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Background: The MAKO Robotic-Arm system is a cutting-edge technology which combines both computed tomography (CT) scanning and three-dimensional planning to determine the ideal size and orientation of implants prior to bone resection. It is typically utilized within a general orthopedic setting for joint replacement procedures, such as total joint arthroplasties. However, its use within orthopedic oncology, which contains a much more compromised patient population and more complex surgical treatment, is not well documented within the literature., Question/purposes: To determine the patient outcomes of those who underwent a total hip arthroplasty (THA) or total knee arthroplasty (TKA) at Morristown Medical Center using the MAKO Robotic-Arm System. Particularly, we aspired to delve into the use of the MAKO in an orthopedic oncology setting for patients with a degenerative hip or knee and a history of cancer or other orthopedic tumor, impending pathological fracture, PVNS, chondromatosis, radiation therapy, or other oncological related conditions., Patients and Methods: Our institution monitored twenty-five individuals with unique orthopedic oncology conditions that underwent MAKO robotic-assisted total hip and knee arthroplasty. This was performed between 2020 and 2022 at Morristown Medical Center in New Jersey. During this time period, 52% (13/25) of the operations were performed on knees and 48% (12/25) were performed on hips. Data regarding patient demographics, body mass index (BMI), medications, hemoglobin, hematocrit, comorbidities, American Society of Anesthesiologists (ASA) Class, operative data, the length of stay (LOS), readmission rates due to infection or periprosthetic fractures, and complications were collected retrospectively. All confidence intervals were calculated at the 95% confidence level., Results: Postoperatively, the average LOS was 3.2 days, and there were no complications after any of the MAKO-assisted joint arthroplasty procedures. Additionally, there were no readmissions at any of our recorded intervals - 1-30, 1-60, 1-90, and 1 year - however one patient presented to the emergency department after falling 4 days post-operatively. X-ray imaging ultimately revealed no periprosthetic fracture or malalignment of the prosthesis., Conclusions: The utilization of the MAKO Robotic-Arm System for joint arthroplasty procedures (THAs and TKAs) on orthopedic oncology patients yielded exceptional outcomes, with no complications or readmissions directly attributed to the use of this innovative robotic technology. Thus, this newly emerging surgical system holds great promise, potentially revolutionizing the approach for selected orthopedic oncology patients undergoing total joint arthroplasty compared to the traditional manual techniques. It further demonstrates that its use in an orthopedic oncology setting - where the cohort of patients are often compromised, leading to more intricate surgeries with heightened risks - elicits safety and provides optimal outcomes for patients. Nevertheless, its role within the field is evolving, and in the coming years, as it gains further popularity and sees broader application by orthopedic oncology surgeons, its potential will become clearer. To solidify its position, future clinical investigations and prospective research should be conducted to support the preference of the MAKO system over traditional manual techniques. This will help provide the necessary evidence to advocate for its widespread adoption and continued advancements in orthopedic oncology procedures., (© 2023 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Purpose: To compare the time to publication of accepted manuscripts and content in orthopaedic sports medicine journals during the first 2 years of the COVID-19 pandemic., Methods: A convenience sample of articles published in January, May, and September during the years 2019-2021 was taken from Arthroscopy , American Journal of Sports Medicine (AJSM) , and Knee Surgery, Sports Traumatology, Arthroscopy ( KSSTA ). The duration between the aspects of the article publication process was compared between journals and years., Results: Overall, 826 journal articles were included. Arthroscopy demonstrated no significant differences in the time from manuscript submission to journal publication from 2019 to 2021, a significant decrease in time from acceptance to e-Pub (140 vs 74 vs 16 days; P < .001), but an increase from e-Pub to journal publication (23 vs 74 vs 130 days; P < .001). In AJSM , there was an overall increase in time from submission to journal publication significant between 2019 and 2021 ( P  = .05) and 2020 and 2021 ( P  = .001). KSSTA demonstrated the longest timelines in 2020. There was a trend toward a greater number of systematic reviews and meta-analyses., Conclusion: Changes in various aspects of the time to publication and journal content occurred in orthopaedic sports medicine journals in the years surrounding the peak of the COVID-19 pandemic in 2020. Although it is not possible to know whether these delays are caused by journal or author-related factors, orthopaedic surgeons should be aware of the possible delay in time to publication and consider online and e-publication resources for the most current evidence-based medicine, while journals may take this information into account to consider ways of improving the publication process and when determining journal content., Clinical Relevance: It is important to understand the impact the COVID-19 pandemic had on the publications which orthopaedic sports medicine surgeons rely on for clinical knowledge and the practice of evidence-based medicine., (© 2023 The Authors.)

