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Summary: The bendamustine–rituximab (BR) schedule is an efficient first‐line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression‐free (PFS) and overall survival (OS). With a median follow‐up of 76.1 months (95% confidence interval [CI] 69.9–80.6), 5‐year outcome is still excellent at 66.63% (95% CI 56.09–79.17) for PFS and 80.01% (95% CI 70.82–90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99–27.64) at 66 months. Relapsed patients who received ibrutinib as second‐line clearly benefited from this schedule. This confirms current recommendations suggesting BR long‐term efficacy as first‐line option in WM. [ABSTRACT FROM AUTHOR]

Background: Promotion of a healthy lifestyle for people with intellectual disabilities is important; however, the effectiveness of lifestyle change interventions is unclear. Aims: This research will examine the effectiveness of lifestyle change interventions for people with intellectual disabilities. Methods and Procedures: Randomized controlled trials (RCTs) of lifestyle change interventions for people with intellectual disabilities were included in a systematic review and meta‐analysis. Data on study and intervention characteristics were extracted, as well as data on outcome measures and results. Internal validity of the selected papers was assessed using the Cochrane Collaboration's risk bias tool. Outcomes and Results: Eight RCTs were included. Multiple outcome measures were used, whereby outcome measures targeting environmental factors and participation were lacking and personal outcome measures were mostly used by a single study. Risks of bias were found for all studies. Meta‐analysis showed some effectiveness for lifestyle change interventions, and a statistically significant decrease was found for waist circumference. Conclusion and Implications: Some effectiveness was found for lifestyle change interventions for people with intellectual disabilities. However, the effects were only statistically significant for waist circumference, so current lifestyle change interventions may not be optimally tailored to meet the needs of people with intellectual disabilities. [ABSTRACT FROM AUTHOR]

Over the past two decades infections due to antibiotic-resistant bacteria have escalated world-wide, affecting patient morbidity, mortality, and health care costs. Among these bacteria, Enterococcus faecium and Enterococcus faecalis represent opportunistic nosocomial pathogens that cause difficult-to-treat infections because of intrinsic and acquired resistance to a plethora of antibiotics. In recent years, a number of novel antimicrobial compound classes have been discovered and developed that target Gram-positive bacteria, including E. faecium and E. faecalis. These new antibacterial agents include teixobactin (targeting lipid II and lipid III), lipopeptides derived from nisin (targeting lipid II), dimeric vancomycin analogues (targeting lipid II), sortase transpeptidase inhibitors (targeting the sortase enzyme), alanine racemase inhibitors, lipoteichoic acid synthesis inhibitors (targeting LtaS), various oxazolidinones (targeting the bacterial ribosome), and tarocins (interfering with teichoic acid biosynthesis). The targets of these novel compounds and mode of action make them very promising for further antimicrobial drug development and future treatment of Gram-positive bacterial infections. Here we review current knowledge of the most favorable anti-enterococcal compounds along with their implicated modes of action and efficacy in animal models to project their possible future use in the clinical setting. [ABSTRACT FROM AUTHOR]

Background and objective One of the treatment options for arteriovenous malformations consists of embolization, with a choice of various embolic agents, with or without subsequent surgical excision. If embolization is offered without subsequent surgery, the embolic material will stay in situ, in which case the consistency and color become important in superficial lesions. The purpose of this case report is to describe if the use of a novel liquid embolic agent (PHIL) is well suited for treatment of superficial AVMs without subsequent surgery. Case description A 30-year-old male presented with a painful reddish, pulsatile swelling of the left ear that had been present for more than 10 years. Angiography confirmed an arteriovenous malformation supplied by the superficial temporal artery and the posterior auricular artery. The lesion was successfully treated by embolization with PHIL, through the superficial temporal artery. A minute residual shunt, from the posterior auricular artery, was accepted. Immediate disappearance of pulsatile tinnitus was reported. Moreover, return of normal skin color was observed without discomfort from the embolic deposits. This result has been stable throughout one year of clinical follow-up. Conclusion To our knowledge, this is the first case report describing PHIL embolization as a treatment option for superficial arteriovenous malformations without the necessity for subsequent surgery. The white color and rubbery consistency are beneficial characteristics of PHIL in treatment of subcutaneous lesions, especially in cosmetically relevant locations. [ABSTRACT FROM AUTHOR]

Arterial coronary bypass grafts [internal mammary arteries and gastroepiploic artery (GEA)] are in widespread use for coronary surgery. Since selective catheterisation of the GEA graft to monitor patency, is often unsuccessful, a non-invasive protocol to visualise the GEA-graft from origin to anastomosis is presented using 16-slice multidetector computed tomography (MDCT). Twenty-six male patients (mean age 58.1+/-6.7 years) with GEA grafts were scanned according to a protocol of an ECG-synchronised cardiac scan followed by a thoracoabdominal scan. To terminate the scan at the correct anatomical level, the lowest level of the GEA was coded based on the lumbar vertebrae level. Scores ranging from one (excellent) to four (bad) were assigned to evaluate visualisation quality of the grafts. GEA grafts were assessable in 62% of the thoracoabdominal scans and 69% of the cardiac scans. On average, the lowest part of the GEA corresponded with a level between L1 and L2, in two cases in the upper part of L3. Mean visualisation score in the thoracoabdominal scans and cardiac scans was good (respectively 1.4+/-0.6 and 1.4+/-1.0). Sixteen-slice MDCT is a promising alternative for catheterisation in evaluating patency of GEA grafts, using the presented protocol with thoracoabdominal scan including L3 for complete coverage of the GEA graft. [ABSTRACT FROM AUTHOR]

Background: For physicians dealing with patients with a limited life expectancy, knowing the time to benefit (TTB) of preventive medication is essential to support treatment decisions. Objective: The aim of this study was to investigate the usefulness of statistical process control (SPC) for determining the TTB in relation to fracture risk with alendronate versus placebo in postmenopausal women. Methods: We performed a post hoc analysis of the Fracture Intervention Trial (FIT), a randomized, controlled trial that investigated the effect of alendronate versus placebo on fracture risk in postmenopausal women. We used SPC, a statistical method used for monitoring processes for quality control, to determine if and when the intervention group benefited significantly more than the control group. SPC discriminated between the normal variations over time in the numbers of fractures in both groups and the variations that were attributable to alendronate. The TTB was defined as the time point from which the cumulative difference in the number of clinical fractures remained greater than the upper control limit on the SPC chart. Results: For the total group, the TTB was defined as 11 months. For patients aged ≥70 years, the TTB was 8 months [absolute risk reduction (ARR) = 1.4 %]; for patients aged <70 years, it was 19 months (ARR = 0.7 %). Conclusion: SPC is a clear and understandable graphical method to determine the TTB. Its main advantage is that there is no need to define a prespecified time point, as is the case in traditional survival analyses. Prescribing alendronate to patients who are aged ≥70 years is useful because the TTB shows that they will benefit after 8 months. Investigators should report the TTB to simplify clinical decision making. [ABSTRACT FROM AUTHOR]

Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-induced chorioamnionitis resulted in pulmonary inflammation with increased effector T cells and decreased regulatory T cell (Treg) numbers. Because Tregs are crucial for immune regulation, we assessed the effects of interleukin (IL)-2-driven selective Treg expansion on the fetal lung in an ovine chorioamnionitis model. Instrumented fetuses received systemic prophylactic IL-2 treatment [118 days gestational age (dGA)] with or without subsequent exposure to intra-amniotic LPS (122 dGA). Following delivery at 129 dGA (term 147 dGA), pulmonary and systemic inflammation, morphological changes, lung gas volume, and phospholipid concentration were assessed. IL-2 pretreatment increased the FoxP3+/CD3+ ratio, which was associated with reduced CD3-positive cells in the fetal lungs of LPS-exposed animals. Prophylactic IL-2 treatment did not prevent pulmonary accumulation of myeloperoxidase- and PU.1-positive cells or elevation of bronchoalveolar lavage fluid IL-8 and systemic IL-6 concentrations in LPS-exposed animals. Unexpectedly, IL-2 treatment improved fetal lung function of control lambs as indicated by increased disaturated phospholipids and improved lung gas volume. In conclusion, systemic IL-2 treatment in utero preferentially expanded Tregs and improved lung gas volume and disaturated phospholipids. These beneficial effects on lung function were maintained despite the moderate immunomodulatory effects of prophylactic IL-2 in the course of chorioamnionitis. [ABSTRACT FROM AUTHOR]

Background: Degenerative lumbosacral stenosis is a common problem in large breed dogs. For severe degenerative lumbosacral stenosis, conservative treatment is often not effective and surgical intervention remains as the last treatment option. The objective of this retrospective study was to assess the middle to long term outcome of treatment of severe degenerative lumbosacral stenosis with pedicle screw-rod fixation with or without evidence of radiological discospondylitis. Results: Twelve client-owned dogs with severe degenerative lumbosacral stenosis underwent pedicle screw-rod fixation of the lumbosacral junction. During long term follow-up, dogs were monitored by clinical evaluation, diagnostic imaging, force plate analysis, and by using questionnaires to owners. Clinical evaluation, force plate data, and responses to questionnaires completed by the owners showed resolution (n=8) or improvement (n = 4) of clinical signs after pedicle screw-rod fixation in 12 dogs. There were no implant failures, however, no interbody vertebral bone fusion of the lumbosacral junction was observed in the follow-up period. Four dogs developed mild recurrent low back pain that could easily be controlled by pain medication and an altered exercise regime. Conclusions: Pedicle screw-rod fixation offers a surgical treatment option for large breed dogs with severe degenerative lumbosacral stenosis with or without evidence of radiological discospondylitis in which no other treatment is available. Pedicle screw-rod fixation alone does not result in interbody vertebral bone fusion between L7 and S1. [ABSTRACT FROM AUTHOR]

Background Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin ( IL)-1β is pivotal in the pathophysiology. Objectives Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS. Methods Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome ( CAPS), delayed-pressure urticaria ( DPU) and cold-contact urticaria ( CCU) were studied. We studied in vivo IL-1β, IL-17 and antimicrobial protein ( AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the in vitro effect of IL-1β, IL-17 and polyinosinic-polycytidylic acid (poly: IC) stimulation on cultured epidermal keratinocytes. Results Remarkably, we found IL-1β-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1β, poly: IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts. Conclusions Dermal mast cells of patients with SchS produce IL-1β. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis. [ABSTRACT FROM AUTHOR]

The aim of this study was to establish the presence of postural deficits in subjects with chronic ankle instability (CAI) and to assess the effect of an 8-week balance training program on dynamic postural control. A total of 43 subjects with CAI and 31 controls participated in this case-control study. Participants with CAI performed an 8-week home-based balance training, including 3 sessions a week. As main outcome measure, postural control was quantified after a vertical drop by means of the dynamic postural stability index (DPSI). Perceptual outcomes were documented using the FADI, FADI-Sport and VAS scales. At baseline, subjects with CAI displayed higher anterior/posterior and vertical postural instability, a poorer DPSI, and lower subjective stability scores compared to the control group. After balance training, all subjective stability scores improved significantly, although no changes were noted for the stability indices. In conclusion, subjects with CAI have an impaired postural control. As a treatment modality, balance training exhibits the capability of improving the subjective feeling of instability in subjects with CAI. However, there was no effect on dynamic postural control. Further research on the explanatory mechanisms of balance training is warranted, and other training modalities should be considered. [ABSTRACT FROM AUTHOR]

The objective of our study was to evaluate the effect of taping on the dynamic postural stability during a jump landing protocol in subjects with chronic ankle instability (CAI). For this purpose, 28 subjects with CAI performed a sagittal and frontal plane landing task in a non-taped and taped condition. As main outcome measure, the dynamic postural stability index (DPSI) was calculated. In addition, subjective feelings of instability and perceived difficulty level were assessed. Furthermore, mechanical effectiveness of the tape on the ankle joint was determined by registering 3D kinematics. 3 subjects were excluded based on discomfort during the landing protocol. Study results indicated that the tape reduced plantar flexion and inversion at the ankle at touchdown and range of motion in the landing phase. There was, however, no effect on the DPSI or on its directional subcomponents. Subjective feelings of stability with tape improved significantly, whereas perceived difficulty did not change. In conclusion, our taping procedure did not improve postural control during a sagittal and frontal plane landing task in subjects with CAI. Perceived instability did improve and is considered an important treatment outcome, which suggests that taping could be considered as a treatment modality by clinicians. [ABSTRACT FROM AUTHOR]

People living with chronic illness often report uncertainty about the future, fear of disease progression, fear of becoming physically disabled, and a reduced life expectancy as important sources of stress. However, little is known about psychological interventions targeting these concerns. The aim of this study is to illustrate an intervention to reduce emotional distress and concerns about the future in a patient with systemic sclerosis (SSc), a rare chronic rheumatic disease with serious consequences for most patients, and to present a preliminary report on its effectiveness using a single-case study design. Because of the complexity of symptoms and complaints due to SSc, the psychological intervention was embedded in an interdisciplinary care program also consisting of physical therapy, occupational therapy, and specialized nurse care. [ABSTRACT FROM AUTHOR]

