Laser welding of fiber array units.

We report the results of fabricating fiber array unit (FAU) connectors using a near IR laser welding process, locking fibers in proper position on planar glass substrates and forming strong glass-to-glass bonds, followed by final assembly using lower coefficient of thermal expansion (CTE) epoxies. A thin metal film deposited on the glass substrate provides the absorption required to attain interfacial temperatures suitable for glass-to-glass bonding. This method allows the elimination of dedicated expensive V-groove plates while still maintaining very good fiber placement accuracy. The use of epoxy is minimized to simply securing macro packaging components and protecting fibers from environmental pressure, temperature, and humidity variation. The thermal expansion properties of the epoxy used were essential for the long-term FAU reliability.

Incretin-based investigational therapies for the treatment of MASLD/MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease. It exists as either simple steatosis or its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), formerly, non-alcoholic steatohepatitis (NASH). The global prevalence of MASLD is estimated to be 32% among adults and is projected to continue to rise with increasing rates of obesity, type 2 diabetes, and metabolic syndrome. While simple steatosis is often considered benign and reversible, MASH is progressive, potentially leading to the development of cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of MASH is therefore directed at slowing, stopping, or reversing the progression of disease. Evidence points to improved liver histology with therapies that result in sustained body weight reduction. Incretin-based molecules, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptor agonists, have shown benefit here, and several are under investigation for MASLD/MASH treatment. In this review, we discuss current published data on GLP-1, GIP/GLP-1, GLP-1/glucagon, and GLP-1/GIP/glucagon RAs in MASLD/MASH, focusing on their efficacy on liver histology, liver fat, and MASH biomarkers.

Exploring stakeholders' perspectives on antibiogram use, development, and implementation in residential aged care settings.

BACKGROUND: Knowledge of local antibiotic resistance data provided by antibiograms (cumulative-antimicrobial-susceptibility-tests) can assist prescribers to make appropriate empirical antibiotic choices. OBJECTIVE: This study explored the perceptions and knowledge of key stakeholders about the role of antibiograms in residential aged care facilities (RACF), and to understand barriers and enablers of antibiogram development and implementation in this setting. METHOD: Semi-structured interviews were conducted with aged-care health professionals ('end-users') and antibiogram content experts. This study was conducted in Queensland, Australia in 2023. Using qualitative techniques, framework thematic analysis was used to identify themes, which were mapped to the 'Integrated Promoting Action on Research Implementation in Health Services' framework constructs. RESULTS: Twenty interviews were conducted comprising of five 'content-experts' and fifteen 'end-users'. Five themes were identified which indicated lack of knowledge about how to use antibiograms, and its availability. Potential insufficient data was the primary issue identified by content experts with regards to feasibility of annual antibiograms. Pragmatic solutions were offered, such as pooling pathology data from facilities in the same geographical location, extending antibiogram data to two-or three-yearly, or utilising local hospital antibiograms. Presenting antibiogram data in a mode and format suiting preferences of individual users would encourage uptake and improve usability. Antimicrobial stewardship (AMS) champions and pharmacists were highlighted as drivers of educating and promoting antibiogram use. CONCLUSION: Clinicians recognised the potential role of antibiograms in improving empirical antibiotic prescribing choices. Establishing their baseline knowledge provides an essential starting point for the education needs of this group. This study provides practical recommendations regarding the presentation of antibiograms to ensure appropriate use and uptake as an AMS tool in RACFs. Pragmatic solutions suggested to overcome challenges of antibiogram development for RACFs should be applied and evaluated to determine feasibility of RACF-specific antibiograms.

The virtual dermatopathology mentorship.

The Covid pandemic necessitated changes in traditional mentorship and educational roles. We offer our experience in structuring a virtual dermatopathology mentorship in the midst of the pandemic. Virtual mentorships have many benefits including ease of access, lack of geographic restrictions, and financial savings, though there still remains an important and irreplaceable role for in-person relationships.

Development and internal validation of a dynamic fall risk prediction and monitoring tool in aged care using routinely collected electronic health data: a landmarking approach.