Primary prevention is the cornerstone of public health. Prevention is especially important for chronic diseases of significant burden such as mental illnesses because many of them have limited treatment options, an onset in childhood or in adolescence, and are linked to adverse childhood experiences requiring a focus on early childhood and maternal-child health (MCH). Despite this need, there appears to be a paucity of research into prevention of mental illnesses within public health. To confirm this, we performed a systematic literature review to quantify the proportion of articles in public health that focus on prevention of mental illness versus intervention for these illnesses after their onset, and the proportion of published articles within MCH that focus on mental health. Between November 2019 and August 2021, we reviewed 211,794 published articles from 147 Scimago-ranked English public health journals with no limit on year of publication. As hypothesized, a very small portion (2.2%) of mental health articles included primary prevention and a small portion of MCH articles (7.8%) included mental health. These results are consistent with the existence of a research gap in mental illness prevention within the public health field. Given the early onset of mental illness, the importance of early childhood experiences in the later development of mental illness, and the importance of the social-emotional connection between mother and child for building resilience, public health professionals must incorporate evidence from the field of MCH to develop and assess more primary prevention programs for mental illness., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)

There is evidence that universal school-based mindfulness training (SBMT) can have positive effects for young people. However, it is unknown who benefits most from such training, how training exerts effects, and how implementation impacts effects. This study aimed to provide an overview of the evidence on the mediators, moderators, and implementation factors of SBMT, and propose a conceptual model that can be used both to summarize the evidence and provide a framework for future research. A scoping review was performed, and six databases and grey literature were searched. Inclusion and exclusion criteria were applied to select relevant material. Quantitative and qualitative information was extracted from eligible articles and reported in accordance with PRISMA-ScR guidelines. The search produced 5479 articles, of which 31 were eligible and included in the review. Eleven studies assessed moderators of SBMT on pupil outcomes, with mixed findings for all variables tested. Five studies examined the mediating effect of specific variables on pupil outcomes, with evidence that increases in mindfulness skills and decreases in cognitive reactivity and self-criticism post-intervention are related to better pupil outcomes at follow-up. Twenty-five studies assessed implementation factors. We discuss key methodological shortcomings of included studies and integrate our findings with existing implementation frameworks to propose a conceptual model. Widespread interest in universal SBMT has led to increased research over recent years, exploring who SBMT works for and how it might work, but the current evidence is limited. We make recommendations for future research and provide a conceptual model to guide theory-led developments., (© 2022. The Author(s).)

