Bacterial enzymes: powerful tools for protein labeling, cell signaling, and therapeutic discovery.

Bacteria have evolved a diverse set of enzymes that enable them to subvert host defense mechanisms as well as to form part of the prokaryotic immune system. Due to their unique and varied biochemical activities, these bacterial enzymes have emerged as key tools for understanding and investigating biological systems. In this review, we summarize and discuss some of the most prominent bacterial enzymes used for the site-specific modification of proteins, in vivo protein labeling, proximity labeling, interactome mapping, signaling pathway manipulation, and therapeutic discovery. Finally, we provide a perspective on the complementary advantages and limitations of using bacterial enzymes compared with chemical probes for exploring biological systems.

Weaponizing the proteasome to overcome antimalarial drug resistance.

In this issue of Cell Chemical Biology, Zhan et al. report dual-pharmacophore molecules ("artezomibs"), combining an artemisinin and proteasome inhibitor that exhibit potent activity against both wild-type and drug-resistant malarial parasites.1 This study indicates that artezomibs offer a promising approach to combat drug resistance encountered by current antimalarial therapies.

Overhead throwing biomechanics in cricketers: The effect of a run-up approach.

Overhead throwing by cricketers when fielding with different approaches has been described using two-dimensional analysis. Currently, the three-dimensional kinematic and kinetic characteristics of an overhead throw performed by cricketers following a run-up are unknown. Fifteen South African cricketers performed six overhead throws, from a stationary position and with a run-up over 15-20 m prior to fielding a ball, respectively. Kinematic data and ground reaction forces were collected throughout the throwing trials. Joint kinetics were calculated using inverse dynamics. An independent t-test or Mann-Whitney U-test was used to determine joint kinetic differences between throwing approaches. Differences between the kinematic waveforms for stationary and run-up throwing approaches were assessed using one-dimensional statistical parametric mapping ANOVA (P < 0.05). The shoulder, elbow and thoraco-lumbar joints displayed similar kinematics between throwing approaches. The run-up approach displayed increased hip flexion between 0-34% and 57-100% (F(1, 28) = 6.726; P = 0.01) of the throwing cycle; and lumbo-pelvic flexion between 57 and 65% (F(1, 28) = 6.823; P = 0.02) of the throwing cycle; greater shoulder compression (F(1, 28) = 1.036; P = 0.02) and posterior force (F(1, 28) = 1.052; P = 0.009) at maximum external rotation; yet less superior shoulder force (F(1, 28) = 1.744; P = 0.005) and elbow compression (F(1, 28) = 4.331; P = 0.03), superior (F(1, 28) = 1.212; P = 0.002) and medial (F(1, 28) = 1.370; P = 0.03) elbow forces at ball release, when compared to a stationary position. Cricketers maintain similar upper limb kinematics between overhead throwing approaches. However, throwing with a run-up approximately doubles the forces exerted on the shoulder at maximum external rotation, which is most likely caused by the greater dominant hip and lumbo-pelvic flexion noted. This may amplify the potential risk for shoulder injury when throwing.HighlightsThrowing arm motion is similar irrespective of the approach used by cricketers to throw.Throwing with a run-up produced increased angles of lumbo-pelvic and dominant hip flexion in various phases of the throwing cycle.Throwing with a run-up resulted in greater shoulder compression and posterior force at maximum external rotation.

The association between gird and overhead throwing biomechanics in cricket.

The development of GIRD is a well-documented adaptation associated with repetitive overhead throwing in numerous sports. In occurrence with total rotational range of motion deficit, GIRD is considered pathological and increases shoulder injury risk. While cricketers demonstrate these deficits in rotational range; the association between GIRD and overhead throwing has yet to be explored. Therefore, the aim of this study was to determine the relationship between GIRD and overhead throwing biomechanics in cricketers. Passive shoulder rotational range of motion was measured in 15 cricketers (elite = 8, amateur = 7). Kinetic and kinematic data were obtained during overhead throws from a stationary and run-up approach. Linear regression was used to determine potential relationships between GIRD and discrete shoulder kinetics for both throwing approaches. One-dimensional statistical parametric mapping regression was conducted to assess relationships between GIRD and throwing kinematics. When throwing overhead from a stationary position, GIRD was associated with reduced hip abduction during the preparatory arc (p = 0.002); superior shoulder (p = 0.003) and elbow compressive (p = 0.009) forces, at cocking. In addition, GIRD was associated with increased posterior shoulder force during arm deceleration for both stationary (p = 0.013) and run-up approaches (p = 0.03) to overhead throwing. Cricketers with GIRD utilise a shorter stride, creating early pelvic rotation and a slow throwing arm with an associated reduction in forces about the shoulder and elbow at cocking, when throwing from a stationary position. Further, overload of the posterior shoulder occurs during arm deceleration, irrespective of throwing approach. These findings highlight potential shoulder injury risk.

RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors.

The human dedicator of cytokinesis (DOCK) family consists of 11 structurally conserved proteins that serve as atypical RHO guanine nucleotide exchange factors (RHO GEFs). These regulatory proteins act as mediators in numerous cellular cascades that promote cytoskeletal remodeling, playing roles in various crucial processes such as differentiation, migration, polarization, and axon growth in neurons. At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process that is otherwise too slow for rapid spatiotemporal control of cellular signaling. Here, we provide an overview of the biological and structural characteristics for the various DOCK proteins and describe how they differ from other RHO GEFs and between DOCK subfamilies. The expression of the family varies depending on cell or tissue type, and they are consequently implicated in a broad range of disease phenotypes, particularly in the brain. A growing body of available structural information reveals the mechanism by which the catalytic DHR2 domain elicits nucleotide dissociation and also indicates strategies for the discovery and design of high-affinity small-molecule inhibitors. Such compounds could serve as chemical probes to interrogate the cellular function and provide starting points for drug discovery of this important class of enzymes.

Predictors of throwing performance in amateur male cricketers: A musculoskeletal approach.

Optimal throwing speed and accuracy is built on a complex interaction of multiple variables. Although strength and power has been associated with throwing speed in cricketers, the individual muscles that contribute to optimal function of the shoulder-complex has not been adequately explored in connection with throwing performance. Consequently, this study aimed to investigate the correlation between musculoskeletal variables and overhead throwing performance in cricketers. Thirty-two amateur male cricketers were tested using a battery of 16 tests (strength, flexibility, scapula positioning) as well as a throwing speed (TS) and a novel accuracy test (TA). Only two of the sixteen tests were correlated with throwing performance in the multiple regression analysis. Non-dominant hip abduction strength correlated positively with TS (p < 0.05): on average, a strength increase of 10 newtons (N) was associated with an increase in TS of 0.60 km/h (95% CI: 0.12-1.08). Non-dominant pectoralis minor length correlated positively with TA (p < 0.01): on average, a one-centimetre increase in the length correlated to an increase, of 0.633 points (95% CI: 0.225-1.041). This cross-sectional study demonstrated that from an array of musculoskeletal variables, only non-dominant hip abduction strength correlated with TS, while only non-dominant pectoralis minor length correlated with TA in amateur cricketers.

Selection for Favorable Health Traits: A Potential Approach to Cope with Diseases in Farm Animals.

Disease is a global problem for animal farming industries causing tremendous economic losses (>USD 220 billion over the last decade) and serious animal welfare issues. The limitations and deficiencies of current non-selection disease control methods (e.g., vaccination, treatment, eradication strategy, genome editing, and probiotics) make it difficult to effectively, economically, and permanently eliminate the adverse influences of disease in the farm animals. These limitations and deficiencies drive animal breeders to be more concerned and committed to dealing with health problems in farm animals by selecting animals with favorable health traits. Both genetic selection and genomic selection contribute to improving the health of farm animals by selecting certain health traits (e.g., disease tolerance, disease resistance, and immune response), although both of them face some challenges. The objective of this review was to comprehensively review the potential of selecting health traits in coping with issues caused by diseases in farm animals. Within this review, we highlighted that selecting health traits can be applied as a method of disease control to help animal agriculture industries to cope with the adverse influences caused by diseases in farm animals. Certainly, the genetic/genomic selection solution cannot solve all the disease problems in farm animals. Therefore, management, vaccination, culling, medical treatment, and other measures must accompany selection solution to reduce the adverse impact of farm animal diseases on profitability and animal welfare.

Overhead throwing in cricketers: A biomechanical description and playing level considerations.

