Kidney-resident innate-like memory γδ T cells control chronic Staphylococcus aureus infection of mice.

γδ T cells are involved in the control of Staphylococcus aureus infection, but their importance in protection compared to other T cells is unclear. We used a mouse model of systemic S. aureus infection associated with high bacterial load and persistence in the kidney. Infection caused fulminant accumulation of γδ T cells in the kidney. Renal γδ T cells acquired tissue residency and were maintained in high numbers during chronic infection. At day 7, up to 50% of renal γδ T cells produced IL-17A in situ and a large fraction of renal γδ T cells remained IL-17A+ during chronic infection. Controlled depletion revealed that γδ T cells restricted renal S. aureus replication in the acute infection and provided protection during chronic renal infection and upon reinfection. Our results demonstrate that kidney-resident γδ T cells are nonredundant in limiting local S. aureus growth during chronic infection and provide enhanced protection against reinfection.

Artificial intelligence for automated detection and measurements of carpal instability signs on conventional radiographs.

OBJECTIVES: To develop and validate an artificial intelligence (AI) system for measuring and detecting signs of carpal instability on conventional radiographs. MATERIALS AND METHODS: Two case-control datasets of hand and wrist radiographs were retrospectively acquired at three hospitals (hospitals A, B, and C). Dataset 1 (2178 radiographs from 1993 patients, hospitals A and B, 2018-2019) was used for developing an AI system for measuring scapholunate (SL) joint distances, SL and capitolunate (CL) angles, and carpal arc interruptions. Dataset 2 (481 radiographs from 217 patients, hospital C, 2017-2021) was used for testing, and with a subsample (174 radiographs from 87 patients), an observer study was conducted to compare its performance to five clinicians. Evaluation metrics included mean absolute error (MAE), sensitivity, and specificity. RESULTS: Dataset 2 included 258 SL distances, 189 SL angles, 191 CL angles, and 217 carpal arc labels obtained from 217 patients (mean age, 51 years ± 23 [standard deviation]; 133 women). The MAE in measuring SL distances, SL angles, and CL angles was respectively 0.65 mm (95%CI: 0.59, 0.72), 7.9 degrees (95%CI: 7.0, 8.9), and 5.9 degrees (95%CI: 5.2, 6.6). The sensitivity and specificity for detecting arc interruptions were 83% (95%CI: 74, 91) and 64% (95%CI: 56, 71). The measurements were largely comparable to those of the clinicians, while arc interruption detections were more accurate than those of most clinicians. CONCLUSION: This study demonstrates that a newly developed automated AI system accurately measures and detects signs of carpal instability on conventional radiographs. CLINICAL RELEVANCE STATEMENT: This system has the potential to improve detections of carpal arc interruptions and could be a promising tool for supporting clinicians in detecting carpal instability.

ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage.

BACKGROUND: Podocytes embrace the glomerular capillaries with foot processes, which are interconnected by a specialized adherens junction to ultimately form the filtration barrier. Altered adhesion and loss are common features of podocyte injury, which could be mediated by shedding of cell-adhesion molecules through the regulated activity of cell surface-expressed proteases. A Disintegrin and Metalloproteinase 10 (ADAM10) is such a protease known to mediate ectodomain shedding of adhesion molecules, among others. Here we evaluate the involvement of ADAM10 in the process of antibody-induced podocyte injury. METHODS: Membrane proteomics, immunoblotting, high-resolution microscopy, and immunogold electron microscopy were used to analyze human and murine podocyte ADAM10 expression in health and kidney injury. The functionality of ADAM10 ectodomain shedding for podocyte development and injury was analyzed, in vitro and in vivo, in the anti-podocyte nephritis (APN) model in podocyte-specific, ADAM10-deficient mice. RESULTS: ADAM10 is selectively localized at foot processes of murine podocytes and its expression is dispensable for podocyte development. Podocyte ADAM10 expression is induced in the setting of antibody-mediated injury in humans and mice. Podocyte ADAM10 deficiency attenuates the clinical course of APN and preserves the morphologic integrity of podocytes, despite subepithelial immune-deposit formation. Functionally, ADAM10-related ectodomain shedding results in cleavage of the cell-adhesion proteins N- and P-cadherin, thus decreasing their injury-related surface levels. This favors podocyte loss and the activation of downstream signaling events through the Wnt signaling pathway in an ADAM10-dependent manner. CONCLUSIONS: ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury.

