Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling.

Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.

Deleting an Nr4a1 Super-Enhancer Subdomain Ablates Ly6Clow Monocytes while Preserving Macrophage Gene Function.

Mononuclear phagocytes are a heterogeneous family that occupy all tissues and assume numerous roles to support tissue function and systemic homeostasis. Our ability to dissect the roles of individual subsets is limited by a lack of technologies that ablate gene function within specific mononuclear phagocyte sub-populations. Using Nr4a1-dependent Ly6Clow monocytes, we present a proof-of-principle approach that addresses these limitations. Combining ChIP-seq and molecular approaches we identified a single, conserved, sub-domain within the Nr4a1 enhancer that was essential for Ly6Clow monocyte development. Mice lacking this enhancer lacked Ly6Clow monocytes but retained Nr4a1 gene expression in macrophages during steady state and in response to LPS. Because Nr4a1 regulates inflammatory gene expression and differentiation of Ly6Clow monocytes, decoupling these processes allows Ly6Clow monocytes to be studied independently.

Moving from ethnic exclusions to cultural safety: how is athlete ethnicity discussed in research on menstrual health in sports? A scoping review.

OBJECTIVE: This study aims to investigate how athlete ethnicity is discussed in the inclusion and exclusion criteria, methodology, findings, and conclusions of research focused on menstrual health in sports science and medicine. DESIGN: A scoping review of sports-based research conducted on athletes related to (1) menstrual health and ethnicity, (2) how researchers include/exclude participants based on ethnicity and (3) how ethnicity is discussed. DATA SOURCES: Electronic search of PubMed and ProQuest. ELIGIBILITY CRITERIA: Articles were included if they met the following criteria: (1) published before September 2023, (2) published in peer-reviewed journals, (3) participants were women athletes, (4) published in English and (5) relating to menstrual health. Articles were assessed as good, fair or poor quality using the Inclusion of Participant Ethnicity Quality Assessment Criteria. RESULTS: From the 1089 studies available from the initial database search, 55 studies considered ethnicity. Nine studies met the inclusion criteria and were assessed as either good (22%), fair (44%) or poor (33%) in quality in their consideration of athlete ethnicity. 81% of research articles on menstrual health in sports do not consider athlete ethnicity, and when ethnicity is discussed, it rarely meets the criteria for cultural safety in the research process. Most studies did not factor ethnicity into the analysis and lacked cultural considerations in the research design and interventions. CONCLUSION: More careful inclusion of ethnicity in sports menstrual health-related research and recognition of social and cultural influences on health and research outcomes for indigenous and other ethnic minority groups is needed. Such research is required to support coaches, medical personnel and support staff in designing culturally safe environments for sportswomen from diverse cultural and ethnic backgrounds.

ZNF423 patient variants, truncations, and in-frame deletions in mice define an allele-dependent range of midline brain abnormalities.

Interpreting rare variants remains a challenge in personal genomics, especially for disorders with several causal genes and for genes that cause multiple disorders. ZNF423 encodes a transcriptional regulatory protein that intersects several developmental pathways. ZNF423 has been implicated in rare neurodevelopmental disorders, consistent with midline brain defects in Zfp423-mutant mice, but pathogenic potential of most patient variants remains uncertain. We engineered ~50 patient-derived and small deletion variants into the highly-conserved mouse ortholog and examined neuroanatomical measures for 791 littermate pairs. Three substitutions previously asserted pathogenic appeared benign, while a fourth was effectively null. Heterozygous premature termination codon (PTC) variants showed mild haploabnormality, consistent with loss-of-function intolerance inferred from human population data. In-frame deletions of specific zinc fingers showed mild to moderate abnormalities, as did low-expression variants. These results affirm the need for functional validation of rare variants in biological context and demonstrate cost-effective modeling of neuroanatomical abnormalities in mice.

Do composite resin polishing systems damage enamel?

