Peptide probes for proteases - innovations and applications for monitoring proteolytic activity.

Proteases are excellent biomarkers for a variety of diseases, offer multiple opportunities for diagnostic applications and are valuable targets for therapy. From a chemistry-based perspective this review discusses and critiques the most recent advances in the field of substrate-based probes for the detection and analysis of proteolytic activity both in vitro and in vivo.

Dielectric perturbations: anomalous resonance frequency shifts in optical resonators.

Small perturbations in the dielectric environment around resonant dielectric structures usually lead to a frequency shift of the resonator modes directly proportional to the polarizability of the perturbation. Here, we report experimental observations of strong frequency shifts that can oppose and even exceed the contribution of the perturbations' polarizability. We show in particular how the mode frequencies of a lithium niobate whispering-gallery-mode resonator are shifted by planar substrates-of refractive indices ranging from 1.50 to 4.22-contacting the resonator rim. Both blue- and redshifts are observed, as well as an increase in mode linewidth, when substrates are moved into the evanescent field of the whispering gallery mode. We compare the experimental results to a theoretical model by Foreman et al. [J. Opt. Soc. Am. B33, 2177 (2016)JOBPDE0740-322410.1364/JOSAB.33.002177] and provide an additional intuitive explanation based on the Goos-Hänchen shift for the optical domain, with applications to dielectric structures ranging from meta-surfaces to photonic crystal cavities.

A Dual Killing Strategy: Photocatalytic Generation of Singlet Oxygen with Concomitant PtIV Prodrug Activation.

A ruthenium-based mitochondrial-targeting photosensitiser that undergoes efficient cell uptake, enables the rapid catalytic conversion of PtIV prodrugs into their active PtII counterparts, and drives the generation of singlet oxygen was designed. This dual mode of action drives two orthogonal cancer-cell killing mechanisms with temporal and spatial control. The designed photosensitiser was shown to elicit cell death of a panel of cancer cell lines including those showing oxaliplatin-resistance.

Investigations and management of complex congenital talipes equinovarus.

Congenital talipes equinovarus (CTEV) is a congenital deformity affecting the feet, commonly idiopathic in nature. We present a previously unreported cause of a non-idiopathic clubfoot and highlight the importance of poor response to initial treatment.A poor response to Ponseti serial casting for CTEV should alert a clinician to the fact that the foot may not be in the 'idiopathic' group and be of a more complex nature. Idiopathic clubfoot should correct with a maximum of eight serial manipulations, cast applications and Achilles tendon tenotomy. If this is not the case, a repeat careful history, full examination, further investigations and review of the treatment method are required.

The combination of atomoxetine and dronabinol for the treatment of obstructive sleep apnea: a dose-escalating, open-label trial.

STUDY OBJECTIVES: The potential sedative effect of dronabinol and the high expression of cannabinoid receptors on the hypoglossal motor nuclei makes this agent a good candidate for obstructive sleep apnea (OSA) pharmacotherapy to be tested with atomoxetine, a noradrenergic reuptake inhibitor that reduced OSA severity in combination with oxybutynin. Here we tested the effect of atomoxetine 80 mg plus dronabinol (Ato-Dro) at 2 different doses (5 and 10 mg) vs. baseline and atomoxetine alone in a 2-center, open-label, dose-escalating trial. The primary outcome was the effect of Ato-Dro vs. baseline on OSA severity (apnea-hypopnea index, hypopneas associated with 4% oxygen desaturation). Safety of the combination and self-reported outcomes were also assessed. METHODS: Fifteen patients with OSA received progressively increasing Ato-Dro doses (dose escalation was performed every week, starting from Ato-Dro 40-2.5 mg, then 80-5 mg and finally 80-10 mg). A clinical, in-lab polysomnography was performed at baseline, on Ato-Dro 80-5 and Ato-Dro 80-10 mg. RESULTS: Ato-Dro 80-10 mg did not significantly reduce apnea-hypopnea index, hypopneas associated with 4% oxygen desaturation, and hypoxic burden and yielded limited clinical benefit vs. baseline and atomoxetine alone. However, Ato-Dro 80-5 mg did improve OSA severity (Δapnea-hypopnea index = 8.3[0.3, 16.3] events/h; mean [confidence interval]; Δhypoxic burden = 37.7[12.5, 62.7] %min/h) and multiple self-reported outcomes vs. baseline and/or atomoxetine alone. Ato-Dro administration was characterized by several potentially harmful side effects and treatment discontinuation in 1/3 of cases. CONCLUSIONS: Ato-Dro 80-5 mg might be useful to reduce OSA severity and lead to self-reported improvement in those who could tolerate the combination. However, given the numerous side effects and the exploratory nature of this open-label study, our results warrant further validation in larger trials. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Study for Efficacy and Dose Escalation of AD313 + Atomoxetine (SEED) (SEED); URL: https://clinicaltrials.gov/ct2/show/NCT05101122; Identifier: NCT05101122. CITATION: Messineo L, Norman D, Ojile J. The combination of atomoxetine and dronabinol for the treatment of obstructive sleep apnea: a dose-escalating, open-label trial. J Clin Sleep Med. 2023;19(7):1183-1190.

