Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening.

Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.

Cartiva interpositional arthroplasty versus arthrodesis in the treatment of Hallux rigidus: A retrospective comparative study with mean 2 year follow up.

BACKGROUND: Hallux rigidus is a common condition characterised by first metatarsophalangeal joint (MTPJ) degeneration, pain and limited range of motion (ROM). The gold standard surgical treatment is arthrodesis, providing good pain relief, but sacrifices ROM. The Cartiva synthetic cartilage implant (SCI) has been utilised as an interpositional arthroplasty, aiming to reduce pain whilst preserving range of motion. Current evidence for Cartiva SCI is limited. The aim was to evaluate the clinical outcomes of Cartiva SCI compared to arthrodesis undertaken in our centre. METHODS: A retrospective cohort study was conducted, enrolling all adult patients who underwent primary first MTPJ SCI arthroplasty or arthrodesis for the treatment hallux rigidus. The primary outcome was a validated patient-reported outcome measure (PROM), the Manchester-Oxford Foot Questionnaire (MOXFQ). Secondary outcomes included EQ-5D, complication rates, VAS Pain and FAAM (ADL). RESULTS: Between 2017 and 2020 there were 33 cases divided into two groups (17 Cartiva SCI, 16 arthrodesis, mean age 59.0 ± 9.9 years) with a mean follow up of 2.3 years. There was no statistically significant difference in any of the MOXFQ, EQ-5D, VAS Pain or FAAM (ADL) outcome scores between the Arthrodesis and SCI groups (p > 0.05). The mean MOXFQ Index score was 7.2 ± 6.4 for the SCI group and 3.9 ± 5.8 for the Arthrodesis group at final follow up (p = 0.15). Although complications were high in both groups, the overall hallux reoperation rate was 29.4 % in the SCI cohort and 0.0 % for arthrodesis. CONCLUSION: This retrospective comparative study found no significant superiority of Cartiva SCI over arthrodesis in terms of PROMs. Due to the higher rate of further surgical intervention in the SCI cohort, we recommend arthrodesis as the preferred surgical option for hallux rigidus. LEVEL OF EVIDENCE: III.

The Retinal Basis of Light Aversion in Neonatal Mice.

Aversive responses to bright light (photoaversion) require signaling from the eye to the brain. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) encode absolute light intensity and are thought to provide the light signals for photoaversion. Consistent with this, neonatal mice exhibit photoaversion before the developmental onset of image vision, and melanopsin deletion abolishes photoaversion in neonates. It is not well understood how the population of ipRGCs, which constitutes multiple physiologically distinct types (denoted M1-M6 in mouse), encodes light stimuli to produce an aversive response. Here, we provide several lines of evidence that M1 ipRGCs that lack the Brn3b transcription factor drive photoaversion in neonatal mice. First, neonatal mice lacking TRPC6 and TRPC7 ion channels failed to turn away from bright light, while two photon Ca2+ imaging of their acutely isolated retinas revealed reduced photosensitivity in M1 ipRGCs, but not other ipRGC types. Second, mice in which all ipRGC types except for Brn3b-negative M1 ipRGCs are ablated exhibited normal photoaversion. Third, pharmacological blockade or genetic knockout of gap junction channels expressed by ipRGCs, which reduces the light sensitivity of M2-M6 ipRGCs in the neonatal retina, had small effects on photoaversion only at the brightest light intensities. Finally, M1s were not strongly depolarized by spontaneous retinal waves, a robust source of activity in the developing retina that depolarizes all other ipRGC types. M1s therefore constitute a separate information channel between the neonatal retina and brain that could ensure behavioral responses to light but not spontaneous retinal waves.SIGNIFICANCE STATEMENT At an early stage of development, before the maturation of photoreceptor input to the retina, neonatal mice exhibit photoaversion. On exposure to bright light, they turn away and emit ultrasonic vocalizations, a cue to their parents to return them to the nest. Neonatal photoaversion is mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs), a small percentage of the retinal ganglion cell population that express the photopigment melanopsin and depolarize directly in response to light. This study shows that photoaversion is mediated by a subset of ipRGCs, called M1-ipRGCs. Moreover, M1-ipRGCs have reduced responses to retinal waves, providing a mechanism by which the mouse distinguishes light stimulation from developmental patterns of spontaneous activity.