Finishing and polishing of composite resin restorations may cause damage to the bordering enamel. Although many studies have investigated the effect of polish on restorative materials, few have quantified the effect on bordering enamel. The objective of this study was to compare enamel loss surrounding composite restorations after finishing and polishing sequences. The null hypothesis was that there would be no difference in enamel loss between different finishing and polishing sequences. Class V preparations on the buccal and lingual surfaces of 15 extracted human molars were restored with a composite resin and assigned to 1 of 2 finishing and polishing sequences, so that each tooth underwent both sequences (n = 15 per sequence). In sequence 1, a tungsten carbide finishing bur and aluminum oxide polishing discs were used; in sequence 2, a diamond finishing bur, aluminum oxide-impregnated finishing cup, and diamond-impregnated polishing cup were used. Tooth surfaces were scanned with an optical scanner after preparation, finishing, initial polishing, and final polishing. The finishing and polishing scans were aligned to the preparation scan using Cumulus software. The depth of enamel surface loss was calculated and statistically analyzed (α = 0.05; paired t test). Most enamel loss (mean [SD]) resulted from the finishing step with the tungsten carbide bur (51.8 [21.3] µm) or diamond bur (43.3 [12.6] µm). Each polishing step increased mean enamel loss by only a few microns. There was no statistically significant difference between the 2 finishing and polishing sequences. The majority of enamel damage during finishing and polishing of composite resin restorations resulted from the finishing burs. Little enamel was removed by either of the tested composite resin polishing systems.

Decision-Making in Sport During a Pandemic.

OBJECTIVE: The COVID-19 pandemic has affected all elements of global society, and sport is not exempt. Many sporting events have been either postponed or canceled, and national sporting organizations have had to make highly complex decisions in the face of scientific uncertainty and risk. This article applies these lessons to the world of sport with the goal of assisting sporting organizations to make sound and reasoned decisions during a pandemic. DATA SOURCES: A narrative approach using both academic literature sources and live examples from the authors' experience. We use Daniels and Sabin's accountability for reasonableness framework to facilitate decision-making in the face of such uncertainty. MAIN RESULTS: Decision-making in the context of uncertainty has the potential to create conflict and disengagement from key stakeholders. Evidence from recent pandemics has illustrated that an ethical approach to decision-making results in reasoned decision-making and confers a legitimacy to decisions that ultimately supports engagement and satisfaction from stakeholders. CONCLUSIONS: The incorporation of ethical considerations into risk assessment and management when making complex decisions, which incorporate high levels of uncertainty, will assist sporting organizations have positive outcomes.

A quantitative and visual examination of sealed restorative specimens following exposure to artificial aging.

Low-viscosity polymer resins, or surface sealants (SSs), have been utilized as a means of finalizing the polishing step following the placement of composite resin restorations. The aim of this study was to measure the surface roughness (Ra) of composite resins treated with different SSs before and after exposure to an accelerated artificial aging protocol. The study included 5 experimental groups of composite resin discs (TPH Spectra ST) treated with different SSs (PermaSeal, Embrace WetBond Seal-n-Shine, OptiGuard, BisCover LV, and DuraFinish) and a control group consisting of untreated discs (n = 6 per group). The discs were prepared by inserting composite resin in 10 × 1-mm rings, covering the ring and material with a transparent strip, compressing the assembly between glass slides, and polymerizing through the slides on each side for 40 seconds with an LED curing light. Each disc except for the control specimens received a coating of the selected SS followed by application of a transparent matrix strip and then light polymerization for 20 seconds using an LED light source. Surface roughness measurements were obtained with a digital contact profilometer at baseline (immediately after polymerization) and following exposure to a thermocycling regimen to simulate aging. The data were analyzed using 2-way analysis of variance and post hoc Student-Newman-Keuls test with significance set at P < 0.05. There were no statistically significant differences among the groups at baseline. There were no statistically significant differences between the baseline and post-thermocycling Ra measurements except among the DuraFinish specimens, which were significantly rougher than all other groups after accelerated artificial aging. The use of SSs for the initial insertion and possibly for the long-term maintenance of composite resins could be minimally beneficial for restoration maintenance if a transparent covering medium is utilized during polymerization. However, due to the effects caused by formation of an oxygen-inhibited layer of unpolymerized monomers if a covering medium is not used, the results suggest the benefits do not offset the costs considering both gloss and Ra surface-testing parameters.

TBR2 antagonizes retinoic acid dependent neuronal differentiation by repressing Zfp423 during corticogenesis.

During cerebral cortex development, neural progenitors are required to elaborate a variety of cell differentiation signals to which they are continuously exposed. RA acid is a potent inducer of neuronal differentiation as it was found to influence cortical development. We report herein that TBR2, a transcription factor specific to Intermediate (Basal) Neural Progenitors (INPs), represses activation of the RA responsive element and expression of RA target genes in cell lines. This repressive action on RA signaling was functionally confirmed by the decrease of RA-mediated neuronal differentiation in neural stem cells stably overexpressing TBR2. In vivo mapping of RA activity in the developing cortex indicated that RA activity is detected in radial glial cells and subsequently downregulated in INPs, revealing a fine cell-type specific regulation of its signaling. Thus, TBR2 might be a molecular player in opposing RA signaling in INPs. Interestingly, this negative regulation is achieved at least in part by directly repressing the critical nuclear RA co-factor ZFP423. Indeed, we found ZFP423 to be expressed in the developing cortex and promote RA-dependent neuronal differentiation. These data indicate that TBR2 contributes to suppressing RA signaling in INPs, thereby enabling them to re-enter the cell cycle and delay neuronal differentiation.

