Sharks Provide Evidence for a Highly Complex TNFSF Repertoire in the Jawed Vertebrate Ancestor.

Cytokines of the TNF superfamily (TNFSF) control many immunological processes and are implicated in the etiology of many immune disorders and diseases. Despite their obvious biological importance, the TNFSF repertoires of many species remain poorly characterized. In this study, we perform detailed bioinformatic, phylogenetic, and syntenic analyses of five cartilaginous fish genomes to identify their TNFSF repertoires. Strikingly, we find that shark genomes harbor ∼30 TNFSF genes, more than any other vertebrate examined to date and substantially more than humans. This is due to better retention of the ancestral jawed vertebrate TNFSF repertoire than any other jawed vertebrate lineage, combined with lineage-specific gene family expansions. All human TNFSFs appear in shark genomes, except for lymphotoxin-α (LTA; TNFSF1) and TNF (TNFSF2), and CD70 (TNFSF7) and 4-1BBL (TNFSF9), which diverged by tandem duplications early in tetrapod and mammalian evolution, respectively. Although lacking one-to-one LTA and TNF orthologs, sharks have evolved lineage-specific clusters of LTA/TNF co-orthologs. Other key findings include the presence of two BAFF (TNFSF13B) genes along with orthologs of APRIL (TNFSF13) and BALM (TNFSF13C) in sharks, and that all cartilaginous fish genomes harbor an ∼400-million-year-old cluster of multiple FASLG (TNFSF6) orthologs. Finally, sharks have retained seven ancestral jawed vertebrate TNFSF genes lost in humans. Taken together, our data indicate that the jawed vertebrate ancestor possessed a much larger and diverse TNFSF repertoire than previously hypothesized and oppose the idea that the cartilaginous fish immune system is "primitive" compared with that of mammals.

EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis.

OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological management of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). METHODS: A task force comprising 7 rheumatologists, 15 other healthcare professionals and 3 patients was established. Following a systematic literature review performed to inform the recommendations, statements were formulated, discussed during online meetings and graded based on risk of bias assessment, level of evidence (LoE) and strength of recommendation (SoR; scale A-D, A comprising consistent LoE 1 studies, D comprising LoE 4 or inconsistent studies), following the European Alliance of Associations for Rheumatology standard operating procedure. Level of agreement (LoA; scale 0-10, 0 denoting complete disagreement, 10 denoting complete agreement) was determined for each statement through online voting. RESULTS: Four overarching principles and 12 recommendations were developed. These concerned common and disease-specific aspects of non-pharmacological management. SoR ranged from A to D. The mean LoA with the overarching principles and recommendations ranged from 8.4 to 9.7. Briefly, non-pharmacological management of SLE and SSc should be tailored, person-centred and participatory. It is not intended to preclude but rather complement pharmacotherapy. Patients should be offered education and support for physical exercise, smoking cessation and avoidance of cold exposure. Photoprotection and psychosocial interventions are important for SLE patients, while mouth and hand exercises are important in SSc. CONCLUSIONS: The recommendations will guide healthcare professionals and patients towards a holistic and personalised management of SLE and SSc. Research and educational agendas were developed to address needs towards a higher evidence level, enhancement of clinician-patient communication and improved outcomes.

The impact of ankle haemarthropathy in patients with moderate haemophilia.