Residual Deformable Split Channel and Spatial U-Net for Automated Liver and Liver Tumour Segmentation.

Accurate segmentation of the liver and liver tumour (LT) is challenging due to its hazy boundaries and large shape variability. Although using U-Net for liver and LT segmentation achieves better results than manual segmentation, it loses spatial and channel features during segmentation, leading to inaccurate liver and LT segmentation. A residual deformable split depth-wise separable U-Net (RDSDSU-Net) is proposed to increase the accuracy of liver and LT segmentation. The residual deformable convolution layer (DCL) with deformable pooling (DP) is used in the encoder as an attention mechanism to adaptively extract liver and LT shape and position characteristics. Afterward, a convolutional spatial and channel features split graph network (CSCFSG-Net) is introduced in the middle processing layer to improve the expression capability of the liver and LT features by capturing spatial and channel features separately and to extract global contextual liver and LT information from spatial and channel features. Sub-pixel convolutions (SPC) are used in the decoder section to prevent the segmentation results from having a chequerboard artefact effect. Also, the residual deformable encoder features are combined with the decoder through summation to avoid increasing the number of feature maps (FM). Finally, the efficiency of the RDSDSU-Net is evaluated on the 3DIRCADb and LiTS datasets. The DICE score of the proposed RDSDSU-Net achieved 98.21% for liver segmentation and 93.25% for LT segmentation on 3DIRCADb. The experimental outcomes illustrate that the proposed RDSDSU-Net model achieved better segmentation results than the existing techniques.

Dynamic Phase Extraction: Applications in Pulse Rate Variability.

Pulse rate variability is a physiological parameter that has been extensively studied and correlated with many physical ailments. However, the phase relationship between inter-beat interval, IBI, and breathing has very rarely been studied. Develop a technique by which the phase relationship between IBI and breathing can be accurately and efficiently extracted from photoplethysmography (PPG) data. A program based on Lock-in Amplifier technology was written in Python to implement a novel technique, Dynamic Phase Extraction. It was tested using a breath pacer and a PPG sensor on 6 subjects who followed a breath pacer at varied breathing rates. The data were then analyzed using both traditional methods and the novel technique (Dynamic Phase Extraction) utilizing a breath pacer. Pulse data was extracted using a PPG sensor. Dynamic Phase Extraction (DPE) gave the magnitudes of the variation in IBI associated with breathing [Formula: see text] measured with photoplethysmography during paced breathing (with premature ventricular contractions, abnormal arrhythmias, and other artifacts edited out). [Formula: see text] correlated well with two standard measures of pulse rate variability: the Standard Deviation of the inter-beat interval (SDNN) (ρ = 0.911) and with the integrated value of the Power Spectral Density between 0.04 and 0.15 Hz (Low Frequency Power or LF Power) (ρ = 0.885). These correlations were comparable to the correlation between the SDNN and the LF Power (ρ = 0.877). In addition to the magnitude [Formula: see text], Dynamic Phase Extraction also gave the phase between the breath pacer and the changes in the inter-beat interval (IBI) due to respiratory sinus arrythmia (RSA), and correlated well with the phase extracted using a Fourier transform (ρ = 0.857). Dynamic Phase Extraction can extract both the phase between the breath pacer and the changes in IBI due to the respiratory sinus arrhythmia component of pulse rate variability ([Formula: see text], but is limited by needing a breath pacer.

A Functional Adenosine Deaminase Polymorphism Associates with Evening Melatonin Levels and Sleep Quality.

