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Fulltext Indonesian primary care physicians profile in 2011: Did practicing hours and conversion program for family medicine differentiate their services and continuing medical education activities?

Widyahening IS, Thuraiappah DM, Han TM, Vidiawati D

Asia Pac Fam Med, 2014;13(1):16.
PMID: 25598700 DOI: 10.1186/s12930-014-0016-x

In Indonesia, Family Medicine as a discipline is being developed through short courses since 12 years ago. A conversion program to become Family Physicians has been introduced recently. Among the 70,000 primary care physicians there are variety of practitioners, from new interns who start general practice to senior general practitioners. This study aims to describe the current Indonesian Primary Care Physicians (PCPs) profile which includes services provided and facilities as well as comparing the profile according to participation in the conversion program and practice hours.
Phylogeny and classification of Dickeya based on multilocus sequence analysis

Marrero G, Schneider KL, Jenkins DM, Alvarez AM

Int J Syst Evol Microbiol, 2013 Sep;63(Pt 9):3524-3539.
PMID: 24003072 DOI: 10.1099/ijs.0.046490-0

Bacterial heart rot of pineapple reported in Hawaii in 2003 and reoccurring in 2006 was caused by an undetermined species of Dickeya. Classification of the bacterial strains isolated from infected pineapple to one of the recognized Dickeya species and their phylogenetic relationships with Dickeya were determined by a multilocus sequence analysis (MLSA), based on the partial gene sequences of dnaA, dnaJ, dnaX, gyrB and recN. Individual and concatenated gene phylogenies revealed that the strains form a clade with reference Dickeya sp. isolated from pineapple in Malaysia and are closely related to D. zeae; however, previous DNA-DNA reassociation values suggest that these strains do not meet the genomic threshold for consideration in D. zeae, and require further taxonomic analysis. An analysis of the markers used in this MLSA determined that recN was the best overall marker for resolution of species within Dickeya. Differential intraspecies resolution was observed with the other markers, suggesting that marker selection is important for defining relationships within a clade. Phylogenies produced with gene sequences from the sequenced genomes of strains D. dadantii Ech586, D. dadantii Ech703 and D. zeae Ech1591 did not place the sequenced strains with members of other well-characterized members of their respective species. The average nucleotide identity (ANI) and tetranucleotide frequencies determined for the sequenced strains corroborated the results of the MLSA that D. dadantii Ech586 and D. dadantii Ech703 should be reclassified as Dickeya zeae Ech586 and Dickeya paradisiaca Ech703, respectively, whereas D. zeae Ech1591 should be reclassified as Dickeya chrysanthemi Ech1591.
Biomechanical assessment of surgical repair of the mitral valve

Al-Atabi M, Espino DM, Hukins DW, Buchan KG

Proc Inst Mech Eng H, 2012 Apr;226(4):275-87.
PMID: 22611868

Repair of the mitral valve is defined (loosely) as a procedure that alters the valve structure, without replacement, enabling the natural valve itself to continue to perform under the physical conditions to which it is exposed. As the mitral valve is driven by flow and pressure, it should be feasible to analyse and assess its function, failure and repair as a mechanical system. This article reviews the current state of mechanical evaluation of surgical repairs of the failed mitral valve of the heart. This review describes the anatomy and physiology of the mitral valve, followed by the failure of the mitral valve from a mechanical point of view. The surgical methods used to repair failed valves are introduced, while the use of engineering analysis to aid understanding of mitral valve repair is also reviewed. Finally, a section on recommendations for development and future uses of engineering techniques to surgical repair are presented.
Ocean warming and hypoxia affect embryonic growth, fitness and survival of small-spotted catsharks, Scyliorhinus canicula

Musa SM, Ripley DM, Moritz T, Shiels HA

J Fish Biol, 2020 Jul;97(1):257-264.
PMID: 32383486 DOI: 10.1111/jfb.14370

Elasmobranchs are key to a healthy marine ecosystem but are under threat from human activities, such as destructive fisheries and shark finning. Embryos of oviparous elasmobranchs may be further challenged during development by rising temperatures and falling dissolved oxygen concentrations in their intertidal environment. However, the impact of climate change on survival and growth of oviparous elasmobranchs is still poorly understood. Here, we investigate the effects of temperature and hypoxia on the growth and survival of small-spotted catshark (Scyliorhinus canicula) embryos by incubating eggs in normoxia 15°C, normoxia 20°C, hypoxia 15°C, or hypoxia 20°C. Incubation under the elevated temperature increased the embryonic growth rate, yolk consumption rate and Fulton's condition factor at hatching, whilst decreasing the total length and body mass of newly hatched sharks. Under low oxygen conditions (50% air saturation) the survival rate of S. canicula embryos dropped significantly and the temperature-induced increase in Fulton's condition factor was reversed. Together, these data demonstrate both the individual and compound effects of elevated temperature and hypoxia on the survival and growth during early ontogeny of a ubiquitous, coastal elasmobranch, S. canicula.
Fulltext Industrial enzymes-producing marine bacteria from marine resources