INTRODUCTION: Moderate haemophilia has traditionally been associated with less complications than severe haemophilia. Changes in treatment recommendations have highlighted the burden of moderate haemophilia with a subset of patients with a severe bleeding phenotype. The ankle joint is disproportionally affected by ankle haemarthropathy however the impact has not been evaluated in moderate haemophilia, nor the effect on health related quality of life (HRQoL) or foot and ankle outcomes. AIMS: To establish the impact of ankle haemarthropathy in patients with moderate haemophilia. METHODS: A multicentre questionnaire study recruited patients from 11 haemophilia centres in England, Scotland and Wales. The HAEMO-QoL-A and Manchester-Oxford foot and ankle questionnaire (MOXFQ) with total and domain scores measured impact. Measures of pain and ankle haemophilia joint health (HJHS) scores were also collected. RESULTS: Twenty-nine participants were recruited. HAEMO-QoL A mean (SD) total scores of 10.8 (5.2) of 100 (best health) and foot and ankle specific MOXFQ total scores of 45.5 (24.7) above zero (best outcome) indicate poor HRQoL and foot and ankle outcomes. Average ankle pain over past 6 months of (0-10) 5.5 (SD2.5) was reported and median (IQR) ankle HJHS of 3.0 (1;12.5) to 4.5 (0;9.5) for the left and right ankles. CONCLUSION: HRQoL and foot and ankle specific outcomes are poor in patients with moderate haemophilia and ankle haemarthropathy, driven by chronic levels of ankle joint pain. Despite moderate haemophilia being considered less affected by haemarthrosis and haemarthropathy, patients with a bleeding or haemarthropathy phenotype are clinically similar to patients with severe haemophilia A.

Supporting patients to prepare for total knee replacement: Evidence-, theory- and person-based development of a 'Virtual Knee School' digital intervention.

INTRODUCTION: Digital delivery of pre-operative total knee replacement (TKR) education and prehabilitation could improve patient outcomes pre- and post-operatively. Rigorously developing digital interventions is vital to help ensure they achieve their intended outcomes whilst mitigating their potential drawbacks. OBJECTIVE: To develop a pre-operative TKR education and prehabilitation digital intervention, the 'Virtual Knee School' (VKS). METHODS: The VKS was developed using an evidence-, theory- and person-based approach. This involved a mixed methods design with four phases. The first three focused on planning the VKS. The final phase involved creating a VKS prototype and iteratively refining it through concurrent think-aloud interviews with nine patients who were awaiting/had undergone TKR. Meta-inferences were generated by integrating findings from all the phases. ISRCTN registration of the overall project was obtained on 24 April 2020 (ISRCTN11759773). RESULTS: Most participants found the VKS prototype acceptable overall and considered it a valuable resource. Conversely, a minority of participants felt the prototype's digital format or content did not meet their individual needs. Participants' feedback was used to refine the prototype's information architecture, design and content. Two meta-inferences were generated and recommend: 1. Comprehensive pre-operative TKR education and prehabilitation support should be rapidly accessible in digital and non-digital formats. 2. Pre-operative TKR digital interventions should employ computer- and self-tailoring to account for patients' individual needs and preferences. CONCLUSIONS: Integrating evidence, theory and stakeholders' perspectives enabled the development of a promising VKS digital intervention for patients awaiting TKR. The findings suggest future research evaluating the VKS is warranted and provide recommendations for optimising pre-operative TKR care. PATIENT OR PUBLIC CONTRIBUTION: Patient and Public Involvement (PPI) was central throughout the project. For example, PPI representatives contributed to the project planning, were valued members of the Project Advisory Group, had key roles in developing the VKS prototype and helped disseminate the project findings.

Person-Specific Template Matching Using a Dynamic Time Warping Step-Count Algorithm for Multiple Walking Activities.

This study aimed to develop and evaluate a new step-count algorithm, StepMatchDTWBA, for the accurate measurement of physical activity using wearable devices in both healthy and pathological populations. We conducted a study with 30 healthy volunteers wearing a wrist-worn MOX accelerometer (Maastricht Instruments, NL). The StepMatchDTWBA algorithm used dynamic time warping (DTW) barycentre averaging to create personalised templates for representative steps, accounting for individual walking variations. DTW was then used to measure the similarity between the template and accelerometer epoch. The StepMatchDTWBA algorithm had an average root-mean-square error of 2 steps for healthy gaits and 12 steps for simulated pathological gaits over a distance of about 10 m (GAITRite walkway) and one flight of stairs. It outperformed benchmark algorithms for the simulated pathological population, showcasing the potential for improved accuracy in personalised step counting for pathological populations. The StepMatchDTWBA algorithm represents a significant advancement in accurate step counting for both healthy and pathological populations. This development holds promise for creating more precise and personalised activity monitoring systems, benefiting various health and wellness applications.

A systematic review and narrative synthesis of footwear and orthotic devices used in the management of ankle haemarthrosis and haemarthropathy in haemophilia.

