance, and change in PRA levels between each activity were compared by t-test. Regression coefficients for total urine volume and creatinine clearance during pool walking were estimated by linear regression and additionally controlled for the change in PRA levels. Land walking served as the reference group.

ResultsWithin each activity, the renin-angiotensin-aldosterone levels were suppressed during pool walking: the mean starting and ending values of PRA and SA were 6.8 vs. 5.5 ng/mL/h (p=0.002) and 654 vs. 473 pg/mL (p=0.02), respectively. Compared to land walking, the decrease in PRA level was more evident in pool walking (-1.27 vs. 0.81 ng/mL/h, p=0.004), resulting in higher total urine volume and creatinine clearance in pool walking (both p<0.05). In regression analysis, after controlling for the change in PRA levels, the significantly elevated regression coefficients for total urine volume and creatinine clearance in pool walking were attenuated.

ConclusionsPool walking may temporarily improve renal function in pregnant women, partly through the suppressed renin-angiotensin-aldosterone system.

Clinical Trial RegistrationURL: https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000010618

Unique Identifier: UMIN000009051

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