Cheng TH, Ismail N, Kamaruding N, Saidin J, Danish-Daniel M

Biotechnol Rep (Amst), 2020 Sep;27:e00482.
PMID: 32514406 DOI: 10.1016/j.btre.2020.e00482

Industrial enzymes are important for various biotechnological applications. Currently, the diversity of industrial enzymes-producing marine bacteria from Malaysia remains mostly unknown. This study investigated the diversity of industrial enzyme-producing marine bacteria from culture collections at the Institute of Marine Biotechnology, Universiti Malaysia Terengganu. Out of 200 bacterial isolates revived, 163 bacteria isolate were successfully growth. Marine bacteria produced enzymes with total scoring higher than four were selected for molecular identification using 16S rDNA. About 161 bacteria isolate secreted amylase (68.7 %), lipase (88.3 %) and protease (68.7 %). The phylogenetic analysis led to the identification of three major phyla, namely Proteobacteria, Firmicutes and Bacteroidetes. These phyla were differentiated into nine genera consisted of Bacillus, Chryseomicrobium, Photobacterium, Pseudoalteromonas, Ruegeria, Shewanella, Solibacillus, Tenacibaculum and Vibrio. Genetic variation was more likely to occur within similar marine bacteria species. The microbial community was found to affect the production of industrial enzymes and the diversity of marine bacteria.
Fulltext Twins! Microsatellite analysis of two embryos within one egg case in oviparous elasmobranchs

Hook SA, Musa SM, Ripley DM, Hibbitt JD, Grunow B, Moritz T, et al.

PLoS One, 2019;14(12):e0224397.
PMID: 31790403 DOI: 10.1371/journal.pone.0224397

Elasmobranchs display various reproductive modes, which have been key to their evolutionary success. In recent decades there has been a rise in the number of reported cases of foetal abnormalities including fertilised, double-embryos held within one egg capsule, hereafter referred to as twins. Previously, the occurrences of twin egg cases have been reported in two batoid and one shark species. We report the first cases of twins in three species of oviparous elasmobranchs: the undulate ray (Raja undulata), the nursehound (Scyliorhinus stellaris), and the small-spotted catshark (Scyliorhinus canicula). We investigated the genetic relationships between the twins in S. stellaris, and S. canicula using microsatellite markers. Whilst the S. stellaris twins displayed the same genotypes, we found that the S. canicula twin individuals arose through heteropaternal superfecundation. This is the first reported incidence of such a paternity in elasmobranchs. The relationship between environmental change and reproductive strategy in elasmobranchs is unclear and further research is needed to determine its effect on the prevalence and mechanisms of formation of elasmobranch twins.
Tropical sharks feasting on and swimming through microplastics: First evidence from Malaysia

Matupang DM, Zulkifli HI, Arnold J, Lazim AM, Ghaffar MA, Musa SM

Mar Pollut Bull, 2023 Apr;189:114762.
PMID: 36870137 DOI: 10.1016/j.marpolbul.2023.114762

Plastic can be degraded into microplastic (<5 mm) and has been polluting worldwide marine environment and negatively impact human health. Microplastics in marine organisms are still understudied in Malaysia, let alone from a subclass Elasmobranchii. Five tropical shark species (Carcharhinus dussumieri, Carcharhinus sorrah, Chiloscyllium hasseltii, Chiloscyllium punctatum, and Scoliodon laticaudus) were examined for the presence of microplastics. 74 sharks were sampled from the local wet market and 100 % of samples contained microplastics. A total of 2211 plastic particles were found in gastrointestinal tracts (GIT) and gills, where 29.88 ± 2.34 particles per shark (mean ± SEM). Black (40.07 %) and fiber (84.44 %) microplastics were the most dominant. Extracted microplastic sizes ranged from 0.007 mm to 4.992 mm. This study suggests that microplastic uptake is gender-related for some shark species. A subsample of microplastics (10 %) was used for polymer type identification, where polyester was recorded the highest (43.95 %).
A systematic review with meta-analysis: Efficacy and safety of potassium-competitive acid blocker compared with proton pump inhibitor in the maintenance of healed erosive esophagitis

Simadibrata DM, Lesmana E, Pratama MIA, Sugiharta AJ, Winarizal AS, Lee YY, et al.

