How long is Long-COVID? Symptomatic improvement between 12 and 18 months in a prospective cohort study.

INTRODUCTION: COVID-19 infection can precede, in a proportion of patients, a prolonged syndrome including fatigue, exercise intolerance, mood and cognitive problems. This study aimed to describe the profile of fatigue-related, exercise-related, mood-related and cognitive-related outcomes in a COVID-19-exposed group compared with controls. METHODS: 113 serving UK Armed Forces participants were followed up at 5, 12 (n=88) and 18 months (n=70) following COVID-19. At 18 months, 56 were in the COVID-19-exposed group with 14 matched controls. Exposed participants included hospitalised (n=25) and community (n=31) managed participants. 43 described at least one of the six most frequent symptoms at 5 months: fatigue, shortness of breath, chest pain, joint pain, exercise intolerance and anosmia. Participants completed a symptom checklist, patient-reported outcome measures (PROMs), the National Institute for Health cognitive battery and a 6-minute walk test (6MWT). PROMs included the Fatigue Assessment Scale (FAS), Generalised Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9) and Patient Checklist-5 (PCL-5) for post-traumatic stress. RESULTS: At 5 and 12 months, exposed participants presented with higher PHQ-9, PCL-5 and FAS scores than controls (ES (effect size) ≥0.25, p≤0.04). By 12 months, GAD-7 was not significantly different to controls (ES <0.13, p=0.292). Remaining PROMs lost significant difference by 18 months (ES ≤0.11, p≥0.28). No significant differences in the cognitive scales were observed at any time point (F=1.96, p=0.167). At 5 and 12 months, exposed participants recorded significantly lower distances on the 6MWT (ηp 2≥0.126, p<0.01). 6MWT distance lost significant difference by 18 months (ηp 2<0.039, p>0.15). CONCLUSIONS: This prospective cohort-controlled study observed adverse outcomes in depression, post-traumatic stress, fatigue and submaximal exercise performance up to 12 months but improved by 18-month follow-up, in participants exposed to COVID-19 compared with a matched control group.

Cardiopulmonary, Functional, Cognitive and Mental Health Outcomes Post-COVID-19, Across the Range of Severity of Acute Illness, in a Physically Active, Working-Age Population.

BACKGROUND: The COVID-19 pandemic has led to significant morbidity and mortality, with the former impacting and limiting individuals requiring high physical fitness, including sportspeople and emergency services. METHODS: Observational cohort study of 4 groups: hospitalised, community illness with on-going symptoms (community-symptomatic), community illness now recovered (community-recovered) and comparison. A total of 113 participants (aged 39 ± 9, 86% male) were recruited: hospitalised (n = 35), community-symptomatic (n = 34), community-recovered (n = 18) and comparison (n = 26), approximately five months following acute illness. Participant outcome measures included cardiopulmonary imaging, submaximal and maximal exercise testing, pulmonary function, cognitive assessment, blood tests and questionnaires on mental health and function. RESULTS: Hospitalised and community-symptomatic groups were older (43 ± 9 and 37 ± 10, P = 0.003), with a higher body mass index (31 ± 4 and 29 ± 4, P < 0.001), and had worse mental health (anxiety, depression and post-traumatic stress), fatigue and quality of life scores. Hospitalised and community-symptomatic participants performed less well on sub-maximal and maximal exercise testing. Hospitalised individuals had impaired ventilatory efficiency (higher VE/V̇CO2 slope, 29.6 ± 5.1, P < 0.001), achieved less work at anaerobic threshold (70 ± 15, P < 0.001) and peak (231 ± 35, P < 0.001), and had a reduced forced vital capacity (4.7 ± 0.9, P = 0.004). Clinically significant abnormal cardiopulmonary imaging findings were present in 6% of hospitalised participants. Community-recovered individuals had no significant differences in outcomes to the comparison group. CONCLUSION: Symptomatically recovered individuals who suffered mild-moderate acute COVID-19 do not differ from an age-, sex- and job-role-matched comparison population five months post-illness. Individuals who were hospitalised or continue to suffer symptoms may require a specific comprehensive assessment prior to return to full physical activity.