Tripartite Separation of Glomerular Cell Types and Proteomes from Reporter-Free Mice.

BACKGROUND: The glomerulus comprises podocytes, mesangial cells, and endothelial cells, which jointly determine glomerular filtration. Understanding this intricate functional unit beyond the transcriptome requires bulk isolation of these cell types for biochemical investigations. We developed a globally applicable tripartite isolation method for murine mesangial and endothelial cells and podocytes (timMEP). METHODS: We separated glomerular cell types from wild-type or mT/mG mice via a novel FACS approach, and validated their purity. Cell type proteomes were compared between strains, ages, and sex. We applied timMEP to the podocyte-targeting, immunologic, THSD7A-associated, model of membranous nephropathy. RESULTS: timMEP enabled protein-biochemical analyses of podocytes, mesangial cells, and endothelial cells derived from reporter-free mice, and allowed for the characterization of podocyte, endothelial, and mesangial proteomes of individual mice. We identified marker proteins for mesangial and endothelial proteins, and outlined protein-based, potential communication networks and phosphorylation patterns. The analysis detected cell type-specific proteome differences between mouse strains and alterations depending on sex, age, and transgene. After exposure to anti-THSD7A antibodies, timMEP resolved a fine-tuned initial stress response, chiefly in podocytes, that could not be detected by bulk glomerular analyses. The combination of proteomics with super-resolution imaging revealed a specific loss of slit diaphragm, but not of other foot process proteins, unraveling a protein-based mechanism of podocyte injury in this animal model. CONCLUSION: timMEP enables glomerular cell type-resolved investigations at the transcriptional and protein-biochemical level in health and disease, while avoiding reporter-based artifacts, paving the way toward the comprehensive and systematic characterization of glomerular cell biology.

Deubiquitinating Enzyme UCH-L1 Promotes Dendritic Cell Antigen Cross-Presentation by Favoring Recycling of MHC Class I Molecules.

The deubiquitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1) is required for the maintenance of axonal integrity in neurons and is thought to regulate the intracellular pool of ubiquitin in the brain. In this study, we show that UCH-L1 has an immunological function in dendritic cell (DC) Ag cross-presentation. UCH-L1 is expressed in mouse kidney, spleen, and bone marrow-derived DCs, and its expression and activity are regulated by the immune stimuli LPS and IFN-γ. UCH-L1-deficient mice have significantly reduced ability to cross-prime CD8 T cells in vivo and in vitro because of a reduced ability of DCs to generate MHC class I (MHC I) peptide complexes for cross-presented Ags. Mechanistically, Ag uptake by phagocytosis and receptor-mediated endocytosis as well as phagosome maturation are unaffected by loss of UCH-L1 in DCs. Rather, MHC I recycling is reduced by loss of UCH-L1, which affects the colocalization of intracellular MHC I with late endosomal/lysosomal compartments necessary for cross-presentation of Ag. These results demonstrate a hitherto unrecognized role of the deubiquitinating enzyme UCH-L1 in DC Ag processing.

Dansyl Emits from a PICT Excited State.

Two derivatives of dansyl (1-dimethylamino-5-naphthalenesulfonyl) in which the amino group is constrained in a ring are prepared as neopentyl esters. Their photophysical behavior is compared with that of the dansyl ester. The solvatochromism and quantum yields are similar for all three. Since the two constrained derivatives cannot twist about the amino group, they must emit from a planar intramolecular charge-transfer excited state. The similar photophysical behavior suggests that dansyl also emits from a PICT excited state instead of a twisted intramolecular charge transfer state.

Distinct Modes of Balancing Glomerular Cell Proteostasis in Mucolipidosis Type II and III Prevent Proteinuria.

