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Exploring cellular changes in ruptured human quadriceps tendons at single-cell resolution.
Tendon ruptures in humans have often been studied during the chronic phase of injury, particularly in the context of rotator cuff disease. However, the early response to acute tendon ruptures remains less investigated. Quadriceps tendons, which require prompt surgical treatment, offer a model to investigate this early response. Therefore, this study aimed to explore the early cellular changes in ruptured compared to healthy human quadriceps tendons. Quadriceps tendon samples were collected from patients undergoing fracture repair (healthy) or tendon repair surgery (collected 7-8 days post-injury). Nuclei were isolated for single-nucleus RNA sequencing, and comprehensive transcriptomic analysis was conducted. The transcriptomes of 12,808 nuclei (7268 from healthy and 5540 from ruptured quadriceps tendons) were profiled, revealing 12 major cell types and several cell subtypes and states. Rupture samples showed increased expression of genes related to extracellular matrix organisation and cell cycle signalling, and a decrease in expression of genes in lipid metabolism pathways. These changes were predominantly driven by gene expression changes in the fibroblast, vascular endothelial cell (VEC), mural cell, and macrophage populations: fibroblasts shift to an activated phenotype upon rupture and there is an increase in the proportion of capillary and dividing VECs. A diverse immune environment was observed, with a shift from homeostatic to activated macrophages following rupture. Cell-cell interactions increased in number and diversity in rupture, and primarily involved fibroblast and VEC populations. Collectively, this transcriptomic analysis suggests that fibroblasts and endothelial cells are key orchestrators of the early injury response within ruptured quadriceps tendon. KEY POINTS: Tendon ruptures in humans have regularly been studied during the chronic phase of injury, but less is known about the early injury response after acute tendon ruptures. This study explored the early cellular changes in ruptured compared to healthy human quadriceps tendons at single-cell resolution. Fibroblasts and endothelial cells seem to be the key orchestrators of the early injury response within ruptured quadriceps tendon. Therefore, these cell types are obvious targets for interventions to enhance tendon healing. Overall, this study highlights that the development of more effective therapeutic options for tendon injury requires better understanding of the cellular, extracellular, and mechanical landscape of tendon tissue.
Striving to recover - wrist splint or plaster cast : a qualitative study of patients' experience of recovery after a distal radius fracture.
AIMS: We sought to explore patients' experience of early recovery from a fracture of the wrist (distal radius). This study was nested in the DRAFT-CASP randomized controlled trial (RCT), which explores the effectiveness of two treatment pathways for patients with a fracture of the distal radius that does not require manipulation: a plaster cast which is removed in fracture clinic, versus a wrist splint that patients remove themselves without returning to hospital. METHODS: Qualitative interviews were undertaken with 21 adults (mean age 58.2 years (SD 13.96), six male), from eight NHS hospitals, four to ten weeks post injury. Interviews were informed by phenomenology and analyzed using reflexive thematic analysis. RESULTS: We identified the overarching theme 'striving to recover', which conveys patients' determination to get back to normal after a wrist fracture. To recover, patients needed to be comfortable, to adapt, and to be certain that their wrist was healing. Early in their recovery, they were unable to complete their daily activities, experienced pain, loss of strength, worry, and were cautious about using their wrist. Overall, both treatments were considered acceptable. The splint was advantageous for the freedom and control it provided. The cast was valued for the protection and safety it provided. Both groups required more information and reassurance, but had varied views on the need for follow-up appointments. CONCLUSION: The splint made life easier for patients and was an acceptable treatment. Patients wanted reassurance that their wrist was healing, but they felt this could be achieved in a variety of ways. Most patients coped without a follow-up appointment. Innovative ways to maximize recovery are required. These include support for patients to, manage their pain and provide comfort, be able to adapt, and feel certain of healing. Sharing patients' experiences may help future patients to make informed treatment and recovery decisions.