Exercise tolerance, fatigue, mental health, and employment status at 5 and 12 months following COVID-19 illness in a physically trained population.

Failure to recover following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may have a profound impact on individuals who participate in high-intensity/volume exercise as part of their occupation/recreation. The aim of this study was to describe the longitudinal cardiopulmonary exercise function, fatigue, and mental health status of military-trained individuals (up to 12-mo postinfection) who feel recovered, and those with persistent symptoms from two acute disease severity groups (hospitalized and community-managed), compared with an age-, sex-, and job role-matched control. Eighty-eight participants underwent cardiopulmonary functional tests at baseline (5 mo following acute illness) and 12 mo; 25 hospitalized with persistent symptoms (hospitalized-symptomatic), 6 hospitalized and recovered (hospitalized-recovered); 28 community-managed with persistent symptoms (community-symptomatic); 12 community-managed, now recovered (community-recovered), and 17 controls. Cardiopulmonary exercise function and mental health status were comparable between the 5 and 12-mo follow-up. At 12 mo, symptoms of fatigue (48% and 46%) and shortness of breath (SoB; 52% and 43%) remain high in hospitalized-symptomatic and community-symptomatic groups, respectively. At 12 mo, COVID-19-exposed participants had a reduced capacity for work at anaerobic threshold and at peak exercise levels of deconditioning persist, with many individuals struggling to return to strenuous activity. The prevalence considered "fully fit" at 12 mo was lowest in symptomatic groups (hospitalized-symptomatic, 4%; hospitalized-recovered, 50%; community-symptomatic, 18%; community-recovered, 82%; control, 82%) and 49% of COVID-19-exposed participants remained medically nondeployable within the British Armed Forces. For hospitalized and symptomatic individuals, cardiopulmonary exercise profiles are consistent with impaired metabolic efficiency and deconditioning at 12 mo postacute illness. The long-term deployability status of COVID-19-exposed military personnel is uncertain.NEW & NOTEWORTHY Subjective exercise limiting symptoms such as fatigue and shortness of breath reduce but remain prevalent in symptomatic groups. At 12 mo, COVID-19-exposed individuals still have a reduced capacity for work at the anaerobic threshold (which best predicts sustainable intensity), despite oxygen uptake comparable to controls. The prevalence of COVID-19-exposed individuals considered "medically non-deployable" remains high at 47%.

Reduced athletic performance post-COVID-19 is associated with reduced anaerobic threshold.

Detailed characterisation of cardiopulmonary limitations in patients post-COVID-19 is currently limited, particularly in elite athletes. A male elite distance runner in his late 30s experienced chest pain following confirmed COVID-19. He underwent cardiopulmonary exercise testing (CPET) at 5 months postacute illness. Subjective exercise tolerance was reduced compared with normal, he described inability to 'kick' (rapidly accelerate). His CPET was compared with an identical protocol 15 months prior to COVID-19. While supranormal maximal oxygen uptake was maintained (155% of peak predicted V̇O2) anaerobic threshold (AT), a better predictor of endurance performance, reduced from 84% to 71% predicted peak V̇O2 maximum. Likewise, fat oxidation at AT reduced by 21%, from 0.35 to 0.28 g/min. Focusing exclusively on V̇O2 maximum risks missing an impairment of oxidative metabolism. Reduced AT suggests a peripheral disorder of aerobic metabolism. This finding may result from virally mediated mitochondrial dysfunction beyond normal 'deconditioning', associated with impaired fat oxidation.

High-Volume Image-Guided Injections in Achilles and Patellar Tendinopathy in a Young Active Military Population: A Double-Blind Randomized Controlled Trial.