Background: A program supporting the initiation of insulin therapy in primary care was introduced in Belgium, as part of a larger quality improvement project on diabetes care. This paper reports on a study exploring factors influencing the engagement of general practitioners (GPs) in insulin therapy initiation (research question 1) and exploring factors relevant for future program development (research question 2). Methods: We have used semi-structured interviews to answer the first research question: two focus group interviews with GPs who had at least one patient in the insulin initiation program and 20 one-to-one interviews with GPs who were not regular users of the overall support program in the region. To explore factors relevant for future program development, the data from the GPs were triangulated with data obtained from individual interviews with patients (n = 10), the diabetes nurse educator (DNE) and the specialist involved in the program, and data extracted from meeting reports evaluating the insulin initiation support program. Results: We found differences between GPs engaged and those not engaged in insulin initiation in attitude, subjective norm and perceived behavioural control regarding insulin initiation. In general the support program was evaluated in a positive way by users of the program. Some aspects need further consideration: job boundaries between the DNE and GPs, job boundaries between GPs and specialists, protocol adherence and limited case load. Conclusion: The study shows that the transition of insulin initiation from secondary care to the primary care setting is a challenge. Although a support program addressing known barriers to insulin initiation was provided, a substantial number of GPs were reluctant to engage in this aspect of care. Important issues for future program development are: an interdisciplinary approach to job clarification, a dynamic approach to the integration of expertise in primary care and feedback on protocol adherence. Trial registration: ClinicalTrials.gov Identifier: NCT00824499 [ABSTRACT FROM AUTHOR]

The article presents three case studies involving patients with acute lymphoblastic leukemia (ALL) who developed L-asparaginase (L-ase)-induced severe acute hepatotoxicity with liver steatosis including a 60-year-old women, a 51-year-old man, and a 64-year-old woman. The article discusses the adverse effect of treatment with L-ase, treatment with the mitochondrial cofactors vitamin B complex and L-carnitine, and the effectiveness of the patients' treatment regimens.

Background. Despite stable overall antibiotic use between 2007 and 2011 in The Netherlands, use of nitrofurantoin and trimethoprim increased by 32%. The background of this increased antibiotic use against uropathogens is unknown. Objectives. To determine whether increased use of urinary tract infection antibiotics is caused by changes in patients’ consultation or physicians’ prescribing behaviour and to investigate attitudes and opinions of women with respect to cystitis management and antibiotics. Methods. Consultation and prescribing for International Classification of Primary Care (ICPC) codes U01 (dysuria), U02 (frequency), U05 (other urination problems), U70 (pyelonephritis) and U71 (cystitis) were determined from 2007 to 2010, using routinely collected primary health care data. Separately, behaviour of women with respect to managing cystitis, consultation and opinions towards (delayed) antibiotic treatment were studied using questionnaires in 2012. Results. Consultation for U02 and U71 significantly increased from 93 to 114/1000 patient-years from 2007 to 2010; proportion of episodes in which an antibiotic was prescribed remained constant. Questionnaires revealed that urination problems and pain were dominant complaints of cystitis; pain medication, however, was not adequately used. One-third of women directly consult upon first symptoms, whereas the majority awaits an average of 4 days. Sixty-six per cent of women report to be willing to postpone antibiotic use. Conclusion. Increased use of urinary tract infection antibiotics may be caused by increased consultation for cystitis in primary care. Future research should focus on the outcomes of adequate pain medication, enhanced diagnostic procedures and of delaying antibiotic use in cystitis management. [ABSTRACT FROM PUBLISHER]

Background: Recently, we have shown that intraplaque mast cell numbers are associated with atherosclerotic plaque vulnerability and with future cardiovascular events, which renders inhibition of mast cell activation of interest for future therapeutic interventions. However, the endogenous triggers that activate mast cells during the progression and destabilization of atherosclerotic lesions remain unidentified. Mast cells can be activated by immunoglobulins and in the present study, we aimed to establish whether specific immunoglobulins in plasma of patients scheduled for carotid endarterectomy were related to (activated) intraplaque mast cell numbers and plasma tryptase levels. In addition, the levels were related to other vulnerable plaque characteristics and baseline clinical data. Methods and Results: OxLDL-IgG, total IgG and total IgE levels were measured in 135 patients who underwent carotid endarterectomy. No associations were observed between the tested plasma immunoglobulin levels and total mast cell numbers in atherosclerotic plaques. Furthermore, no associations were found between IgG levels and the following plaque characteristics: lipid core size, degree of calcification, number of macrophages or smooth muscle cells, amount of collagen and number of microvessels. Interestingly, statin use was negatively associated with plasma IgE and oxLDL-IgG levels. Conclusions: In patients suffering from carotid artery disease, total IgE, total IgG and oxLDL-IgG levels do not associate with plaque mast cell numbers or other vulnerable plaque histopathological characteristics. This study thus does not provide evidence that the immunoglobulins tested in our cohort play a role in intraplaque mast cell activation or grade of atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Rapid detection of extended-spectrum β-lactamase (ESBL)–producing Gram-negative bacilli in surveillance samples of high-risk patients allows early optimization of antimicrobial therapy and timely introduction of infection control procedures. This study evaluated the BLSE (AES Chemunex), chromID ESBL (bioMérieux), and Brilliance ESBL agar (Oxoid) for rapid detection of ESBL-producing Enterobacteriaceae from surveillance samples. A total of 139 perineal and nose samples were processed. Isolated bacterial strains were identified by mass spectrometry. ESBL confirmation was performed by phenotypical and molecular tests. Overall, 16 ESBL-producing Enterobacteriaceae were recovered. The sensitivities after 24 h of incubation were comparable (BLSE, 87.5%; Brilliance ESBL, 87.5%; and chromID, 81.3%). The specificity of chromogenic media (80.7–82.1%) was significantly higher compared to BLSE (60.8%). All 3 media are reliable to screen for ESBL-producing Enterobacteriaceae from surveillance samples. Yet, the main advantages of chromogenic media over BLSE reside in their chromogenic character and higher specificity, reducing the total number of isolates that require further identification and ESBL confirmation testing. [Copyright &y& Elsevier]

To allow the rational design of effective treatment strategies for human mitochondrial disorders, a proper understanding of their biochemical and pathophysiological aspects is required. The development and evaluation of these strategies require suitable model systems. In humans, inherited complex I (CI) deficiency is one of the most common deficiencies of the mitochondrial oxidative phosphorylation system. During the last decade, various cellular and animal models of CI deficiency have been presented involving mutations and/or deletion of the Ndufs4 gene, which encodes the NDUFS4 subunit of CI. In this review, we discuss these models and their validity for studying human CI deficiency. © 2013 IUBMB Life, 65(3):202-208, 2013 [ABSTRACT FROM AUTHOR]

Enterococcus faecalis and Enterococcus faecium are among the leading causative agents of nosocomial infections and are infamous for their resistance to many antibiotics. They cause difficult-to-treat infections, often originating from biofilm-mediated infections associated with implanted medical devices or endocarditis. Biofilms protect bacteria against antibiotics and phagocytosis, and physical removal of devices or infected tissue is often needed but is frequently not possible. Currently there are no clinically available compounds that disassemble biofilms. In this review we discuss all known structural and regulatory genes involved in enterococcal biofilm formation, the compounds directed against biofilm formation that have been studied, and potentially useful targets for future drugs to treat enterococcal biofilm-associated infections. [ABSTRACT FROM AUTHOR]

