Cost-effectiveness of posterior versus anterior surgery for cervical radiculopathy: results from a multicentre randomised non-inferiority trial (FACET).

PURPOSE: For cervical nerve root compression, anterior cervical discectomy with fusion (anterior surgery) or posterior foraminotomy (posterior surgery) are safe and effective options. Posterior surgery might have a more beneficial economic profile compared to anterior surgery. The purpose of this study was to analyse if posterior surgery is cost-effective compared to anterior surgery. METHODS: An economic evaluation was performed as part of a multicentre, noninferiority randomised clinical trial (Foraminotomy ACDF Cost-effectiveness Trial) with a follow-up of 2 years. Primary outcomes were cost-effectiveness based on arm pain (Visual Analogue Scale (VAS; 0-100)) and cost-utility (quality adjusted life years (QALYs)). Missing values were estimated with multiple imputations and bootstrap simulations were used to obtain confidence intervals (CIs). RESULTS: In total, 265 patients were randomised and 243 included in the analyses. The pooled mean decrease in VAS arm at 2-year follow-up was 44.2 in the posterior and 40.0 in the anterior group (mean difference, 4.2; 95% CI, - 4.7 to 12.9). Pooled mean QALYs were 1.58 (posterior) and 1.56 (anterior) (mean difference, 0.02; 95% CI, - 0.05 to 0.08). Societal costs were €28,046 for posterior and €30,086 for the anterior group, with lower health care costs for posterior (€12,248) versus anterior (€16,055). Bootstrapped results demonstrated similar effectiveness between groups with in general lower costs associated with posterior surgery. CONCLUSION: In patients with cervical radiculopathy, arm pain and QALYs were similar between posterior and anterior surgery. Posterior surgery was associated with lower costs and is therefore likely to be cost-effective compared with anterior surgery.

The vanishing of the ACoA syndrome after aneurysmal subarachnoid haemorrhage: New era, different management, fewer problems?

Historically, a specific set of symptoms has been related to the rupture and repair of anterior communicating artery (ACoA) aneurysms. These consequences were defined as the 'ACoA syndrome' and included observations of severe memory loss, confabulation and personality or behavioural changes. These observations correspond to neuropsychological impairments in memory, executive functions and social cognition. However, in more recent studies, the existence of such a distinct syndrome has been called into question. We aimed to investigate the existence of the ACoA syndrome, by combining analysis of our own data with a systematic review of the literature. Memory, executive functions and social cognition of subarachnoid haemorrhage patients with ACoA aneurysms (N = 28) were compared to patients with aneurysms in other locations (N = 66). Results showed no significant differences. Subsequently, a systematic review of the existing literature on the ACoA syndrome was performed using Embase and PubMed until October 2022. Studies that investigated cognitive functions after rupture and repair of ACoA aneurysms were included. The search yielded 847 unique entries and after screening titles and abstracts, 648 records were excluded. 199 full-text articles were assessed for eligibility and 55 articles were included. Evidence was found for the ACoA syndrome in studies between 1960 and 2000, with impairments in memory and executive problems in the majority of studies. However, the majority of studies from 2000 did not demonstrate a distinct ACoA syndrome, although neuropsychological measurements improved. This coincides with the changes in the management of ACoA aneurysms over the past decades, such as the emergence of endovascular treatment and improvement of neurointensive care. Therefore, we hypothesize that the management techniques of ACoA aneurysms until around 2000, i.e. mainly conventional clipping, could be related to the presence of symptoms of the ACoA syndrome.

Stimulation parameters for motor evoked potentials during intraoperative spinal cord monitoring. A systematic review.

OBJECTIVE: The aim of this systematic review was to find the optimal stimulation parameters for muscle recorded transcranial electrical stimulation motor evoked potential (mTc-MEP) and D-wave monitoring during spinal cord monitoring. METHODS: A PRISMA systematic search in Medline and EMBASE and a QUADAS-2 quality evaluation was performed to identify studies that compared stimulation parameters consisting of stimulation location, number of pulses, pulse duration, interstimulus interval, double train (DTS) or recurrent train stimulation (RTS) and intertrain interval (ITI) for performing mTc-MEP and D-wave monitoring. Only studies that used total intravenous anaesthesia (TIVA) were included. RESULTS: Ten studies that compared stimulation parameters for performing mTc-MEP monitoring (stimulation location n = 4, number of pulses n = 2, pulse duration n = 1, interstimulus interval n = 4, DTS n = 1, RTS n = 2, ITI n = 2) were included. No studies compared stimulation parameters (stimulation location and pulse duration) for performing D-wave monitoring. CONCLUSIONS: Few studies examined the optimal stimulation parameters for monitoring mTc-MEPs and no studies were included for D-wave monitoring. There is a need for prospective research to investigate the optimal stimulation parameters for mTc-MEP with the use of TIVA and D-wave monitoring. SIGNIFICANCE: For mTc-MEP monitoring, a table is provided in which the recommended stimulation parameters are stated.