JGH Open, 2024 Mar;8(3):e13053.
PMID: 38523708 DOI: 10.1002/jgh3.13053

INTRODUCTION: Proton pump inhibitor (PPI) is the mainstay therapy for the maintenance of healed erosive esophagitis (EE). It is unknown whether potassium-competitive acid blockers (PCABs) are more efficacious and safer than PPIs.
METHODS: Only randomized controlled trials (RCTs) comparing PCABs to PPIs in the maintenance of healing rates of endoscopically proven healed EE and indexed in MEDLINE, EMBASE, and CENTRAL until 3 February 2024, were included. A fixed-effects model meta-analysis was performed to pool primary efficacy outcome (maintenance of healing rates at week 24) and safety data (any treatment-emergent adverse event or TEAE). The risk of bias was assessed using Cochrane's Risk of Bias 2 (RoB2) tool.
RESULTS: Four RCTs with a total of 2554 patients were eligible for inclusion. All trials were of low risk of bias. Compared to lansoprazole 15 mg, the maintenance rates of healed EE at week 24 were significantly higher with vonoprazan 10 mg (RR 1.13; 95% CI 1.07-1.19) and vonoprazan 20 mg (RR 1.15; 95% CI 1.10-1.21). Likewise, compared to lansoprazole 15 mg, any TEAEs were significantly greater with vonoprazan 20 mg (RR 1.10; 95% CI 1.01-1.20) but not vonoprazan 10 mg.
CONCLUSION: Vonoprazan 10 and 20 mg were superior to lansoprazole 15 mg in the maintenance of the healing of EE. Any TEAEs were greater with vonoprazan 20 mg.
Fulltext The Impact of Anticholinergic Burden on Functional Capacity in Persons With Schizophrenia Across the Adult Life Span

Khan WU, Ghazala Z, Brooks HJ, Subramaniam P, Mulsant BH, Kumar S, et al.

Schizophr Bull, 2021 Jan 23;47(1):249-257.
PMID: 32619225 DOI: 10.1093/schbul/sbaa093

Anticholinergic burden (ACB) from medications impairs cognition in schizophrenia. Cognition is a predictor of functional capacity; however, little is known about ACB effect on functional capacity in this population. This study assesses the relationship between ACB and functional capacity across the life span in individuals with schizophrenia after controlling for ACB effect on cognition. A cross-sectional analysis was performed with data collected from 6 academic tertiary health centers. Two hundred and twenty-three community-dwelling participants with schizophrenia or schizoaffective disorder were included in this study. Main variables were ACB, antipsychotic olanzapine equivalents, functional capacity, cognition, and negative symptoms. Simultaneous linear regression analyses were performed to assess the association between ACB, functional capacity, and cognition and then between ACB and cognition. A mediation analysis was then performed to examine whether cognition mediated ACB effect on functional capacity if there was an association between ACB and cognition. Mean age of participants was 49.0 years (SD = 13.1, range 19-79), and 63.7% of participants had severe ACB, ie, a total score of 3 or above. Regression analyses revealed that ACB, age, education, and cognition independently predicted functional capacity and that ACB predicted cognition among those aged 55 years and older. Mediation analysis showed that cognition did partially mediate the effect of ACB on functional capacity in this older cohort. In conclusion, people with schizophrenia are exposed to severe ACB that can have a direct negative impact on functional capacity after controlling for its impact on cognition. Reducing ACB could improve functional capacity and potentially real-world function in schizophrenia.
Contralateral Nasofrontal Trephination: A Novel Corridor for a "Dual Port" Approach to the Petrous Apex

Abouammo MD, Narayanan MS, Alsavaf MB, Alwabili M, Gosal JS, Bhuskute GS, et al.