Background: Chronic Achilles and patellar tendinopathy are a significant burden in physically active populations. High-volume image-guided injection (HVIGI) proposes to strip away associated neovascularity, disrupt painful nerve ingrowth, and facilitate rehabilitation. Purpose: To investigate the efficacy of HVIGI with and without steroid relative to placebo. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 62 participants were recruited between May 25, 2016, and March 5, 2020. Participants were men aged 18 to 55 years with Achilles or patellar tendinopathy of at least 6-month chronicity that had not improved with nonoperative management (including physical therapy and shockwave therapy), with ultrasound evidence of neovascularization, tendon thickening, and echogenic changes. They were assigned to the following groups: control (3 mL of subcutaneous 0.5% bupivacaine), HVIGI (10 mL of 0.5% bupivacaine and 30 mL of normal saline, ultrasound-guided between tendon and underlying fat pad), or HVIGI with steroid (HVIGIwSteroid; 0.25 mL of 100 mg/mL hydrocortisone). Clinicians and assessors were blinded. All participants were supervised through a pain-guided progressive loading program for 6 months postinjection. The main outcome measures were the Victoria Institute of Sport Assessments (VISA) for Achilles and patellar tendinopathy and the visual analog scale (VAS) for pain at 6 months postinjection. Results: The VISA score improved by a mean of 22.8 points (95% CI, 10.4-35.3 points; effect size [ES], 1.51) in the control group (n = 21), 18.6 points (95% CI, 9.1-28.0 points; ES, 1.31) in the HVIGI group (n = 21), and 18.5 points (95% CI, 3.4-33.6 points; ES, 0.88) in the HVIGIwSteroid group (n = 20). VAS pain improved by a mean of 15 points (interquartile range [IQR], -38.75, 8 points; ES, 0.39) in controls, 13 points (IQR,-34.0, 3.75 points; ES, 0.47) in the HVIGI group, and 27 points (IQR,-38.0, -1.0 points; ES, 0.54) in the HVIGIwSteroid group. The main effects were significant for time (P < .001) but not group (P ≥ .48), with no group × time interaction (P = .71). One participant was lost to follow-up from each group, multiple imputation was used for missing data points. No adverse events occurred. Conclusion: Study findings did not demonstrate superiority of HVIGI over control injection. Registration: EU Clinical Trials Register (EudraCT: 2015-003587-36).

Biomechanical differences between military patients with patellar tendinopathy and asymptomatic controls during single-leg squatting and gait - A statistical parametric mapping study.

BACKGROUND: Prior identification of biomechanical differences between patients with patellar tendinopathy and healthy controls has utilised time-discrete analysis which is susceptible to type I error when multiple comparisons are uncorrected. We employ statistical parametric mapping to minimise the risk of such error, enabling more appropriate clinical decision-making. METHODS: Lower-limb biomechanics of 21 patients with patellar tendinopathy and 22 controls were captured during walking and three types of squats. A statistical parametric mapping two-sample t-test was used to identify kinematic and kinetic differences between groups for each joint. Paired t-tests were used to compare pain before and after tasks, in patients with patellar tendinopathy. FINDINGS: During walking, cases demonstrated reduced knee joint power during initial contact and hip joint power during terminal stance. In squatting, cases demonstrated increased knee abduction angles at various time points of the small knee bend and single-leg squat. Cases demonstrated reduced knee internal rotation moment during the deepest portion of the single-leg squat and single-leg decline squat. INTERPRETATION: Gait appears unaffected by patellar tendinopathy, likely due to low task difficulty. Elevated knee abductions angles during squatting were confirmed as a key difference in patients with patellar tendinopathy. Reduced knee internal rotation moments in patients were attributed to a potential reduction in hip external rotator strength and possible pain avoidance strategy; however further evidence is required to substantiate these claims. Findings provide a clear rationale for rehabilitation programs to focus on knee stabilisation and strengthening of the muscles surrounding the hip.