Medical consequences and associations with untreated sleep-related breathing disorders and outcomes of treatments.

Sleep-related breathing disorders are a broad group of disorders that include obstructive sleep apnea, central sleep apnea, and periodic breathing disorders. This article reviews the scientific literature that links SRBD to various medical conditions including hypertension, coronary artery disease, cardiac arrhythmias, stroke, diabetes mellitus, obesity, and depression. Pathophysiologic mechanisms by which SRBD may contribute to these disorders will be discussed, as will data on the degree to which treatment of SRBD may improve these conditions.

Irisin-A Pancreatic Islet Hormone.

Irisin is a myokine involved in glucose homeostasis. It is primarily expressed in skeletal muscle, but also in the pancreas. This study aimed to elucidate its presence and role in the islets of Langerhans-i.e., its effect on insulin and glucagon secretion as well as on blood flow in the pancreas. The precursor of irisin, fibronectin type III domain-containing protein 5 (FNDC5), was identified in rat and human islets by both qPCR and immunohistochemistry. Both α- and ß-cells stained positive for FNDC5. In human islets, we found that irisin was secreted in a glucose-dependent manner. Neither irisin nor an irisin-neutralizing antibody affected insulin or glucagon secretion from human or rat islets in vitro. The insulin and glucagon content in islets was not altered by irisin. The intravenous infusion of irisin in Sprague Dawley rats resulted in nearly 50% reduction in islet blood flow compared to the control. We conclude that irisin is an islet hormone that has a novel role in pancreatic islet physiology, exerting local vascular effects by diminishing islet blood flow without affecting insulin secretion per se.

Personalized Data Science and Personalized (N-of-1) Trials: Promising Paradigms for Individualized Health Care.

The term 'data science' usually refers to the process of extracting value from big data obtained from a large group of individuals. An alternative rendition, which we call personalized data science (Per-DS), aims to collect, analyze, and interpret personal data to inform personal decisions. This article describes the main features of Per-DS, and reviews its current state and future outlook. A Per-DS investigation is of, by, and for an individual, the Per-DS investigator, acting simultaneously as her own investigator, study participant, and beneficiary, and making personalized decisions for study design and implementation. The scope of Per-DS studies may include systematic monitoring of physiological or behavioral patterns, case-crossover studies for symptom triggers, pre-post trials for exposure-outcome relationships, and personalized (N-of-1) trials for effectiveness. Per-DS studies produce personal knowledge generalizable to the individual's future self (thus benefiting herself) rather than knowledge generalizable to an external population (thus benefiting others). This endeavor requires a pivot from data mining or extraction to data gardening, analogous to home gardeners producing food for home consumption-the Per-DS investigator needs to 'cultivate the field' by setting goals, specifying study design, identifying necessary data elements, and assembling instruments and tools for data collection. Then, she can implement the study protocol, harvest her personal data, and mine the data to extract personal knowledge. To facilitate Per-DS studies, Per-DS investigators need support from community-based, scientific, philanthropic, business, and government entities, to develop and deploy resources such as peer forums, mobile apps, 'virtual field guides,' and scientific and regulatory guidance.

Australian hospital paediatricians and nurses' perspectives and practices for influenza vaccine delivery in children with medical comorbidities.