OBJECTIVES: Falls pose a significant challenge in residential aged care facilities (RACFs). Existing falls prediction tools perform poorly and fail to capture evolving risk factors. We aimed to develop and internally validate dynamic fall risk prediction models and create point-based scoring systems for residents with and without dementia. MATERIALS AND METHODS: A longitudinal cohort study using electronic data from 27 RACFs in Sydney, Australia. The study included 5492 permanent residents, with a 70%-30% split for training and validation. The outcome measure was the incidence of falls. We tracked residents for 60 months, using monthly landmarks with 1-month prediction windows. We employed landmarking dynamic prediction for model development, a time-dependent area under receiver operating characteristics curve (AUROCC) for model evaluations, and a regression coefficient approach to create point-based scoring systems. RESULTS: The model identified 15 independent predictors of falls in dementia and 12 in nondementia cohorts. Falls history was the key predictor of subsequent falls in both dementia (HR 4.75, 95% CI, 4.45-5.06) and nondementia cohorts (HR 4.20, 95% CI, 3.87-4.57). The AUROCC across landmarks ranged from 0.67 to 0.87 for dementia and from 0.66 to 0.86 for nondementia cohorts but generally remained between 0.75 and 0.85 in both cohorts. The total point risk score ranged from -2 to 57 for dementia and 0 to 52 for nondementia cohorts. DISCUSSION: Our novel risk prediction models and scoring systems provide timely person-centered information for continuous monitoring of fall risk in RACFs. CONCLUSION: Embedding these tools within electronic health records could facilitate the implementation of targeted proactive interventions to prevent falls.

An Interval Throwing Program for Baseball Pitchers Based upon Workload Data.

Background: Interval throwing programs (ITP) have been used for decades to enable baseball pitchers to return to competition after injury or surgery by gradually applying load to the throwing arm. Past programs have been based on personal experience; however, advances in our understanding of the biomechanics and workloads of throwing allow for a more modern data-based program to be developed. Hypothesis/Purpose: To 1) develop a updated ITP for rehabilitation of modern baseball pitchers based upon biomechanical and throwing workload data, and 2) compare the updated program with a past program to determine differences in chronic workload and acute:chronic workload ratios (ACWR). Study Design: Cross-sectional study. Methods: Workloads (i.e. daily, acute, chronic, and ACWR) for the original ITP were built from the prescribed throwing schedule. Elbow varus torque per throw was calculated based upon a relationship between elbow varus torque and throwing distance. Throw counts, daily/chronic/acute workloads, and ACWR were calculated and plotted over time. A new ITP was built to model current pitcher's throwing schedules and gradually increased ACWR over time. Results: The original ITP had a throwing schedule of 136 days, final chronic workload 15.0, and the ACWR above or below the "safe" range (i.e. 0.7 - 1.3) for 18% of the program with a peak of 1.61. The updated ITP was built to consist of a 217-day schedule, final chronic workload of 10.8, and deviated from the safe range for 9% of the program, with a peak of 1.33. Conclusion: The newly created ITP is more familiar to modern baseball pitchers while exhibiting a more gradual buildup of chronic workload than traditional ITP programs. This ITP may be used to return baseball pitchers back to competition as safely and efficiently as possible, and potentially with less risk of setbacks or reinjury. The ITP may be used following common injuries or surgeries to the throwing shoulder and elbow, such as Tommy John surgery, while also serving as a basis for future development of shorter duration ITPs. Level of Evidence: 2c.

Symposium summary: epigenetic inheritance-impact for biology and society 23-25 August 2023, Zürich, Switzerland.

The possibility that acquired traits can be transmitted across generations has been the subject of intense research in the past decades. This biological process is of major interest to many scientists and has profound implications for biology and society but has complex mechanisms and is therefore challenging to study. Because it involves factors independent from the DNA sequence, this form of heredity is classically referred to as epigenetic inheritance. Many studies have examined how life experiences and various environmental factors can cause phenotypes that are heritable and be manifested in subsequent generations. Recognizing the major importance and complexity of this research, the fourth edition of the Epigenetic Inheritance Symposium Zürich brought together experts from diverse disciplines to address current questions in the field of epigenetic inheritance and present recent findings. The symposium had sessions dedicated to epidemiological evidence and animal models, transmission mechanisms, methodologies and the far-reaching impact on society and evolution. This report summarizes the talks of speakers and describes additional activities offered during the symposium including poster sessions and an art competition on the topic of epigenetic inheritance.

Prognostic factors for overall survival of conventional osteosarcoma of the appendicular skeleton.