This study aimed to describe stationary overhead throwing biomechanics in South African cricketers, considering playing level, and relative to baseball. Kinematics and ground reaction forces were collected during throwing trials. Inverse dynamics was used to calculate joint kinetics. Inter-subject variability was calculated using the coefficient of variance. A one-dimensional statistical parametric mapping ANOVA was conducted to assess differences between the kinematic waveforms in elite and amateur cricketers (p < 0.05). Fifteen cricketers (elite = 8; amateur = 7) participated in this study. The basic parameters of a cricketer's throwing action are described. Substantial inter-subject variability was noted for all variables, except lumbopelvic movement. Cricketers presented with 74.9 ± 27.3° glenohumeral external rotation and 94.8 ± 23.7° elbow flexion, at maximum external rotation (MER). Amateur cricketers displayed decreased elbow flexion range of motion between 2-14% of the throwing cycle (F = 9.365;p = 0.01); greater shoulder (121.0vs85.9 N; F = 0.36,p = 0.021) and elbow compression (105.6vs72.8 N;F = 0.007,p = 0.043), and superior shoulder force (203.1vs115.5 N;F = 2.43,p = 0.022) at MER, when compared with elite cricketers. Cricketers display similarities to baseball pitchers when throwing overhead from a stationary position. The "preparatory arc" utilised is different to the wind-up noted for baseball. The forces exerted on the shoulder and elbow, in amateur cricketers specifically, are substantially greater at MER and may indicate the potential risk for injury.

Targeting the Small GTPase Superfamily through Their Regulatory Proteins.

The Ras superfamily of small GTPases are guanine-nucleotide-dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as "undruggable". The GTP-dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re-evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell-based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins.

Incidence and impact of time loss and non-time-loss shoulder injury in elite South African cricketers: A one-season, prospective cohort study.

OBJECTIVES: To determine the incidence, prevalence and impact of shoulder injury in elite South African cricketers. DESIGN: Prospective longitudinal cohort study. METHODS: One hundred and six senior national/franchise cricketers completed a pre-season Kerlan-Jobe Orthopaedic Clinic shoulder and elbow (KJOC) score. All injuries sustained during the 2016/2017 season were captured on an injury reporting system. Injuries were verified by the respective squad physiotherapist at the end of the season and post-season KJOC score was obtained from all the players. RESULTS: Eighteen percent (95% CI: 11-25%) of cricketers sustained a shoulder injury, at a rate of 0.19 injuries per player per year. Annual injury prevalence was 1.1%. Shoulder injury occurred primarily while throwing (58%). Fielding performance was maintained by adapting throwing technique (58%) or fielding position (21%). Thirty-two percent of shoulder injuries resulted in time lost to matches and/or training. A history of shoulder injury increased the risk of sustaining another injury by 1.91 times (95% CI: 1.73-2.15). Irrespective of injury, cricketers demonstrated consistently low pre- (78.5 ±â€¯15.6) and post-season (81.2 ±â€¯17.1) KJOC scores. Pre-season KJOC scores were significantly lower (r2 = 0.106, p = 0.001) in those cricketers with a history of shoulder injury. Cricketers who sustained a seasonal shoulder injury had significantly lower (r2 = 0.112, p < 0.001) post-season KJOC scores, indicating persistent shoulder pain or dysfunction. CONCLUSION: This is the first study to report both time- and non-time-loss shoulder injury in elite South African cricketers. All non-time-loss shoulder injuries compromised primary skill, while some resulted in changes to throwing technique and fielding position. Thus shoulder injury, whether it results in time loss or not, potentially impacts match performance.

The cricketer's shoulder: Not a classic throwing shoulder.

OBJECTIVES: To describe the musculoskeletal adaptations inherent to the cricketers' shoulder and determine potential predictors of shoulder injury in elite South African cricketers. DESIGN: Prospective longitudinal cohort study; SETTING: Non-clinical, at national cricket indoor training venues. PARTICIPANTS: One hundred and six elite cricketers, representing 82% of the South African national and franchise teams, consent. A total of 105 cricketers (27 ±â€¯4 years) were eligible for participation in this study. MAIN OUTCOME MEASURES: A pre-season shoulder screening battery including a shoulder function questionnaire, two ultrasonographic shoulder measurements and 14 musculoskeletal tests including pain provocation, range of motion, strength and flexibility was assessed. Non-contact dominant shoulder injuries were documented throughout the 2016/2017 season. RESULTS: The musculoskeletal profile of a cricketer's shoulder is described. 17% (95%CI: 9-24%) of cricketers sustained an injury during the 2016/2017 season. Two of the 17 screening tests predicted seasonal dominant shoulder injury (p < 0.05): a dominant supraspinatus tendon thickness ≥5.85 mm (sensitivity: 72%, specificity: 63%) and non-dominant pectoralis minor length ≤12.85 cm (sensitivity: 83%, specificity: 55%). CONCLUSION: The musculoskeletal adaptations inherent to cricketing shoulders are distinctly different to the classic "thrower's shoulder" described in baseball. A thickened dominant supraspinatus tendon and a shortened non-dominant pectoralis minor muscle are risk factors for developing shoulder injury in this group. This identifies the need to investigate preventative strategies (strengthening/flexibility) and throwing workload management in cricketers with shoulder injury.