INTRODUCTION: Influenza vaccination of children with medical comorbidities is critical due their increased risks for severe influenza disease. In Australia, hospitals are an avenue for influenza vaccine delivery to children with comorbidities but are not always effectively utilised. Qualitative enquiry sought to ascertainment the barriers and enablers for influenza vaccination recommendation, delivery, and recording of these children at Australian hospitals. METHODS: Semi-structured interviews and discussion group sessions were conducted with paediatricians and nurses at four tertiary paediatric specialist hospitals and two general community hospitals in three Australian states. Transcripts from interviews and group sessions were inductively analysed for themes. The Capability, Opportunity, Motivation, and Behaviour (COM-B) model was used to explore the elements of each theme and identify potential interventions to increase influenza vaccination recommendation and delivery behaviours by providers. RESULTS: Fifteen discussion sessions with 28 paediatricians and 26 nurses, and nine in-depth interviews (five paediatricians and four nurses) were conducted. Two central thematic domains were identified: 1. The interaction between hospital staff and parents/patients for influenza vaccine recommendation, and 2. Vaccination delivery and recording in the hospital environment. Six themes across these domains emerged detailing the importance of dedicated immunisation services, hospital leadership, paediatricians' vaccine recommendation role, the impact of comorbidities, vaccination recording, and cocooning vaccinations. Supportive hospital leadership, engaged providers, and dedicated immunisation services were identified as essential for influenza vaccination of children with comorbidities in Australian hospital. CONCLUSION: Recommendation of influenza vaccination for Australian children with comorbidities is impacted by the beliefs of paediatricians and the perceived impact of influenza disease on children's comorbidities. Dedicated immunisation services and supportive hospital leadership were drivers for influenza vaccine delivery at hospitals. Future interventions targeting hospital-based influenza vaccine delivery for children with comorbidities should take a rounded approach targeting providers' attitudes, the hospital environment and leadership support.

Influenza hospitalizations in Australian children 2010-2019: The impact of medical comorbidities on outcomes, vaccine coverage, and effectiveness.

BACKGROUND: Children with comorbidities are at greater risk of severe influenza outcomes compared with healthy children. In Australia, influenza vaccination was funded for those with comorbidities from 2010 and all children aged <5 years from 2018. Influenza vaccine coverage remains inadequate in children with and without comorbidities. METHODS: Children ≤16 years admitted with acute respiratory illness and tested for influenza at sentinel hospitals were evaluated (2010-2019). Multivariable regression was used to identify predictors of severe outcomes. Vaccine effectiveness was estimated using the modified incidence density test-negative design. RESULTS: Overall, 6057 influenza-confirmed hospitalized cases and 3974 test-negative controls were included. Influenza A was the predominant type (68.7%). Comorbidities were present in 40.8% of cases. Children with comorbidities were at increased odds of ICU admission, respiratory support, longer hospitalizations, and mortality. Specific comorbidities including neurological and cardiac conditions increasingly predisposed children to severe outcomes. Influenza vaccine coverage in influenza negative children with and without comorbidities was low (33.5% and 17.9%, respectively). Coverage improved following introduction of universal influenza vaccine programs for children <5 years. Similar vaccine effectiveness was demonstrated in children with (55% [95% confidence interval (CI): 45; 63%]) and without comorbidities (57% [(95%CI: 44; 67%]). CONCLUSIONS: Comorbidities were present in 40.8% of influenza-confirmed admissions and were associated with more severe outcomes. Children with comorbidities were more likely experience severe influenza with ICU admission, mechanical ventilation, and in-hospital morality. Despite demonstrated vaccine effectiveness in those with and without comorbidities, vaccine coverage was suboptimal. Interventions to increase vaccination are expected to reduce severe influenza outcomes.

CART decreases islet blood flow, but has no effect on total pancreatic blood flow and glucose tolerance in anesthetized rats.