Coronary calcium score in COVID-19 survivors: Association with cardiac injury and cardiac function after 6 weeks.

Aims: Cardiac manifestations are common in COVID-19, often elevated serum troponin levels or myocardial dysfunction on trans-thoracic echocardiography (TTE) is observed. Both parameters are associated with increased in-hospital mortality. Possibly, subclinical coronary atherosclerosis plays a role, of which severity can be assessed by calculating the coronary artery calcium (CAC) score. This study aims to determine the relation between coronary atherosclerosis and cardiac manifestations in COVID-19 survivors. Methods: This study was conducted at the Leiden University Medical Center. All patients admitted for COVID-19 were included and scheduled for a 6-week follow-up visit with trans-thoracic echocardiography (TTE). CAC was assessed according to an ordinal score on non-gated, non-contrast enhanced computed tomography of the chest. Patients with and without CAC were compared on cardiac injury as reflected by elevated serum troponin levels and impaired cardiac function assessed through TTE. Results: In total, 146 patients were included. Mean age was 62 years and 62 % of the patients were male. During admission, patients with CAC showed significantly higher levels of troponin (19 ng/L vs 10 ng/L; p < 0.01). Overall, mild echocardiographic abnormalities were seen; 12 % showed reduced left ventricular function (left ventricular ejection fraction of <50 %) and 14 % reduced right ventricular function (tricuspid annular planar systolic excursion ≤17 mm). Following multivariable adjustments, there was no significant relation between CAC and myocardial function at 6 weeks. Conclusion: The present study shows that coronary atherosclerosis is associated with cardiac injury in COVID-19 survivors. However, no significant relation with impaired cardiac function was demonstrated.

Feasibility and optimal choice of stimulation parameters for supramaximal stimulation of motor evoked potentials.

PURPOSE: The aim was to investigate the feasibility and optimal stimulation parameters for supramaximal stimulation of muscle recorded transcranial electrical stimulation motor evoked potentials (mTc-MEP). METHODS: Forty-seven consecutive patients that underwent scoliosis surgery were included. First, the feasibility of supramaximal stimulation was assessed for two settings (setting 1: pulse duration 0.075ms, interstimulus interval (ISI) 1.5ms; setting 2: pulse duration 0.300ms, ISI 3ms). Thereafter, three mTc-MEP parameters were considered for both settings; (1) elicitability, (2) amplitude, and (3) if supramaximal stimulation was achieved with ≥ 20 V below maximum output. Finally, ISIs (1ms-4ms) were optimized for setting 1. RESULTS: Nine patients (19.15%) were excluded. Of the remaining patients, supramaximal stimulation was achieved in all patients for setting 1, and in 26 (68.42%) for setting 2. In one patient, mTc-MEPs were elicitable in more muscles for setting (1) Amplitudes were not significantly different. Stimulation voltage could be increased ≥ 20 V in all 38 patients for setting 1 and in 10 (38.46%) for setting (2) Optimal ISI's differed widely. CONCLUSION: We recommend using setting 1 when monitoring mTc-MEPs with supramaximal stimulation, after which an individualized ISI optimization can be performed. Moreover, when using supramaximal stimulation, short ISI's (i.e. 1ms or 1.5ms) can be the optimal ISI for obtaining the highest mTc-MEP amplitude.

The influence of depth of anesthesia and blood pressure on muscle recorded motor evoked potentials in spinal surgery. A prospective observational study protocol.