Background: More and more quantitative information is becoming available about the risks of complications arising from medical treatment. In everyday practice, this raises the question whether each and every risk, however low, should be disclosed to patients. What could be good reasons for doing or not doing so? This will increasingly become a dilemma for practitioners. Objective: To report doctors' views on whether to disclose or withhold information on low risks of complications. Methods: In a qualitative study design, 37 respondents (gastroenterologists and gynaecologists or obstetricians) were included. Focus group interviews were held with 22 respondents and individual in-depth interviews with 15. Results: Doctors have doubts about disclosing or withholding information on complication risk, especially in a risk range of 1 in 200 to 1 in 10 000. Their considerations on whether to disclose or to withhold information depend on a complicated mix of patient and doctor-associated reasons; on medical and personal considerations; and on the kind and purpose of intervention. Discussion: Even though the degree of a risk is important in a doctor's considerations, the severity of the possible complications and patients' wishes and competencies have an important role as well. Respondents said that low risks should always be communicated when there are alternatives for the intervention or when the patient may prevent or mitigate the risk. When the appropriateness of disclosing risks is doubtful, doctors should always tell their patients that no intervention is without risk, give them the opportunity to gather all the information they need or want, and enable them to detect a complication at an early stage. [ABSTRACT FROM AUTHOR]

Objective: The most recent WHO definition of palliative care regards living as actively as possible as an important aim. We explored, over a 1-year period, the work this involves for patients with end-stage heart failure. Design: Prospective longitudinal multiple case study using qualitative interview techniques. Participants: Thirty-one respondents from two hospitals who fulfilled one or more of the following criteria: NYHA III or IV, ejection fraction < 25%, at least one hospitalization for heart failure. Main outcomes: Types and content of patient work involved in living with end-stage heart failure. Results: For patients with advanced heart failure, work consisted mainly of four types of tasks, as identified by Glaser and Strauss: 'managing illness', 'everyday work to keep life going', 'biographical work' and 'arrangement work'. Conclusions: Systematic attention to patient work, for example using these four categories, could improve the quality of care from the patient's perspective. [ABSTRACT FROM AUTHOR]

Abstract: The capacity of two forms of porous beta-tricalcium phosphate bone substitutes (TCP) to promote bone healing in open wedge high tibial osteotomy (OWHTO) was studied. We reviewed the X-rays of 27 osteotomies, with either TCP wedges or TCP granules as filling material, to compare the bone healing rates and bone remodelling, at specific postoperative intervals. A new radiologic rating system for OWHTO was created and tested for clinical applicability. All osteotomies healed uneventfully and complete resorption of TCP was demonstrated at 1 year postoperative in 85% (n=23) of the procedures. In 44% (n=10) of these 23 procedures, the osteotomy site was no longer visible. No difference in bone healing rate and bone remodelling was found when comparing the use of granules to a wedge, and no adverse effects of TCP were observed. The good inter- (k=0.7) and intraobserver (k=0.6) reliability of the new radiologic rating system enables clinical use. Good bone healing was found in OWHTO with both wedges and granules of TCP. [Copyright &y& Elsevier]

Background: Culturally sensitive care is integral to effective and equitable healthcare delivery, necessitating an understanding and acknowledgment of patients' cultural needs, preferences, and expectations. This study investigates the perceptions of cultural sensitivity among general practitioners (GPs), focusing on their intentions, willingness and perceived responsibilities in providing care tailored to cultural needs. Methods: In-depth interviews were conducted with 21 Flemish GPs to explore their perspectives on culturally sensitive care. Data analysis followed a conventional qualitative content analysis approach within a constructivist framework. A coding scheme was developed to identify recurring themes and patterns in the GPs' responses. Results: Findings reveal that culturally sensitive care provision is perceived as a multifaceted process, initiated by an exploration phase where GPs inquire about patients' cultural needs and preferences. Two pivotal factors shaping culturally sensitive care emerged: patients' specific cultural expectations and GPs' perceived responsibilities. These factors guided the process of culturally sensitive care towards three distinct outcomes, ranging from complete adaptation to patients' cultural requirements driven by a high sense of responsibility, through negotiation and compromise, to a paternalistic approach where GPs expect patients to conform to GPs' values and expectations. Three typologies of GPs in providing culturally sensitive care were identified: genuinely culturally sensitive, surface-level culturally sensitive, and those perceiving diversity as a threat. Stereotyping and othering persist in healthcare, underscoring the importance of critical consciousness and cultural reflexivity in providing patient-centered and equitable care. Conclusions: This study emphasizes the significance of empathy and underscores the necessity for GPs to embrace the exploration and acknowledgement of patients' preferences and cultural needs as integral aspects of their professional role. It highlights the importance of shared decision-making, critical consciousness, cultural desire and empathy. Understanding these nuances is essential for enhancing culturally sensitive care and mitigating healthcare disparities. [ABSTRACT FROM AUTHOR]

Reports the case of a 19-year-old construction worker from Virginia who had traveled in Bolivia had sporotrichoid lesions on the left arm. Drug treatment for sporotrichosis; Clinical diagnosis of sporotrichosis; What the physical examination reveals.

A letter to the editor is presented in response to the article about the specification and drug response for delirium in the 2015 issue.

Internalized HIV stigma is prevalent and research on internalized HIV stigma has increased during the past 10 years. The aim of this systematic review was to synthesize research on internalized HIV stigma and relationships with various health-related variables in order to better inform the development of interventions aimed at reducing internalized HIV stigma. We reviewed 176 studies with a quantitative design reporting correlates that were peer-reviewed, published in English before January 2021, drawn from PubMed, PSYCHINFO, Web of Science, EBSCO, and Scopus. Synthesis showed consistent associations between internalized stigma and negative psychological (e.g., depression, anxiety), social (e.g., lack of social support, discrimination, nondisclosure, and intersecting stigmas), and health (e.g., substance use, treatment nonadherence, negative clinical HIV outcomes) variables. We argue for a more socioecological approach to internalized stigma, with greater attention for intersectional stigmas, and more longitudinal research, if we are to effectively develop interventions that reduce internalized stigma. [ABSTRACT FROM AUTHOR]

