Alterations in the innate and adaptive immune system in a real-world cohort of multiple sclerosis patients treated with ocrelizumab.

B cell depletion by the anti-CD20 antibody ocrelizumab is effective in relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS). We investigated immunological changes in peripheral blood of a real-world MS cohort after 6 and 12 months of ocrelizumab. All RRMS and most PPMS patients (15/20) showed treatment response. Ocrelizumab not only reduced CD20+ B cells, but also numbers of CD20+ T cells. Absolute numbers of monocytes, dendritic cells and CD8+ T cells were increased, while CD56hi natural killer cells were reduced after ocrelizumab. The residual B cell population shifted towards transitional and activated, IgA+ switched memory B cells, double negative B cells, and antibody-secreting cells. Delaying the treatment interval by 2-3 months increased mean B cell frequencies and enhanced naive B cell repopulation. Ocrelizumab reduced plasma levels of interleukin(IL)-12p70 and interferon(IFN)-α2. These findings will contribute to understanding ineffective treatment responses, dealing with life-threatening infections and further unravelling MS pathogenesis.

Specific suppression of microgliosis cannot circumvent the severe neuropathology in peroxisomal ß-oxidation-deficient mice.

An important hallmark of various neurodegenerative disorders is the proliferation and activation of microglial cells, the resident immune cells of the central nervous system (CNS). Mice that lack multifunctional protein-2 (MFP2), the key enzyme in peroxisomal ß-oxidation, develop excessive microgliosis that positively correlates with behavioral deficits whereas no neuronal loss occurs. However, the precise contribution of neuroinflammation to the fatal neuropathology of MFP2 deficiency remains largely unknown. Here, we first attempted to suppress the inflammatory response by administering various anti-inflammatory drugs but they failed to reduce microgliosis. Subsequently, Mfp2-/- mice were treated with the selective colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 as microglial proliferation and survival is dependent on CSF1R signaling. This resulted in the elimination of >95% of microglia from control mice but only 70% of the expanded microglial population from Mfp2-/- mice. Despite microglial diminution in Mfp2-/- brain, inflammatory markers remained unaltered and residual microglia persisted in a reactive state. CSF1R inhibition did not prevent neuronal dysfunction, cognitive decline and clinical deterioration of Mfp2-/- mice. Collectively, the unaltered inflammatory profile despite suppressed microgliosis concurrent with persevering clinical decline strengthens our hypothesis that neuroinflammation importantly contributes to the Mfp2-/- phenotype.

Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice.

BACKGROUND: Immune processes contribute to the development of obesity and its complications, such as insulin resistance, type 2 diabetes mellitus and cardiovascular disease. Approaches that target the inflammatory response are promising therapeutic strategies for obesity. In this context, we recently demonstrated that the interaction between the costimulatory protein CD40 and its downstream adaptor protein tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes adipose tissue inflammation, insulin resistance and hepatic steatosis in mice in the course of diet-induced obesity (DIO). METHODS: Here we evaluated the effects of a small-molecule inhibitor (SMI) of the CD40-TRAF6 interaction, SMI 6860766, on the development of obesity and its complications in mice that were subjected to DIO. RESULTS: Treatment with SMI 6860766 did not result in differences in weight gain, but improved glucose tolerance. Moreover, SMI 6860766 treatment reduced the amount of CD45(+) leucocytes in the epididymal adipose tissue by 69%. Especially, the number of adipose tissue CD4(+) and CD8(+) T cells, as well as macrophages, was significantly decreased. CONCLUSIONS: Our results indicate that small-molecule-mediated inhibition of the CD40-TRAF6 interaction is a promising therapeutic strategy for the treatment of metabolic complications of obesity by improving glucose tolerance, by reducing the accumulation of immune cells to the adipose tissue and by skewing of the immune response towards a more anti-inflammatory profile.

The adductor ratio: a new tool for joint line reconstruction in revision TKA.