Background: Education is broader than academic teaching. It includes teaching students social-emotional skills both directly and indirectly through a positive school climate., Objective: To evaluate if a universal school-based mindfulness training (SBMT) enhances teacher mental health and school climate., Methods: The My Resilience in Adolescence parallel group, cluster randomised controlled trial (registration: ISRCTN86619085; funding: Wellcome Trust (WT104908/Z/14/Z, WT107496/Z/15/Z)) recruited 85 schools (679 teachers) delivering social and emotional teaching across the UK. Schools (clusters) were randomised 1:1 to either continue this provision (teaching as usual (TAU)) or include universal SBMT. Data on teacher mental health and school climate were collected at prerandomisation, postpersonal mindfulness and SBMT teacher training, after delivering SBMT to students, and at 1-year follow-up., Finding: Schools were recruited in academic years 2016/2017 and 2017/2018. Primary analysis (SBMT: 43 schools/362 teachers; TAU: 41 schools/310 teachers) showed that after delivering SBMT to students, SBMT versus TAU enhanced teachers' mental health (burnout) and school climate. Adjusted standardised mean differences (SBMT minus TAU) were: exhaustion (-0.22; 95% CI -0.38 to -0.05); personal accomplishment (-0.21; -0.41, -0.02); school leadership (0.24; 0.04, 0.44); and respectful climate (0.26; 0.06, 0.47). Effects on burnout were not significant at 1-year follow-up. Effects on school climate were maintained only for respectful climate. No SBMT-related serious adverse events were reported., Conclusions: SBMT supports short-term changes in teacher burnout and school climate. Further work is required to explore how best to sustain improvements., Clinical Implications: SBMT has limited effects on teachers' mental and school climate. Innovative approaches to support and preserve teachers' mental health and school climate are needed., Competing Interests: Competing interests: WK is the Director of the Oxford Mindfulness Centre and receives royalties for several books on mindfulness. JMGW is former Director of the Oxford Mindfulness Centre and receives royalties for several books on mindfulness., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Systematic reviews suggest school-based mindfulness training (SBMT) shows promise in promoting student mental health., Objective: The My Resilience in Adolescence (MYRIAD) Trial evaluated the effectiveness and cost-effectiveness of SBMT compared with teaching-as-usual (TAU)., Methods: MYRIAD was a parallel group, cluster-randomised controlled trial. Eighty-five eligible schools consented and were randomised 1:1 to TAU (43 schools, 4232 students) or SBMT (42 schools, 4144 students), stratified by school size, quality, type, deprivation and region. Schools and students (mean (SD); age range=12.2 (0.6); 11-14 years) were broadly UK population-representative. Forty-three schools (n=3678 pupils; 86.9%) delivering SBMT, and 41 schools (n=3572; 86.2%) delivering TAU, provided primary end-point data. SBMT comprised 10 lessons of psychoeducation and mindfulness practices. TAU comprised standard social-emotional teaching. Participant-level risk for depression, social-emotional-behavioural functioning and well-being at 1 year follow-up were the co-primary outcomes. Secondary and economic outcomes were included., Findings: Analysis of 84 schools (n=8376 participants) found no evidence that SBMT was superior to TAU at 1 year. Standardised mean differences (intervention minus control) were: 0.005 (95% CI -0.05 to 0.06) for risk for depression; 0.02 (-0.02 to 0.07) for social-emotional-behavioural functioning; and 0.02 (-0.03 to 0.07) for well-being. SBMT had a high probability of cost-effectiveness (83%) at a willingness-to-pay threshold of £20 000 per quality-adjusted life year. No intervention-related adverse events were observed., Conclusions: Findings do not support the superiority of SBMT over TAU in promoting mental health in adolescence., Clinical Implications: There is need to ask what works, for whom and how, as well as considering key contextual and implementation factors., Trial Registration: Current controlled trials ISRCTN86619085. This research was funded by the Wellcome Trust (WT104908/Z/14/Z and WT107496/Z/15/Z)., Competing Interests: Competing interests: WK is the Director of the Oxford Mindfulness Centre and receives royalties for several books on mindfulness. JMGW is former Director of the Oxford Mindfulness Centre and receives royalties for several books on mindfulness., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: The effectiveness of mindfulness-based programs (MBPs) has been established in many randomized controlled trials. However, effect sizes are often modest, and there remains ample scope to improve their effectiveness. One approach to this challenge is to offer a "follow-on" course to people who have completed an MBP and are interested in further skill development. We developed and tested a new 8-week course for this purpose based on awareness of feeling tone ( vedanā ), an understudied aspect of mindfulness in many current MBPs, incorporating new developments in neuroscience and trauma sensitivity. We examined its effectiveness and the frequency and severity of unpleasant experience and harm., Methods: In an open trial, 83 participants, 78 of whom had previously taken part in an MBP (majority MBSR or MBCT), completed the program in nine groups. Participants completed questionnaires before and after and gave qualitative written feedback at completion., Results: Participants reported significantly reduced depression ( d  = 0.56), stress ( d  = 0.36), and anxiety ( d  = 0.53) and increased well-being ( d  = 0.54) and mindfulness ( d  = 0.65) with 38% meeting criteria for reliable change on anxiety and depression. As expected, about three-quarters of participants reported some unpleasant experiences associated with mindfulness practice during the course, but none reported harm. Five participants showed "reliable deterioration" (an increase) in either depression or anxiety, but four of these five also gave anonymous qualitative feedback describing benefits of the course., Conclusions: Findings support the added value of a follow-on course based on the exploration of feeling tone for participants who have a range of previous mindfulness experience., Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-01929-0., Competing Interests: Conflict of InterestMark Williams, Chris Cullen, and Ruth Baer are affiliated with the Oxford Mindfulness Centre and receive occasional payments for training workshops and presentations related to mindfulness. Ruth Baer and Chris Cullen both have part-time employment with the Oxford Mindfulness Centre. Mark Williams and Ruth Baer also receive royalties for several books related to mindfulness. At the outset of the study, Laura Taylor, Emma Medlicott, Kath De Wilde, and Lucy Radley were affiliated with the Oxford Mindfulness Centre and funded by the Wellcome Trust on a strategic award exploring the role of mindfulness training in adolescence. They do not receive additional remuneration for training workshops or presentations related to mindfulness. Barbara Gerber, Mandy Johnson, Linda Kantor, Janine Kirby, and Matthew Watkin are affiliated to the Institute of Mindfulness South Africa and receive payment as mindfulness teachers as well as occasional payments for training workshops and presentations related to mindfulness. Melanie Fennell was a former member of The Department of Psychiatry at the University of Oxford and associated with the Oxford Mindfulness Centre. She receives occasional payments for training workshops and presentations related to mindfulness, and royalties from a book related to mindfulness. Helen Ma was formerly Director of the Hong Kong Mindfulness Centre and is associated with the Oxford Mindfulness Centre as their China Advisor. Ee-Lin Ong and Andy Phee are affiliated to the Oxford Mindfulness Centre as Teaching Partners, and receive payment as mindfulness teachers as well as occasional payments for training workshops and presentations related to mindfulness. Rebecca Crane is Director of the Bangor University Centre for Mindfulness Research and Practice, School of Psychology, and receives royalties from two books related to mindfulness. Danny Penman is an independent scholar and author and receives occasional payments for training workshops and presentations related to mindfulness. He also receives royalties for several books related to mindfulness. John Peacock and Martine Batchelor receive occasional payments for retreats, trainings, and presentations related to mindfulness and Buddhist psychology., (© The Author(s) 2022.)