Facilitating trial recruitment: A qualitative study of patient and staff experiences of an orthopaedic trauma trial
<jats:title>Abstract</jats:title> <jats:p>Background Qualitative research has been used to explore patients’ and healthcare professionals’ experiences of surgical randomised controlled trials (RCTs). From this research, reasons why patients accept or decline participation and barriers to engaging clinicians in trials have been identified. In a trauma setting, recruitment to surgical trials can be particularly difficult as patients may require urgent treatment and their ability to consider their options, ask questions and reach a decision may be hindered by the impact of their injury. Little research however, has explored patients’ and healthcare professionals’ experiences of surgical RCTs in a trauma setting. This study aimed to understand participants’ and staffs’ experiences of an orthopaedic trauma trial. Methods We carried out semi-structured interviews with 11 participants and 24 staff (10 surgeons and 14 research associates) participating in a UK multi-centre feasibility trial comparing intramedullary nails versus distal locking plates for fractures of the distal femur (TrAFFix). Interviews explored patients’ experience of TrAFFix and their reason for participating and staffs’ experience of recruiting to TrAFFix and trauma trials more generally. Interviews were audio recorded and transcribed verbatim. Transcripts were analysed using thematic analysis. Results Three themes were identified. These were i) navigating research with patients after orthopaedic trauma, ii) knowing that it is the right decision and iii) making it work. These themes reflect: i) how research associates supported and guided patients through the consent process enabling them to participate, ii) the difficulty in engaging surgeons in a trial when individual equipoise and experience of the interventions is low despite the presence of community equipoise and iii) the way in which research teams worked together and encouraged the development of a research culture within the clinical teams in order to facilitate recruitment. Conclusions Our findings highlight the pivotal role of research associates (RAs) in facilitating trial recruitment. RAs supported patients to enable them to make a decision about participation and assisted in developing a research culture within the team by promoting studies and communicating research to clinical staff. Our findings also reinforce surgeons’ difficulty with equipoise and suggest that accepting community equipoise could facilitate recruitment.</jats:p>
A phase 1b, multicentre, dose escalation, safety and pharmacokinetics study of tilvestamab (BGB149) in relapsed, platinum-resistant, high-grade serous ovarian cancer (PROC) patients.
BackgroundTilvestamab is a highly selective humanised immunoglobulin G1 anti-AXL monoclonal antibody. This phase 1 study evaluated its optimal dose, safety, tolerability, immunogenicity and pharmacokinetics (PK) in relapsed platinum-resistant HGSOC patients.MethodsPatients received tilvestamab in three dose levels (1 mg/kg, 3 mg/kg and 5 mg/kg) via IV infusion every 2 weeks. Primary objectives included safety, tolerability and PK. Exploratory objectives included overall response, progression-free survival (PFS) and quality-of-life measures. Pharmacodynamic included AXL expression, gene and protein changes by transcriptomic and proteomic analysis.ResultsBetween 25 February 2021 and 4 February 2022, 16 patients were enroled across 8 sites in Singapore, Korea, United Kingdom, and Norway. Median treatment duration was 6.1 weeks. Grade 3 or higher treatment-emergent adverse events occurred in 62.5% patients, but none were tilvestamab-related. Common events included fatigue (38%), anorexia (38%) infections (31%), anaemia (25%) and dyspnoea (25%). No objective responses were observed, but 7 (44%) had stable disease at 6 weeks. PK showed dose-proportional exposure and steady-state by the second dose. Pharmacodynamic analyses revealed reduced fibrosis-related gene signatures and AXL protein expression. Epithelial-mesenchymal transition reversal was seen in 2 patients.ConclusionTilvestamab was well-tolerated and further studies to examine the efficacy of AXL inhibition in other indications are required.Clinical trial registrationThis trial is registered at https://clinicaltrials.gov .Registration numberNCT04893551. EudraCT Number: 2020-001382-36.
A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding.
BACKGROUND: Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood. METHODS: To correlate systematically genetic, transcriptional and proteomic phenotypes, we conducted an integrative multi-omic approach utilising targeted DNA sequencing, RNA sequencing and proteomic methodologies, encompassing fibroid, myometrium, and endometrium tissues from 91 patients. RESULTS: In addition to confirming the presence of MED12 mutations, we identify variants in AHR and COL4A6. Multi-omic analysis of endometrium identifies latent factors that correlate with HMB and fibroid presence with driver mutations of MED12, AHR, and COL4A6, which are associated with pathways involved in angiogenesis, extracellular matrix organisation and RNA splicing. We propose a model, supported by in vivo evidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding. CONCLUSIONS: This study presents a comprehensive integrative approach, revealing that genetic alterations in UF may influence endometrial function via signalling impacts on the RNA splicing mechanism. Our findings advance the understanding of complex molecular pathways in UF pathogenesis and UF-associated endometrial dysfunction, offering insights for targeted therapeutic development.