For high-risk spinal surgeries, intraoperative neurophysiological monitoring (IONM) is used to detect and prevent intraoperative neurological injury. The motor tracts are monitored by recording and analyzing muscle transcranial electrical stimulation motor evoked potentials (mTc-MEPs). A mTc-MEP amplitude decrease of 50-80% is the most common warning criterion for possible neurological injury. However, these warning criteria often result in false positive warnings. False positives may be caused by inadequate depth of anesthesia and blood pressure on mTc-MEP amplitudes. The aim of this paper is to validate the study protocol in which the goal is to investigate the effects of depth of anesthesia (part 1) and blood pressure (part 2) on mTc-MEPs. Per part, 25 patients will be included. In order to investigate the effects of depth of anesthesia, a processed electroencephalogram (pEEG) monitor will be used. At pEEG values of 30, 40 and 50, mTc-MEP measurements will be performed. To examine the effect of blood pressure on mTc-MEPs the mean arterial pressure will be elevated from 60 to 100 mmHg during which mTc-MEP measurements will be performed. We hypothesize that by understanding the effects of depth of anesthesia and blood pressure on mTc-MEPs, the mTc-MEP monitoring can be interpreted more reliably. This may contribute to fewer false positive warnings. By performing this study after induction and prior to incision, this protocol provides a unique opportunity to study the effects of depths of anesthesia and blood pressure on mTc-MEPs alone with as little confounders as possible. Trial registration number NL7772.

Exploring temporal relationships among worrying, anxiety, and somatic symptoms.

OBJECTIVES: The role of anxiety symptoms in the development of functional somatic symptoms (FSS) is unknown. Somatic symptoms may be triggered by or give rise to anxiety symptoms. This study aimed to 1) explore interrelationships among within-day worrying, feeling anxious, and somatic symptoms, and 2) investigate the association between these interrelationships and overall level of FSS. METHODS: This study included 767 participants (83% females, mean age 39 years), who were recruited through an online crowdsourcing study in the Dutch general population. Somatic, and anxiety symptoms were reported thrice daily (6-h intervals) for 30 days using electronic diaries. FSS were assessed at baseline (PHQ-15). Temporal relationships among worrying, feeling anxious, and somatic symptoms were modeled using a multilevel vector autoregressive model. RESULTS: We observed large heterogeneity in the within-person interrelationships among worrying, feeling anxious and somatic symptoms. Averaged over participants, higher-than-usual somatic symptoms were associated with increases in levels of worrying six hours later (B = 0.017, 95% CI [0.006, 0.027]). At the between-person level, FSS levels predicted the persistence of feeling anxious (B = 0.230 95% CI [0.105, 0.350]) and the carry-over of worrying to feeling anxious over six-hours (B = 0.159, 95% CI [0.031, 0.283]). CONCLUSIONS: In contrast to what we expected, higher levels of somatic symptoms over multiple weeks were associated with the persistence and carry-over of within-day anxiety-related symptoms. One within-person association between psychological and somatic symptoms during the day was observed, suggesting that, over a time span of 6-h, anxiety symptoms relate to somatic symptoms only in a minority of people from the general population.

Ex vivo cultures and drug testing of primary acute myeloid leukemia samples: Current techniques and implications for experimental design and outcome.

New treatment options of acute myeloid leukemia (AML) are rapidly emerging. Pre-clinical models such as ex vivo cultures are extensively used towards the development of novel drugs and to study synergistic drug combinations, as well as to discover biomarkers for both drug response and anti-cancer drug resistance. Although these approaches empower efficient investigation of multiple drugs in a multitude of primary AML samples, their translational value and reproducibility are hampered by the lack of standardized methodologies and by culture system-specific behavior of AML cells and chemotherapeutic drugs. Moreover, distinct research questions require specific methods which rely on specific technical knowledge and skills. To address these aspects, we herein review commonly used culture techniques in light of diverse research questions. In addition, culture-dependent effects on drug resistance towards commonly used drugs in the treatment of AML are summarized including several pitfalls that may arise because of culture technique artifacts. The primary aim of the current review is to provide practical guidelines for ex vivo primary AML culture experimental design.

Intraoperative neurophysiological monitoring during scoliosis surgery in patients with Duchenne muscular dystrophy.