PURPOSE: In this study, the value of the adductor tubercle as landmark for joint line reconstruction in revision total knee arthroplasty (TKA) was investigated. METHODS: On 100 calibrated full-leg standing radiographs obtained from healthy volunteers, distances from the medial epicondyle, the lateral epicondyle, the adductor tubercle, the fibular head and the centre of the knee to the joint line were determined. RESULTS: The average distance to the joint line from the medial epicondyle, the lateral epicondyle, the adductor tubercle and the fibular head was found to be 27.7 mm (SD 3.0), 27.1 mm (SD 2.7), 44.6 mm (SD 4.3) and 15.1 mm (SD 3.7), respectively. The distance from the adductor tubercle (R = 0.82) and the centre of the knee (R = 0.86) to the joint line showed a strong and linear correlation with the femoral width. The medial epicondyle, the lateral epicondyle and the fibular head showed less strong correlations. There was no significant correlation with the limb alignment. The adductor ratio was defined as the distance from adductor tubercle to the joint line divided by the femoral width and was found to be 0.52 (SD 0.027) with only small inter-individual variation. The adductor ratio was the most accurate ratio and reconstructed the joint line within 4 mm of its original level in 92% of the cases. CONCLUSION: The adductor ratio is a reliable and accurate tool for joint line reconstruction in revision TKA. It was found to be more accurate then the use of absolute distances and the epicondylar ratios. This study supports the use of the adductor tubercle for joint line reconstruction in revision TKA. LEVEL OF EVIDENCE: II.

Outpatient interdisciplinary multimodal pain treatment programme for patients with chronic musculoskeletal pain: a longitudinal cohort study.

PURPOSE: To describe the outcomes of an interdisciplinary multimodal pain treatment (IMPT) for chronic musculoskeletal pain (CMP) patients up until 12 months post-treatment. MATERIALS AND METHODS: Data were gathered during routine clinical practice during a 3-year period (2019-2021) at six Dutch rehabilitation centres. Assessments included patient-reported outcome measures for multiple domains including disability, pain and fatigue. Longitudinal data were analysed using repeated-measures models and by quantifying responder rates. RESULTS: Included were 2309 patients with a mean age of 43.7 (SD 12.9) years, of which 73% female. All outcomes showed significant improvements at each timepoint. At discharge, large effect sizes were found for disability, average and worst pain, fatigue and health-related quality of life. Improvements were largely sustained at 12-months. Relatively large proportions of patients had clinically relevant improvements after treatment (pain-related disability: 60%; average pain: 52%; worst pain: 37.4%; work capacity: 50%; concentration: 50%; fatigue: 46%). Patients who received a treatment extension showed further improvements for all outcome measures, except average pain. CONCLUSIONS: At group level, all outcomes significantly improved with mainly large effect sizes. The results were mostly sustained. The proportion of patients showing clinically relevant improvements tends to be larger than previously reported for mixed CMP patients.

Chronic musculoskeletal pain can be very disabling and impacting participation and quality of life.Often several psychosocial factors contribute to the maintenance of pain and its evolving consequences.In this study, a 61 hours highly individualized interdisciplinary multimodal pain treatment resulted in significant improvements with moderate to very large effect sizes for all important domains like pain, fatigue, disability, work capacity, and quality of life.Care providers as well as health insurers should acknowledge the interdisciplinary multimodal pain programme as an effective treatment in their clinical decision making.

Measurement properties of patient-reported outcome measures used in rehabilitation of adults with chronic musculoskeletal pain: A mapping review.

BACKGROUND: Choosing measurement tools for diagnostic, prognostic, or evaluative purposes in a chronic musculoskeletal pain (CMP) population is challenging for rehabilitation practice. Implementation of measurement tools for clinical practice is impaired by gaps in knowledge about measurement properties. OBJECTIVE: Identifying evidence about the measurement properties of tools frequently used in Dutch pain rehabilitation practice. METHODS: A mapping review was conducted of eligible studies that investigated reliability, validity, or responsiveness, and interpretability, as defined by the COSMIN taxonomy, of original versions or Dutch translations of predefined Patient-Reported Outcome Measures (PROMs) in a CMP population. MEDLINE, PsycINFO, EMBASE, and CINAHL were searched in March 2021. Results were visually mapped. RESULTS: Thirty-five studies were included. The results show many knowledge gaps in both original and translated versions. In general, aspects of validity were most frequently reported. The Pain Disability Index, Pain Catastrophizing Scale, and the 12-Item Short Form Health Survey were the most studied measurement tools. No results were found for the Checklist Individual Strength, Illness Perception Questionnaire, and Utrecht Coping List. CONCLUSION: Little evidence of the measurement properties of PROMs used in rehabilitation of patients with CMP in the Netherlands was found. PROMs need to be used and interpreted with caution in daily practice.

Systematic description of an interdisciplinary multimodal pain treatment programme for patients with chronic musculoskeletal pain, using the TIDieR checklist.