Identification of novel loci affecting circulating chromogranins and related peptides.

Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (P = 3.40 × 10-30 for rs4253311 and 1.85 × 10-19 for rs2731672, respectively). Genes in these regions include the proteolytic enzymes kallikrein (KLKB1) and Factor XII (F12). In chromaffin cells, CHGA and KLKB1 proteins co-localized in catecholamine storage granules. In vitro, kallikrein cleaved recombinant human CHGA to catestatin, verified by mass spectrometry. The peptide identified from this digestion (CHGA360-373) selectively inhibited nicotinic cholinergic stimulated catecholamine release from chromaffin cells. A proteolytic cascade involving kallikrein and Factor XII cleaves chromogranins to active compounds both in vivo and in vitro.

Economic Evaluation of Stem Cell Therapies in Neurological Diseases: A Systematic Review.

OBJECTIVES: To examine economic evaluation studies of stem cell therapies (SCTs) in neurological disorders and to provide an overview of the quality of the economic evidence available on this topic. METHODS: The review examined studies that performed an economic evaluation of the use of stem cells in adult patients with neurological diseases and that were published in English during the period 2007 to 2017. Data analyzed and reported included study population, disease indication, main analytical approaches for the economic analysis and perspective, key assumptions made or tested in sensitivity analyses, cost outcomes, estimates of incremental cost effectiveness, and approaches to quantifying decision uncertainty. RESULTS: A total of three studies reporting on the findings of the economic evaluation of the use of SCT in stroke, Parkinson disease, and secondary progressive multiple sclerosis, respectively, were identified. All three studies conducted a cost-utility analysis using decision-analytic models and reported an incremental cost per quality-adjusted life-years gained (incremental cost-effectiveness ratio) versus standard care. These studies reported meaningful cost savings in stroke, Parkinson disease, and secondary progressive multiple sclerosis in the base-case scenarios. CONCLUSIONS: Despite significant progress in clinical research in the use of SCT in neurological diseases, economic evaluation of these therapies is still at a nascent stage. Given the early stage of research inputs (clinical and cost outcomes data) into the models per se, further research is urgently needed to enable meaningful assessment of the cost effectiveness of these advanced therapies and to ensure sustainable access for population groups most likely to benefit in clinical practice.

PERSPECTIVES: Stroke survivors' views on the design of an early-phase cell therapy trial for patients with chronic ischaemic stroke.

BACKGROUND: Stem cell research holds the potential for a paradigm shift in the management of diseases such as stroke. Patient and public involvement in research (PPIR) can bring a focus to issues of clinical relevance and accelerate translation to real-world clinical practice. OBJECTIVE: A qualitative thematic analysis of the perspectives of stroke survivors regarding the conduct and design aspects of a proposed phase I clinical cell therapy study in stroke. DESIGN: Twelve stroke survivors were purposively recruited in July 2016-August 2017 and participated in semi-structured, face-to-face interviews for input into the design of a proposed phase I clinical study of autologous dental pulp stem cells. Concurrent thematic analysis was conducted until data saturation was achieved. DISCUSSION AND CONCLUSIONS: Participants conveyed that the most relevant outcomes to them were regaining participation, decreased dependence on caregivers and improvement in cognition, memory, mood, pain and fatigue. The perception of risk vs. benefit was likely influenced by the time elapsed since stroke, with participants being more willing to accept a higher level of risk early in the post-stroke disease course. They believed that all stroke survivors should be given an opportunity to participate in research, irrespective of their cognitive capacity. A relatively small sample population of 12 stroke survivors was studied as thematic saturation was achieved. PERSPECTIVES study applied principles of PPIR to early-phase cell research. Incorporation of outcomes relevant to patients' need within the study design is critical to generate data that will enable personalized application of regenerative medicine in stroke.

Zfp423 Regulates Sonic Hedgehog Signaling via Primary Cilium Function.