Increased adenosine levels throughout the day promote sleepiness. A single nucleotide polymorphism (SNP) in the adenosine deaminase ADA gene (rs73598374) has been shown to affect sleep regulation. The extent to which lower ADA enzymatic activity is associated with the homeostatic sleep factor, melatonin, is uncertain. To test this possibility, we assessed the relationship between the ADA polymorphism and evening melatonin levels, as well as self-reported sleep behavior. Given the close relationship between mood and sleep behavior, we further tested the impact of ADA genotype on self-reported mood. We show that relative to the GG homozygotes, the A allele carriers (higher adenosine levels) had significantly higher evening melatonin levels as well as significantly better sleep quality. We further show the correlations between sleep and mood measures were altered by ADA genotype, with a stronger relationship observed in the GG (lower adenosine) group. Combined, these findings advance our understanding of the biochemistry of melatonin production by showing that there is a relationship between ADA genotype and melatonin levels. The differential relationships between sleep and psychological health between the genotype groups may reveal novel insights about the development of genotype-specific progression of various psychological disorders such as chronic anxiety and stress.

Introducing and Controlling Water Vapor in Closed-Cell In Situ Electron Microscopy Gas Reactions.

Protocols for conducting in situ transmission electron microscopy (TEM) reactions using an environmental TEM with dry gases have been well established. However, many important reactions that are relevant to catalysis or high-temperature oxidation occur at atmospheric pressure and are influenced by the presence of water vapor. These experiments necessitate using a closed-cell gas reaction TEM holder. We have developed protocols for introducing and controlling water vapor concentrations in experimental gases from 2% at a full atmosphere to 100% at ~17 Torr, while measuring the gas composition using a residual gas analyzer (RGA) on the return side of the in situ gas reactor holder. Initially, as a model system, cube-shaped MgO crystals were used to help develop the protocols for handling the water vapor injection process and confirming that we could successfully inject water vapor into the gas cell. The interaction of water vapor with MgO triggered surface morphological and chemical changes as a result of the formation of Mg(OH)2, later validated with mass spectra obtained with our RGA system with and without water vapor. Integrating an RGA with an in situ scanning/TEM closed-cell gas reaction system can thus provide critical measurements correlating gas composition with dynamic surface restructuring of materials during reactions.

Temperature Measurement by a Nanoscale Electron Probe Using Energy Gain and Loss Spectroscopy.

Heat dissipation in integrated nanoscale devices is a major issue that requires the development of nanoscale temperature probes. Here, we report the implementation of a method that combines electron energy gain and loss spectroscopy to provide a direct measurement of the local temperature in the nanoenvironment. Loss and gain peaks corresponding to an optical-phonon mode in boron nitride were measured from room temperature to ∼1600 K. Both loss and gain peaks exhibit a shift towards lower energies as the sample is heated up. First-principles calculations of the temperature-induced phonon frequency shifts provide insights into the origin of this effect and confirm the experimental data. The experiments and theory presented here open the doors to the study of anharmonic effects in materials by directly probing phonons in the electron microscope.

Nasal obstructive disorders induce medical treatment failure in paediatric persistent allergic rhinitis (The NODPAR Study).

BACKGROUND: Allergic rhinitis (AR) is the most common chronic disease among children. To characterize the disease, a modified classification of severity (m-ARIA) has recently been validated in AR children. When medical treatment fails, surgery for nasal obstructive disorders (NOD) may be a therapeutic option. Our objective was to assess the prevalence of NOD and their influence in medical treatment response among children with persistent AR (PER). METHODS: In a prospective, real-life study, 130 paediatric PER patients (13.1 ± 2.8 years, females 31.5%, severe rhinitis 49%) referred from Allergy to ENT department were assessed for their response (R, responders; NR, non-responders) to medical treatment (intranasal steroids and antihistamines or antileukotrienes) by direct questioning and nasal symptom visual analogue scale, the presence of NOD (septal deformity, turbinate enlargement and adenoidal hyperplasia), comorbidities, nasal symptoms, rhinitis severity (modified ARIA criterion) and asthma control (International Consensus On Pediatric Asthma criterion). RESULTS: After 2 months of treatment, the NR group presented a higher prevalence of obstructive septal deformity and severe inferior turbinate enlargement when compared with the R group. Higher septal deformity and turbinate enlargement scores were strongly associated with treatment refractoriness. The prevalence of severe PER was also higher for the NR group. Higher asthma control scores were associated with the probability of treatment-induced improvement. CONCLUSIONS: In paediatric PER patients, medical therapy refractoriness was associated with NOD, mainly septal deformity and turbinate enlargement. In those patients, ENT examination will facilitate an early NOD diagnosis in order to indicate potential corrective surgery.