Refget: standardized access to reference sequences.

MOTIVATION: Reference sequences are essential in creating a baseline of knowledge for many common bioinformatics methods, especially those using genomic sequencing. RESULTS: We have created refget, a Global Alliance for Genomics and Health API specification to access reference sequences and sub-sequences using an identifier derived from the sequence itself. We present four reference implementations across in-house and cloud infrastructure, a compliance suite and a web report used to ensure specification conformity across implementations. AVAILABILITY AND IMPLEMENTATION: The refget specification can be found at: https://w3id.org/ga4gh/refget. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

HTSlib: C library for reading/writing high-throughput sequencing data.

BACKGROUND: Since the original publication of the VCF and SAM formats, an explosion of software tools have been created to process these data files. To facilitate this a library was produced out of the original SAMtools implementation, with a focus on performance and robustness. The file formats themselves have become international standards under the jurisdiction of the Global Alliance for Genomics and Health. FINDINGS: We present a software library for providing programmatic access to sequencing alignment and variant formats. It was born out of the widely used SAMtools and BCFtools applications. Considerable improvements have been made to the original code plus many new features including newer access protocols, the addition of the CRAM file format, better indexing and iterators, and better use of threading. CONCLUSION: Since the original Samtools release, performance has been considerably improved, with a BAM read-write loop running 5 times faster and BAM to SAM conversion 13 times faster (both using 16 threads, compared to Samtools 0.1.19). Widespread adoption has seen HTSlib downloaded >1 million times from GitHub and conda. The C library has been used directly by an estimated 900 GitHub projects and has been incorporated into Perl, Python, Rust, and R, significantly expanding the number of uses via other languages. HTSlib is open source and is freely available from htslib.org under MIT/BSD license.

Twelve years of SAMtools and BCFtools.

BACKGROUND: SAMtools and BCFtools are widely used programs for processing and analysing high-throughput sequencing data. They include tools for file format conversion and manipulation, sorting, querying, statistics, variant calling, and effect analysis amongst other methods. FINDINGS: The first version appeared online 12 years ago and has been maintained and further developed ever since, with many new features and improvements added over the years. The SAMtools and BCFtools packages represent a unique collection of tools that have been used in numerous other software projects and countless genomic pipelines. CONCLUSION: Both SAMtools and BCFtools are freely available on GitHub under the permissive MIT licence, free for both non-commercial and commercial use. Both packages have been installed >1 million times via Bioconda. The source code and documentation are available from https://www.htslib.org.

GA4GH: International policies and standards for data sharing across genomic research and healthcare.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

The Stanford Hall consensus statement for post-COVID-19 rehabilitation.

The highly infectious and pathogenic novel coronavirus (CoV), severe acute respiratory syndrome (SARS)-CoV-2, has emerged causing a global pandemic. Although COVID-19 predominantly affects the respiratory system, evidence indicates a multisystem disease which is frequently severe and often results in death. Long-term sequelae of COVID-19 are unknown, but evidence from previous CoV outbreaks demonstrates impaired pulmonary and physical function, reduced quality of life and emotional distress. Many COVID-19 survivors who require critical care may develop psychological, physical and cognitive impairments. There is a clear need for guidance on the rehabilitation of COVID-19 survivors. This consensus statement was developed by an expert panel in the fields of rehabilitation, sport and exercise medicine (SEM), rheumatology, psychiatry, general practice, psychology and specialist pain, working at the Defence Medical Rehabilitation Centre, Stanford Hall, UK. Seven teams appraised evidence for the following domains relating to COVID-19 rehabilitation requirements: pulmonary, cardiac, SEM, psychological, musculoskeletal, neurorehabilitation and general medical. A chair combined recommendations generated within teams. A writing committee prepared the consensus statement in accordance with the appraisal of guidelines research and evaluation criteria, grading all recommendations with levels of evidence. Authors scored their level of agreement with each recommendation on a scale of 0-10. Substantial agreement (range 7.5-10) was reached for 36 recommendations following a chaired agreement meeting that was attended by all authors. This consensus statement provides an overarching framework assimilating evidence and likely requirements of multidisciplinary rehabilitation post COVID-19 illness, for a target population of active individuals, including military personnel and athletes.