Objective: Recent studies suggest mental health in youths is deteriorating. The current policy in the United Kingdom emphasizes the role of schools for mental health promotion and prevention, but little data exist on what aspects of schools influence mental health in pupils. This study explored school-level influences on the mental health of young people in a large school-based sample from the United Kingdom., Method: Baseline data from a large cluster randomized controlled trial collected between 2016 and 2018 from mainstream secondary schools selected to be representative in relation to their quality rating, size, deprivation, mixed or single-sex pupil population, and country were analyzed. Participants were pupils in their first or second year of secondary school. The study assessed whether school-level factors were associated with pupil mental health., Results: The study included 26,885 pupils (response rate = 90%; age range, 11‒14 years; 55% female) attending 85 schools in the United Kingdom. Schools accounted for 2.4% (95% CI: 2.0%‒2.8%; p < .0001) of the variation in psychopathology, 1.6% (95% CI: 1.2%‒2.1%; p < .0001) of depression, and 1.4% (95% CI: 1.0%‒1.7%; p < .0001) of well-being. Schools in urban locations, with a higher percentage of free school meals and of White British, were associated with poorer pupil mental health. A more positive school climate was associated with better mental health., Conclusion: School-level variables, primarily related to contextual factors, characteristics of pupil population, and school climate, explain a small but significant amount of variability in mental health of young people. This information might be used to identify schools that are in need of more resources to support mental health of young people., Clinical Trial Registration Information: MYRIAD: My Resilience in Adolescence, a Study Examining the Effectiveness and Cost-Effectiveness of a Mindfulness Training Programme in Schools Compared With Normal School Provision; https://www.isrctn.com/; 86619085., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Streptococcus zooepidemicus is an animal commensal with the potential of zoonotic transmission through ingestion of contaminated dairy products, leading to outbreaks of Post-Streptococcal Glomerulonephritis (PSGN). We report for the first time acute renal failure with need for renal replacement therapy, as a complication of S. zooepidemicus bacteremia resulting from direct horse to human transmission in a young adult. Both clinical disease course and immunohistochemical staining patterns on renal biopsy had some atypical features of PSGN suggesting persistent activation of the alternative complement pathway but no known complement factor dysregulations could be identified.