Keywords: osteoporosis; patient preference; burden of disease; quality of life EN osteoporosis patient preference burden of disease quality of life 107 118 12 02/08/23 20230101 NES 230101 Kyriakos Souliotis, SP 1, sp SP 2 sp Christina Golna, SP 2 sp Christina Poimenidou, SP 2 sp Tatiana Drakopoulou, SP 3 sp Memi Tsekoura, SP 2 sp Damon Willems, SP 4 sp Vasileios Kountouris, SP 5 sp Polyzois Makras SP 6 sp SP 1 sp Department of Social and Education Policy, University of Peloponnese, Corinth, Greece; SP 2 sp Research Department, Health Policy Institute, Maroussi, Greece; SP 3 sp Greek Bone Health Association "Petalouda", Perama, Greece; SP 4 sp Market Access Lead, UCB Pharma, Brussels, Belgium; SP 5 sp External Engagement Lead, UCB Pharma, Athens, Greece; SP 6 sp Department of Endocrinology and Diabetes and Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece Correspondence: Kyriakos Souliotis, Email [email protected] Plain Language Summary This study aimed to describe patient-reported health status and quality of life in postmenopausal women with severe osteoporosis in Greece, and to understand patient preferences for osteoporosis therapies. Finally, when participants in this study were asked to select their preferred treatment scenario between two unlabeled anabolic treatments, 70% opted for the scenario that shared treatment characteristics with romosozumab over a scenario that shared treatment characteristics with teriparatide. Around half of participants (58%) would consider their osteoporosis treatment to be effective if it led to a 50% reduction in future fracture risk, 10% would consider their osteoporosis treatment to be effective only if it led to an 80% reduction in risk, and almost 20% only if it led to at least a 90% reduction in risk. [Extracted from the article]

In this article the author replies back to a professor regarding external quality assurance surveys (EQAS). The results of EQAS should be a reflection of the quality of patients' samples in the analytical sense as well as in the pre- and post-analytical aspects. The samples coming from the external quality programs cannot be delivered as blind samples to the medical laboratories. The professionals should be aware of a standard procedure for the treatment of such samples. It is the aim of EQAS organizers to make it possible to judge the own overall quality compared with the other laboratories in the same field.

Purpose: Many systematic reviews have been published on surgical interventions for low back disorders. The objective of this overview was to evaluate the available evidence from systematic reviews on the effectiveness of surgical interventions for disc herniation, spondylolisthesis, stenosis, and degenerative disc disease (DDD). An earlier version of this review was published in 2006 and since then, many new, better quality reviews have been published. Methods: A comprehensive search was performed in the Cochrane database of systematic reviews (CDSR), database of reviews of effectiveness (DARE) and Pubmed. Two reviewers independently performed the selection of studies, risk of bias assessment, and data extraction. Included are Cochrane reviews and non-Cochrane systematic reviews published in peer-reviewed journals. The following conditions were included: disc herniation, spondylolisthesis, and DDD with or without spinal stenosis. The following comparisons were evaluated: (1) surgery vs. conservative care, and (2) different surgical techniques compared to one another. The methodological quality of the systematic reviews was evaluated using AMSTAR. We report (pooled) analyses from the individual reviews. Results: Thirteen systematic reviews on surgical interventions for low back disorders were included for disc herniation ( n = 6), spondylolisthesis ( n = 2), spinal stenosis ( n = 4), and DDD ( n = 4). Nine (69 %) were of high quality. Five reviews provided a meta-analysis of which two showed a significant difference. For the treatment of spinal stenosis, intervertebral process devices showed more favorable results compared to conservative treatment on the Zurich Claudication Questionnaire [mean difference (MD) 23.2 95 % CI 18.5-27.8]. For degenerative spondylolisthesis, fusion showed more favorable results compared to decompression for a mixed aggregation of clinical outcome measures (RR 1.40 95 % CI 1.04-1.89) and fusion rate favored instrumented fusion over non-instrumented fusion (RR 1.37 95 % CI 1.07-1.75). Conclusions: For most of the comparisons, the included reviews were not significant and/or clinically relevant differences between interventions were identified. Although the quality of the reviews was quite acceptable, the quality of the included studies was poor. Future studies are likely to influence our assessment of these interventions. [ABSTRACT FROM AUTHOR]

Tenascin-X is a large extracellular matrix glycoprotein that is widely distributed within connective tissues and is associated with an autosomal recessive type of Ehlers-Danlos syndrome (EDS). Tenascin-X represents the first EDS susceptibility gene that does not code for a fibrillar collagen or collagen-processing enzyme. We describe a paediatric case of tenascin-X deficiency and review the literature. [ABSTRACT FROM AUTHOR]

Abstract: Parabutoporin (PP) from the South African scorpion Parabuthus schlechteri is a 45-mer lysine-rich and cysteine-free peptide. At micromolar concentrations it has antimicrobial effects against G+ and G− bacteria and is antifungal as well. However, at submicromolar concentrations, parabutoporin also directly interferes with cellular functions of the human innate immune system, especially polymorphonuclear neutrophils (PMN): parabutoporin acts as a chemoattractant for neutrophils, induces their degranulation, while delaying constitutive neutrophil apoptosis. In addition, it potently inhibits induced superoxide production. Different signalling pathways regulating these biochemical processes were identified as targets of parabutoporin. Therefore, parabutoporin is a well documented scorpion venom peptide with immuno-regulatory properties beyond its antibiotic effects. [Copyright &y& Elsevier]

Objective: Excessive frontal plane knee movement during forward lunge movements might be associated with the occurrence of knee in juries in tennis. Here, we attempt to determine whether hip muscle strength is related to the frontal plane motion of the knee during a functional lunge movement. Design: A correlational study. Participants: A total of 84 healthy subjects (76 men, 8 women), with no history of knee or lower leg complaints. Interventions: Muscle strength of six hip muscle groups was measured using a handheld dynamometer. Subjects were videotaped during a forward lunge and peak knee valgus or varus angles were determined using a digital video analysis software program. Main outcome measurements: A correlation was examined between hip muscle strength and the amount of frontal plane movement of the knee during a forward lunge. Results: There were no significant differences in hip muscle strength between the valgus group and the varus group during the forward lunge movement. No significant correlation was found between the strength of the assessed hip muscles and the amount of movement into valgus/varus. In the varus group a moderate positive correlation was found between the External Rotation/Internal Rotation force ratio and the amount of knee during the forward lunge movement (r = 0.31, p = 0.03). Conclusions: The findings suggest that in healthy subjects hip muscle strength is not correlated to the amount of valgus/varus movement of the knee during a forward lunge. This suggests that other factors (eg, proprioception, core hip stability) might be more important in controlling knee movement during this tennis-specific movement. [ABSTRACT FROM AUTHOR]