INTRODUCTION: Haemarthrosis is a clinical feature of haemophilia leading to haemarthropathy. The ankle joint is most commonly affected, resulting in significant pain, disability and a reduction in health-related quality of life. Footwear and orthotic devices are effective in other diseases that affect the foot and ankle, such as rheumatoid arthritis, but little is known about their effect in haemophilia. AIMS: To review the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia. METHODS: A systematic literature review was conducted. Two review authors independently screened studies for inclusion and appraised methodological quality using Joanna Briggs Institute Critical Appraisal checklists. A narrative analysis was undertaken. RESULTS: Ten studies involving 271 male participants were eligible for inclusion. All studies were quasi-experimental; three employed a within-subject design. Two studies included an independent comparison or control group. A range of footwear and orthotic devices were investigated. Limited evidence from non-randomised studies suggested that footwear and orthotic devices improve the number of ankle joint bleeding episodes, gait parameters and patient-reported pain. CONCLUSION: This review demonstrates a lack of robust evidence regarding the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia. Methodological heterogeneities and limitations with the study designs, small sample sizes and limited follow-up of participants exist. Future studies utilising randomised designs, larger sample sizes, long-term follow-up and validated patient-reported outcome measures are needed to inform the clinical management of ankle joint haemarthrosis and haemarthropathy.

Consensus on a standardised treatment pathway algorithm for lumbar spinal stenosis: an international Delphi study.

BACKGROUND: Lumbar spinal stenosis (LSS) is a common degenerative spinal condition in older adults associated with disability, diminished quality of life, and substantial healthcare costs. Individual symptoms and needs vary. With sparse and sometimes inconsistent evidence to guide clinical decision-making, variable clinical care may lead to unsatisfactory patient outcomes and inefficient use of healthcare resources. METHODS: A three-phase modified Delphi study comprising four consensus rounds was conducted on behalf of the International Taskforce for the Diagnosis and Management of LSS to develop a treatment algorithm based on multi-professional international expert consensus. Participants with expertise in the assessment and management of people with LSS were invited using an international distribution process used for two previous Delphi studies led by the Taskforce. Separate treatment pathways for patients with different symptom types and severity were developed and incorporated into a proposed treatment algorithm through consensus rounds 1 to 3. Agreement with the proposed algorithm was evaluated in the final consensus round. RESULTS: The final algorithm combines stratified and stepped approaches. When indicated, immediate investigation and surgery is advocated. Otherwise, a stepped approach is suggested when self-directed care is unsatisfactory. This starts with tailored rehabilitation, then more complex multidisciplinary care, investigations and surgery options if needed. Treatment options in each step depend on clinical phenotype and symptom severity. Treatment response guides pathway entrance and exit points. Of 397 study participants, 86% rated their agreement ≥ 4 for the proposed algorithm on a 0-6 scale, of which 22% completely agreed. Only 7% disagreed. Over 70% of participants felt that the algorithm would be useful for clinicians in public healthcare (both primary care and specialist settings) and in private healthcare settings, and that a simplified version would help patients in shared decision-making. CONCLUSIONS: International and multi-professional agreement was achieved for a proposed LSS treatment algorithm developed through expert consensus. The algorithm advocates different pathway options depending on clinical indications. It is not intended as a treatment protocol and will require evaluation against current care for clinical and cost-effectiveness. It may, however, serve as a clinical guide until evidence is sufficient to inform a fully stratified care model.

Consensus on pre-operative total knee replacement education and prehabilitation recommendations: a UK-based modified Delphi study.