Objectives: A20 is an important endogenous regulator of inflammation. Single nucleotide polymorphisms in A20 have been associated with various immune-mediated inflammatory diseases, and cell-specific deletion of A20 results in diverse inflammatory phenotypes. Our goal was to delineate the underlying mechanisms of joint inflammation in myeloid-specific A20-deficient mice (A20 myelKO mice)., Methods: Inflammation in A20 myelKO mice was assessed in a time-dependent manner. Western blot analysis and quantitative PCR analysis were performed on bone marrow-derived macrophages from A20 myelKO and littermate control mice to study the effect of A20 on STAT1/STAT3 expression and STAT1/STAT3-dependent gene transcription in myeloid cells. The in vivo role of Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling in the development of enthesitis in A20 myelKO mice was assessed following administration of a JAK inhibitor versus placebo control., Results: Enthesitis was found to be an early inflammatory lesion in A20 myelKO mice. A20 negatively modulated STAT1-dependent, but generally not STAT3-dependent gene transcription in myeloid cells by suppressing STAT1 but not STAT3 expression, both in unstimulated conditions and after interferon-γ or interleukin-6 stimulation. The increase in STAT1 gene transcription in the absence of A20 was shown to be JAK-STAT-dependent. Moreover, JAK inhibition in vivo resulted in significant reduction of enthesitis, both clinically and histopathologically., Conclusions: Our data reveal an important and novel interplay between myeloid cells and tissue resident cells at entheseal sites that is regulated by A20. In the absence of A20, STAT1 but not STAT3 expression is enhanced leading to STAT1-dependent inflammation. Therefore, A20 acts as a novel endogenous regulator of STAT1 that prevents onset of enthesitis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: The European Scleroderma Study Group (EScSG) activity index meets nearly all the OMERACT-standards of truth, discrimination and feasibility. The sensitivity to change remains to be attested. This study assesses sensitivity to change of the EScSG activity index in patients with early and severe diffuse cutaneous Systemic Sclerosis (dcSSc) treated with rituximab., Methods: 12-month follow-up (open-label study) of 14 consecutive patients with early dcSSc. Patients received an infusion of two times 1000 mg rituximab at month 0 and 6, together with 100 mg methylprednisolone. Clinical read outs (modified Rodnan skin score [mRSS], lung function and echocardiography) and EScSG activity index were performed at month 0, 3, 6 and 12. Mixed models analyses (MMA) were used to evaluate changes in parameters over time., Results: There was a clinically significant change in skin score with a mean (SD) mRSS of 24.8 (4.44) at baseline and 10.4 (3.12) at month 12 (MMA p<0.001). Also the EScSG activity index decreased significantly, with a mean (SD) of 4.3 (1.79) at baseline and 0.7 (0.83) at month 12 (MMA p<0.001). The estimated mean change of the EScSG activity index was -3.6 (95%CI -4.9; -2.4) over 12 months. Indices of internal organ involvement remained stable throughout the study., Conclusions: A significant improvement of the EScSG activity index was observed, in line with the significant improvement of the mRSS and the stabilisation of internal organ involvement. To our knowledge, this is the first study to attest sensitivity to change of the EScSG activity index in the subset of 'early' dcSSc., Trial Registration: ClinicalTrials.gov Registration, http://clinicaltrials.gov, number NCT00379431.

Objectives: The objectives of our study were (1) to explore knowledge, beliefs and practice among midwives and gynecologists concerning a smoking cessation policy for pregnant women and their partners and (2) to examine if midwives and gynecologists do have a role in smoking cessation in pregnant women., Method: We performed a qualitative study using semi-structured interviews with nine midwives and eight gynecologists. Data were analyzed using deductive content analysis, based on the 5 A's framework (Ask-Advise-Assess-Assist-Arrange)., Results: The national smoking cessation policy seemed to be insufficiently known. "Ask" and "Advise" were part of a standard prenatal consultation, the next three steps were rarely implemented. Participants had a negative image of "the smoking pregnant woman": a low educated woman with a smoking partner and "bad examples" in their history. Reported barriers were fear of provoking resistance and lack of time and communication skills regarding smoking cessation., Conclusions: These findings suggest that training in communication skills and dealing with resistance should be offered, i.e. by using motivational interviewing. It could be considered that a trained midwife or tobaccologist is part of an obstetrical team or that the AAR-method (Ask-Advise-Refer) is used instead of the 5 A's framework., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose of Review: The association between spondyloarthritis (SpA) and inflammatory bowel disease (IBD) is well known. Additionally, about half of SpA patients show microscopic gut inflammation. Substantial progress has been made in understanding the pathogenesis of SpA and IBD, with new therapeutic targets for either of them in clinical development., Recent Findings: Microscopic gut inflammation was found in early forms of SpA in about 50% of cases and is associated with age, sex, disease activity and degree of MRI inflammation on sacroiliac joints. Although prospective follow-up data in men and murine animal studies show a parallelism between gut and joint evolution in SpA, therapeutic outcomes are not always the same in SpA and IBD. These differences can be ascribed to differences in not only the cytokine pathways and cells involved in disease, tissue localization and environmental factors but also in pharmacokinetics and biodistribution., Summary: A significant amount of data all point in the direction of arthritis and gut inflammation being pathogenetically closely linked in the SpA concept. However, when it comes to therapeutic effectiveness, the gut and the joints do not always react in the same way. These differences in therapeutic effect could be attributed to the different ways in which cytokine pathways are involved in SpA and IBD.