OBJECTIVE: To provide a thorough and systematic description of an interdisciplinary multimodal pain treatment programme (IMPT) for patients with chronic musculoskeletal pain (CMP), using the TIDieR checklist as a guide. RESULTS: The main goal of the 'Centre for Integral Rehabilitation (CIR) Excellent' IMPT is to improve daily functioning, participation and quality of life of patients with CMP by helping them to adapt their behaviour so as to better manage their symptoms. A combination of physical and psychosocial treatment methods is employed, including Emotional Awareness and Expression Therapy (EAET), Pain Neuroscience Education (PNE), Acceptance and Commitment Therapy (ACT), graded activity, exposure in vivo, and experiential learning through physical training. The interdisciplinary treatment team comprises physiotherapists, psychologists and a physiatrist. The programme lasts 10 weeks (61 h in total) and consists of three phases: a start (Week 1), education (Weeks 2-3), and skills learning phase (Weeks 4-10). Patients come in twice a week and participate in 2-4 sessions (3-4 h) per treatment day. The programme consists of both individual (physical and mental coaching) and group sessions (education, movement and behaviour outdoors/indoors). Individualisation through personal goal-setting is an important characteristic of the treatment, as well as frequent interdisciplinary consultation between care providers.

Patient- and clinician-reported outcomes for the additively manufactured sub-periosteal jaw implant (AMSJI) in the maxilla: a prospective multicentre one-year follow-up study.

The clinical outcomes of maxillary rehabilitation with the additively manufactured sub-periosteal jaw implant (AMSJI; CADskills BV) were evaluated in edentulous patients with a Cawood-Howell atrophy classification ≥5 in all regions of the maxilla. Fifteen consecutive patients were included in the study and followed up for 1 year. They were interviewed using a survey protocol and were examined clinically and radiographically preoperatively (T0) and at 1 (T1), 6 (T2), and 12 (T3) months after permanent upper prosthesis placement. The patients reported an increased oral health-related quality of life. The overall mean Oral Health Impact Profile-14 score at T0 was 17.20 (standard deviation (SD) 6.42). When results at T0 were compared to those at T1 (mean 8.93, SD 5.30), a statistically significant difference was seen (P = 0.001). At T3, the mean value was 5.80 (SD 4.18). Compared to T0, there was also a statistically significant difference at T3 (P = 0.001). General satisfaction based on the numerical rating scale was a mean 49.93 at T1, which was less than patient expectation prior to treatment at T0 (52.13). A higher overall value was seen at T3 (53.20) when compared to T0. Within the constraints of the short follow-up, the AMSJI appears to be a promising tool for patients with extreme jaw atrophy. The high patient expectations were met without complications.

Reduced bone activity in the native compartments after medial mobile-bearing unicompartmental knee arthroplasty. A prospective SPECT/CT study.

AIMS: Altered alignment and biomechanics are thought to contribute to the progression of osteoarthritis (OA) in the native compartments after medial unicompartmental knee arthroplasty (UKA). The aim of this study was to evaluate the bone activity and remodelling in the lateral tibiofemoral and patellofemoral compartment after medial mobile-bearing UKA. PATIENTS AND METHODS: In total, 24 patients (nine female, 15 male) with 25 medial Oxford UKAs (13 left, 12 right) were prospectively followed with sequential 99mTc-hydroxymethane diphosphonate single photon emission CT (SPECT)/CT preoperatively and at one and two years postoperatively, along with standard radiographs and clinical outcome scores. The mean patient age was 62 years (40 to 78) and the mean body mass index (BMI) was 29.7 kg/m2 (23.6 to 42.2). Mean osteoblastic activity was evaluated using a tracer localization scheme with volumes of interest (VOIs). Normalized mean tracer values were calculated as the ratio between the mean tracer activity in a VOI and background activity in the femoral diaphysis. RESULTS: Significant reduction of normalized tracer activity was observed one year postoperatively in tibial and femoral VOIs adjacent to the joint line in the lateral compartment. Patellar VOIs and remaining femoral VOIs demonstrated a significant, diminished normalized tracer activity at final follow-up. CONCLUSION: The osteoblastic bone activity in the native compartments decreased significantly after treatment of medial end-stage OA with a UKA, implying reduced stress to the subchondral bone in the retained compartments after a UKA. Cite this article: Bone Joint J 2019;101-B:915-921.

Barriers to recruitment of children with cerebral palsy in a trial of home-based training.