PURPOSE: Little is known about the reliability and value of intraoperative neurophysiological monitoring (IONM) in patients with Duchenne muscular dystrophy (DMD) undergoing scoliosis correction surgery. The aim of this study was to investigate the feasibility of IONM and the cortical excitability in these patients. METHODS: Fifteen patients with DMD and scoliosis and 15 patients with adolescent idiopathic scoliosis (AIS) underwent scoliosis correction surgery with the use of IONM. IONM consisted of transcranial electrical stimulation motor evoked potential (Tc-MEP) and somatosensory evoked potential (SSEP) monitoring. The highest Tc-MEP amplitudes were collected to test the feasibility. Preoperative compound muscle action potentials (CMAPs) and transcranial magnetic stimulation (TMS)-MEPs were recorded to test the cortical excitability. SSEPs were scored as elicitable or not elicitable. RESULTS: Tc-MEP amplitudes were significantly lower in the DMD group for both the gastrocnemius and tibialis anterior muscles. However, the abductor hallucis muscle had similar amplitudes in both the DMD as the AIS group. TMS/CMAP and Tc-MEP/CMAP ratios were similar in the DMD and AIS group (P = 0.126 and P = 0.792 respectively). CONCLUSIONS: Tc-MEP and SSEP monitoring is feasible, particularly when Tc-MEPs are recorded from the abductor hallucis muscle in patients with DMD. Similar TMS/CMAP and Tc-MEP/CMAP ratios show that there were no differences observed in cortical excitability between the groups. IONM seems a feasible and valuable neurophysiological tool to signal possible surgically induced damage to the spinal cord during scoliosis correction surgery in patients with DMD.

Availability, procurement, training, usage, maintenance and complications of electrosurgical units and laparoscopic equipment in 12 African countries.

BACKGROUND: Strategies are needed to increase the availability of surgical equipment in low- and middle-income countries (LMICs). This study was undertaken to explore the current availability, procurement, training, usage, maintenance and complications encountered during use of electrosurgical units (ESUs) and laparoscopic equipment. METHODS: A survey was conducted among surgeons attending the annual meeting of the College of Surgeons of East, Central and Southern Africa (COSECSA) in December 2017 and the annual meeting of the Surgical Society of Kenya (SSK) in March 2018. Biomedical equipment technicians (BMETs) were surveyed and maintenance records collected in Kenya between February and March 2018. RESULTS: Among 80 participants, there were 59 surgeons from 12 African countries and 21 BMETs from Kenya. Thirty-six maintenance records were collected. ESUs were available for all COSECSA and SSK surgeons, but only 49 per cent (29 of 59) had access to working laparoscopic equipment. Reuse of disposable ESU accessories and difficulties obtaining carbon dioxide were identified. More than three-quarters of surgeons (79 per cent) indicated that maintenance of ESUs was available, but only 59 per cent (16 of 27) confirmed maintenance of laparoscopic equipment at their centre. CONCLUSION: Despite the availability of surgical equipment, significant gaps in access to maintenance were apparent in these LMICs, limiting implementation of open and laparoscopic surgery.

ANTECEDENTES: En países de bajos y medianos ingresos (low- and middle-income countries, LMIC) hay que desarrollar estrategias de futuro para incrementar la disponibilidad de equipos quirúrgicos, adquisición, capacitación, uso, mantenimiento y complicaciones relacionadas con las unidades electroquirúrgicas (electrosurgical unit, ESU) y los equipos de laparoscopia. MÉTODOS: Se realizó una encuesta entre los cirujanos que asistieron a la reunión anual del Colegio de Cirujanos de África Oriental, Central y Meridional (College Of Surgeons of East, Central and Southern Africa, COSECSA) en diciembre de 2017 y a la reunión anual de la Sociedad Quirúrgica de Kenia (Surgical Society of Kenya, SSK) en marzo de 2018. Se encuestaron también a los técnicos de equipos biomédicos (Biomedical Equipment Technicians, BMET) y se recopilaron los registros de mantenimiento en Kenia entre febrero y marzo de 2018. RESULTADOS: Participaron 80 sujetos, 59 cirujanos de 11 países africanos y 21 BMET de Kenia. Se recopilaron 36 registros de mantenimiento. Todos los cirujanos de COSECSA y SSK disponían de ESU, pero menos de la mitad (49%) disponían de equipos de laparoscopia. Como principales problemas se detectaron la reutilización de accesorios desechables en las ESU y las dificultades para disponer de CO2. Más de las tres cuartas partes (78%) de los cirujanos contaban con equipos de mantenimiento para las ESU, pero solo el 59% disponía de mantenimiento para los equipos de laparoscopia en su centro. CONCLUSIÓN: A pesar de la disponibilidad de equipos quirúrgicos, en estos LMIC se detectaron serias dificultades en su mantenimiento, hecho que limita la implementación de la cirugía abierta y laparoscópica.