BACKGROUND: The mechanisms balancing proteostasis in glomerular cells are unknown. Mucolipidosis (ML) II and III are rare lysosomal storage disorders associated with mutations of the Golgi-resident GlcNAc-1-phosphotransferase, which generates mannose 6-phosphate residues on lysosomal enzymes. Without this modification, lysosomal enzymes are missorted to the extracellular space, which results in lysosomal dysfunction of many cell types. Patients with MLII present with severe skeletal abnormalities, multisystemic symptoms, and early death; the clinical course in MLIII is less progressive. Despite dysfunction of a major degradative pathway, renal and glomerular involvement is rarely reported, suggesting organ-specific compensatory mechanisms. METHODS: MLII mice were generated and compared with an established MLIII model to investigate the balance of protein synthesis and degradation, which reflects glomerular integrity. Proteinuria was assessed in patients. High-resolution confocal microscopy and functional assays identified proteins to deduce compensatory modes of balancing proteostasis. RESULTS: Patients with MLII but not MLIII exhibited microalbuminuria. MLII mice showed lysosomal enzyme missorting and several skeletal alterations, indicating that they are a useful model. In glomeruli, both MLII and MLIII mice exhibited reduced levels of lysosomal enzymes and enlarged lysosomes with abnormal storage material. Nevertheless, neither model had detectable morphologic or functional glomerular alterations. The models rebalance proteostasis in two ways: MLII mice downregulate protein translation and increase the integrated stress response, whereas MLIII mice upregulate the proteasome system in their glomeruli. Both MLII and MLIII downregulate the protein complex mTORC1 (mammalian target of rapamycin complex 1) signaling, which decreases protein synthesis. CONCLUSIONS: Severe lysosomal dysfunction leads to microalbuminuria in some patients with mucolipidosis. Mouse models indicate distinct compensatory pathways that balance proteostasis in MLII and MLIII.

Cumulative incidence and treatment of non-simultaneous bilateral femoral neck fractures in a cohort of one thousand two hundred and fifty patients.

PURPOSE: In the Netherlands, over 20,000 patients sustain a hip fracture yearly. A first hip fracture is a risk factor for a second, contralateral fracture. Data on the similarity of the treatment of bilateral femoral neck fractures is only scarcely available. The objectives of this study were to determine the cumulative incidence of non-simultaneous bilateral femoral neck fractures and to describe the patient characteristics and treatment characteristics of these patients. METHODS: A database of 1,250 consecutive patients with a femoral neck fracture was available. Patients with a previous contralateral femoral neck fractures were identified by reviewing radiographs and patient files. Patient characteristics, previous fractures, hip fracture type and details on treatment were collected from the patient files. RESULTS: One hundred nine patients (9%, 95% confidence interval 7-10%) had sustained a non-simultaneous bilateral femoral neck fracture. The median age at the first fracture was 81 years; the median interval between the fractures was 25 months. Overall, 73% was treated similarly for both fractures in terms of non-operative treatment, internal fixation or arthroplasty. In patients with identical Garden classification (30%), treatment similarity was 88%. CONCLUSIONS: The cumulative incidence of non-simultaneous bilateral femoral neck fractures was 9%. Most patients with identical fracture types were treated similarly. The relatively high risk of sustaining a second femoral neck fracture supports the importance of secondary prevention, especially in patients with a prior wrist or vertebral fracture.

Adherence to a femoral neck fracture treatment guideline.

PURPOSE: In 2007 the Dutch Surgical Society published a clinical practice guideline for the treatment of hip fracture patients, based on the best available international evidence at that time. We investigated to what extent treatment of femoral neck fracture patients in the Netherlands corresponded with these guidelines, and determined differences in patient characteristics between the treatment groups. METHODS: All femoral neck fracture patients treated in 14 hospitals between February 2008 and August 2009 were included. Patient characteristics, X-rays, and treatment data were collected retrospectively. RESULTS: From a total of 1,250 patients 59% had been treated with arthroplasty, 39% with internal fixation, and 2% with a non-operative treatment. While 74% of the treatment choices complied with the guideline, 12% did not. In 14% adherence could not be determined from the available data. Arthroplasty was preferred over internal fixation in elderly patients with severe comorbidity, pre-fracture osteoporosis and a displaced fracture, who were ambulatory with aids pre-fracture (odds ratio, OR 2.2-58.1). Sliding hip screws were preferred over cancellous screws in displaced fractures (OR 1.9). CONCLUSIONS: Overall guideline adherence was good. Most deviations concerned treatment of elderly patients with a displaced fracture and implant use in internal fixation. Additional data on these issues, preferably at a higher scientific level of evidence, is needed in order to improve the guideline and to reinforce a more uniform treatment of these patients.

Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis.

Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1.

The classical pathway triggers pathogenic complement activation in membranous nephropathy.

Membranous nephropathy (MN) is an antibody-mediated autoimmune disease characterized by glomerular immune complexes containing complement components. However, both the initiation pathways and the pathogenic significance of complement activation in MN are poorly understood. Here, we show that components from all three complement pathways (alternative, classical and lectin) are found in renal biopsies from patients with MN. Proximity ligation assays to directly visualize complement assembly in the tissue reveal dominant activation via the classical pathway, with a close correlation to the degree of glomerular C1q-binding IgG subclasses. In an antigen-specific autoimmune mouse model of MN, glomerular damage and proteinuria are reduced in complement-deficient mice compared with wild-type littermates. Severe disease with progressive ascites, accompanied by extensive loss of the integral podocyte slit diaphragm proteins, nephrin and neph1, only occur in wild-type animals. Finally, targeted silencing of C3 using RNA interference after the onset of proteinuria significantly attenuates disease. Our study shows that, in MN, complement is primarily activated via the classical pathway and targeting complement components such as C3 may represent a promising therapeutic strategy.

Single-cell transcriptomics reveals a mechanosensitive injury signaling pathway in early diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and histopathologic glomerular lesions are among the earliest structural alterations of DN. However, the signaling pathways that initiate these glomerular alterations are incompletely understood. METHODS: To delineate the cellular and molecular basis for DN initiation, we performed single-cell and bulk RNA sequencing of renal cells from type 2 diabetes mice (BTBR ob/ob) at the early stage of DN. RESULTS: Analysis of differentially expressed genes revealed glucose-independent responses in glomerular cell types. The gene regulatory network upstream of glomerular cell programs suggested the activation of mechanosensitive transcriptional pathway MRTF-SRF predominantly taking place in mesangial cells. Importantly, activation of MRTF-SRF transcriptional pathway was also identified in DN glomeruli in independent patient cohort datasets. Furthermore, ex vivo kidney perfusion suggested that the regulation of MRTF-SRF is a common mechanism in response to glomerular hyperfiltration. CONCLUSIONS: Overall, our study presents a comprehensive single-cell transcriptomic landscape of early DN, highlighting mechanosensitive signaling pathways as novel targets of diabetic glomerulopathy.

Surviving a site audit: tips for good clinical practice in an implant trial.

The number of clinical trials involving implants for trauma and orthopedic surgery is increasing. The International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guideline has been developed in order to assure that the rights, safety, and well-being of trial subjects (i.e., patients) are protected. Not performing a trial according to legal requirements including this guideline is no longer acceptable, and trial audits are increasingly being performed as an independent quality check for data validity and credibility. This manuscript provides an overview of the guideline for Good Clinical Practice (GCP) in the context of conducting an implant trial in trauma and orthopedic surgery. As long as all guidelines are adequately adhered to and all paperwork is in order, there is no reason to fear a trial audit.

The Identification of Psychosocial Risk Factors Associated With Child Neglect Using the WE-CARE Screening Tool in a High-Risk Population.

INTRODUCTION: Neglect accounts for over 70% of child maltreatment and carries significant sequelae. Identification of psychosocial determinants of health may allow pediatric providers to ameliorate precursors of child neglect. METHODS: Data were collected 1 month before and after implementation of the Well-Child Care Visit, Evaluation, Community Resources, Advocacy, Referral, Education (i.e., WE-CARE) screen at all well-child visits. Social workers recorded number and types of referrals, and providers completed surveys. RESULTS: Analysis of 602 completed screens (75% capture rate) showed 377 families (63%) with at least one need and 198 (33% overall, 53% of those with positive results) indicating a desire to discuss. Of families requesting assistance, 122 (62%) connected with a social worker, and total referrals increased after implementation. Provider surveys supported an increased frequency of and comfort with assessing families for certain risk factors, and screening was not perceived to interrupt clinic flow. CONCLUSION: Standardized screening identifies families at risk for neglect, improves provider comfort, and minimally affects flow. Identification of psychosocial needs should be part of routine preventive care.

Implant Removal After Internal Fixation of a Femoral Neck Fracture: Effects on Physical Functioning.