BACKGROUND: Over 90,000 total knee replacement (TKR) procedures are performed annually in the United Kingdom (UK). Patients awaiting TKR face long delays whilst enduring severe pain and functional limitations. Almost 20% of patients who undergo TKR are not satisfied post-operatively. Optimising pre-operative TKR education and prehabilitation could help improve patient outcomes pre- and post-operatively; however, current pre-operative TKR care varies widely. Definitive evidence on the optimal content and delivery of pre-operative TKR care is lacking. This study aimed to develop evidence- and consensus-based recommendations on pre-operative TKR education and prehabilitation. METHODS: A UK-based, three-round, online modified Delphi study was conducted with a 60-member expert panel. All panellists had experience of TKR services as patients (n = 30) or professionals (n = 30). Round 1 included initial recommendations developed from a mixed methods rapid review. Panellists rated the importance of each item on a five-point Likert scale. Panellists could also suggest additional items in Round 1. Rounds 2 and 3 included all items from Round 1, new items suggested in Round 1 and charts summarising panellists' importance ratings from the preceding round. Free-text responses were analysed using content analysis. Quantitative data were analysed descriptively. All items rated as 'Important' or 'Very important' by at least 70% of all respondents in Round 3 were included in the final set of recommendations. RESULTS: Fifty-five panellists (92%) (patients n = 26; professionals n = 29) completed Round 3. Eighty-six recommendation items were included in Round 1. Fifteen new items were added in Round 2. Rounds 2 and 3 therefore included 101 items. Seventy-seven of these reached consensus in Round 3. Six items reached consensus amongst patient or professional panellists only in Round 3. The final set of recommendations comprises 34 education topics, 18 education delivery approaches, 10 exercise types, 13 exercise delivery approaches and two other treatments. CONCLUSIONS: This modified Delphi study developed a comprehensive set of recommendations that represent a useful resource for guiding decision-making on the content and delivery of pre-operative TKR education and prehabilitation. The recommendations will need to be interpreted and reviewed periodically in light of emerging evidence.

Morphological variation of the hemophilic talus.

Flattening of the trochlear tali is clinically observed as structural and functional changes advance in patients with hemarthropathy of the ankle. However, the degree of this flattening has not yet been quantified, and distribution of the morphological changes across the talus not yet defined. Chronologically sequential MR images of both a hemophilic patient group (N = 5) and a single scan from a nondiseased, sex-matched, control group (N = 11) were used to take four measurements of the trochlear talus morphology at three locations (medial, central and lateral) along the sagittal plane. Three ratios of interest were defined from these to assess whether the talar dome flattens with disease. The control group MRI measurements were validated against literature data obtained from CT scans or planar X-Rays. The influence of disease on talar morphology was assessed by direct comparison of the hemophilic cases with the control group. The values for all three ratios, in all locations, differed between the control and the hemophilic group. Flattening was indicated in the hemophilic group in the medial and lateral talus, but differences in the central talus were not statistically significant. This work demonstrates that morphological assessment of the talus from MR images is similar to that from CT scans or planar X-Rays. Talar flattening does occur with hemarthropathy, especially at the medial and lateral edges of the joint surface. General flattening of the trochlear talus was confirmed in this small patient sample, however the degree and rate of change is unique to each ankle.

Haptoglobin Is a Divergent MASP Family Member That Neofunctionalized To Recycle Hemoglobin via CD163 in Mammals.

In mammals, haptoglobin (Hp) is an acute-phase plasma protein that binds with high affinity to hemoglobin (Hb) released by intravascular hemolysis. The resultant Hp-Hb complexes are bound and cleared by the scavenger receptor CD163, limiting Hb-induced oxidative damage. In this study, we show that Hp is a divergent member of the complement-initiating MASP family of proteins, which emerged in the ancestor of jawed vertebrates. We demonstrate that Hp has been independently lost from multiple vertebrate lineages, that characterized Hb-interacting residues of mammals are poorly conserved in nonmammalian species maintaining Hp, and that the extended loop 3 region of Hp, which mediates CD163 binding, is present only in mammals. We show that the Hb-binding ability of cartilaginous fish (nurse shark, Ginglymostoma cirratum; small-spotted catshark, Scyliorhinus canicula; and thornback ray, Raja clavata) and teleost fish (rainbow trout, Oncorhynchus mykiss) Hp is species specific, and where binding does occur it is likely mediated through a different structural mechanism to mammalian Hp. The continued, high-level expression of Hp in cartilaginous fishes in which Hb binding is not evident signals that Hp has (an)other, yet unstudied, role(s) in these species. Previous work indicates that mammalian Hp also has secondary, immunomodulatory functions that are independent of Hb binding; our work suggests these may be remnants of evolutionary more ancient functions, retained after Hb removal became the primary role of Hp in mammals.