The regulatory role of the thymic microenvironment during trafficking and differentiation of the invariant NKT (iNKT) cell lineage remains poorly understood. In this study, we show that fractalkine receptor expression marks emigrating subpopulations of the NKT1, NKT2, and NKT17 sublineages in the thymus and peripheral organs of naive mice. Moreover, NKT1 sublineage cells can be subdivided into two subsets, namely NKT1(a) and NKT1(b), which exhibit distinct developmental and tissue-specific distribution profiles. More specifically, development and trafficking of the NKT1(a) subset are selectively dependent upon lymphotoxin (LT)α1β2-LTβ receptor-dependent differentiation of thymic stroma, whereas the NKT1(b), NKT2, and NKT17 sublineages are not. Furthermore, we identify a potential cellular source for LTα1β2 during thymic organogenesis, marked by expression of IL-7Rα, which promotes differentiation of the NKT1(a) subset in a noncell-autonomous manner. Collectively, we propose a mechanism by which thymic differentiation and retention of the NKT1 sublineage are developmentally coupled to LTα1β2-LTβ receptor-dependent thymic organogenesis., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Objective: Transforming growth factor β superfamily members are involved in the pathogenesis of systemic sclerosis (SSc). Growth differentiation factor 15 (GDF-15) is a distant member of this family. We undertook this study to evaluate the role of GDF-15 in SSc pathogenesis., Methods: A longitudinal prospective cohort of SSc patients was screened for serum GDF-15 levels using enzyme-linked immunosorbent assay, and associations with clinical data were analyzed. In vitro stimulation experiments were performed on lung fibroblasts. The role of GDF-15 in fibrosis development in vivo was evaluated in the bleomycin lung fibrosis model in GDF-15-deficient mice., Results: GDF-15 was measured at baseline in serum samples from 119 SSc patients. An increase in GDF-15 levels was observed in patients classified as having no skin involvement, those with limited cutaneous SSc, and those with diffuse cutaneous SSc. Moreover, baseline serum GDF-15 levels correlated strongly with disease activity and extent of organ involvement, particularly clinical symptoms of lung fibrosis, including impact on lung function at prospective followup. This was mimicked in the bleomycin model of SSc, in which animals exposed to bleomycin had elevated expression levels of GDF-15 in lung tissue. Lung fibroblasts isolated from GDF-15-deficient mice showed reduced induction of interleukin-6 and CCL2 upon bleomycin stimulation. Surprisingly, no differences in fibrosis development were observed between wild-type and GDF-15-deficient animals., Conclusion: An intriguing profile of serum GDF-15 levels was found in SSc patients. GDF-15 expression is induced during fibrosis development and markedly correlates with lung function impairment in this disease. The protein may participate in fibrosis initiation, but is not indispensable in the course of fibrosis development in vivo., (Copyright © 2014 by the American College of Rheumatology.)

Nanobodies® (VHHs) provide powerful tools in therapeutic and biotechnological applications. Nevertheless, for some applications, bivalent antibodies perform much better, and for this, an Fc chain can be fused to the VHH domain, resulting in a bivalent homodimeric VHH-Fc complex. However, the production of bivalent antibodies in Escherichia coli is rather inefficient. Therefore, we compared the production of VHH7 and VHH7-Fc as antibodies of interest in Arabidopsis seeds for detecting prostate-specific antigen (PSA), a well-known biomarker for prostate cancer in the early stages of tumour development. The influence of the signal sequence (camel versus plant) and that of the Fc chain origin (human, mouse or pig) were evaluated. The accumulation levels of VHHs were very low, with a maximum of 0.13% VHH of total soluble protein (TSP) in homozygous T3 seeds, while VHH-Fc accumulation levels were at least 10- to 100-fold higher, with a maximum of 16.25% VHH-Fc of TSP. Both the camel and plant signal peptides were efficiently cleaved off and did not affect the accumulation levels. However, the Fc chain origin strongly affected the degree of proteolysis, but only had a slight influence on the accumulation level. Analysis of the mRNA levels suggested that the low amount of VHHs produced in Arabidopsis seeds was not due to a failure in transcription, but rather to translation inefficiency, protein instability and/or degradation. Most importantly, the plant-produced VHH7 and VHH7-Fc antibodies were functional in detecting PSA and could thus be used for diagnostic applications., (© 2013 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.)