OBJECTIVES: The effect of implant removal after internal fixation of a femoral neck fracture on physical functioning was analyzed. Characteristics of patients who had their implant removed were studied, as it is currently unknown from which type of patients implants are removed and what effect removal has on function. DESIGN: Secondary cohort study alongside a randomized controlled trial. SETTING: Multicenter study in 14 hospitals. PATIENTS AND INTERVENTION: Patients who had their implant removed after internal fixation of a femoral neck fracture are compared with patients who did not. MAIN OUTCOME MEASUREMENTS: Patient characteristics and quality of life (Short Form 12, Western Ontario McMaster Osteoarthritis Index) were compared. Matched pairs were selected based on patient/fracture characteristics and prefracture physical functioning. RESULTS: Of 162 patients, 37 (23%) had their implant removed. These patients were younger (median age: 67 vs. 72 years, P = 0.024) and more often independently ambulatory prefracture (100% vs. 84%, P = 0.008) than patients who did not. They more often had evident implant back-out on x-rays (54% vs. 34%, P = 0.035), possibly related to a higher rate of Pauwels 3 fractures (41% vs. 22%, P = 0.032). In time, quality of life improved more in implant removal patients [+2 vs. -4 points, Short Form 12 (physical component), P = 0.024; +9 vs. 0 points, Western Ontario McMaster Osteoarthritis Index, P = 0.019]. CONCLUSIONS: Implant removal after internal fixation of a femoral neck fracture positively influenced quality of life. Implant removal patients were younger and more often independently ambulatory prefracture, more often had a Pauwels 3 fracture, and an evident implant back-out. Implant removal should be considered liberally for these patients if pain persists or functional recovery is unsatisfactory. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Reliability, validity, and responsiveness of the Western Ontario and McMaster Universities Osteoarthritis Index for elderly patients with a femoral neck fracture.

BACKGROUND: The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) has been extensively evaluated in groups of patients with osteoarthritis, yet not in patients with a femoral neck fracture. This study aimed to determine the reliability, construct validity, and responsiveness of the WOMAC compared with the Short Form-12 (SF-12) and the EuroQol 5D (EQ-5D) questionnaires for the assessment of elderly patients with a femoral neck fracture. METHODS: Reliability was tested by assessing the Cronbach alpha. Construct validity was determined with the Pearson correlation coefficient. Change scores were calculated from ten weeks to twelve months of follow-up. Standardized response means and floor and ceiling effects were determined. Analyses were performed to compare the results for patients less than eighty years old with those for patients eighty years of age or older. RESULTS: The mean WOMAC total score was 89 points before the fracture in the younger patients and increased from 70 points at ten weeks to 81 points at two years postoperatively. In the older age group, these scores were 86, 75, and 78 points. The mean WOMAC pain scores before the fracture and at ten weeks and two years postoperatively were 92, 76, and 87 points, respectively, in the younger age group and 92, 84, and 93 points in the older age group. Function scores were 89, 68, and 79 points for the younger age group and 84, 71, and 73 points for the older age group. The Cronbach alpha for pain, stiffness, function, and the total scale ranged from 0.83 to 0.98 for the younger age group and from 0.79 to 0.97 for the older age group. Construct validity was good, with 82% and 79% of predefined hypotheses confirmed in the younger and older age groups, respectively. Responsiveness was moderate. No floor effects were found. Moderate to large ceiling effects were found for pain and stiffness scales at ten weeks and twelve months in younger patients (18% to 36%) and in the older age group (38% to 53%). CONCLUSIONS: The WOMAC showed good reliability, construct validity, and responsiveness in both age groups of elderly patients with a femoral neck fracture who had been physically and mentally fit before the fracture. The instrument is suitable for use in future clinical studies in these populations. CLINICAL RELEVANCE: The results are based on two clinical trials. The questionnaires used concern pure, clinically relevant issues (ability to walk, climb stairs, etc.). Moreover, the results can be used for future research comparing clinical outcomes (or treatments) for populations with a femoral neck fracture.

Functional outcome after successful internal fixation versus salvage arthroplasty of patients with a femoral neck fracture.