Kinematic and kinetic differences between military patients with patellar tendinopathy and asymptomatic controls during single leg squats.

BACKGROUND: Knee valgus alignment has been associated with lower-limb musculoskeletal injury. This case-control study aims to: assess biomechanical differences between patients with patellar tendinopathy and healthy controls. METHODS: 43 military participants (21 cases, 22 controls) were recorded using 3D-motion capture performing progressively demanding, small knee bend, single leg and single leg decline squats. Planned a priori analysis of peak: hip adduction, knee flexion, pelvic tilt, pelvic obliquity and trunk flexion was conducted using MANOVA. Kinematic and kinetic data were graphed with bootstrapped t-tests and 95% CI's normalised to the squat cycle. ANOVA and correlations in SPSS were used for exploratory analysis. FINDINGS: On their symptomatic side cases squatted to less depth (-6.62°, p < 0.05) than controls with exploratory curve analysis revealing a pattern of increased knee valgus collapse throughout the squatting movement (p < 0.05). Greater patella tendon force was generated by: the eccentric than concentric phase of squatting (+30-43%, ES 0.52-1.32, p < 0.01), declined (plantarflexed) compared to horizontal surface (+36-51%, ES 1.19-1.68, p < 0.01) and deeper knee flexion angles (F ≥ 658.3, p < 0.01) with no difference between groups (F ≤ 1.380, p > 0.05). Cases experienced more pain on testing on decline board (ES = 0.69, p < 0.01). For symptomatic limbs pain (rs = 0.458-0.641, p ≤ 0.05), but not VISA-P (Victoria Institute of Sport Assessment) (rs = 0.053-0.090, p > 0.05), correlated with extensor knee moment. INTERPRETATION: Knee valgus alignment is a plausible risk factor for patellar tendinopathy. Conclusions relating to causation are limited by the cross-sectional study design. Increasing squat depth, use of a declined surface and isolating the eccentric phase enable progression of loading prescription guided by pain.

Sport and exercise medicine consultants are reliable in assessing tendon neovascularity using ultrasound Doppler.

OBJECTIVE: Several lower limb tendinopathy treatment modalities involve identification of pathological paratendinous or intratendinous neovascularisation to target proposed co-location of painful neoneuralisation. The ability to reliably locate and assess the degree of neovascularity is therefore clinically important. The Modified Ohberg Score (MOS) is frequently used to determine degree of neovascularity, but reliability has yet to be established among Sport and Exercise Medicine (SEM) consultants. This study aims to determine inter-rater and intra-rater reliability of an SEM consultant cohort when assessing neovascularity using the 5-point MOS. METHOD: Eleven participants (7 male and 4 female) provided 16 symptomatic Achilles and patella tendons. These were sequentially examined using power Doppler (PD) enabled ultrasound (US) imaging by 6 SEM consultants who rated neovascular changes seen using the MOS. Representative digital scan images were saved for rescoring 3 weeks later. Inter-rater and intra-rater reliability of the MOS was examined using intraclass correlation coefficient (ICC) and Kappa Agreement scores. RESULTS: Neovascular changes were reported in 65.6% of 96 scans undertaken. ICC for inter-rater reliability was 0.86 and Fleiss Kappa 0.52. ICC for intra-rater reliability was 0.95 and Weighted Kappa 0.91. CONCLUSIONS: Neovascular changes were present in two-thirds of symptomatic tendons. Excellent SEM consultant inter-rater and intra-rater reliability was demonstrated. These findings support the use of PD-enabled US to assess neovascularity by appropriately experienced SEM consultants. Furthermore, future interventional research using a similarly experienced SEM consultant cohort can be undertaken with assurance that assessment of neovascularity will be reliable.