Many trials fail to include the targeted number of participants, causing scientific and ethical problems. The COAD trial of home-based training programs (HBTPs) for children with unilateral cerebral palsy (CP) encountered recruitment problems, even though the parent-delivered home-based approach complies with recent health-care developments in the Netherlands. The current project aimed to identify the barriers to recruitment in the COAD trial. This summative, multidimensional evaluation comprised informal conversational interviews in which stakeholders who had been involved reflected on the factors that impeded successful recruitment of participants into the COAD trial. Barriers to implementation and recruitment were clustered according to the constructs of the Consolidated Framework for Implementation Research (CFIR). Member checking validated the findings. A total of 41 stakeholders contributed to the evaluation. Barriers to the implementation of the HBTPs were identified within every domain of the CFIR (intervention characteristics, outer setting, inner setting, characteristics of individuals, and process). Parent-delivered home-based training was perceived as highly complex and in conflict with the pressures on and the needs of parents. Many parents preferred the alternative center-based group interventions. The involvement of a resonance group was highly valued, and opportunities for further enhancements emerged. Additionally, the importance of research consortia was emphasized. The appropriateness of the RCT as the study design was criticized. The findings of this study are summarized in a tool which provides a dozen directions for the successful recruitment of participants in pediatric rehabilitation research.

Cytomegalovirus pleuropericarditis after orthotopic liver transplantation.

Cytomegalovirus (CMV) reactivation is a common complication after liver transplantation. In patients with CMV infection, indicated by a positive CMV DNA titer, the presence of any clinical symptom is termed CMV disease. The most common organ affected in CMV disease is the gastrointestinal tract, causing esophagitis, gastritis, enteritis or colitis. CMV infection of the pleura and pericard has been reported in immunocompromised patients, but is rarely seen following liver transplantation.We report a case of a 59-year-old male who developed CMV pleuropericarditis after liver transplantation. Initial ganciclovir treatment did not improve the patient's symptoms and therapy was switched to Foscarnet which ultimately resulted in resolution of infection. However, a few weeks after Foscarnet cessation, the patient again developed bilateral pleural effusion. Ultimate biochemical and clinical response was achieved with IV ganciclovir treatment. The patient was discharged from the hospital with oral Valganciclovir for 3 weeks and has since remained relapse free for >1 year.

Feasibility and effect of home-based therapy programmes for children with cerebral palsy: a protocol for a systematic review.

INTRODUCTION: Given the promising advantages of upper extremity home-based programmes in children with cerebral palsy (CP), a systematic review of the available literature on this topic is warranted. The purpose of the systematic review described in this protocol is to investigate currently available home-based occupational therapy and physiotherapy programmes regarding both their feasibility and effect. METHODS AND ANALYSIS: This protocol describes a systematic review, developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015. Studies will be included in which primary data are collected, participants are children aged <18 years with any type of CP and the intervention of interest is a home-based occupational therapy or physiotherapy intervention. Comparators of interest are: no therapy, care as usual, centre-based occupational therapy or physiotherapy, an alternative home-based programme and a medical intervention. Studies will be included that report either on feasibility (ie, acceptability, demand, implementation, practicality, adaptation, expansion or integration) or on efficacy/effectiveness (ie, child-related upper extremity outcomes within all International Classification of Functioning, Disability and Health levels or parent-related/caregiver-related outcomes on the psychological and social domain). Relevant studies will be identified by searching the databases MEDLINE, EMBASE, CINAHL, PsycINFO, PEDro, OTSeeker and CPCI-S as well as the trial registers ICTRP and CENTRAL, the reference lists of included records and by circulating a bibliography of the included records to authors of included studies. There will be no restrictions on language or year of publication. The search strategy consists of terms related to the population and intervention. Data will be extracted in duplicate using a digital data extraction form. ETHICS AND DISSEMINATION: The proposed study does not involve collection of primary data. Accordingly, no ethical approval is required. The authors will disseminate the findings of this systematic review through publication in a peer-reviewed journal and conference presentation(s). TRIAL REGISTRATION NUMBER: CRD42016043743; pre-results.

Leukocyte CD40L deficiency affects the CD25(+) CD4 T cell population but does not affect atherosclerosis.