Evaluation of the impact of artificial intelligence-assisted image interpretation on the diagnostic performance of clinicians in identifying endotracheal tube position on plain chest X-ray: a multi-case multi-reader study.
BACKGROUND: Incorrectly placed endotracheal tubes (ETTs) can lead to serious clinical harm. Studies have demonstrated the potential for artificial intelligence (AI)-led algorithms to detect ETT placement on chest X-Ray (CXR) images, however their effect on clinician accuracy remains unexplored. This study measured the impact of an AI-assisted ETT detection algorithm on the ability of clinical staff to correctly identify ETT misplacement on CXR images. METHODS: Four hundred CXRs of intubated adult patients were retrospectively sourced from the John Radcliffe Hospital (Oxford) and two other UK NHS hospitals. Images were de-identified and selected from a range of clinical settings, including the intensive care unit (ICU) and emergency department (ED). Each image was independently reported by a panel of thoracic radiologists, whose consensus classification of ETT placement (correct, too low [distal], or too high [proximal]) served as the reference standard for the study. Correct ETT position was defined as the tip located 3-7 cm above the carina, in line with established guidelines. Eighteen clinical readers of varying seniority from six clinical specialties were recruited across four NHS hospitals. Readers viewed the dataset using an online platform and recorded a blinded classification of ETT position for each image. After a four-week washout period, this was repeated with assistance from an AI-assisted image interpretation tool. Reader accuracy, reported confidence, and timings were measured during each study phase. RESULTS: 14,400 image interpretations were undertaken. Pooled accuracy for tube placement classification improved from 73.6 to 77.4% (p = 0.002). Accuracy for identification of critically misplaced tubes increased from 79.3 to 89.0% (p = 0.001). Reader confidence improved with AI assistance, with no change in mean interpretation time at 36 s per image. CONCLUSION: Use of assistive AI technology improved accuracy and confidence in interpreting ETT placement on CXR, especially for identification of critically misplaced tubes. AI assistance may potentially provide a useful adjunct to support clinicians in identifying misplaced ETTs on CXR.
Pharmacoepidemiologic Research Based on Common Data Models: Systematic Review and Bibliometric Analysis.
BACKGROUND: The adoption of common data models (CDMs) has transformed pharmacoepidemiologic research by enabling standardized data formatting and shared analytical tools across institutions. These models facilitate large-scale, multicenter studies and support timely real-world evidence generation. However, no comprehensive global evaluation of CDM applications in pharmacoepidemiology has been conducted. OBJECTIVE: This study aimed to conduct a systematic review and bibliometric analysis to map the landscape of CDM usage in pharmacoepidemiology, including publication trends, institutional authors and collaborations, and citation impacts. METHODS: In total, 5 English databases (PubMed, Web of Science, Embase, Scopus, and Virtual Health Library) and 4 Chinese databases (CNKI, Wan-Fang Data, VIP, and SinoMed) were searched for studies applying CDMs in pharmacoepidemiology from database inception to January 2024. Two reviewers independently screened studies and extracted information about basic publication details, methodological details, and exposure and outcome information. The studies were categorized into 2 groups according to their Total Citations per Year (TCpY), and a comparative analysis was conducted to examine the differences in characteristics between the 2 groups. RESULTS: A total of 308 studies published between 1997 and 2024 were included, involving 1580 authors across 32 countries and 140 journals. The United States led in both publication volume and citation counts, followed by South Korea. Among the 10 most cited studies, 7 used the Vaccine Safety Datalink, 2 used Sentinel, and one used Observational Medical Outcomes Partnership. Studies were stratified by TCpY to reduce citation bias from publication timing. Comparative analysis showed that high-TCpY studies were significantly more associated with multicenter collaboration (P=.008), United States-based institutions (P=.04), and vaccine-related research (P=.009). These studies commonly featured larger sample sizes, cross-regional data, and enhanced generalizability. International collaborations primarily occurred among North America, Europe, and East Asia, with limited involvement from limited-income countries. CONCLUSIONS: This study presents the first bibliometric overview of CDM-based pharmacoepidemiologic research. The consistent output from United States institutions and increasing engagement from South Korea underscore their central roles in this field. High-TCpY studies tend to be multicenter, collaborative, and vaccine-focused, reflecting structural factors linked to research visibility and influence. Stratified citation analysis supports the value of real-world data integration and international cooperation in producing impactful studies. The dominance of limited-income countries in collaboration networks highlights a need for broader inclusion of underrepresented regions. These findings can help researchers identify key contributors, guide partner selection, and target appropriate journals. As CDM-based methods continue to expand, fostering diverse and collaborative research efforts will be crucial for advancing pharmacoepidemiologic knowledge globally.