Background: Selective photothermolysis of diseased capillaries by pulsed dye laser (PDL) treatment has been described as a mechanism for long-lasting clearance of psoriatic plaques. Aim: To evaluate PDL and a two-compound formulation of calcipotriol/betamethasone dipropionate ointment for the treatment of localized, recalcitrant plaque psoriasis. Methods: Eight psoriatic patients were treated for 4 weeks with both PDL and topical calcipotriol/betamethasone dipropionate in an open, intra-patient, left-right comparison. Biopsies were analyzed for T-cell subsets, cells expressing NK-receptors, epidermal proliferation, differentiation and epidermal thickness. Results: After active treatment, both treatments showed statistically significant but comparable improvements of T-cell subsets, epidermal proliferation, differentiation and epidermal thickness. In line with the clinical results, after an 8-week follow-up period statistically significant further reductions were observed for dermal CD3+, CD4+, CD45RO+, CD2+ T cells, epidermal CD3+, CD8+, CD45RO+, CD2+, CD25+ T cells and the epidermal parameters for the PDL-treated plaques, in contrast to the topically treated plaques. Conclusion: After 8 weeks of follow-up, PDL treatment for localized and recalcitrant plaque psoriasis resulted in persistent reductions of activated and memory effector T-helper cells in the dermis, cytotoxic T cells in the epidermis, and normalization of epidermal proliferation and keratinization, in contrast to treatment with calcipotriol/betamethasone dipropionate ointment. [ABSTRACT FROM AUTHOR]

Simple Summary: A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In malignant mesothelioma (MM), tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis. In this paper, we propose a paradigm based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response. Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response. [ABSTRACT FROM AUTHOR]

Oncology and hematology physicians aim during the COVID-19 pandemic to protect their patients from COVID-19 infection without impairing the prognosis of the disease. We describe how at-home treatment was used in our department to maintain multiple myeloma treatment while protecting the patient. [Extracted from the article]

Rationale: This study evaluates the lymphatic drainage patterns and determines the accuracy of the sentinel lymph node biopsy (SLNB) in patients diagnosed with a cT1-2N0 OSCC and a history of neck surgery or radiotherapy in three Dutch head and neck centers.Materials and Methods: Retrospective analysis of 53 cT1-2N0 OSCC patients, who underwent SLNB between 2007 and 2016, after a history of neck surgery or radiotherapy. Ten patients had previous treatment of the neck only contralateral from the current tumour. These ten patients were not used for the analysis of lymphatic drainage patterns. The 43 patients with previous ipsilateral or bilateral treatment of the neck had a history of ipsilateral SLN extirpation (n = 9; 21%), neck dissection (n = 16; 37%), radiotherapy (n = 10; 23%), or combined neck dissection and radiotherapy (n = 8; 19%).Results: SLNs were detected in 45 patients, resulting in an identification rate of 85% (45/53). Three patients (7%) had at least one positive SLN. One patient (1/45; 2%) was diagnosed with regional recurrence during the follow-up after a negative SLNB (sensitivity 75%, negative predictive value 98%). The first SLN was detected in level I-III in 58% of the patients, unexpected drainage patterns were observed in 30% (first SLN level IV 9% and level V 5% and contralateral neck in well-lateralized tumours 16%). In 12% no lymphatic drainage pattern was visible.Conclusions: SLNB seems to be a reliable procedure for neck staging of cT1-2N0 OSCC patients with a previously treated neck. SLNB determines the individual lymphatic drainage patterns, enabling visualization of unexpected drainage pattern variability in 30% of these patients. [ABSTRACT FROM AUTHOR]

Localized Scleroderma (LoS) encompasses a group of idiopathic skin conditions characterized by (sub)cutaneous inflammation and subsequent development of fibrosis. Currently, lack of accurate tools enabling disease activity assessment leads to suboptimal treatment approaches. To investigate serum concentrations of cytokines and chemokines implicated in inflammation and angiogenesis in LoS and explore their potential to be utilized as biomarker of disease activity. Additionally, to investigate the implication of potential biomarkers in disease pathogenesis. A 39-plex Luminex immuno-assay was performed in serum samples of 74 LoS and 22 Healthy Controls. The relation between a validated clinical measure of disease activity (mLoSSI) and serum analytes was investigated. Additionally, gene and protein expression were investigated in circulating cells and skin biopsies. From the total of 39, 10 analytes (CCL18, CXCL9, CXCL10, CXCL13, TNFRII, Galectin-9, TIE-1, sVCAM, IL-18, CCL19) were elevated in LoS serum. Cluster analysis of serum samples revealed CCL18 as most important analyte to discriminate between active and inactive disease. At individual patient level, CCL18 serum levels correlated strongest with mLoSSI-scores (r s = 0.4604, P < 0.0001) and in longitudinal measures CCL18 concentrations normalised with declining disease activity upon treatment initiation. Additionally, CCL18 was elevated in LoS serum, and not in (juvenile) dermatomyositis or spinal muscular atrophy. Importantly, CCL18 gene and protein expression was increased at the inflammatory border of cutaneous LoS lesions, with normal expression in unaffected skin and circulating immune cells. CCL18 is specific for disease activity in LoS thereby providing relevance as a biomarker for this debilitating disease. • Localized Scleroderma (LoS) is characterized by (sub)cutaneous inflammation and subsequent development of fibrosis. • Currently, lack of accurate tools enabling disease activity assessment leads to suboptimal treatment approaches. • In this study, we demonstrate that serum concentration of CCL18 (PARC) is a biomarker for disease activity in LoS patients. • In this study, CCL18 gene and protein expression is increased at the inflammatory border of cutaneous LoS lesions. Tools to determine the disease activity in localized scleroderma (LoS) are lacking. Here, we identified CCL18 as promising biomarker to distinguish between LoS patients with active and inactive disease. [ABSTRACT FROM AUTHOR]

Introduction: The MARVEL study demonstrated at a single time point that accelerometer (ACC)‐based atrial sensing improves atrioventricular (AV) synchrony (AVS) in patients with AV block and a Micra pacemaker (Medtronic, Minneapolis, MN, USA). The purpose of the MARVEL Evolve substudy was to assess the performance over time. Methods: This prospective single‐center study compared AVS and ACC signals at two visits ≥6 months apart. Custom software was temporarily downloaded into the Micra at each visit and AVS was measured during 30 min at rest. Results: Nine patients from the MARVEL study were enrolled. The mean (±standard deviation) age was 82.3 ± 6.0 years old, 67% were male, and a Micra was implanted for 6.0 ± 6.4 months. High‐degree AV block was present in four patients, whereas five with predominantly intrinsic conduction required intermittent pacing for bradycardia. The mean interval between visits was 7.1 ± 0.6 months. Seven patients had normal sinus node function at both visits and were included in a paired analysis. Both ACC signal amplitude (visit 2‐visit 1 = 1.4 mG; 95% confidence interval [CI] [−25.8 to 28.4 mG]; P = 0.933) and AVS (visit 1: 90.8%, 95% CI [72.4, 97.4] and visit 2: 91.4%, 95% CI [63.8, 98.5]; P = 0.740) remained stable. Three patients had spontaneous atrial tachycardia. During atrial fibrillation, no atrial contraction was detected or tracked. During atrial flutter, intermittent tracking resulted in a ventricular rate of 60 ± 8 beats per minute (bpm); there was no ventricular pacing >100 bpm. Conclusion: ACC signals amplitude and performance of AVS pacing were stable over time. During atrial arrhythmias, the AV synchronous pacing mode behaved safely. [ABSTRACT FROM AUTHOR]