Single leg squat ratings by clinicians are reliable and predict excessive hip internal rotation moment.

BACKGROUND: Single leg squats are commonly used subjective assessments of general biomechanical function, injury risk, as a predictor for recovery and as an outcome measure of rehabilitation. While 3D motion capture is a useful tool for elite sports performance and research it is impractical for routine clinical use. RESEARCH QUESTION: This cross-sectional study aims to: assess reliability and validity of clinicians' subjective ratings of single leg squats compared to 3D motion capture, and to identify whether performance predicts joint moments. METHODS: 22 healthy military volunteers were simultaneously recorded on video and 3D motion capture performing single leg squats. Videos were reviewed twice by 5 physiotherapists rating performance on a 0-5 scale assessing squat depth, hip adduction, pelvic obliquity, pelvic tilt and trunk flexion summated into a composite score. RESULTS: Hip adduction and trunk flexion exhibited moderate to substantial inter- and intra-rater reliability (range κ = 0.408-0.699) other individual criteria were mostly fair (κ ≤ 0.4). Composite scores for inter-rater reliability were ICC(1,1) = 0.419 and ICC(1,κ) = 0.783 and intra-rater reliability were ICC(1,1) = 0.672 and κ(w) = 0.526. Validity against 3D kinematics was poor with only 6/75 individually rated criteria reaching κ > 0.40. Correlation was found between composite scores and hip internal rotation moment (rs = 0.571, p = 0.009). SIGNIFICANCE: Repeated use of single leg squats by a single practitioner is supported. Comparisons between clinicians are unreliable but improved by average measures from multiple raters. Heterogeneous reliability across scoring components suggests a qualitative description of the criteria scored is less ambiguous than using composite scores in a clinical setting. Composite scores may be more useful for analysis at a population level. Poor validity against kinematic data suggests clinicians use additional information upon which they find agreement such as estimating kinetics. Correlation between hip internal rotation moment and subjective ratings may be such an example of clinicians trying to identify excessive abnormal loading.

De novo yeast genome assemblies from MinION, PacBio and MiSeq platforms.

Long-read sequencing technologies such as Pacific Biosciences and Oxford Nanopore MinION are capable of producing long sequencing reads with average fragment lengths of over 10,000 base-pairs and maximum lengths reaching 100,000 base- pairs. Compared with short reads, the assemblies obtained from long-read sequencing platforms have much higher contig continuity and genome completeness as long fragments are able to extend paths into problematic or repetitive regions. Many successful assembly applications of the Pacific Biosciences technology have been reported ranging from small bacterial genomes to large plant and animal genomes. Recently, genome assemblies using Oxford Nanopore MinION data have attracted much attention due to the portability and low cost of this novel sequencing instrument. In this paper, we re-sequenced a well characterized genome, the Saccharomyces cerevisiae S288C strain using three different platforms: MinION, PacBio and MiSeq. We present a comprehensive metric comparison of assemblies generated by various pipelines and discuss how the platform associated data characteristics affect the assembly quality. With a given read depth of 31X, the assemblies from both Pacific Biosciences and Oxford Nanopore MinION show excellent continuity and completeness for the 16 nuclear chromosomes, but not for the mitochondrial genome, whose reconstruction still represents a significant challenge.

Study protocol: a double blind randomised control trial of high volume image guided injections in Achilles and patellar tendinopathy in a young active population.