Musculoskeletal predictors of non-contact injury in cricketers - Few and far between? A longitudinal cohort study.

OBJECTIVE: To determine the musculoskeletal risk factors for injury amongst professional, domestic cricket players. DESIGN: Longitudinal cohort study. SETTING: Medical suites associated with the respective cricket franchises. PARTICIPANTS: Professional, domestic cricket players (n = 97). MAIN OUTCOME MEASURES: A pre-participatory musculoskeletal screening battery consisting of 21 tests including flexibility, neural tension, stability, strength, balance and pain provocation tests at the start of the cricket season. Non-contact, low back and lower limb (lower quarter) injuries were monitored throughout the season. Binary logistic regression and receiver operating curves were used to determine predictive value of each test. RESULTS: During the course of the cricket season, 38 of the 97 (39.2%) cricketers sustained a non-contact low back and/or lower limb injury. Increased hip internal rotation ROM on the dominant side (OR = 1.065; p = 0.036), no symptoms on active slump dominant side (OR = 0.289; p = 0.014), decreased combined elevation (OR = 0.934; p = 0.029), increased shoulder internal rotation ROM on the non-dominant side (OR = 1.022; p = 0.035) and increased GIRD (glenohumeral internal rotation deficit) (OR = 1.026; p = 0.042) predicted in-season non-contact lower quarter injuries. Although statistically significant, none of these variables were strong predictors of injury as shown by the logistic regression models (accuracy in classification rate: 59.8-62.9%), the area under the curve (AUC) of the receiver operating characteristic (ROC) curves (AUC≤0.652) and the cut-off scores which revealed high sensitivity (68.4-86.8%), but low specificity (25.4-54.2%). CONCLUSION: Although only a few of the many tests included in the battery showed predictive validity, the value of screening procedures should not be underestimated due to other benefits such as building patient rapport, identification of pre-existing injuries, establishing clinical and functional baselines upon which individualised management programmes can be based.

The mental wellbeing of current and retired professional cricketers: an observational prospective cohort study.

OBJECTIVE: Scientific knowledge about symptoms of common mental disorders in professional cricket is non-existent. Consequently, the aims of the study were to determine the prevalence and the 6 months incidence of symptoms of common mental disorders (CMD: distress, anxiety/depression, sleep disturbance, adverse alcohol use) among current and former professional cricketers and to explore the association of potential stressors (significant injury, surgery, adverse life events, career dissatisfaction) and CMD. METHODS: An observational prospective cohort study with a follow-up period of 6 months was conducted among current and former professional cricketers from South Africa. Using validated questionnaires to assess symptoms of common mental disorders as well as several stressors, an electronic questionnaire was set up and distributed by the South African Cricketers Association (SACA). RESULTS: A total of 116 participants enrolled at baseline (overall response rate of 33%) and 76 of those participants completed the 6 month follow-up (follow up rate of 66%). The prevalence of symptoms of CMD in current professional cricketers was 38% for distress, 38% for sleep disturbance, 37% for anxiety/depression and 26% for adverse alcohol use. Among former professional cricketers, baseline prevalence as was 26% for distress, 24% for anxiety/depression, 21% for sleep disturbance and 22% for adverse alcohol use. Career dissatisfaction led to an increased risk of distress, anxiety/depression and sleep disturbance in current professional cricketers. Surgeries and adverse life events led to an increase in reported symptoms of distress and anxiety/depression in current professional cricketers. CONCLUSIONS: It was concluded that symptoms of CMD are prevalent in both current and former professional cricketers and the association with surgery, adverse life events and cricket career dissatisfaction may provide some insight into possible mechanisms.

Osteoarthritis is associated with symptoms of common mental disorders among former elite athletes.