Oper Neurosurg (Hagerstown), 2024 Mar 20.
PMID: 38506519 DOI: 10.1227/ons.0000000000001119

BACKGROUND AND OBJECTIVES: Expanded endonasal approaches (EEAs) have proven safe and effective in treating select petrous apex (PA) pathologies. Angled endoscopes and instruments have expanded indications for such approaches; however, the complex neurovascular anatomy surrounding the petrous region remains a significant challenge. This study evaluates the feasibility, anatomic aspects, and limitations of a contralateral nasofrontal trephination (CNT) route as a complementary corridor improving access to the PA.
METHODS: Expanded endonasal and CNT approaches to the PA were carried out bilaterally in 15 cadaveric heads with endovascular latex injections. The distance to the PA, angle between instruments through the 2 approach portals, and surgical freedom were measured and compared.
RESULTS: Three-dimensional DICOM-based modeling and visualization indicate that the CNT route reduces the distance to the target located within the contralateral PA by an average of 3.33 cm (19%) and affords a significant increase in the angle between instruments (15.60°; 54%). Furthermore, the vertical vector of approach is improved by 28.97° yielding a caudal reach advantage of 2 cm. The area of surgical freedom afforded by 3 different approaches (endonasal, endonasal with an endoscope in CNT portal, and endonasal with an instrument in CNT portal) was compared at 4 points: the dural exit point of the 6th cranial nerve, jugular foramen, foramen lacerum, and petroclival fissure. The mean area of surgical freedom provided by both approaches incorporating the CNT corridor was superior to EEA alone at each of the surgical targets (P =
Fulltext Genome Sequence of Nitratireductor basaltis Strain UMTGB225, a Marine Bacterium Isolated from a Green Barrel Tunicate in Bidong Island, Malaysia

Danish-Daniel M, Gan HY, Gan HM, Saari NA, Usup G

Genome Announc, 2014;2(5).
PMID: 25301654 DOI: 10.1128/genomeA.01015-14

Nitratireductor basaltis strain UMTGB225 is a Gram-negative bacterium isolated from a marine tunicate found in Bidong Island, Terengganu, Malaysia. In this study, the genome of Nitratireductor basaltis UMTGB225 was sequenced to gain insight into the role of this bacterium and its association with tunicate hosts in a coral reef habitat.
Fulltext Genome Sequence of Vibrio campbellii Strain UMTGB204, a Marine Bacterium Isolated from a Green Barrel Tunicate

Gan HY, Noor ME, Saari NA, Musa N, Mustapha B, Usup G, et al.

Genome Announc, 2015;3(2).
PMID: 25814609 DOI: 10.1128/genomeA.00210-15

Vibrio campbellii strain UMTGB204 was isolated from a green barrel tunicate. The genome of this strain comprises 5,652,224 bp with 5,014 open reading frames, 9 rRNAs, and 116 tRNAs. It contains genes related to virulence and environmental tolerance. Gene clusters for the biosynthesis of nonribosomal peptides and bacteriocin were also identified.
Fulltext Hidden genetic diversity in snakeskin gourami, Trichopodus pectoralis (Perciformes, Osphronemidae), inferred from the mitochondrial DNA CO1 gene

Tan MP, Amornsakun T, Siti Azizah MN, Habib A, Sung YY, Danish-Daniel M

Mitochondrial DNA B Resour, 2019 Sep 12;4(2):2966-2969.
PMID: 33365813 DOI: 10.1080/23802359.2019.1662741

Eighty-four specimens collected from 13 populations from Malaysia, Thailand, and Vietnam were analysed, revealing 21 putative haplotypes with overall estimated haplotype and nucleotide diversities of 0.79 and 0.0079, respectively. High levels of diversity and an absence of founder effects were observed among populations in peninsular Malaysia. In contrast, populations from Sarawak exhibited low genetic diversity, which is a typical sign of colonies introduced from a single source. Historical translocation of Trichopodus pectoralis from Thailand to Malaysia, as well as to the Philippines, Indonesia, and Myanmar was apparent. Historical introduction of T. pectoralis from Vietnam was also detected in peninsular Malaysia.
Fulltext Draft genome sequence of Mameliella alba strain UMTAT08 isolated from clonal culture of toxic dinoflagellate Alexandrium tamiyavanichii