Current Preclinical Testing of New Hip Arthroplasty Technologies Does Not Reflect Real-World Loadings: Capturing Patient-Specific and Activity-Related Variation in Hip Contact Forces.

BACKGROUND: Total hip arthroplasty (THA) implants are routinely tested for their tribological performance through regulatory preclinical wear testing (eg, ISO-14242). The standardized loading conditions defined in these tests consist of simplified waveforms, which do not specifically represent in vivo loads in different groups of patients. The aim of this study is to investigate, through musculoskeletal modeling, patient-specific and activity-related variation in hip contact forces (HCFs) in a large cohort of THA patients during common activities of daily living (ADLs). METHODS: A total of 132 THA patients participated in a motion-capture analysis while performing different ADLs, including walk, fast walk, stair ascent, and descent (locomotor); sit to stand, stand to sit, squat, and lunge (nonlocomotor). HCFs were then calculated using the AnyBody Modeling System and qualitatively compared across all activities. The influence of gender on HCFs was analyzed through statistical parametric mapping analysis. RESULTS: Systematic differences were found in HCF magnitudes and individual components in both locomotor and nonlocomotor ADLs. The qualitative analysis of the ADLs revealed a large range and a large variability in forces experienced at the hip during different activities. Significant differences in the 3-dimensional loading patterns were observed between males and females across most activities. CONCLUSION: THA patients present a large variability in the forces experienced at the hip joint during their daily life. The interpatient variation might partially explain the heterogeneity observed in implant survival rates. A more extensive preclinical implant testing standard under clinically relevant loading conditions has been advocated to better predict and avoid clinical wear problems.

Risk Factors for Intraoperative Periprosthetic Femoral Fractures During Primary Total Hip Arthroplasty. An Analysis From the National Joint Registry for England and Wales and the Isle of Man.

BACKGROUND: The aim of this study is to estimate risk factors for intraoperative periprosthetic femoral fractures (IOPFF) and each anatomic subtype (calcar crack, trochanteric fracture, femoral shaft fracture) during primary total hip arthroplasty. METHODS: This retrospective cohort study included 793,823 primary total hip arthroplasties between 2004 and 2016. Multivariable regression modeling was used to estimate relative risk of patient, surgical, and implant factors for any IOPFF and for all anatomic subtypes of IOPFF. Clinically important interactions were assessed using multivariable regression. RESULTS: Patient factors significantly increasing the risk of fracture were female gender, American Society of Anesthesiologists grade 3 to 5, and preoperative diagnosis including avascular necrosis of the hip, previous trauma, inflammatory disease, pediatric disease, and previous infection. Overall risk of IOPFF associated with age was greatest in patients below 50 years and above 80 years. Risk of any fracture reduced with computer-guided surgery and in non-National Health Service hospitals. Nonposterior approaches increased the risk of shaft and trochanteric fracture only. Cementless implants significantly increased the risk of only calcar cracks and shaft fractures and not trochanteric fractures. CONCLUSION: Fracture risk increases in patients younger than 50 and older than 80 years, females, American Society of Anesthesiologists grade 3 to 5, and indications other than primary osteoarthritis. Large cumulative reduction in IOPFF risk may occur with use of cemented implants, posterior approach, and computer-guided surgery. LEVEL OF EVIDENCE: Level 3b (cohort study).

Phylotranscriptomics suggests the jawed vertebrate ancestor could generate diverse helper and regulatory T cell subsets.