Aims: The aim of this study is to determine the predictors of overall survival (OS) and predictive factors of poor prognosis of conventional high-grade osteosarcoma of the limbs in a single-centre in South Africa. Methods: We performed a retrospective cross-sectional analysis to identify the prognostic factors that predict the OS of patients with histologically confirmed high-grade conventional osteosarcoma of the limbs over ten years. We employed the Cox proportional regression model and the Kaplan-Meier method for statistical analysis. Results: This study comprised 77 patients at a three-year minimum follow-up. The predictors of poor OS were: the median age of ≤ 19 years (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.92 to 0.99; p = 0.021); median duration of symptoms ≥ five months (HR 0.91; 95% CI 0.83 to 0.99; p < 0.037); metastasis at diagnosis (i.e. Enneking stage III) (HR 3.33; 95% CI 1.81 to 6.00; p < 0.001); increased alkaline phosphatase (HR 3.28; 95% CI 1.33 to 8.11; p < 0.010); palliative treatment (HR 7.27; 95% CI 2.69 to 19.70); p < 0.001); and amputation (HR 3.71; 95% CI 1.12 to 12.25; p < 0.032). In contrast, definitive surgery (HR 0.11; 95% CI 0.03 to 0.38; p < 0.001) and curative treatment (HR 0.18; 95% CI 0.10 to 0.33; p < 0.001) were a protective factor. The Kaplan-Meier median survival time was 24 months, with OS of 57.1% at the three years. The projected five-year event-free survival was 10.3% and OS of 29.8% (HR 0.76; 95% CI 0.52 to 1.12; p = 0.128). Conclusion: In this series of high-grade conventional osteosarcoma of the appendicular skeleton from South Africa, 58.4% (n = 45) had detectable metastases at presentation; hence, an impoverished OS of five years was 29.8%. Large-scale future research is needed to validate our results.

Identification and information management of cognitive impairment of patients in acute care hospitals: An integrative review.

Objectives: Recognition of the cognitive status of patients is important so that care can be tailored accordingly. The objective of this integrative review was to report on the current practices that acute care hospitals use to identify people with cognitive impairment and how information about cognition is managed within the healthcare record as well as the approaches required and recommended by policies. Methods: Following Whittemore & Knafl's five-step method, we systematically searched Medline, CINAHL, and Scopus databases and various grey literature sources. Articles relevant to the programs that have been implemented in acute care hospitals regarding the identification of cognitive impairment and management of cognition information were included. The Mixed Methods Appraisal Tool and AACODS (Authority, Accuracy, Coverage, Objectivity, Date, Significance) Checklist were used to evaluate the quality of the studies. Thematic analysis was used to present and synthesise results. This review was pre-registered on PROSPERO ( CRD42022343577). Results: Twenty-two primary studies and ten government/industry publications were included in the analysis. Findings included gaps between practice and policy. Although identification of cognitive impairment, transparency of cognition information, and interaction with patients, families, and carers (if appropriate) about this condition were highly valued at a policy level, sometimes in practice, cognitive assessments were informal, patient cognition information was not recorded, and interactions with patients, families, and carers were lacking. Discussion: By incorporating cognitive assessment, developing an integrated information management system using information technology, establishing relevant laws and regulations, providing education and training, and adopting a national approach, significant improvements can be made in the care provided to individuals with cognitive impairment.

Outcomes of surgically managed adult traumatic brachial plexus injuries in an upper-middle-income country.

Background: Traumatic brachial plexus injuries (TBPIs) are debilitating and complex to treat. The last five decades have seen advances in surgical management, and consequently improved functional outcomes in patients with these injuries. There is limited data available describing the outcomes of surgically managed TBPIs within the South African context. This study aimed to identify the common causes of injury, injury characteristics, and functional outcomes of surgically managed patients with TBPIs. Methods: We conducted a retrospective chart review of all adult patients that underwent surgery for TBPIs over a period of ten years at a specialised hand unit in South Africa. The minimum follow-up period was one year. Patient demographic details, injury characteristics and functional outcomes were collected. Statistical analysis was performed to determine factors associated with functional outcomes. A good functional outcome for recovery was defined as a Medical Research Council (MRC) grade of three or more for the affected elements of the plexus at the most recent follow-up. Results: Forty-seven patients of median age 32 years were included in the final analysis. Most patients were male (87.2 %). The majority of patients were injured in motor vehicle accidents (MVAs) or from penetrating stab wounds (48.9 % and 38.3 % respectively). The median pre-operative MRC grade of the affected elements of the brachial plexus was 0.0, and post-operatively was 2.0. Fourteen patients (14 of 47, 29.8 %) had a good outcome and 33 had a poor outcome (33 of 47, 70.2 %). There was no difference in outcome comparing penetrating injury mechanisms to closed traction or blunt injuries, (p = 0.386, OR 1.75, 95 % CI 0.49-6.20). All patients with pan-plexal injuries had a poor outcome (15 of 33, 46 %). All patients who received intercostal (6 of 33, 18 %) or phrenic nerve transfers (3 of 33, 9 %) had a poor outcome. Conclusion: Adult traumatic BPIs in this South African sample typically presented more than two months after injury and were comprised of a high proportion of penetrating injuries. Just under a third of surgically managed patients had a good outcome. Pan plexal injuries have uniformly poor outcomes. We recommend early referral for all TBPIs to a unit that manages BPI to improve outcomes.