Cocaine- and amphetamine-regulated transcript (CART) is a neurotransmitter and hormone, involved in the regulation of e.g. food intake, body weight, reward and addiction, and stress response. CART has also been found to affect insulin secretion and beta cell morphology, both in vivo and in vitro. Furthermore, CART affects regulation of the cardiovascular system and helps to modulate vascular tone. The present study evaluated the local effect of CART on the pancreatic and islet circulation and function. CART (25 µg/h) or saline, combinations of CART and endothelin-A receptor antagonist (BQ123; 100 µg/kg), and glucose (2 g/kg) were intravenously infused in Sprague Dawley rats followed by blood flow measurements using a microsphere technique. Separately, CART-infused animals underwent an intravenous glucose tolerance test (ivGTT). The direct effect of CART on insulin release was investigated using isolated islets from Sprague Dawley rats. CART reduced islet blood flow, without reduction in total pancreatic blood flow. The normal glucose-induced islet blood flow increase was diminished by CART, albeit still present. Simultaneously, CART had no effect on systemic-, intestinal- or renal blood flow. The endothelin-A receptor antagonist BQ123 together with CART had no pancreatic vascular effects. We found that CART has pronounced vascular constrictive actions restricted to the pancreatic islet circulation but had no effect on insulin release neither in vivo nor in vitro. The mechanisms behind the vascular effects are still unknown, but may reflect a direct action on pancreatic blood vessels.

Improving Influenza Vaccination in Children With Comorbidities: A Systematic Review.

CONTEXT: Children with medical comorbidities are at greater risk for severe influenza and poorer clinical outcomes. Despite recommendations and funding, influenza vaccine coverage remains inadequate in these children. OBJECTIVE: We aimed to systematically review literature assessing interventions targeting influenza vaccine coverage in children with comorbidities and assess the impact on influenza vaccine coverage. DATA SOURCES: PubMed, Scopus, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Allied and Complementary Medicine Database, and Web of Science databases were searched. STUDY SELECTION: Interventions targeting influenza vaccine coverage in children with medical comorbidities. DATA EXTRACTION: Two reviewers independently screened articles, extracting studies' methods, interventions, settings, populations, and results. Four reviewers independently assessed risk of bias. RESULTS: From 961 screened articles, 35 met inclusion criteria. Published studies revealed that influenza vaccine coverage was significantly improved through vaccination reminders and education directed at either patients' parents or providers, as well as by vaccination-related clinic process changes. Interventions improved influenza vaccine coverage by an average 60%, but no significant differences between intervention types were detected. Significant bias and study heterogeneity were also identified, limiting confidence in this effect estimate. LIMITATIONS: A high risk of bias and overall low quality of evidence limited our capacity to assess intervention types and methods. CONCLUSIONS: Interventions were shown to consistently improve influenza vaccine coverage; however, no significant differences in coverage between different intervention types were observed. Future well-designed studies evaluating the effectiveness of different intervention are required to inform future optimal interventions.

A rare case report of an ilio-psoas abscess due to entero-retroperitoneal fistula from gallstones post cholecystectomy.

INTRODUCTION AND IMPORTANCE: This is a novel case of a 50-year-old female presenting with several months of left iliac fossa pain, on a background of a cholecystectomy 5 years prior. The aetiology of her pain was an ilio-psoas abscess secondary to an entero-retroperitoneal gallstone fistula, a condition not previously reported in the literature. CASE PRESENTATION: CT imaging revealed an abscess superior to the left psoas muscle, with a clear fistula to the small bowel and two calcified stones at the site of the fistula. The patient was managed operatively, with the fistula disconnected and a 5 cm section of small bowel disconnected. CLINICAL DISCUSSION: This is a novel case whereby a left sided iliopsoas abscess occurred due to entero-retroperitoneal fistulation of gallstones several years after the patient underwent laparoscopic cholecystectomy. Gallstone fistulation from within the small bowel does not appear to have previously been documented and the exact pathogenesis is unknown. CONCLUSION: Gallstones should remain an important, albeit rare, differential diagnosis of small bowel fistulation and abscess formation following cholecystectomy.

Bilateral inguinoscrotal hernia with gastric contents and subsequent perforation: Lessons in operative management.

INTRODUCTION: Inguinoscrotal hernias often contain bowel, but it is rare to see it contain part or all of the stomach. These patients tend to present in extremis. PRESENTATION OF CASE: This is the case of a 74 year old gentleman who presented in obstruction and acutely unwell from giant bilateral inguinoscrotal hernias. CT scan confirmed the left hernia contained the majority of the bowel and stomach. He underwent laparotomy and repair of the left sided hernia. Intraoperatively he was also found to have a gastric perforation and underwent distal gastrectomy. 7 days post operatively he returned to theatre for repair of his right sided hernia. The patient made a full recovery. DISCUSSION: Review of similar literature highlights numerous surgical methods in repairing these hernias. A two-stage approach appears to mitigate the risk of abdominal compartment syndrome, whilst also allowing for an interval hernia repair in a non-hostile environment. Gastric perforation repair technique also varies, with majority of literature reporting primary repair. CONCLUSION: We hope our approach to management can help guide others faced with similar challenging cases. Moreover, it highlights some operative challenges including dealing with associated gastric perforation and mitigating the risk of abdominal compartment syndrome.