BACKGROUND: The cartilaginous fishes diverged from other jawed vertebrates ~ 450 million years ago (mya). Despite this key evolutionary position, the only high-quality cartilaginous fish genome available is for the elephant shark (Callorhinchus milii), a chimaera whose ancestors split from the elasmobranch lineage ~ 420 mya. Initial analysis of this resource led to proposals that key components of the cartilaginous fish adaptive immune system, most notably their array of T cell subsets, was primitive compared to mammals. This proposal is at odds with the robust, antigen-specific antibody responses reported in elasmobranchs following immunization. To explore this discrepancy, we generated a multi-tissue transcriptome for small-spotted catshark (Scyliorhinus canicula), a tractable elasmobranch model for functional studies. We searched this, and other newly available sequence datasets, for CD4+ T cell subset-defining genes, aiming to confirm the presence or absence of each subset in cartilaginous fishes. RESULTS: We generated a new transcriptome based on a normalised, multi-tissue RNA pool, aiming to maximise representation of tissue-specific and lowly expressed genes. We utilized multiple transcriptomic datasets and assembly variants in phylogenetic reconstructions to unambiguously identify several T cell subset-specific molecules in cartilaginous fishes for the first time, including interleukins, interleukin receptors, and key transcription factors. Our results reveal the inability of standard phylogenetic reconstruction approaches to capture the site-specific evolutionary processes of fast-evolving immune genes but show that site-heterogeneous mixture models can adequately do so. CONCLUSIONS: Our analyses reveal that cartilaginous fishes are capable of producing a range of CD4+ T cell subsets comparable to that of mammals. Further, that the key molecules required for the differentiation and functioning of these subsets existed in the jawed vertebrate ancestor. Additionally, we highlight the importance of considering phylogenetic diversity and, where possible, utilizing multiple datasets for individual species, to accurately infer gene presence or absence at higher taxonomic levels.

Common measure of quality of life for people with systemic sclerosis across seven European countries: a cross-sectional study.

OBJECTIVES: The aim of this study was to adapt the Systemic Sclerosis Quality of Life Questionnaire (SScQoL) into six European cultures and validate it as a common measure of quality of life in systemic sclerosis (SSc). METHODS: This was a seven-country (Germany, France, Italy, Poland, Spain, Sweden and UK) cross-sectional study. A forward-backward translation process was used to adapt the English SScQoL into target languages. SScQoL was completed by patients with SSc, then data were validated against the Rasch model. To correct local response dependency, items were grouped into the following subscales: function, emotion, sleep, social and pain and reanalysed for fit to the model, unidimensionality and cross-cultural equivalence. RESULTS: The adaptation of the SScQoL was seamless in all countries except Germany. Cross-cultural validation included 1080 patients with a mean age 58.0 years (SD 13.9) and 87% were women. Local dependency was evident in individual country data. Grouping items into testlets corrected the local dependency in most country specific data. Fit to the model, reliability and unidimensionality was achieved in six-country data after cross-cultural adjustment for Italy in the social subscale. The SScQoL was then calibrated into an interval level scale. CONCLUSION: The individual SScQoL items have translated well into five languages and overall, the scale maintained its construct validity, working well as a five-subscale questionnaire. Measures of quality of life in SSc can be directly compared across five countries (France, Poland Spain, Sweden and UK). Data from Italy are also comparable with the other five countries although require an adjustment.

Cost-Effectiveness of a Multifaceted Podiatry Intervention for the Prevention of Falls in Older People: The REducing Falls with Orthoses and a Multifaceted Podiatry Intervention Trial Findings.