Unveiling breast cancer metastasis through an advanced X-ray imaging approach.

Breast cancer is a significant global health burden, causing a substantial number of deaths. Systemic metastatic tumour cell dissemination is a major cause of poor outcomes. Understanding the mechanisms underlying metastasis is crucial for effective interventions. Changes in the extracellular matrix play a pivotal role in breast cancer metastasis. In this work, we present an advanced multimodal X-ray computed tomography, by combining Small-angle X-ray Scattering Tensor Tomography (SAXS-TT) and X-ray Fluorescence Computed Tomography (XRF-CT). This approach likely brings out valuable information about the breast cancer metastasis cascade. Initial results from its application on a breast cancer specimen reveal the collective influence of key molecules in the metastatic mechanism, identifying a strong correlation between zinc accumulation (associated with matrix metalloproteinases MMPs) and highly oriented collagen. MMPs trigger collagen alignment, facilitating breast cancer cell intravasation, while iron accumulation, linked to angiogenesis and vascular endothelial growth factor VEGF, supports cell proliferation and metastasis. Therefore, these findings highlight the potential of the advanced multimodal X-ray computed tomography approach and pave the way for in-depth investigation of breast cancer metastasis, which may guide the development of novel therapeutic approaches and enable personalised treatment strategies, ultimately improving patient outcomes in breast cancer management.

Quantifying the proportion of different cell types in the human cortex using DNA methylation profiles.

BACKGROUND: Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the proportion of different cell types using DNA methylation data. Here, we validate and profile the use of an expanded reference DNA methylation dataset incorporating two neuronal and three glial cell subtypes for quantifying the cellular composition of the human cortex. RESULTS: We tested eight reference panels containing different combinations of neuronal- and glial cell types and characterised their performance in deconvoluting cell proportions from computationally reconstructed or empirically derived human cortex DNA methylation data. Our analyses demonstrate that while these novel brain deconvolution models produce accurate estimates of cellular proportions from profiles generated on postnatal human cortex samples, they are not appropriate for the use in prenatal cortex or cerebellum tissue samples. Applying our models to an extensive collection of empirical datasets, we show that glial cells are twice as abundant as neuronal cells in the human cortex and identify significant associations between increased Alzheimer's disease neuropathology and the proportion of specific cell types including a decrease in NeuNNeg/SOX10Neg nuclei and an increase of NeuNNeg/SOX10Pos nuclei. CONCLUSIONS: Our novel deconvolution models produce accurate estimates for cell proportions in the human cortex. These models are available as a resource to the community enabling the control of cellular heterogeneity in epigenetic studies of brain disorders performed on bulk cortex tissue.

The quality of care delivered to residents in long-term care in Australia: an indicator-based review of resident records (CareTrack Aged study).

BACKGROUND: This study estimated the prevalence of evidence-based care received by a population-based sample of Australian residents in long-term care (LTC) aged ≥ 65 years in 2021, measured by adherence to clinical practice guideline (CPG) recommendations. METHODS: Sixteen conditions/processes of care amendable to estimating evidence-based care at a population level were identified from prevalence data and CPGs. Candidate recommendations (n = 5609) were extracted from 139 CPGs which were converted to indicators. National experts in each condition rated the indicators via the RAND-UCLA Delphi process. For the 16 conditions, 236 evidence-based care indicators were ratified. A multi-stage sampling of LTC facilities and residents was undertaken. Trained aged-care nurses then undertook manual structured record reviews of care delivered between 1 March and 31 May 2021 (our record review period) to assess adherence with the indicators. RESULTS: Care received by 294 residents with 27,585 care encounters in 25 LTC facilities was evaluated. Residents received care for one to thirteen separate clinical conditions/processes of care (median = 10, mean = 9.7). Adherence to evidence-based care indicators was estimated at 53.2% (95% CI: 48.6, 57.7) ranging from a high of 81.3% (95% CI: 75.6, 86.3) for Bladder and Bowel to a low of 12.2% (95% CI: 1.6, 36.8) for Depression. Six conditions (skin integrity, end-of-life care, infection, sleep, medication, and depression) had less than 50% adherence with indicators. CONCLUSIONS: This is the first study of adherence to evidence-based care for people in LTC using multiple conditions and a standardised method. Vulnerable older people are not receiving evidence-based care for many physical problems, nor care to support their mental health nor for end-of-life care. The six conditions in which adherence with indicators was less than 50% could be the focus of improvement efforts.