Danish-Daniel M, Han Ming G, Noor ME, Yeong YS, Usup G

Genom Data, 2016 Dec;10:12-4.
PMID: 27625991 DOI: 10.1016/j.gdata.2016.08.015

Mameliella alba strain UMTAT08 was isolated from clonal culture of paralytic shellfish toxin producing dinoflagellate, Alexandrium tamiyavanichii. Genome of the strain UMTAT08 was sequenced in order to gain insights into the dinoflagellate-bacteria interactions. The draft genome sequence of strain UMTAT08 contains 5.84Mbp with an estimated G + C content of 65%, 5717 open reading frames, 5 rRNAs and 49 tRNAs. It contains genes related to nutrients uptake, quorum sensing and environmental tolerance related genes. Gene clusters for the biosynthesis of type 1 polyketide synthase, bacteriocin, microcin, terpene and ectoine were also identified. This is suggesting that the bacterium possesses diverse adaptation strategy to survive within the dinoflagellate phycosphere. The draft genome sequence and annotation have been deposited at DDBJ/EMBL/GenBank under the accession number JSUQ00000000.
Fulltext Genome Sequence of Bacillus sp. Strain UMTAT18 Isolated from the Dinoflagellate Alexandrium tamiyavanichii Found in the Straits of Malacca

Danish-Daniel M, Ming GH, Mohd Noor ME, Sung YY, Usup G

Genome Announc, 2016 Oct 6;4(5).
PMID: 27795265 DOI: 10.1128/genomeA.01106-16

Bacillus sp. strain UMTAT18 was isolated from the harmful dinoflagellate Alexandrium tamiyavanichii Its genome consists of 5,479,367 bp with 5,546 open reading frames, 102 tRNAs, and 29 rRNAs. Gene clusters for biosynthesis of nonribosomal peptides, bacteriocin, and lantipeptide were identified. It also contains siderophore and genes related to stress tolerance.
Virulence properties and pathogenicity of multidrug-resistant Vibrio harveyi associated with luminescent vibriosis in Pacific white shrimp, Penaeus vannamei

Nurhafizah WWI, Lee KL, Laith A AR, Nadirah M, Danish-Daniel M, Zainathan SC, et al.

J Invertebr Pathol, 2021 11;186:107594.
PMID: 33878330 DOI: 10.1016/j.jip.2021.107594

Global high demand for Pacific white shrimp Penaeus vannamei has led to intensified cultivation and a wide range of disease problems, including bacterial diseases due to vibrios. Three presumptive luminescent Vibrio harveyi strains (Vh5, Vh8 and Vh10) were isolated from the hepatopancreas (Vh5) and haemolymph (Vh8 and Vh10) of diseased growout Pacific white shrimp from a farm in Setiu, Terengganu, Malaysia, using Vibrio harveyi agar (VHA) differential medium. All three strains were identified as V. harveyi by biochemical characteristics. 16S rRNA gene-based phylogenetic analyses by neighbour-joining, maximum likelihood and maximum parsimony methods showed all three strains in the V. harveyi cluster. All three strains were β-haemolytic and positive for motility, biofilm formation and extracellular products (caseinase, gelatinase, lipase, DNase, amylase and chitinase). Vh10 was subjected to pathogenicity test in Pacific white shrimp by immersion challenge and determined to have a LC50 of 6.0 × 108 CFU mL-1 after 168 h of exposure. Antibiotic susceptibility tests showed that all strains were resistant to oxytetracycline (OXT30), oleandomycin (OL15), amoxicillin (AML25), ampicillin (AMP10) and colistin sulphate (CT25) but sensitive to doxycycline (DO30), flumequine (UB30), oxolinic acid (OA2), chloramphenicol (C30), florfenicol (FFC30), nitrofurantoin (F5) and fosfomycin (FOS50). Each strain was also resistant to a slightly different combination of eight other antibiotics, with an overall multiple antibiotic resistance (MAR) index of 0.40, suggesting prior history of heavy exposure to the antibiotics. Vh10 infection resulted in pale or discoloured hepatopancreas, empty guts, reddening, necrosis and luminescence of uropods, as well as melanised lesions in tail muscle. Histopathological examination showed necrosis of intertubular connective tissue and tubule, sloughing of epithelial cells in hepatopancreatic tubule, haemocytic infiltration, massive vacuolation and loss of hepatopancreatic tubule structure.
Fulltext Diet and the evolution of ADH7 across seven orders of mammals

Pinto SL, Janiak MC, Dutyschaever G, Barros MAS, Chavarria AG, Martin MP, et al.