Intern Boot Camp: Feasibility and impact of a 1-hour session to ensure graduating medical student competency in falls risk assessment.

The authors evaluated the feasibility of a 1-hour session to ensure competency in gait and falls risk assessment for medical students at their institution. The session included a history and exam with faculty and staff as standardized patients, gait recognition videos, and case evaluation for falls risk assessment and prevention. Student perceptions were evaluated using a retrospective pre-post survey, scored on a 5-point Likert-type scale. Wilcoxon signed-rank tests were used to assess change and Kruskal-Wallis tests were used to analyze differences by residency choice. A range of five to 11 faculty and staff certified 238 medical students during eight 1-hour sessions. Overall self-perception of competence in falls risk assessment and prevention improved (p ≤ .001), and did not differ by residency choice, both before and after the training program (p = .73 and p = .25). Feedback was positive. This session is a feasible way to teach and assess the competency for falls risk assessment with modest time commitment.

Genetic and environmental effects on early growth and performance in purebred Holstein, Jersey, and reciprocal crossbred calves.

For this designed experiment, Holstein × Holstein (n=28), Jersey × Jersey (n=10), Holstein × Jersey (n=15), and Jersey × Holstein (n=15) bull and heifer calves were compared for body weight (BW), dry matter intake, feed efficiency, hip height, BW gain to 42 and 56 d, and days to weaning from birth to 8 wk. All traits were examined for purebred, maternal, and heterotic genetic effects. Purebred genetic effects significantly favored the Holstein breed for BW, dry matter intake, hip height, and BW gain to 42 and 56 d. Heterotic genetic effects were present for dry matter intake and hip height. Calf sex affected BW and BW gain to 56 d. Our results indicate that early calf growth is influenced primarily by purebred effects favoring the Holstein breed and to a lesser extent heterosis.

Plasmodium vivax chloroquine resistance and anemia in the western Brazilian Amazon.

Data on chloroquine (CQ)-resistant Plasmodium vivax in Latin America is limited, even with the current research efforts to sustain an efficient malaria control program in all these countries where P. vivax is endemic and where malaria still is a major public health issue. This study estimated in vivo CQ resistance in patients with uncomplicated P. vivax malaria, with use of CQ and primaquine simultaneously, in the Brazilian Amazon. Of a total of 135 enrolled subjects who accomplished the 28-day follow-up, parasitological failure was observed in 7 (5.2%) patients, in whom plasma CQ and desethylchloroquine (DCQ) concentrations were above 100 ng/dl. Univariate analysis showed that previous exposure to malaria and a higher initial mean parasitemia were associated with resistance but not with age or gender. In the multivariate analysis, only high initial parasitemia remained significant. Hemoglobin levels were similar at the beginning of the follow-up and were not associated with parasitemia. However, at day 3 and day 7, hemoglobin levels were significantly lower in patients presenting CQ resistance. The P. vivax dhfr (pvdhfr), pvmrp1, pvmdr1, and pvdhps gene mutations were not related to resistance in this small sample. P. vivax CQ resistance is already a problem in the Brazilian Amazon, which could be to some extent associated with the simultaneous report of anemia triggered by this parasite, a common complication of the disease in most of the areas of endemicity.

Quantitative electrochemical measurements using in situ ec-S/TEM devices.

Insight into dynamic electrochemical processes can be obtained with in situ electrochemical-scanning/transmission electron microscopy (ec-S/TEM), a technique that utilizes microfluidic electrochemical cells to characterize electrochemical processes with S/TEM imaging, diffraction, or spectroscopy. The microfluidic electrochemical cell is composed of microfabricated devices with glassy carbon and platinum microband electrodes in a three-electrode cell configuration. To establish the validity of this method for quantitative in situ electrochemistry research, cyclic voltammetry (CV), choronoamperometry (CA), and electrochemical impedance spectroscopy (EIS) were performed using a standard one electron transfer redox couple [Fe(CN)6]3-/4--based electrolyte. Established relationships of the electrode geometry and microfluidic conditions were fitted with CV and chronoamperometic measurements of analyte diffusion coefficients and were found to agree with well-accepted values that are on the order of 10-5 cm2/s. Influence of the electron beam on electrochemical measurements was found to be negligible during CV scans where the current profile varied only within a few nA with the electron beam on and off, which is well within the hysteresis between multiple CV scans. The combination of experimental results provides a validation that quantitative electrochemistry experiments can be performed with these small-scale microfluidic electrochemical cells provided that accurate geometrical electrode configurations, diffusion boundary layers, and microfluidic conditions are accounted for.