The surgical management of fracture-related infection. Surgical strategy selection and the need for early surgical intervention.

The aim of this narrative review is to describe the various surgical management strategies employed in fracture-related infection (FRI), to explore how they are selected and discuss the rationale for early surgical intervention. Surgical treatment options in patients with FRI include debridement, antibiotics and implant retention (DAIR), revision (exchange) or removal. In selecting a treatment strategy, a variety of factors need to be considered, including the condition of the bone, soft tissues, host and causative microorganism. Irrespective of the selected treatment strategy, prompt surgical intervention should be considered in order to confirm the diagnosis of an FRI, to identify the causative organism, remove necrotic or non-viable tissue that can serve as a nidus for ongoing infection, ensure a healthy soft tissue envelope and to prevent the vicious cycle of infection associated with skeletal and/or implant instability. Ultimately, the objective is to prevent the establishment of a persistent infection. Urgent surgery may be indicated in case of active, progressive disease with systemic deterioration, local progression of infection, deterioration of soft tissues, or progressive fracture instability. In case of static disease, the patient should be monitored closely and surgery can be performed on an elective basis, allowing adequate time for optimisation of the host through risk factor modification, optimisation of the soft tissues and careful planning of the surgery.

Feasibility and Validity of In-Home Self-Collected Capillary Blood Spot Screening for Type 1 Diabetes Risk.

Aims: Self-collection of a blood sample for autoantibody testing has potential to facilitate screening for type 1 diabetes risk. We sought to determine the feasibility and acceptability of this approach and the performance of downstream antibody assays. Methods: People living with type 1 diabetes and their family members (N = 97) provided paired capillary blood spot and serum samples collected, respectively, by themselves and a health worker. They provided feedback on the ease, convenience, and painfulness of blood spot collection. Islet antibodies were measured in blood spots by antibody detection by agglutination PCR (ADAP) or multiplex enzyme-linked immunoassay (ELISA), and in serum by radioimmunoassay (RIA) or ELISA. Results: Using serum RIA and ELISA to define antibody status, 50 antibody-negative (Abneg) and 47 antibody-positive (Abpos) participants enrolled, of whom 43 and 47, respectively, returned testable blood spot samples. The majority indicated that self-collection was easier, more convenient, and less painful than formal venesection. The sensitivity and specificity for detection of Abpos by blood spot were, respectively, 85% and 98% for ADAP and 87% and 100% for multiplex ELISA. The specificities by ADAP for each of the four antigen specificities ranged from 98% to 100% and areas under the receiver operator curve from 0.841 to 0.986. Conclusions: Self-collected blood spot sampling is preferred over venesection by research participants. ADAP and multiplex ELISA are highly specific assays for islet antibodies in blood spots with acceptable performance for use alone or in combination to facilitate screening for type 1 diabetes risk. Clinical Trial Registration number: ACTRN12620000510943.

Clinical impact of antibiograms as an intervention to optimize antimicrobial prescribing and patient outcomes-A systematic review.

BACKGROUND: Antimicrobial stewardship (AMS) guidelines advocate for the use of antibiograms (cumulative antimicrobial susceptibility test data) as a tool to guide empirical antibiotic prescribing and inform local treatment guidelines. The objective of this review is to evaluate the effectiveness of antibiograms as an intervention to optimize antimicrobial prescribing and patient outcomes. METHODS: Embase, PubMed, CINAHL, and International Pharmacy Abstracts (IPA) databases were searched from inception until September 2022, to identify studies of antibiogram-related interventions in all health care settings. The National Institutes of Health Quality Assessment Tools were used to assess the methodological quality of the included studies. RESULTS: Of the 37 included studies, the majority of studies were conducted in the United States (n = 25) and in hospital settings (n = 27). All interventions were multifaceted and in 26 (70%) studies, facility-specific antibiograms could be considered as an integral component of the interventions. A positive impact on antibiotic consumption trends (17 studies), appropriateness of prescribing (16 studies), and cost of treatment (6 studies) was found, with minimal evidence for improvement in mortality, hospitalization, and resistance profiles. Due to the heterogeneity in study designs and outcomes, a meta-analysis was not performed. CONCLUSIONS: AMS interventions including antibiograms may improve antibiotic use, appropriateness, and costs. Multifaceted interventions were often used, which precludes drawing conclusions about the effectiveness of antibiograms alone as an AMS tool.