Background: Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs.Patients and Methods: We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence.Results: Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0-18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1-29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033).Conclusion: With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone. [ABSTRACT FROM AUTHOR]

Background: The approach to treat device infection in patients with implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) is a challenging procedure. Optimal treatment is complete extraction of the infected device. To protect these patients from sudden cardiac arrest while waiting for reimplantation and to avoid recurrent infection, a wearable cardioverter defibrillator (WCD) seems to be a valuable solution. Therefore, we investigated the management and outcome of patients with ICD or CRT-D infections using the WCD as a bridge to re-implantation after lead extraction procedures.Methods: We conducted a retrospective study on consecutive patients who underwent ICD or CRT-D removal due to device-related local or systemic infections. All patients were prescribed a WCD at our center between 01/2012 and 10/2015. All patients returned to our outpatient clinic for regular ICD or CRT-D monitoring initially 1 and 3 months after reimplantation followed by 6-months intervals.Results: Twenty-one patients (mean age 65.0 ± 8.0 years, male 76.2%) were included in the study. Complete lead extraction was achieved in all patients. While waiting for reimplantation one patient experienced a symptomatic episode of sustained ventricular tachycardia. This episode was converted successfully into sinus rhythm by a single 150 J shock. Mean follow-up time 392 ± 206 days, showing survival rate of 100% and freedom from reinfection in all patients.Conclusion: The WCD seems to be a valuable bridging option for patients with ICD or CRT-D infections, showing no recurrent device infection. [ABSTRACT FROM AUTHOR]

Background: The use of low intra-abdominal pressure (<10 mmHg) reduces postoperative pain scores after laparoscopic surgery. Objective: To investigate whether low-pressure pneumoperitoneum with deep neuromuscular blockade improves the quality of recovery after laparoscopic donor nephrectomy (LDN). Design, setting and participants: In a single-center randomized controlled trial, 64 live kidney donors were randomly assigned to 6 or 12 mmHg insufflation pressure. A deep neuromuscular block was used in both groups. Surgical conditions were rated by the five-point Leiden-surgical rating scale (L-SRS), ranging from 5 (optimal) to 1 (extremely poor) conditions. If the L-SRS was insufficient, the pressure was increased stepwise. Main outcome measure: The primary outcome measure was the overall score on the quality of recovery-40 (QOR-40) questionnaire at postoperative day 1. Results: The difference in the QOR-40 scores on day 1 between the low- and standard-pressure group was not significant ( p = .06). Also the overall pain scores and analgesic consumption did not differ. Eight procedures (24%), initially started with low pressure, were converted to a standard pressure (≥10 mmHg). A L-SRS score of 5 was significantly more prevalent in the standard pressure as compared to the low-pressure group at 30 min after insufflation ( p < .01). Conclusions: Low-pressure pneumoperitoneum facilitated by deep neuromuscular blockade during LDN does not reduce postoperative pain scores nor improve the quality of recovery in the early postoperative phase. The question whether the use of deep neuromuscular blockade during laparoscopic surgery reduces postoperative pain scores independent of the intra-abdominal pressure should be pursued in future studies. Trial registration: The trial was registered at clinicaltrial.gov before the start of the trial (NCT02146417). [ABSTRACT FROM AUTHOR]

Background: Adenoid cystic carcinoma (AdCC) of the head and neck is an uncommon malignant epithelial tumour of the secretory glands. Many patients develop slowly growing local recurrence and/or distant metastasis, for which treatment options are limited. A retrospective analysis of 9 AdCC patients was conducted to analyse the visualization of AdCC on PSMA PET/CT and to investigate the expression of PSMA on primary, recurrent and metastatic AdCC tumour tissue using immunohistochemistry. Results: Local recurrence occurred in six patients and eight developed distant metastasis. All PET/CTs depicted PSMA-ligand uptake. Four PSMA PET/CTs showed suspected residual disease, eight scans depicted uptake in areas suspected of distant metastasis. Median Maximum Standardized Uptake Value (SUV) in local recurrent and distant metastatic AdCC was 2.52 (IQR 2.41-5.95) and 4.01 (IQR 2.66-8.71), respectively. All primary tumours showed PSMA expression on immunohistochemistry (5-90% expression), as well as all available specimens of local recurrence and distant metastases. Conclusion: PSMA PET/CT is able to detect and visualize local recurrent and distant metastatic AdCC. PSMA-specific targeting is supported by PSMA expression on immunohistochemistry. [ABSTRACT FROM AUTHOR]

Background: The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy. Patients and methods: A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n=279) or observation (n=279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status. Results: RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69-97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39-0.84); RASmutant: HR 0.74 (0.55-0.98); V600EBRAF-mutant: HR 0.28 (0.12-0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment. Conclusions: CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF-mutant tumours. [ABSTRACT FROM AUTHOR]

Endothelial cells are the first non-self-barrier encountered by the recipient's immune system after allograft transplantation and thus are involved early during alloimmune response. Our goal was to study processes of endothelial cell injury/activation in a mouse model of lung transplantation. Mouse orthotopic left lung transplantation was performed in isografts (C57BL/6 to C57BL/6) and allografts (Balbc to C57BL/6), both received daily immunosuppression (10 mg/kg cyclosporin A and 1.6 mg/kg methylprednisolone) and were serially sacrificed at day 1, 7 and 35 post-transplant (n=6/timepoint/group). Left transplanted lungs were made into single cell suspension and absolute cell numbers were quantified by flow cytometry for CD31+ endothelial cells, CD45+ leukocytes and MHCI/II, VCAM-1 and ICAM-1 for cell activation. One additional allograft and isograft were scanned with high resolution (HR) ex vivo microCT (µCT) to visualize airways and blood vessels at day 70 post transplantation. Endothelial cell numbers decreased from day 1 until day 7 (p=0.03) in allografts and recovered slightly at day 35. While in isografts, endothelial cells seemed to increase non-significantly over time. In contrast, leukocytes significantly increased at day 7 in allografts versus day 1 (p=0.036) and isografts at day 7 (p=0.003). Leukocytes remained stable in isografts over time (p=0.3). Mean fluorescence intensity (MFI) was increased for MHC I/II and VCAM-1 (p=0.003; p<0.0001; p=0.04) on endothelial cells, the MFI of MHC I/II and ICAM-1 on leukocytes was increased in allografts versus isografts (p=0.0002; p=0.006; p=0.002). HR µCT showed normal airway morphology while lumen of arteries and veins was narrowed in allograft compared to isograft. Arterioles and venules were occluded in allograft. Destruction of endothelial cells may represent the very first onset of alloimmune response post lung transplantation and warrant further investigations towards diagnostic and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Objective IQSEC2 is an X-linked gene associated with intellectual disability ( ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. Methods Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. Results Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic ( GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging ( MRI) were prominent features. Significance The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy. [ABSTRACT FROM AUTHOR]