Utilizing a Meals on Wheels program to teach falls risk assessment to medical students.

Falls are a critical public health issue for older adults, and falls risk assessment is an expected competency for medical students. The aim of this study was to design an innovative method to teach falls risk assessment using community-based resources and limited geriatrics faculty. The authors developed a Fall Prevention Program through a partnership with Meals-on-Wheels (MOW). A 3rd-year medical student accompanies a MOW client services associate to a client's home and performs a falls risk assessment including history of falls, fear of falling, medication review, visual acuity, a Get Up and Go test, a Mini-Cog, and a home safety evaluation, reviewed in a small group session with a faculty member. During the 2010 academic year, 110 students completed the in-home falls risk assessment, rating it highly. One year later, 63 students voluntarily completed a retrospective pre/postsurvey, and the proportion of students reporting moderate to very high confidence in performing falls risk assessments increased from 30.6% to 87.3% (p < .001). Students also reported using most of the skills learned in subsequent clerkships. A single educational intervention in the MOW program effectively addressed geriatrics competencies with minimal faculty effort and could be adopted by many medical schools.

Stakeholder perceptions of thoroughbred yearling sales endoscopy in Australia: can we do better?

OBJECTIVE: To identify thoroughbred industry stakeholders' views on the yearling sales endoscopy in Australia. DESIGN: Semi-structured qualitative group interviews with equine veterinarians, thoroughbred breeders and yearling purchasers. METHODS: Twenty-nine experienced thoroughbred industry stakeholders participated in online focus groups: (1) equine veterinarians involved in yearling endoscopy; (2) thoroughbred breeders; and (3) yearling buyers. The focus groups were audio and video recorded and digital whiteboards were available. Data was transcribed, live-coded and analysed thematically. RESULTS: The main themes identified included the uncertainty surrounding the relationship between yearling laryngeal function and future performance, especially the significance of yearlings with grade 3 out of 5 laryngeal function; interobserver variability in the laryngeal function grade assigned by veterinarians to the same endoscopic exam; and the presence of intra-horse variability in laryngeal function over different time points. DISCUSSION: Stakeholders raised multiple concerns about the current yearling sales endoscopy process in Australia. Recommendations to address these concerns include further investigation into the race performance of yearlings identified with grade 3 laryngeal function; training of veterinarians to reduce inter-observer variability; and the need to determine the most appropriate grading system to use in yearlings. Future research should evaluate the significance of intra-horse variability in a yearling population.

Review of the clinical diagnosis of sacroiliac dysfunction in horses - Challenges and limitations.

Sacroiliac dysfunction (SID) is a condition seen in horses associated with poor performance that affects hind limb gait and impulsion. The condition comprises pain and dysfunction but there lacks clarity around the aetiopathogenesis and whether SID encompasses abnormal joint pathology, abnormal joint movement, abnormal regional biomechanical function, joint laxity and pain, or various combinations of these that may vary over time. Clinical assessment remains challenging for equine clinicians due to the deep location of the sacroiliac joint (SIJ) and surrounding structures which limits access for palpation, diagnostic imaging and joint-specific injection. There is no recognised single reference standard diagnostic test for SID. Clinical diagnosis has been based on ruling out other causes of hind limb lameness, along with combinations of ultrasonography, scintigraphy and periarticular anaesthesia of the SIJ. Recent studies have highlighted the lack of specificity of injections targeting the SIJ, with significant dispersal of injectate into surrounding structures including around the lumbosacral joint (LSJ). Advanced imaging modalities such as computed tomography offers promise for assessment of the structure and pathology of the SIJ and surrounding bony structures. However, there is a need to improve the understanding of the significance of anatomic variation of the sacroiliac region structures, with recent studies reporting detailed anatomic variation in groups of horses with and without SID. There are also limitations around functional assessment of the joint which is still largely reliant on a thorough clinical examination. This review aims to present an update on clinical approaches to the diagnosis of horses with SID, and to consider the challenges and limitations.