Association of a Healthy Lifestyle With All-Cause and Cause-Specific Mortality Among Individuals With Probable Sarcopenia: Population-Based Cohort Study.
BACKGROUND: Individuals with probable sarcopenia have shown excess mortality, yet no specific treatment regimen has been established. While lifestyle factors improve health and longevity in general populations, their role in probable patients with sarcopenia remains unclear due to differing lifestyle patterns. Clarifying this could inform strategies to address this unmet need. OBJECTIVE: We aim to quantify the impact of a healthy lifestyle on all-cause and cause-specific mortality in probable sarcopenic populations using a large-scale prospective cohort study. METHODS: Participants were selected from the UK Biobank, aged 40-69 years, during 2006-2010. Probable sarcopenia was identified according to EWGSOP2 (European Working Group on Sarcopenia in Older People 2) criteria, resulting in 20,654 participants being included in this study. Death dates and underlying causes were obtained from the National Health Service Information Center. Cox proportional hazard models and population-attributable risk were used to assess the associations between healthy lifestyle factors and premature mortality risk. RESULTS: A total of 20,654 individuals with probable sarcopenia were included in this study. The median age of the population was 62.0 (IQR 56.0-66.0) years, and 60.6% (n=12,528) were women. During a median follow-up duration of 11.5 (IQR 10.8-12.3) years, 2447 participants died. All healthy lifestyle factors, including nonsmoking (P
Randomised controlled trial of a behaviour change physiotherapy intervention to increase physical activity following hip and knee replacement: the PEP-TALK trial.
OBJECTIVE: To test the effectiveness of a behaviour change physiotherapy intervention to increase physical activity compared with usual rehabilitation after total hip replacement (THR) or total knee replacement (TKR). DESIGN: Multicentre, pragmatic, two-arm, open, randomised controlled, superiority trial. SETTING: National Health Service providers in nine English hospitals. PARTICIPANTS: 224 individuals aged ≥18 years, undergoing a primary THR or TKR deemed 'moderately inactive' or 'inactive'. INTERVENTION: Participants received either six, 30 min, weekly, group-based exercise sessions (usual care) or the same six weekly, group-based, exercise sessions each preceded by a 30 min cognitive behaviour discussion group aimed at challenging barriers to physical inactivity following surgery (experimental). RANDOMISATION AND BLINDING: Initial 75 participants were randomised 1:1 before changing the allocation ratio to 2:1 (experimental:usual care). Allocation was based on minimisation, stratifying on comorbidities, operation type and hospital. There was no blinding. MAIN OUTCOME MEASURES: Primary: University of California Los Angeles (UCLA) Activity Score at 12 months. Secondary: 6 and 12-month assessed function, pain, self-efficacy, kinesiophobia, psychological distress and quality of life. RESULTS: Of the 1254 participants assessed for eligibility, 224 were included (139 experimental: 85 usual care). Mean age was 68.4 years (SD: 8.7), 63% were women, 52% underwent TKR. There was no between-group difference in UCLA score (mean difference: -0.03 (95% CI -0.52 to 0.45, p=0.89)). There were no differences observed in any of the secondary outcomes at 6 or 12 months. There were no important adverse events in either group. The COVID-19 pandemic contributed to the reduced intended sample size (target 260) and reduced intervention compliance. CONCLUSIONS: There is no evidence to suggest attending usual care physiotherapy sessions plus a group-based behaviour change intervention differs to attending usual care physiotherapy alone. As the trial could not reach its intended sample size, nor a proportion of participants receive their intended rehabilitation, this should be interpreted with caution. TRIAL REGISTRATION NUMBER: ISRCTN29770908.