Zfp423 encodes a 30-zinc finger transcription factor that intersects several canonical signaling pathways. Zfp423 mutations result in ciliopathy-related phenotypes, including agenesis of the cerebellar vermis in mice and Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) in humans. Unlike most ciliopathy genes, Zfp423 encodes a nuclear protein and its developmental expression is complex, leading to alternative proposals for cellular mechanisms. Here we show that Zfp423 is expressed by cerebellar granule cell precursors, that loss of Zfp423 in these precursors leads to cell-intrinsic reduction in proliferation, loss of response to Shh, and primary cilia abnormalities that include diminished frequency of both Smoothened and IFT88 localization. Loss of Zfp423 alters expression of several genes encoding key cilium components, including increased expression of Tulp3. Tulp3 is a direct binding target of Zfp423 and reducing the overexpression of Tulp3 in Zfp423-deficient cells suppresses Smoothened translocation defects. These results define Zfp423 deficiency as a bona fide ciliopathy, acting upstream of Shh signaling, and indicate a mechanism intrinsic to granule cell precursors for the resulting cerebellar hypoplasia.

Zika Virus and the Rio Olympic Games.

OBJECTIVE: To evaluate the impact of Zika virus on preparation and management of the New Zealand (NZ) Olympic team. DESIGN: Descriptive manuscript. SETTING: New Zealand Olympic Health team preparation and management during the Rio de Janeiro Olympic Games, 2016. PATIENTS (OR PARTICIPANTS): New Zealand Olympic Team members. INTERVENTIONS (OR ASSESSMENT OF RISK FACTORS): This manuscript describes the approaches used by the NZ Olympic Health team to the minimization of risk from Zika virus. MAIN OUTCOME MEASURES: Although descriptive of approach forms most of the article, the results of Zika virus serology are presented. RESULTS: The NZ Olympic Health team took a proactive approach to risk mitigation, including extensive education, clothing changes, mosquito spray, mosquito nets, and voluntary postexposure testing. No positive serology was observed in those tested. CONCLUSIONS: The outbreak of Zika virus in Brazil, the associated complication of microcephaly, and the evolving understanding of virus transmission created significant uncertainty for NZ Olympic team members. The proactive approach taken by the health team to the mitigation of risk, combined with the anticipated low risk of arbovirus transmission over the period of the games, resulted in enhanced confidence from team members and no reports of positive serology.

Genetic variation at 16q24.2 is associated with small vessel stroke.

OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. METHODS: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10-9 ). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10-5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10-7 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10-6 ). INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394.

New MRI muscle classification systems and associations with return to sport after acute hamstring injuries: a prospective study.

OBJECTIVES: To determine agreement between modified Peetrons, Chan acute muscle strain injury classification and British Athletics Muscle Injury Classification (BAMIC) and to investigate their associations and ability to predict time to return to sport (RTS). METHODS: Male athletes (n=176) with acute hamstring injury and MRI (1.5T) ≤5 days were followed until RTS. MRIs were scored using standardised forms. RESULTS: For MRI-positive injuries there was moderate agreement in severity grading (κ = 0.50-0.56). Substantial variance in RTS was demonstrated within and between MRI categories. Mean differences showed an overall main effect for severity grading (p < 0.001), but post hoc pairwise comparisons for BAMIC (grade 0a/b vs. 1, p = 0.312; 1 vs 2, p = 0.054; 0a/b vs 2, p < 0.001; 1 vs 3, p < 0.001) and mean differences for anatomical sites (BAMIC a-c, p < 0.001 [a vs b, p = 0.974; a vs c, p = 0.065; b vs c, p = 0.007]; Chan anatomical sites 1-5, p < 0.077; 2A-C, p = 0.373; 2a-e, p = 0.008; combined BAMIC, p < 0.001) varied. For MRI-positive injuries, total explained RTS variance was 7.6-11.9% for severity grading and BAMIC anatomical sites. CONCLUSIONS: There was wide overlap between/variation within the grading/classification categories. Therefore, none of the classification systems could be used to predict RTS in our sample of MRI-positive hamstring injuries. KEY POINTS: • Days to RTS varied greatly within the grading and classification categories. • Days to RTS varied greatly between the grading and classification categories. • Using MRI classification systems alone to predict RTS cannot be recommended. • The specific MRI classification used should be reported to avoid miscommunication.

Using microgels to control the morphology and optoelectronic properties of hybrid organic-inorganic perovskite films.