PURPOSE: The primary aim was to establish the association between osteoarthritis (OA) and the occurrence and comorbidity of symptoms of common mental disorders (CMD: distress, anxiety/depression, sleep disturbance, adverse alcohol use) in a group of former elite athletes (rugby, football, ice hockey, Gaelic sports and cricket). A secondary aim was to explore this association in the subgroups of sports. METHODS: Cross-sectional analysis was performed on the baseline questionnaires from five prospective cohort studies conducted between April 2014 and January 2016 in former elite athletes of rugby, football, ice hockey, Gaelic sports and cricket. The presence of OA (diagnosed by a medical professional) was examined with a single question, and symptoms of CMD were evaluated through multiple validated questionnaires (4DSQ, GHQ-12, PROMIS, AUDIT-C). RESULTS: There was a significant association between OA and symptoms of distress (OR 1.7, 95 % CI 1.2-2.6), sleep disturbance (OR 1.6, 95 % CI 1.1-2.3), adverse alcohol use (OR 1.8, 95 % CI 1.2-2.6) and a comorbidity of symptoms of CMD (OR 1.5, 95 % CI 1.0-2.1) in former elite athletes. CONCLUSION: OA might be a risk factor for developing symptoms of CMD in former elite athletes. The clinical relevance of this study is that an interdisciplinary approach to the clinical care and support of former elite athletes after their careers is advocated as the interaction between the physical and mental health issues occurring on the long term is complex. Monitoring OA among former elite athletes should be empowered while strategies to prevent symptoms worsening should be developed and implemented. The self-awareness, prevention and care of mental health problems that might occur after a professional sports career should also be addressed. LEVEL OF EVIDENCE: Level III.

Substrate Fragmentation for the Design of M.†tuberculosis CYP121 Inhibitors.

The cyclo-dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor-like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other Mtb P450s. Spectroscopic characterisation of the inhibitors' binding mode provides insight into the effect of weak nitrogen-donor ligands on the P450 heme, an improved understanding of factors governing CYP121-ligand recognition and speculation into the biological role of the enzyme for Mtb.

International consensus statement on injury surveillance in cricket: a 2016 update.

Cricket was the first sport to publish recommended methods for injury surveillance in 2005. Since then, there have been changes to the nature of both cricket and injury surveillance. Researchers representing the major cricket playing nations met to propose changes to the previous recommendations, with an agreed voting block of 14. It was decided that 10 of 14 votes (70%) were required to add a new definition element and 11 of 14 (80%) were required to amend a previous definition. In addition to the previously agreed 'Match time-loss' injury, definitions of 'General time-loss', 'Medical presentation', 'Player-reported' and 'Imaging-abnormality' injuries are now provided. Further, new injury incidence units of match injuries per 1000 player days, and annual injuries per 100 players per year are recommended. There was a shift towards recommending a greater number of possible definitions, due to differing contexts and foci of cricket research (eg, professional vs amateur; injury surveillance systems vs specific injury category studies). It is recommended that researchers use and report as many of the definitions as possible to assist both comparisons between studies within cricket and with those from other sports.

Symmetry, not asymmetry, of abdominal muscle morphology is associated with low back pain in cricket fast bowlers.

OBJECTIVES: Although abdominal muscle morphology is symmetrical in the general population, asymmetry has been identified in rotation sports. This asymmetry includes greater thickness of obliquus internus abdominis (OI) on the non-dominant side in cricketers. Cricket fast bowlers commonly experience low back pain (LBP) related to bowling action, and this depends on trunk muscle control. This study aimed to compare abdominal muscle thickness between fast bowlers with and without LBP. DESIGN: Cross sectional descriptive study. METHODS: Twenty-five adolescent provincial league specialist fast bowlers (16 with and 9 without LBP) participated. Static ultrasound images (US) of OI, and obliquus externus (OE) and transversus abdominis (TrA) were captured on the dominant and non-dominant side in supine. RESULTS: Total combined thickness of OE, OI and TrA muscles was greater on the non-dominant than dominant side (p=0.02) for fast bowlers without LBP, but symmetrical for those with pain. Total thickness was less on the non-dominant side for bowlers with pain than those without (p=0.03). When individual muscles were compared, only the thickness of OI was less in bowlers with LBP than those without (p=0.02). All abdominal muscles were thicker on the non-dominant side in controls (p<0.001) but symmetrical in LBP. CONCLUSIONS: Asymmetry of abdominal muscle thickness in fast bowlers is explained by the asymmetrical biomechanics of fast bowling. Lesser OI muscle thickness in fast bowlers with LBP suggests modified trunk control in the transverse/frontal plane and may underpin the incidence of lumbar pathology. The implications for rehabilitation following LBP in fast bowlers require further investigation.

Foot orthoses in the treatment of symptomatic midfoot osteoarthritis using clinical and biomechanical outcomes: a randomised feasibility study.