Platelet rich plasma injection for acute Achilles tendon rupture: PATH-2 randomised, placebo controlled, superiority trial.
OBJECTIVE: To determine whether an injection of platelet rich plasma improves outcomes after acute Achilles tendon rupture. DESIGN: Randomised, placebo controlled, two arm, parallel group, participant and assessor masked, superiority trial. SETTING: Secondary care trauma units across 19 hospitals in the United Kingdom's health service. PARTICIPANTS: Recruitment commenced in July 2015 and follow-up was completed in March 2018. 230 adults aged 18 years and over were included, with acute Achilles tendon rupture presenting within 12 days of injury and managed with non-surgical treatment. Exclusions were injury at the insertion or musculotendinous junction, major leg injury or deformity, diabetes mellitus, platelet or haematological disorder, systemic corticosteroids, anticoagulation treatment, and other contraindicating conditions. INTERVENTIONS: Participants were randomised 1:1 to platelet rich plasma (n=114) or placebo (dry needle; n=116) injection. All participants received standard rehabilitation care (ankle immobilisation followed by physiotherapy). MAIN OUTCOMES AND MEASURES: Primary outcome was muscle tendon function at 24 weeks, measured objectively with the limb symmetry index (injured/uninjured×100) in maximal work done during the heel rise endurance test (an instrumented measure of repeated single leg heel rises until fatigue). Secondary outcomes included patient reported function (Achilles tendon rupture score), quality of life (short form 12 version 2®), pain (visual analogue scale), goal attainment (patient specific functional scale), and adverse events. A central laboratory analysed the quality and content of platelet rich plasma. Analyses were by modified intention to treat. RESULTS: Participants were 46 years old on average, and 57 (25%) of 230 were female. At 24 weeks, 202 (88%) participants completed the heel rise endurance test and 216 (94%) the patient reported outcomes. The platelet rich plasma was of good quality, with expected growth factor content. No difference was detected in muscle tendon function between participants receiving platelet rich plasma injections and those receiving placebo injections (limb symmetry index, mean 34.7% (standard deviation 17.7%) v 38.5% (22.8%); adjusted mean difference -3.9% (95% confidence interval -10.5% to 2.7%)) or in any secondary outcomes or adverse event rates. Complier average causal effect analyses gave similar findings. CONCLUSIONS: There is no evidence to indicate that injections of platelet rich plasma can improve objective muscle tendon function, patient reported function, or quality of life after acute Achilles tendon rupture compared with placebo, or that they offer any patient benefit. TRIAL REGISTRATION: ISRCTN54992179.
O-substituted alkyl aldehydes for rhodium-catalyzed intermolecular alkyne hydroacylation: the utility of methylthiomethyl ethers.
Combining α-methylthiomethyl (MTM) ether substituted aldehydes and 1-alkynes in the presence of [Rh(dppe)]ClO(4) results in efficient intermolecular alkyne hydroacylation to deliver α-O-MTM-substituted enone products. The product MTM ethers can be converted to the free hydroxyl group either in situ, by the addition of water to the completed reaction, or in a separate operation, by the action of silver nitrate.
Platelet-rich plasma in Achilles tendon healing 2 (PATH-2) trial: statistical analysis plan for a multicentre, double-blinded, parallel-group, placebo-controlled randomised clinical trial.