Caregiver's attitudes, beliefs, and experiences for influenza vaccination in Australian children with medical comorbidities.

BACKGROUND: Influenza vaccination is recommended and funded for Australian children with medical comorbidities that increase their risk of severe influenza. Despite this, influenza vaccine coverage remains low within this population. We examined caregivers' attitudes and practices for influenza vaccination in children with medical comorbidities. METHODS: Cross-sectional surveys were conducted with caregivers of children (6 months to <18 years old) with medical comorbidities attending sub-speciality paediatric outpatient clinics at the Royal Children's Hospital (Melbourne), Princess Margaret Hospital (Perth), and Leading Steps private paediatric clinic (Gold Coast). Multivariate linear regression was used to identify surveys responses predictive of receipt of influenza vaccination in 2017. RESULTS: From the 611 surveys collected, 556 were suitable for analysis. Caregiver reported 2017 influenza vaccine coverage was 52.2% in children with medical comorbidities. Caregivers who believed influenza vaccines to be ≥50% effective were more likely to vaccinate their children (adjusted Odds Ratio [aOR]:3.79 (2.41; 5.96). Those who expressed concerns about vaccine side effects were less likely to vaccinate their children (aOR: 0.49 [95% CI: 0.30; 0.80]). Influenza vaccine uptake was significantly more likely for children who had been previously recommended influenza vaccination by their hospital-based physician (aOR: 4.33 [95% CI: 2.58; 7.27]) and had previously received a hospital-based vaccination (aOR: 3.11 [95% CI 1.79; 5.40]). Hospital-based physicians were also caregivers' most commonly reported source of trusted vaccination information (63.5%). Whilst only 29.3% of caregivers reported their child had been recommended influenza vaccination during a previous admission, 80.1% of caregivers stated they were receptive to their child receiving potential future influenza vaccinations during hospitalisations. CONCLUSIONS: Reported influenza vaccination coverage in children with medical comorbidities remains inadequate. An important finding of this study is that influenza vaccination recommendation by children's hospital physicians and previous vaccine receipt in hospital was associated with vaccine uptake. Opportunities for vaccination, especially during hospitalisation, must be examined.

Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea.

STUDY OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a disorder that often presents with elevated serum aminotransferase levels. Although it has classically been linked with the metabolic syndrome, recent studies suggest NAFLD may also be associated with obstructive sleep apnea (OSA). This study evaluates the association between serum aminotransferase levels and factors connected with: either the metabolic syndrome (elevated body mass index [BMI], lipid profile, blood pressure, fasting glucose), or with OSA severity (apnea hypopnea index, lowest oxygen saturation level, oxygen desaturation index, percent of time below 90% saturation [%T<90]). DESIGN: Retrospective case series. PATIENTS AND SETTING: 109 adult patients with OSA at a university hospital general clinical research center. MEASUREMENTS AND RESULTS: Markers of hypoxia (lowest oxygen saturation level and %T<90), correlated significantly with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (Pearson's r = -0.31 to -0.38, P <0.003), while apnea hypopnea index, body mass index, blood pressure, fasting glucose, triglyceride, and cholesterol levels did not. Hierarchical linear regression was then done to determine the best predictors of aminotransferase levels. Markers of metabolic syndrome were entered as one block and markers of sleep apnea as another. Regression analyses explained 16.3% of the variance in AST and 18.9% of the variance in ALT, with %T<90 playing the largest role. CONCLUSIONS: In patients with obstructive sleep apnea, serum aminotransferase levels are better predicted by markers of oxygen desaturation than by factors traditionally associated with the metabolic syndrome.

Obstructive sleep apnea in older adults.