R Soc Open Sci, 2023 Jul;10(7):230451.
PMID: 37448478 DOI: 10.1098/rsos.230451

Dietary variation within and across species drives the eco-evolutionary responsiveness of genes necessary to metabolize nutrients and other components. Recent evidence from humans and other mammals suggests that sugar-rich diets of floral nectar and ripe fruit have favoured mutations in, and functional preservation of, the ADH7 gene, which encodes the ADH class 4 enzyme responsible for metabolizing ethanol. Here we interrogate a large, comparative dataset of ADH7 gene sequence variation, including that underlying the amino acid residue located at the key site (294) that regulates the affinity of ADH7 for ethanol. Our analyses span 171 mammal species, including 59 newly sequenced. We report extensive variation, especially among frugivorous and nectarivorous bats, with potential for functional impact. We also report widespread variation in the retention and probable pseudogenization of ADH7. However, we find little statistical evidence of an overarching impact of dietary behaviour on putative ADH7 function or presence of derived alleles at site 294 across mammals, which suggests that the evolution of ADH7 is shaped by complex factors. Our study reports extensive new diversity in a gene of longstanding ecological interest, offers new sources of variation to be explored in functional assays in future study, and advances our understanding of the processes of molecular evolution.
Fulltext The Pandemic Experience in Southeast Asia: Interface Between SARS-CoV-2, Malaria, and Dengue

Yek C, Nam VS, Leang R, Parker DM, Heng S, Souv K, et al.

Front Trop Dis, 2021;2.
PMID: 35373190 DOI: 10.3389/fitd.2021.788590

Southeast Asia (SEA) emerged relatively unscathed from the first year of the global SARS-CoV-2 pandemic, but as of July 2021 the region is experiencing a surge in case numbers primarily driven by Alpha (B.1.1.7) and subsequently the more transmissible Delta (B.1.617.2) variants. While initial disease burden was mitigated by swift government responses, favorable cultural and societal factors, the more recent rise in cases suggests an under-appreciation of prior prevalence and over-appreciation of possible cross-protective immunity from exposure to endemic viruses, and highlights the effects of vaccine rollout at varying tempos and of variable efficacy. This burgeoning crisis is further complicated by co-existence of malaria and dengue in the region, with implications of serological cross-reactivity on interpretation of SARS-CoV-2 assays and competing resource demands impacting efforts to contain both endemic and pandemic disease.
Fulltext Current vector research challenges in the greater Mekong subregion for dengue, Malaria, and Other Vector-Borne Diseases: A report from a multisectoral workshop March 2019

Christofferson RC, Parker DM, Overgaard HJ, Hii J, Devine G, Wilcox BA, et al.

PLoS Negl Trop Dis, 2020 Jul;14(7):e0008302.
PMID: 32730249 DOI: 10.1371/journal.pntd.0008302
Fulltext A balanced randomised placebo controlled blinded phase IIa multi-centre study to investigate the efficacy and safety of AUT00063 versus placebo in subjective tinnitus: The QUIET-1 trial

Hall DA, Ray J, Watson J, Sharman A, Hutchison J, Harris P, et al.

Hear Res, 2019 06;377:153-166.
PMID: 30939361 DOI: 10.1016/j.heares.2019.03.018

AUT00063 is an experimental new medicine that has been demonstrated to suppress spontaneous hyperactivity by modulating the action of voltage-gated potassium-channels in central auditory cortical neurons of a rodent model. This neurobiological property makes it a good candidate for treating the central component of subjective tinnitus but this has not yet been tested in humans. The main purpose of the QUIET-1 (QUest In Eliminating Tinnitus) trial was to examine the effect of AUT00063 on the severity of tinnitus symptoms in people with subjective tinnitus. The trial was a randomised, placebo-controlled, observer, physician and participant blinded multi-centre superiority trial with two parallel groups and a primary endpoint of functional impact on tinnitus 28 days after the first drug dosing day. The trial design overcame the scale and logistical challenges of delivering a scientifically robust, statistically powered multi-centre study for subjective tinnitus within the National Health Service in England. The trial was terminated early for futility. Overall, 212 participants consented across 18 sites with 91 participants randomised to groups using age, gender, tinnitus symptom severity and hearing status as minimisation factors. While the pharmacokinetic markers confirm the uptake of AUT00063 in the body, within the expected therapeutic range, with respect to clinical benefit findings indicated that AUT00063 was not effective in alleviating tinnitus symptoms (1.56 point change in Tinnitus Functional Index). In terms of clinical harms, results indicated that a daily dose of 800 mg capsules of AUT00063 taken for 28 days was safe and well tolerated. These findings provide significant advances in the drug development field for hearing sciences, but raise questions about the predictive validity of certain rodent models of noise-induced hearing loss and tinnitus, as least for the mechanism evaluated in the present study. Trial Registration: (EudraCT) 2014-002179-27; NCT02315508.

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