BACKGROUND: There has been a recent steep growth in platelet-rich plasma (PRP) use for musculoskeletal conditions, but findings from high quality clinical trial data are lacking in the literature. Here, we describe the statistical analysis plan (SAP) for the Platelet-rich plasma in Achilles Tendon Healing 2 (PATH-2) trial. METHODS: PATH-2 is a pragmatic, parallel-group, multi-centre, double-blinded, randomised, placebo-controlled, superiority trial. The study aims to evaluate the clinical efficacy of PRP in acute Achilles tendon rupture in terms of muscle-tendon function. Patients are identified in the orthopaedic/trauma outpatient clinic. The primary outcome is muscle-tendon work capacity from the Heel Rise Endurance Test result, expressed as the Limb Symmetry Index (work, in joules), at 24 weeks post randomisation. Multivariate linear regression adjusting for the stratification factors (centre and age) and additional prognostic factors will be used to investigate the adjusted effect of the intervention. The analysis will be by modified intention-to-treat. Sensitivity analysis will assess the internal validity of the trial results by performing a per-protocol analysis. Safety will be summarised by treatment arm for all patients who started treatment. Secondary patient-reported outcome measures will be analysed using linear mixed effects models to allow all data collected at all follow-up points to be considered. Missing data will be summarised and reported by treatment arm. Missing data imputation will be performed, if appropriate. DISCUSSION: The PATH-2 trial will be reported in accordance with the CONSORT statement. This SAP publication will avoid bias arising from prior knowledge of the study results. Any changes or deviations from the current SAP will be described and justified in the final report. TRIAL REGISTRATION: ISRCTN registry: ISRCTN54992179 , assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850.
SWAT 110: Printing the primary outcomE on Pink PapER versus standard paper to increase participant engagement to postal questionnaires (PEPPER)
Background: Missing data is a common issue in randomised controlled trials. There is a need to rigorously test means of participant retention. This embedded trial aims to examine the effect on postal response rates of printing a randomised controlled trial’s primary outcome on pink versus white paper. Methods: Our randomised Study Within A Trial (SWAT) was run within a behaviour-change intervention host trial for patients following hip or knee replacements. Participants were randomised to receive the host trial’s primary outcome measure printed on either a sheet of pink or white paper within the 11 sheet (21 page) six-month follow-up questionnaire. The SWAT’s primary outcome was host trial primary outcome measure completion. Number of reminders sent, proportion of remaining questions completed and overall questionnaire returns were secondary outcomes. Results: 176 participants were randomised: 88 received pink paper, 88 white paper. Host trial primary outcome measures were returned by 84.1% (74/88 participants) in the pink paper group and in 90.9% (80/88 participants) in the white paper group (risk ratio, 0.92 [95% CI 0.80, 1.06]; p=0.24). Reminders were sent to 48.9% (43/88 participants) in the pink paper group and in 30.7% (27/88 participants) in the white paper group (risk ratio 1.59 [95% CI 1.09, 2.33]; p=0.01). No other results were statistically significant. Conclusion: Printing the primary outcome on pink paper does not increase data return. From this small randomised study, there is some evidence that it potentially decreases response and is more burdensome to collect postal data by increasing the necessity for reminders.
Characteristics of L-PRP preparations for treating Achilles tendon rupture within the PATH-2 study.
Platelet-rich plasma (PRP) is an autologous preparation that has been claimed to improve healing and mechanobiological properties of tendons both in vitro and in vivo. In this sub-study from the PATH-2 (PRP in Achilles Tendon Healing-2) trial, we report the cellular and growth factor content and quality of the Leukocyte-rich PRP (L-PRP) (N = 103) prepared using a standardized commercial preparation method across 19 different UK centers. Baseline whole blood cell counts (red cells, leukocyte and platelets) demonstrated that the two groups were well-matched. L-PRP analysis gave a mean platelet count of 852.6 x 109/L (SD 438.96), a mean leukocyte cell count of 15.13 x 109/L (SD 10.28) and a mean red blood cell count of 0.91 x 1012/L (SD 1.49). The activation status of the L-PRP gave either low or high expression levels of the degranulation marker CD62p before and after ex-vivo platelet activation respectively. TGF-β, VEGF, PDGF, IGF and FGFb mean concentrations were 131.92 ng/ml, 0.98 ng/ml, 55.34 ng/ml, 78.2 ng/ml and 111.0 pg/ml respectively with expected correlations with both platelet and leukocyte counts. While PATH-2 results demonstrated that there was no evidence L-PRP is effective for improving clinical outcomes at 24 weeks after Achilles tendon rupture, our findings support that the majority of L-PRP properties were within the method specification and performance.