OBJECTIVES: To determine patient independency, health-related and disease-specific quality of life (QOL), gait pattern, and muscle strength in patients after salvage arthroplasty for failed internal fixation of a femoral neck fracture. DESIGN: Secondary cohort study to a randomized controlled trial. SETTING: Multicenter trial in the Netherlands, including 14 academic and nonacademic hospitals. PATIENTS: Patients after salvage arthroplasty for failed internal fixation of a femoral neck fracture were studied. A comparison was made with patients who healed uneventfully after internal fixation. INTERVENTION: None (observatory study). MAIN OUTCOME MEASUREMENTS: Patient characteristics, SF-12, and Western Ontario McMaster osteoarthritis index scores were collected. Gait parameters were measured using plantar pressure measurement. Maximum isometric forces of the hip muscles were measured using a handheld dynamometer. Differences between the fractured and contralateral leg were calculated. Groups were compared using univariate analysis. RESULTS: Of 248 internal fixation patients (median age, 72 years), salvage arthroplasty was performed in 68 patients (27%). Salvage arthroplasty patients had a significantly lower Western Ontario McMaster osteoarthritis index score (median, 73 vs. 90; P = 0.016) than patients who healed uneventfully after internal fixation. Health-related QOL (SF-12) and patient independency did not differ significantly between the groups. Gait analysis showed a significantly impaired progression of the center of pressure in the salvage surgery patients (median ratio, -8.9 vs. 0.4, P = 0.013) and a significant greater loss of abduction strength (median, -25.4 vs. -20.4 N, P = 0.025). CONCLUSIONS: Despite a similar level of dependency and QOL, salvage arthroplasty patients have inferior functional outcome than patients who heal after internal fixation of a femoral neck fracture. LEVEL OF EVIDENCE: Therapeutic level III.

Femoral neck shortening after internal fixation of a femoral neck fracture.

This study assesses femoral neck shortening and its effect on gait pattern and muscle strength in patients with femoral neck fractures treated with internal fixation. Seventy-six patients from a multicenter randomized controlled trial participated. Patient characteristics and Short Form 12 and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were collected. Femoral neck shortening, gait parameters, and maximum isometric forces of the hip muscles were measured and differences between the fractured and contralateral leg were calculated. Variables of patients with little or no shortening, moderate shortening, and severe shortening were compared using univariate and multivariate analyses. Median femoral neck shortening was 1.1 cm. Subtle changes in gait pattern, reduced gait velocity, and reduced abductor muscle strength were observed. Age, weight, and Pauwels classification were risk factors for femoral neck shortening. Femoral neck shortening decreased gait velocity and seemed to impair gait symmetry and physical functioning. In conclusion, internal fixation of femoral neck fractures results in permanent physical limitations. The relatively young and healthy patients in our study seem capable of compensating. Attention should be paid to femoral neck shortening and proper correction with a heel lift, as inadequate correction may cause physical complaints and influence outcome.

Central coordination as an alternative for local coordination in a multicenter randomized controlled trial: the FAITH trial experience.

BACKGROUND: Surgeons in the Netherlands, Canada and the US participate in the FAITH trial (Fixation using Alternative Implants for the Treatment of Hip fractures). Dutch sites are managed and visited by a financed central trial coordinator, whereas most Canadian and US sites have local study coordinators and receive per patient payment. This study was aimed to assess how these different trial management strategies affected trial performance. METHODS: Details related to obtaining ethics approval, time to trial start-up, inclusion, and percentage completed follow-ups were collected for each trial site and compared. Pre-trial screening data were compared with actual inclusion rates. RESULTS: Median trial start-up ranged from 41 days (P25-P75 10-139) in the Netherlands to 232 days (P25-P75 98-423) in Canada (p = 0.027). The inclusion rate was highest in the Netherlands; median 1.03 patients (P25-P75 0.43-2.21) per site per month, representing 34.4% of the total eligible population. It was lowest in Canada; 0.14 inclusions (P25-P75 0.00-0.28), representing 3.9% of eligible patients (p < 0.001). The percentage completed follow-ups was 83% for Canadian and Dutch sites and 70% for US sites (p = 0.217). CONCLUSIONS: In this trial, a central financed trial coordinator to manage all trial related tasks in participating sites resulted in better trial progression and a similar follow-up. It is therefore a suitable alternative for appointing these tasks to local research assistants. The central coordinator approach can enable smaller regional hospitals to participate in multicenter randomized controlled trials. Circumstances such as available budget, sample size, and geographical area should however be taken into account when choosing a management strategy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00761813.