BACKGROUND: Chronic tendinopathy is a significant problem particularly in active populations limiting sporting and occupational performance. The prevalence of patellar tendinopathy in some sports is near 50% and the incidence of lower limb tendinopathy is 1.4% p.a. in the UK Military. Management includes isometric, eccentric, heavy slow resistance exercises and extracorporeal shockwave therapy (ESWT). Often these treatments are inadequate yet there is no good evidence for injection therapies and success rates from surgery can be as low as 50%. High Volume Image Guided Injection (HVIGI) proposes to strip away the neovascularity and disrupt the nerve ingrowth seen in chronic cases and has shown promising results in case series. This study aims to investigate the efficacy of HVIGI in a randomised controlled trial (RCT). METHODS: RCT comparing 40ml HVIGI, with or without corticosteroid, with a 3ml local anaesthetic sham-control injection. Ninety-six participants will be recruited. INCLUSION CRITERIA: male, 18-55 years old, chronic Achilles or patellar tendinopathy of at least 6 months, failed conservative management including ESWT, and Ultrasound (US) evidence of neovascularisation, tendon thickening and echogenic changes. Outcome measures will be recorded at baseline, 6 weeks, 3, 6 and 12 months. Primary outcome measures include The Victoria Institute of Sport Assessments for Achilles and patellar tendinopathy (VISA-A and VISA-P) and VAS pain. Secondary outcome measures include Modified Ohberg score, maximum tendon diameter and assessment of hypoechoic appearance on US, and Functional Activity Assessment. DISCUSSION: Despite previous interventional trials and reviews there is still insufficient evidence to guide injectable therapy for chronic tendinopathy that has failed conservative treatment. The scant evidence available suggests HVIGI has the greatest potential however there is no level one RCT evidence to support this. Investigating the efficacy of HVIGI against control in a RCT and separating the effect of HVIGI and corticosteroid will add high level evidence to the management of chronic tendinopathy resistant to conservative treatment. TRIAL REGISTRATION: EudraCT: 2015-003587-36 3 Dec 2015.

Indazole-6-phenylcyclopropylcarboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy.

GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.

The genome of the kinetoplastid parasite, Leishmania major.

Leishmania species cause a spectrum of human diseases in tropical and subtropical regions of the world. We have sequenced the 36 chromosomes of the 32.8-megabase haploid genome of Leishmania major (Friedlin strain) and predict 911 RNA genes, 39 pseudogenes, and 8272 protein-coding genes, of which 36% can be ascribed a putative function. These include genes involved in host-pathogen interactions, such as proteolytic enzymes, and extensive machinery for synthesis of complex surface glycoconjugates. The organization of protein-coding genes into long, strand-specific, polycistronic clusters and lack of general transcription factors in the L. major, Trypanosoma brucei, and Trypanosoma cruzi (Tritryp) genomes suggest that the mechanisms regulating RNA polymerase II-directed transcription are distinct from those operating in other eukaryotes, although the trypanosomatids appear capable of chromatin remodeling. Abundant RNA-binding proteins are encoded in the Tritryp genomes, consistent with active posttranscriptional regulation of gene expression.

Transcriptome analysis for the chicken based on 19,626 finished cDNA sequences and 485,337 expressed sequence tags.

We present an analysis of the chicken (Gallus gallus) transcriptome based on the full insert sequences for 19,626 cDNAs, combined with 485,337 EST sequences. The cDNA data set has been functionally annotated and describes a minimum of 11,929 chicken coding genes, including the sequence for 2260 full-length cDNAs together with a collection of noncoding (nc) cDNAs that have been stringently filtered to remove untranslated regions of coding mRNAs. The combined collection of cDNAs and ESTs describe 62,546 clustered transcripts and provide transcriptional evidence for a total of 18,989 chicken genes, including 88% of the annotated Ensembl gene set. Analysis of the ncRNAs reveals a set that is highly conserved in chickens and mammals, including sequences for 14 pri-miRNAs encoding 23 different miRNAs. The data sets described here provide a transcriptome toolkit linked to physical clones for bioinformaticians and experimental biologists who wish to use chicken systems as a low-cost, accessible alternative to mammals for the analysis of vertebrate development, immunology, and cell biology.