Among the many plant-based production systems that are being tested for molecular farming, seeds are very attractive, as they provide a stable environment in which the accumulating recombinant proteins can be stored. However, it is not known exactly how high production levels of recombinant antibodies influence the endogenous transcriptome and proteome of the developing seed. To address this question, we studied the transcriptomic status in developing Arabidopsis (Arabidopsis thaliana) seeds 13 d post anthesis of three transgenic lines, producing varying levels of recombinant VHH or single-chain Fv antibody fragments fused to the human immunoglobulin G1-derived Fc fragment under the control of the β-PHASEOLIN seed-specific promoter. Using genome-wide Tiling arrays, we demonstrated that only a small proportion of the transcriptome was significantly changed in each of the lines compared with the wild type. Strikingly, in all three lines, we found a large overlap of up-regulated genes corresponding to protein folding, glycosylation/modification, translocation, vesicle transport, and protein degradation, suggestive of a state of cellular stress called the unfolded protein response. Moreover, the gene up-regulation amplitude was similar in all three lines. We hypothesize that the production of recombinant antibodies in the endoplasmic reticulum triggers endoplasmic reticulum stress, causing a disturbance of the normal cellular homeostasis.

We report on a 27-year-old woman who developed severe arterial hypertension on a background of general malaise within 48 hours after vaginal delivery, suggesting severe acute-onset pre-eclampsia. Concomitant biochemical observations of haemolysis, elevated liver tests and low platelets lead to the diagnosis of (post-partum) HELLP syndrome. Our patient was transferred immediately to the intensive care unit (ICU), where she underwent plasmapheresis in combination with intravenous glucocorticoids, nicardipine and labetalol. Our patient recovered fully after three plasmapheresis sessions. Genetic testing of mutations responsible for complement deficits was negative.

Transgenic plants for the production of high-value recombinant complex and/or glycosylated proteins are a promising alternative for conventional systems, such as mammalian cells and bacteria. Many groups use plants as production platform for antibodies and antibody fragments. Here, we describe how bivalent camel-like antibodies can be produced in leaves and seeds. Camel-like antibodies are fusions of the antigen-binding domain of heavy chain camel antibodies (VHH) with an Fc fragment of choice. Transient expression in Nicotiana benthamiana leaves allows the production of VHH-Fc antibodies within a few days after the expression plasmid has been obtained. Generation of stable Arabidopsis thaliana transformants allows production of scalable amounts of VHH-Fc antibodies in seeds within a year. Further, we describe how the in planta-produced VHH-Fc antibodies can be quantified by Western blot analysis with Fc-specific antibodies.

We describe an attractive cloning system for the seed-specific expression of recombinant proteins using three non-food/feed crops. A vector designed for direct subcloning by Gateway® recombination was developed and tested in Arabidopsis, tobacco and petunia plants for the production of a chimeric form (GAD67/65) of the 65 kDa isoform of glutamic acid decarboxylase (GAD65). GAD65 is one of the major human autoantigens involved in type 1 diabetes (T1D). The murine anti-inflammatory cytokine interleukin-10 (IL-10) was expressed with the described system in Arabidopsis and tobacco, whereas proinsulin, another T1D major autoantigen, was expressed in Arabidopsis. The cost-effective production of these proteins in plants could allow the development of T1D prevention strategies based on the induction of immunological tolerance. The best yields were achieved in Arabidopsis seeds, where GAD67/65 reached 7.7% of total soluble protein (TSP), the highest levels ever reported for this protein in plants. IL-10 and proinsulin reached 0.70% and 0.007% of TSP, respectively, consistent with levels previously reported in other plants or tissues. This versatile cloning vector could be suitable for the high-throughput evaluation of expression levels and stability of many valuable and difficult to produce proteins., (© 2011 The Authors. Plant Biotechnology Journal © 2011 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.)