Microgels (MGs) are crosslinked polymer colloid particles that swell in a good solvent. Although MGs have been studied for over 80 years their ability to control the morphology and optoelectronic properties of composite films containing photoactive materials is in its infancy. Solution processable hybrid organic-inorganic perovskites such as CH3NH3PbI3-zClz have attracted enormous fundamental and applied interest because of their outstanding optoelectronic properties. There is considerable interest in establishing methods to control perovskite film morphology, for example, using micropatterning. Here, hydrophilic poly(N-vinylformamide)-based MGs were dispersed in perovskite precursor solution which was then spin coated to deposit CH3NH3PbI3-zClz/MG films for the first time. Remarkably, the CH3NH3PbI3-zClz/MG composites formed disordered inverse opal (DIO) films. The CH3NH3PbI3-zClz/MG composition ranges which gave DIO films are identified using a phase diagram. The pore wall thickness is shown to be controlled by the volume fraction of MGs used and a simple model is presented to explain this behaviour. The MGs not only caused CH3NH3PbI3-zClz to be more efficiently deposited but also increased light absorption and photoluminescence intensity. Demonstration solar cells constructed containing the DIO CH3NH3PbI3-zClz/MG films had an average conversion efficiency of 6.58 ± 0.81%. A mechanism for DIO film formation is discussed. The principles established in this study wherein MGs control the morphology and properties of CH3NH3PbI3-zClz/MG films should also apply to other perovskite/MG composites.

Nxf1 natural variant E610G is a semi-dominant suppressor of IAP-induced RNA processing defects.

Endogenous retroviruses and retrotransposons contribute functional genetic variation in animal genomes. In mice, Intracisternal A Particles (IAPs) are a frequent source of both new mutations and polymorphism across laboratory strains. Intronic IAPs can induce alternative RNA processing choices, including alternative splicing. We previously showed IAP I∆1 subfamily insertional mutations are suppressed by a wild-derived allele of the major mRNA export factor, Nxf1. Here we show that a wider diversity of IAP insertions present in the mouse reference sequence induce insertion-dependent alternative processing that is suppressed by Nxf1CAST alleles. These insertions typically show more modest gene expression changes than de novo mutations, suggesting selection or attenuation. Genome-wide splicing-sensitive microarrays and gene-focused assays confirm specificity of Nxf1 genetic modifier activity for IAP insertion alleles. Strikingly, CRISPR/Cas9-mediated genome editing demonstrates that a single amino acid substitution in Nxf1, E610G, is sufficient to recreate a quantitative genetic modifier in a co-isogenic background.

Nmf9 Encodes a Highly Conserved Protein Important to Neurological Function in Mice and Flies.

Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited null mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei. Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9. Intriguingly, homozygotes for null mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes. These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

Intramuscular tendon involvement on MRI has limited value for predicting time to return to play following acute hamstring injury.

BACKGROUND: Hamstring injury with intramuscular tendon involvement is regarded as a serious injury with a delay in return to play (RTP) of more than 50 days and reinjury rates up to 63%. However, this reputation is based on retrospective case series with high risk of bias. OBJECTIVE: Determine whether intramuscular tendon involvement is associated with delayed RTP and elevated rates of reinjury. METHODS: MRI of male athletes with an acute hamstring injury was obtained within 5 days of injury. Evaluation included standardised MRI scoring and scoring of intramuscular tendon involvement. Time to RTP and reinjury rate were prospectively recorded. RESULTS: Out of 70 included participants, intramuscular tendon disruption was present in 29 (41.4%) injuries. Injuries without intramuscular tendon disruption had a mean time to RTP of 22.2±7.4 days. Injuries with <50%, 50%-99% and 100% disruption of tendon cross-sectional area had a mean time to RTP of 24.0±9.7, 25.3±8.6 and 31.6±10.9 days, respectively. Injuries with full-thickness disruption took longer to RTP compared with injuries without disruption (p=0.025). Longitudinal intramuscular tendon disruption was not significantly associated with time to RTP. Waviness was present in 17 (24.3%) injuries. Mean time to RTP for injuries without and with waviness was 22.6±7.5 and 30.2±10.8 days (p=0.014). There were 11 (15.7%) reinjuries within 12 months, five (17.2%) in the group with intramuscular tendon disruption and six (14.6%) in the group without intramuscular tendon disruption. CONCLUSION: Time to RTP for injuries with full-thickness disruption of the intramuscular tendon and waviness is significantly longer (by slightly more than 1 week) compared with injuries without intramuscular tendon involvement. However, due to the considerable overlap in time to RTP between groups with and without intramuscular tendon involvement, its clinical significance for the individual athlete is limited.