Automated prediction of acute promyelocytic leukemia from flow cytometry data using a graph neural network pipeline.

OBJECTIVES: Our study aimed to develop a machine learning (ML) model to accurately classify acute promyelocytic leukemia (APL) from other types of acute myeloid leukemia (other AML) using multicolor flow cytometry (MFC) data. Multicolor flow cytometry is used to determine immunophenotypes that serve as disease signatures for diagnosis. METHODS: We used a data set of MFC files from 27 patients with APL and 41 patients with other AML, including those with uncommon immunophenotypes. Our ML pipeline involved training a graph neural network (GNN) to output graph-level labels and identifying the most crucial MFC parameters and cells for predictions using an input perturbation method. RESULTS: The top-performing GNN achieved 100% accuracy on the training/validation and test sets on classifying APL from other AML and used MFC parameters similarly to expert pathologists. Pipeline performance is amenable to use in a clinical decision support system, and our deep learning architecture readily enables prediction explanations. CONCLUSIONS: Our ML pipeline shows robust performance on predicting APL and could be used to screen for APL using MFC data. It also allowed for intuitive interrogation of the model's predictions by clinicians.

Predisposing risk factors for cleft lip and palate in an Amazonian population by focusing on nutritional factors: A case-control study.

BACKGROUND: Orofacial clefts (OFC) are the most common congenital malformation of the craniofacial skeleton. Attempts have been made to correlate the components of maternal diet as triggers for the development or prevention of OFC. OBJECTIVE: To analyze nutritional status as a predictive factor for the development of cleft lip and palate in an Amazonian population. METHODS: A total of 152 mothers within 3 months of delivery were interviewed for comparison: 51 mothers of children with nonsyndromic cleft lip and palate (CLP) (study group) and 101 mothers of children without OFC (control group). A food frequency questionnaire was used to assess maternal nutrition and to analyze the influence of macro- and micronutrients on the possible predisposition or protection for CLP. RESULTS: The study group showed higher percentage of lipid intake than did the control group (p = 0.01). Among the participants with no family history of OFC, the study group had a higher percentage of lipid intake (p = 0.002) and lower vegetable intake (p = 0.037). Maternal micronutrient intake among the participants with a positive family history was lower in the study group for vitamins B2 (p = 0.03), B5 (p = 0.036), E (p = 0.03), and folate (p = 0.022). CONCLUSIONS: Nutritional analysis indicated that higher maternal lipid intake increased the likelihood of having offsprings with nonsyndromic CLP. Moreover, families with a history of OFC and low maternal folate intake showed heightened risk of nonsyndromic CLP in their offsprings.

Histological evaluation of cardiac remodelling in equine athletes.

Approximately 1-2 per 100,000 young athletes die from sudden cardiac death (SCD) and extreme exercise may be associated with myocardial scar and arrhythmias. Racehorses have a high prevalence of atrial fibrillation (AF) and SCD but the presence of myocardial scar and inflammation has not been evaluated. Cardiac tissues from the left (LAA) and right (RAA) atrial appendages, left ventricular anterior (LVAPM) and posterior (LVPPM) papillary muscles, and right side of the interventricular septum (IVS-R) were harvested from racehorses with sudden cardiac death (SCD, n = 16) or other fatal injuries (OFI, n = 17), constituting the athletic group (ATH, n = 33), and compared to sedentary horses (SED, n = 10). Horses in the ATH group had myocyte hypertrophy at all sites; increased fibrosis at all sites other than the LAA; increased fibroblast infiltration but a reduction in the overall extracellular matrix (ECM) volume in the RAA, LVAPM, and IVS-R compared to SED horses. In this horse model, athletic conditioning was associated with myocyte hypertrophy and a reduction in ECM. There was an excess of fibrocyte infiltration and focal fibrosis that was not present in non-athletic horses, raising the possibility of an exercise-induced pro-fibrotic substrate.