This randomised feasibility study aimed to examine the clinical and biomechanical effects of functional foot orthoses (FFOs) in the treatment of midfoot osteoarthritis (OA) and the feasibility of conducting a full randomised controlled trial. Participants with painful, radiographically confirmed midfoot OA were recruited and randomised to receive either FFOs or a sham control orthosis. Feasibility measures included recruitment and attrition rates, practicality of blinding and adherence rates. Clinical outcome measures were: change from baseline to 12 weeks for severity of pain (numerical rating scale), foot function (Manchester Foot Pain and Disability Index) and patient global impression of change scale. To investigate the biomechanical effect of foot orthoses, in-shoe foot kinematics and plantar pressures were evaluated at 12 weeks. Of the 119 participants screened, 37 were randomised and 33 completed the study (FFO = 18, sham = 15). Compliance with foot orthoses and blinding of the intervention was achieved in three quarters of the group. Both groups reported improvements in pain, function and global impression of change; the FFO group reporting greater improvements compared to the sham group. The biomechanical outcomes indicated the FFO group inverted the hindfoot and increased midfoot maximum plantar force compared to the sham group. The present findings suggest FFOs worn over 12 weeks may provide detectable clinical and biomechanical benefits compared to sham orthoses. This feasibility study provides useful clinical, biomechanical and statistical information for the design and implementation of a definitive randomised controlled trial to evaluate the effectiveness of FFOs in treating painful midfoot OA.

Which Extrinsic and Intrinsic Factors are Associated with Non-Contact Injuries in Adult Cricket Fast Bowlers?

BACKGROUND: The high prevalence of injury amongst cricket fast bowlers exposes a great need for research into the risk factors associated with injury. Both extrinsic (environment-related) and intrinsic (person-related) risk factors are likely to be implicated within the high prevalence of non-contact injury amongst fast bowlers in cricket. Identifying and defining the relative importance of these risk factors is necessary in order to optimize injury prevention efforts. OBJECTIVE: The objective of this review was to assess and summarize the scientific literature related to the extrinsic and intrinsic factors associated with non-contact injury inherent to adult cricket fast bowlers. METHOD: A systematic review was performed in compliance with the PRISMA guidelines. This review considered both experimental and epidemiological study designs. Studies that included male cricket fast bowlers aged 18 years or above, from all levels of play, evaluating the association between extrinsic/intrinsic factors and injury in fast bowlers were considered for inclusion. The three-step search strategy aimed at finding both published and unpublished studies from all languages. The searched databases included MEDLINE via PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Controlled Trials Register in the Cochrane Library, Physiotherapy Evidence Database (PEDro), ProQuest 5000 International, ProQuest Health and Medical Complete, EBSCO MegaFile Premier, Science Direct, SPORTDiscus with Full Text and SCOPUS (prior to 28 April 2015). Initial keywords used were 'cricket', 'pace', 'fast', 'bowler', and 'injury'. Papers which fitted the inclusion criteria were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). RESULTS: A total of 16 studies were determined to be suitable for inclusion in this systematic review. The mean critical appraisal score of the papers included in this study was 6.88 (SD 1.15) out of a maximum of 9. The following factors were found to be associated with injury: bowling shoulder internal rotation strength deficit, compromised dynamic balance and lumbar proprioception (joint position sense), the appearance of lumbar posterior element bone stress, degeneration of the lumbar disc on magnetic resonance imaging (MRI), and previous injury. Conflicting results were found for the association of quadratus lumborum (QL) muscle asymmetry with injury. Technique-related factors associated with injury included shoulder-pelvis flexion-extension angle, shoulder counter-rotation, knee angle, and the proportion of side-flexion during bowling. Bowling workload was the only extrinsic factor associated with injury in adult cricket fast bowlers. A high bowling workload (particularly if it represented a sudden upgrade from a lower workload) increased the subsequent risk to sustaining an injury 1, 3 or 4 weeks later. CONCLUSION: Identifying the factors associated with injury is a crucial step which should precede the development of, and research into, the effectiveness of injury prevention programs. Once identified, risk factors may be included in pre-participation screening tools and injury prevention programs, and may also be incorporated in future research projects. Overall, the current review highlights the clear lack of research on factors associated with non-contact injury, specifically in adult cricket fast bowlers. SYSTEMATIC REVIEW REGISTRATION NUMBER: Johanna Briggs Institute Database of Systematic Reviews and Implementation Reports 1387 (Olivier et al., JBI Database Syst Rev Implement Rep 13(1):3-13. doi: 10.11124/jbisrir-2015-1387 , 2015).