Plants offer a number of attractive benefits over conventional mammalian or bacterial cell culture systems for the production of valuable pharmaceutical and industrial proteins. Currently, antibodies and their derived fragments represent the largest and most important group of biotechnological products in clinical trials. In particular, single-chain antibodies are an interesting class of biopharmaceuticals because they are able to overcome specific problems associated with full-length antibodies. Another valuable antibody format is the scFv-Fc: fusion of the Fc domain to a single-chain variable fragment restores antibody effector functions, allows purification, and mimics, despite being a 'single-gene' product, the bivalent properties of a full-length IgG. Although many different plant-based production platforms have been evaluated for antibody production, seeds are especially attractive because, as natural storage organs, they provide an optimal biochemical environment for the accumulation and long-term storage of large amounts of functional proteins. This chapter describes how to achieve high-level seed-specific expression of antibody fragments, how to select the best transgenic lines, and how to evaluate the accumulation level in the seed stocks from the selected lines.

Online hemodiafiltration (HDF) is an extracorporeal technique for solute removal in renal failure, which takes advantage of an enhancement of convective treatment by the large amount of ultrapure nonpyrogen dialysate being used for substitution of the ultrafiltered volume. It offers many advantages aside from its safe inflammatory profile, which is attributable to the use of ultrapure dialysate and highly biocompatible dialysis membranes. Due to an improved convective clearance, significantly increased removal of large or protein-bound uremic retention solutes can be achieved, with a potential benefit on cardiovascular morbidity and mortality. Recent observational data indicate that online HDF offers a survival advantage even after adjustment for comorbidity and dialysis efficiency. Research has been ongoing to maximize further the effectiveness of the technique by new technical innovations such as transmembrane-pressure feedback control or mid-dilution online HDF.

Primers targeting 16S rRNA genes were designed to detect and quantify Eikelboom type 021N organisms by real-time PCR. Eikelboom type 021N filamentous bulking was induced in a laboratory-scale sequencing batch reactor and the evolution of Eikelboom type 021N 16S rRNA and 16S rRNA genes was monitored. A significant correlation was found between the sludge volume index and the amount of these filamentous organisms present in the sludge (r (2)=94.6%, n=10, P<0.01), as measured by real-time PCR. The amount of Eikelboom type 021N 16S rRNA genes increased by a factor of 21 during the experiment, while the 16S rRNA increased by a factor of 33. Moreover, Eikelboom type 021N 16S rRNA increased with increased feeding frequency. It was observed that the RNA:DNA ratio peaked before the sludge volume index increased. In parallel, a fluorescence in situ hybridization study indicated a factor of four increase in the length of Eikelboom type 021N filaments, due to a factor of two increase in both length and number of Eikelboom type 021N filaments. Further, an increase in the fraction of filaments extending outside the activated sludge flocs was observed (19-55%). Monitoring of 16S rRNA genes and 16S rRNA of Eikelboom type 021N was shown to be valuable in evaluating activated sludge settling characteristics; and measuring RNA:DNA ratios may be used as an early warning tool for sludge bulking.

From 1948, when WHO was established, the Organisation has relied on the assessed contributions of its member states for its regular budget. However, since the early 1980s the WHO World Health Assembly has had a policy of zero real growth for the regular budget and has had to rely increasingly, therefore, on attracting additional voluntary contributions, called extrabudgetary funds (EBFs). Between 1984-85 and 1992-93 the real value of the EBFs apparently increased by more than 60% and in the 1990-91 biennium expenditure of extrabudgetary funds exceeded the regular budget for the first time. All WHO programmes, except the Assembly and the Executive Board, receive some EBFs. However, three cosponsored and six large regular programmes account for about 70% of these EBFs, mainly for vertically managed programmes in the areas of disease control, health promotion and human reproduction. Eighty percent of all EBFs received by WHO for assisted activities have been contributed by donor governments, with the top 10 countries (in Europe, North America and Japan) contributing about 90% of this total, whereas the UN funds and the World Bank have donated only about 6% of the total to date. By contrast, about 70% of the regular budget expenditure has been for organisational expenses and for the support of programmes in the area of health systems. Despite the fact that the more successful programmes are heavily reliant on EBFs, there are strong indications that donors, particularly donor governments, are reluctant to maintain the current level of funding without major reforms in the leadership and management of the Organisation. This has major implications for WHO's international role as the leading UN specialised agency for health.