Different follow-up methods have been used to report success rates after AF ablation. Recent studies have shown that intermittent rhythm monitoring underestimates the actual AF recurrence rate. We therefore report our experience with continuous rhythm monitoring by implantable loop recorder (ILR) in a large patient cohort. Between 09/2008 and 12/2012, 343 cardiac surgical patients underwent concomitant surgical AF ablation. ILR implantation was performed in 206 patients. ILR interrogation was accomplished at 3, 6 and 12 months postoperatively. Successful ablation was defined as AF Burden <0.5 %. Primary outcome of the study was freedom from AF at 12-month follow-up. Mean patient's age was 70.5 ± 7.4 years. No major ablation- or ILR-related complications occurred. In 4 patients (1.9 %) ILR had to be explanted due to ILR-related wound infection ( n = 2) or chronic pain ( n = 2). Survival rate at 1-year follow-up was 96.6 %. Freedom from AF rate after 1-year follow-up was 68.5 and 63.6 % off antiarrhythmic drugs, respectively. Statistically significant predictors for successful ablation at 1-year follow-up were smaller LA diameter, shorter duration of AF and preoperative paroxysmal AF. Demographic data, indication for surgery, lesion set and used energy source had no impact on freedom from AF after 1 year. Continuous ILR monitoring after concomitant surgical AF ablation was safe and feasible, with registered freedom from AF rate of 68.5 % at 1-year follow-up. Thus continuous rhythm monitoring provides reliable outcome data and helps to guide antiarrhythmic therapy. [ABSTRACT FROM AUTHOR]

Background: Lumbar spinal fusion for degenerative disorders of the lumbar spine is frequently used, despite current research presenting inconclusive evidence. This study aims to systematically review and meta-analyse the natural course of pain and disability in patients with degenerative disorders of the lumbar spine such as spinal stenosis, spondylolisthesis, disc herniation, or discogenic low back pain to improve lumbar spinal fusion management. Methods/design: An electronic database search will be conducted up to 30 September 2015 using MEDLINE, EMBASE, CINAHL, and ZETOC database. In addition, a search for articles in press and published ahead of print, British National Bibliography for Report Literature, and OpenGrey will be conducted. Prospective cohort studies using outcome measures of pain and disability will be eligible for inclusion. Two reviewers will screen titles, abstracts, and full-text independently using predetermined inclusion and exclusion criteria. The risk of bias of included studies will be assessed with the modified version of the Quality in Prognostic Studies tool. If metaanalysis of outcome data is deemed appropriate, variance-weighted pooled means will be calculated. Discussion: The results of this systematic review and meta-analysis may improve understanding of recovery after lumbar spinal fusion and improve lumbar spinal fusion management. [ABSTRACT FROM AUTHOR]

Background: High-resolution peripheral quantitative computed tomography (HR-pQCT) is a promising tool to assess the fracture-healing process at the microscale in vivo. Since casts are often used during fracture treatment, they might affect the assessment of bone density, microarchitectural, and biomechanical parameters and the short-term reproducibility of those parameters, e.g., as a result of beam-hardening. The aim of this study was to assess the effect of a plaster-of-Paris and/or fiberglass cast on bone parameters and on the short-term reproducibility of the HR-pQCT measurements of those parameters.Methods: The effects of a cast on HR-pQCT-derived bone parameters were evaluated by comparing HR-pQCT scans of fifteen human cadaveric distal radial specimens from one male and fourteen female donors (median age, eighty-four years [range, sixty-two to ninety years] at the time of death) in three conditions: with a plaster-of-Paris cast, with a fiberglass cast, or without a cast. Short-term reproducibility was assessed using duplicate scans of the distal end of the radius in sixteen healthy volunteers without a fracture (nine men and seven women with a median age of twenty-six years; range, twenty-two to thirty-nine years) while wearing and not wearing a fiberglass cast.Results: Compared with measurements made with no cast, the plaster-of-Paris cast introduced a systematic error in the bone parameters ranging from -2.6% in trabecular separation to -9.8% in cortical thickness. Bone parameters were affected only marginally by fiberglass, with errors between -0.6% and -1.6% in trabecular separation and cortical thickness, respectively. Short-term reproducibility with a fiberglass cast was similar to that with no cast: approximately 1% for bone density parameters, 4% to 5% for microarchitectural parameters, and 3% to 4% for biomechanical parameters.Conclusions: A plaster-of-Paris cast has a considerable effect on HR-pQCT measurements. A fiberglass cast only marginally affects the bone parameters, and the short-term reproducibility of HR-pQCT measurements in patients with a fiberglass cast is comparable with that in patients without a cast. In studies on fracture-healing using HR-pQCT, a fiberglass cast is desirable if immobilization is indicated. The use of a plaster-of-Paris cast should be avoided if possible; however, if not avoidable, corrections after the scan are desirable to adjust for the error introduced in the bone parameters. [ABSTRACT FROM AUTHOR]

Study Design: An in vitro biomechanical study in porcine thoracic spine segments comparing range of motion (ROM) in segmental versus multiple nonsegmental ultrahigh molecular weight polyethylene (UHMWPE) sublaminar wire constructs.Objective: To determine the effect of varying instrumentation (wire) density in an UHMWPE sublaminar wire construct for patients with early-onset scoliosis (EOS) to find an optimal wire density, which allows maximum growth whereas still providing adequate correction and fixation.Summary Of Background Data: UHMWPE sublaminar wires in a segmental construct did not negatively affect longitudinal spinal growth during a 24-week period in an ovine model; application in growth guidance system for EOS may therefore be feasible. To avoid ectopic bone formation as much as possible, a reduction of instrumented levels, without affecting spinal stabilization, is desirable.Methods: ROM of 9 porcine thoracic spines (T6-T14) was determined in flexion/extension (FE), lateral bending (LB), and axial rotation up to ± 4 Nm. Tests were performed for the uninstrumented spine in a segmental construct with UHMWPE sublaminar wires and dual pedicle screws at the most caudal level, and in four nonsegmental constructs that were attained by stepwise removal of the most caudal wire.Results: Segmental instrumentation led to a decrease in total ROM by approximately 70% for both FE and LB. A stepwise increase in ROM with decreasing number of consecutively instrumented levels was most clearly observed in LB. However, consistent significant but also relevant substantial differences in ROM for both FE and LB were noted only when comparing two and one consecutively instrumented end levels (P < 0.05).Conclusion: A construct with two consecutive end levels instrumented with UHMWPE sublaminar wires seems to provide the best balance between spinal stabilization and minimizing the number of instrumented levels and thereby surgical exposure, which is crucial for allowing longitudinal growth.Level Of Evidence: N/A. [ABSTRACT FROM AUTHOR]