Impact of Positive Cultures During the Second Stage of a Two-Stage Exchange: Systematic Review and Meta-Analysis.

BACKGROUND: Two-stage exchange is a frequently performed procedure in patients who have a periprosthetic joint infection. Positive cultures when performing the second stage are perceived as a risk factor for reinfection. This study aimed to determine the impact of positive cultures during the second stage on the outcome of patients undergoing a 2-stage septic exchange and the impact of stopping the antibiotic treatment before reimplantation. METHODS: We systematically searched four databases. We performed a meta-analysis on the risk of complications after positive cultures during second stage and a subgroup analysis by antibiotic holiday period. We included 24 studies. RESULTS: Failure in the positive group was 37.0% and in the negative group was 13.7% with an odds ratio (OR) of 4.05. In the subgroup analysis by antibiotic holidays, failure rate without holidays was 15% and with holidays was 17.3% (P = .21). Failure in each group was higher when cultures were positive (without holidays, 25 versus 12.2%, P = .0003, and with holidays 41.1 versus 12.7%, P < .0001), but the risk of failure when cultures were positive was higher in the holiday group (OR 4.798) than in the nonholiday group (OR 2.225) in comparison to those patients who were culture negative at the second stage. CONCLUSIONS: Microbiological eradication at second stage was not obtained in 18% of cases and it was associated with a higher failure rate. In patients with positive cultures, withholding antibiotic treatment was associated with lower failure rate. Further studies to define the antibiotic strategy in 2-stage exchange procedure are necessary.

Key aspects of soft tissue management in fracture-related infection: recommendations from an international expert group.

A judicious, well-planned bone and soft tissue debridement remains one of the cornerstones of state-of-the-art treatment of fracture-related infection (FRI). Meticulous surgical excision of all non-viable tissue can, however, lead to the creation of large soft tissue defects. The management of these defects is complex and numerous factors need to be considered when selecting the most appropriate approach. This narrative review summarizes the current evidence with respect to soft tissue management in patients diagnosed with FRI. Specifically we discuss the optimal timing for tissue closure following debridement in cases of FRI, the need for negative microbiological culture results from the surgical site as a prerequisite for definitive wound closure, the optimal type of flap in case of large soft tissue defects caused by FRI and the role of negative pressure wound therapy (NPWT) in FRI. Finally, recommendations are made with regard to soft tissue management in FRI that should be useful for clinicians in daily clinical practice.Level of evidence Level V.

Micro- and nanostructure specific X-ray tomography reveals less matrix formation and altered collagen organization following reduced loading during Achilles tendon healing.

Recovery of the collagen structure following Achilles tendon rupture is poor, resulting in a high risk for re-ruptures. The loading environment during healing affects the mechanical properties of the tendon, but the relation between loading regime and healing outcome remains unclear. This is partially due to our limited understanding regarding the effects of loading on the micro- and nanostructure of the healing tissue. We addressed this through a combination of synchrotron phase-contrast X-ray microtomography and small-angle X-ray scattering tensor tomography (SASTT) to visualize the 3D organization of microscale fibers and nanoscale fibrils, respectively. The effect of in vivo loading on these structures was characterized in early healing of rat Achilles tendons by comparing full activity with immobilization. Unloading resulted in structural changes that can explain the reported impaired mechanical performance. In particular, unloading led to slower tissue regeneration and maturation, with less and more disorganized collagen, as well as an increased presence of adipose tissue. This study provides the first application of SASTT on soft musculoskeletal tissues and clearly demonstrates its potential to investigate a variety of other collagenous tissues. STATEMENT OF SIGNIFICANCE: Currently our understanding of the mechanobiological effects on the recovery of the structural hierarchical organization of injured Achilles tendons is limited. We provide insight into how loading affects the healing process by using a cutting-edge approach to for the first time characterize the 3D micro- and nanostructure of the regenerating collagen. We uncovered that, during early healing, unloading results in a delayed and more disorganized regeneration of both fibers (microscale) and fibrils (nanoscale), as well as increased presence of adipose tissue. The results set the ground for the development of further specialized protocols for tendon recovery.