BACKGROUND: Falls are a major cause of morbidity among older people. Multifaceted interventions may be effective in preventing falls and related fractures. OBJECTIVE: To evaluate the cost-effectiveness alongside the REducing Falls with Orthoses and a Multifaceted podiatry intervention (REFORM) trial. METHODS: REFORM was a pragmatic multicentre cohort randomised controlled trial in England and Ireland; 1,010 participants (> 65 years) were randomised to receive either a podiatry intervention (n = 493), including foot and ankle strengthening exercises, foot orthoses, new footwear if required, and a falls prevention leaflet, or usual podiatry treatment plus a falls prevention leaflet (n = 517). PRIMARY OUTCOME: incidence of falls per participant in the 12 months following randomisation. SECONDARY OUTCOMES: proportion of fallers and quality of life (EQ-5D-3L) which was converted into quality-adjusted life years (QALYs) for each participant. Differences in mean costs and QALYs at 12 months were used to assess the cost-effectiveness of the intervention relative to usual care. Cost-effectiveness analyses were conducted in accordance with National Institute for Health and Clinical Excellence reference case standards, using a regression-based approach with costs expressed in GBP (2015 price). The base case analysis used an intention-to-treat approach on the imputed data set using multiple imputation. RESULTS: There was a small, non-statistically significant reduction in the incidence rate of falls in the intervention group (adjusted incidence rate ratio 0.88, 95% CI 0.73-1.05, p = 0.16). Participants allocated to the intervention group accumulated on average marginally higher QALYs than the usual care participants (mean difference 0.0129, 95% CI -0.0050 to 0.0314). The intervention costs were on average GBP 252 more per participant compared to the usual care participants (95% CI GBP -69 to GBP 589). Incremental cost-effectiveness ratios ranged between GBP 19,494 and GBP 20,593 per QALY gained, below the conventional National Health Service cost-effectiveness thresholds of GBP 20,000 to GBP 30,000 per additional QALY. The probability that the podiatry intervention is cost-effective at a threshold of GBP 30,000 per QALY gained was 0.65. The results were robust to sensitivity analyses. CONCLUSION: The benefits of the intervention justified the moderate cost. The intervention could be a cost-effective option for falls prevention when compared with usual care in the UK.

Outgroup, alignment and modelling improvements indicate that two TNFSF13-like genes existed in the vertebrate ancestor.

The molecular machinery required for lymphocyte development and differentiation appears to have emerged concomitantly with distinct B- and T-like lymphocyte subsets in the ancestor of all vertebrates. The TNFSF superfamily (TNFSF) members BAFF (TNFSF13/Blys) and APRIL (TNFSF13) are key regulators of B cell development survival, and activation in mammals, but the temporal emergence of these molecules, and their precise relationship to the newly identified TNFSF gene BALM (BAFF and APRIL-like molecule), have not yet been elucidated. Here, to resolve the early evolutionary history of this family, we improved outgroup sampling and alignment quality, and applied better fitting substitution models compared to past studies. Our analyses reveal that BALM is a definitive TNFSF13 family member, which split from BAFF in the gnathostome (jawed vertebrate) ancestor. Most importantly, however, we show that both the APRIL and BAFF lineages existed in the ancestors of all extant vertebrates. This implies that APRIL has been lost, or is yet to be found, in cyclostomes (jawless vertebrates). Our results suggest that lineage-specific gene duplication and loss events have caused lymphocyte regulation, despite shared origins, to become secondarily distinct between gnathostomes and cyclostomes. Finally, the structure of lamprey BAFF-like, and its phylogenetic placement as sister to BAFF and BALM, but not the more slowly evolving APRIL, indicates that the primordial lymphocyte regulator was more APRIL-like than BAFF-like.

Patellofemoral morphology is not related to pain using three-dimensional quantitative analysis in an older population: data from the Osteoarthritis Initiative.

Objectives: Current structural associations of patellofemoral pain (PFP) are based on 2D imaging methodology with inherent measurement uncertainty due to positioning and rotation. This study employed novel technology to create 3D measures of commonly described patellofemoral joint imaging features and compared these features in people with and without PFP in a large cohort. Methods: We compared two groups from the Osteoarthritis Initiative: one with localized PFP and pain on stairs, and a control group with no knee pain; both groups had no radiographic OA. MRI bone surfaces were automatically segmented and aligned using active appearance models. We applied t-tests, logistic regression and linear discriminant analysis to compare 13 imaging features (including patella position, trochlear morphology, facet area and tilt) converted into 3D equivalents, and a measure of overall 3D shape. Results: One hundred and fifteen knees with PFP (mean age 59.7, BMI 27.5 kg/m2, female 58.2%) and 438 without PFP (mean age 63.6, BMI 26.9 kg/m2, female 52.9%) were included. After correction for multiple testing, no statistically significant differences were found between groups for any of the 3D imaging features or their combinations. A statistically significant discrimination was noted for overall 3D shape between genders, confirming the validity of the 3D measures. Conclusion: Challenging current perceptions, no differences in patellofemoral morphology were found between older people with and without PFP using 3D quantitative imaging analysis. Further work is needed to see if these findings are replicated in a younger PFP population.