Inhibition of CD40-CD40L interactions results in a reduction of innate regulatory T cells (Tregs) in CD40(-/-) mice and induces a stable plaque phenotype in atherosclerosis-prone mouse strains. Here we investigated the effects of leukocyte CD40L on the Treg population and on atherosclerosis. LDLR(-/-) mice were reconstituted with wild-type or CD40L(-/-) bone marrow (BM). These BM chimeras were analysed by flow cytometry for the presence of innate Tregs (CD45RB(low) CD25(+) CD4) in lymphoid organs and peripheral blood. As in CD40(-/-) mice, the CD45RB(high):CD45RB(low) CD4 T cell ratio significantly increased and the CD25(+) CD4(+) subpopulation significantly decreased in LDLR(-/-) mice receiving CD40L(-/-) BM compared to LDLR(-/-) mice receiving wild-type BM. However, atherosclerotic plaque progression and plaque phenotype did not change in LDLR(-/-) mice reconstituted with CD40L(-/-) BM. In conclusion, the present study shows that CD40-CD40L interactions on leukocytes are essential for the size of the CD45RB(low) CD25(+) CD4 Treg subpopulation. Nevertheless, CD40L deficiency on hemopoietic cells did not affect atherosclerosis, implying that CD40L expressing leukocytes alone are not responsible for the stable plaque phenotype observed after total CD40L blockade.

Deep decortication in nonunion of shaft fractures.

For many years we have used the "petal" technique of Jarry and Uhthoff in all cases of delayed union or nonunion of long bones. With a chisel or a gouge, cuts are made in the cortical surface of the bone on both sides of the fracture line, and numerous scales are lifted but remain attached at the base, like the petals of a flower. Depending on the cortical thickness, the petals are 2 to 4 mm thick. The surface area of the bone is increased and the haversian canals under the cortical surface (and the blood vessels) are cut open, exposing numerous areas of well-vascularized and highly osteogenetic tissue on all of the exposed surface of the bone. We were able to retrace 26 cases treated in this way between 1968 and 1988. Different types of fixation were used, depending on type and location of the fracture, but sometimes also because we preferred not to change the fixation that had been applied before the patient was referred to us. All fractures united after one operation, in 3 to 18 months. In one case of nonunion of the ulna, with bone loss by gunshot wound, the fracture united, but a stress fracture through a screw hole occurred distally to the fracture site. It did not unite and reoperation was refused. In most cases we have added autogenous spongiosa only grafts, but we think now that their use is questionable in many instances. This technique is quite similar to the subperiosteal decortication of Judet or the shingling technique as described by Forbes.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of lordosis.

A majority of degenerative changes in the vertebral discs, the facet joints or even the interspinous ligaments, as in Baastrup's disease, are probably caused by pressure damage. Among the various causes of overloading, hyperlordosis--alone or in combination with other adjuvant causes--is presumably the most important one. Its detrimental influence is most noticeable in some peculiar situations, where lordosis is the common denominator of malformations of different origins, as, for instance, dorsal and dorsolumbar kyphosis, L4-5 facetarthrosis with L5-S1 spondylolisthesis, and posterior or posterolateral distraction arthrodesis. It is now recognized that arthrodesis in the lumbar spine should be done in normal lordosis or even slight hyperlordosis in order to respect, or even to improve the stress distribution in the mobile segments. After lumbosacral arthrodesis, as well as in common "everyday" low back pain problems, protection of the disks and facet joints from prolonged continuous loading is essential for the prevention of continuing degeneration.

Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis.

The growth arrest-specific gene 6 (Gas6) plays a role in pro-atherogenic processes such as endothelial and leukocyte activation, smooth muscle cell migration and thrombosis, but its role in atherosclerosis remains uninvestigated. Here, we report that Gas6 is expressed in all stages of human and mouse atherosclerosis, in plaque endothelial cells, smooth muscle cells and macrophages. Gas6 expression is most abundant in lesions containing high amounts of macrophages, ie thin fibrous cap atheroma and ruptured plaque. Genetic loss of Gas6 does not affect the number and size of initial and advanced plaques in ApoE(-/-) mice, but alters its plaque composition. Compared to Gas6(+/+): ApoE(-/-) mice, initial and advanced plaques of Gas6(-/-): ApoE(-/-) mice contained more smooth muscle cells and more collagen and developed smaller lipid cores, while the expression of TGFbeta was increased. In addition, fewer macrophages were found in advanced plaques of Gas6(-/-): ApoE(-/-) mice. Hence, loss of Gas6 promotes the formation of more stable atherosclerotic lesions by increasing plaque fibrosis and by attenuating plaque inflammation. These findings identify a role for Gas6 in plaque composition and stability.