The "typical" presentation of obstructive sleep apnea (OSA) is chronic loud snoring and excessive daytime sleepiness in middle-aged obese men. OSA can result in increased risk for cardiovascular morbidity and mortality. The diagnostic features of OSA in older adults are similar to those in younger adults; however, the older adult may be less likely to seek medical attention or have the sleep disorder recognized because symptoms of snoring, sleepiness, fatigue, nocturia, unintentional napping, and cognitive dysfunction may be ascribed to the aging process itself or to other disorders. This article reviews the basic terminology and pathophysiology of sleep-disordered breathing, discusses why OSA may be even more prevalent in older adults than in the middle-aged group, and reviews similarities and differences between the two groups in the manifestations, consequences, and treatments of OSA.

Electrodrugs: an electrochemical prodrug activation strategy.

The term electroceutical has been used to describe implanted devices that deliver electrical stimuli to modify biological function. Herein, we describe a new concept in electroceuticals, demonstrating for the first time the electrochemical activation of metal-based prodrugs. This is illustrated by the controlled activation of Pt(iv) prodrugs into their active Pt(ii) forms within a cellular context allowing selectivity and control of where, when and how much active drug is generated.

Inflammation and sleep in healthy individuals.

STUDY OBJECTIVES: Inflammation is relatively common in individuals with a sleep disorder and is associated with quality of sleep. The purpose of this study was to examine whether inflammation is associated with quality of sleep in healthy individuals. DESIGN & SETTING: Observational study in a General Clinical Research Center. PARTICIPANTS: This study characterized inflammation and polysomno-graphically verified sleep in 124 African American and Caucasian American women and men without a sleep disorder. MEASUREMENTS AND RESULTS: Circulating levels of 3 markers and/or mediators of inflammation known to be elevated in sleep disorders and in cardiovascular disease were determined (interleukin-6 [IL-6] endothelin-1 [ET-1], soluble intercellular adhesion molecule-1 [sICAM-1]). Sleep was characterized by polysomnography. Multiple linear regression analyses showed that increasing age, male sex, and African American ethnicity were independently associated with poorer sleep. After controlling for these variables, higher levels of ET-1 were independently associated with greater sleep latency (P < or = 0.01), greater rapid eye movement (REM) latency (P < or = 0.01), more slow wave sleep (P < or = 0.05), and less stage 1 sleep (P < or = 0.01). Higher IL-6 levels were independently associated with greater REM latency (P < or = 0.05). CONCLUSIONS: The findings suggest that, in individuals without a known sleep disorder, ET-1, a potent vasoconstrictor and mediator of inflammation, is associated with more deep sleep, whereas both ET-1 and IL-6 are associated with increased latency of sleep and of REM. The findings underscore the complex relationships between peripheral markers of inflammation and sleep.

Cortical Bony Thickening of the Lateral Intercondylar Wall: The Functional Attachment of the Anterior Cruciate Ligament.

BACKGROUND: The anatomy of the anterior cruciate ligament (ACL) has become the subject of much debate. There has been extensive study into attachment points of the native ligament, especially regarding the femoral attachment. Some of these studies have suggested that fibers in the ACL are of differing functional importance. Fibers with higher functional importance would be expected to exert larger mechanical stress on the bone. According to Wolff's law, cortical thickening would be expected in these areas. PURPOSE: To examine cortical thickening in the region of the ACL footprint (ie, the functional footprint of the ACL). STUDY DESIGN: Descriptive laboratory study. METHODS: Using micro-computed tomography with resolutions ranging from 71 to 91 µm, the cortical thickness of the lateral wall of the intercondylar notch in 17 cadaveric knees was examined, along with surface topography. After image processing, the relationship between the cortical thickening and surface topology was visually compared. RESULTS: A pattern of cortical thickening consistent with the functional footprint of the ACL was found. On average, this area was 3 times thicker than the surrounding bone and significantly thicker than the remaining lateral wall ( P < .0001). This thickening was roughly elliptical in shape (with a mean centroid at 23.5 h:31 t on a Bernard and Hertel grid) and had areas higher on the wall where greater thickness was present. The relationship to previously reported osseous landmarks was variable, although the patterns were broadly consistent with those reported in previous studies describing direct and indirect fibers of the ACL. CONCLUSION: The findings of this study are consistent with those of recent studies describing fibers in the ACL of differing functional importance. The area in which the thickening was found has been defined and is likely to represent the functional footprint of the ACL. CLINICAL RELEVANCE: This information is of value to surgeons when determining the optimal place to position the femoral attachment site of the reconstructed ACL.