Cervical spondylodiscitis following cricopharyngeal botulinium toxin injection.

BACKGROUND: Iatrogenic cervical spondylodiscitis is rare, but may occur after various medical interventions. METHODS: We report a case of a diabetic 70-years-old female with C5-C6 spondylodiscitis and symptomatic epidural abscess with neck pain and upper limb paresis after endoscopic botulinum toxin injection for the treatment of dysphagia. Treatment included antibiotic therapy with amoxicillin and later on benzylpenicillin for the next ten weeks and corporectomy with spondylodesis. RESULT: The patient made an excellent recovery, with complete resolution of paresis and only minor residual hypoesthesia at one year after operation. CONCLUSION: Cervical spondylodiscitis should be considered early, in patients with neck pain after endoscopic cricopharyngeal injection, as timely diagnosis and treatment can prevent serious and irreversible neurological deficit.

Mental versus physical fatigue after subarachnoid hemorrhage: differential associations with outcome.

BACKGROUND AND PURPOSE: Fatigue is a major consequence of subarachnoid hemorrhage (SAH), but the specific characteristics are unclear. Our objective was to investigate the nature of post-SAH fatigue (mental or physical) and to determine the relationship with functional outcome in the chronic stage. Also, the possible influence of mood disorders and acute SAH-related factors [SAH type and external cerebrospinal fluid (CSF) drainage] on the presence of fatigue was investigated. METHODS: Patients with an aneurysmal SAH (aSAH) or angiographically negative SAH (anSAH) were assessed 3-10 years post-SAH (N = 221). Questionnaires were used to investigate mental and physical fatigue and mood. Functional outcome was examined with the Glasgow Outcome Scale Extended. Between-group comparisons and binary logistic regression analysis were performed. RESULTS: Frequencies of mental and physical fatigue were 48.4% and 38.5%, respectively, with prevalence of mental fatigue being significantly higher. A two-way anova with SAH type and external CSF drainage as independent variables and mental fatigue as dependent variable showed a significant main effect of CSF drainage only (P < 0.001). Only mental fatigue explained a significant part of the variance in long-term functional outcome (model χ2 = 52.99, P < 0.001; Nagelkerke R² = 0.32). CONCLUSIONS: Mental fatigue after SAH is a serious burden to the patient and is associated with impaired long-term functional outcome. Distinguishing different aspects of fatigue is relevant as mental post-SAH fatigue might be a target for treatment aimed to improve long-term outcome.

SSTR-2 as a potential tumour-specific marker for fluorescence-guided meningioma surgery.

BACKGROUND: Meningiomas are the most frequently occurring primary intracranial tumours in adults. Surgical removal can only be curative by complete resection; however surgical access can be challenging due to anatomical localization and local invasion of bone and soft tissues. Several intraoperative techniques have been tried to improve surgical resection, including intraoperative fluorescence guided imaging; however, no meningioma-specific (fluorescent) targeting has been developed yet. Here, we aimed to identify the most promising biomarkers for targeted intra-operative fluorescence guided meningioma surgery. METHODS: One hundred forty-eight meningioma specimens representing all meningioma grades were analysed using immunohistochemistry (IHC) on tissue microarrays (TMAs) to determine expression patterns of meningioma biomarkers epithelial membrane antigen (EMA), platelet-derived growth factor ß (PDGF-ß), vascular endothelial growth factor α (VEGF-α), and somatostatin receptor type 2 (SSTR-2). Subsequently, the most promising biomarker was selected based on TArget Selection Criteria (TASC). Marker expression was examined by IHC in 3D cell culture models generated from freshly resected tumour material. RESULTS: TMA-IHC showed strongest staining for SSTR-2. All cases were positive, with 51.4% strong/diffuse, 30.4% moderate/diffuse and only 18.2% focal/weak staining patterns. All tested biomarkers showed at least weak positivity in all meningiomas, regardless of WHO grade. TASC analysis showed that SSTR-2 was the most promising target for fluorescence guided imaging, with a total score of 21 (out of 22). SSTR-2 expression was determined on original patient tumours and 3D cultures of three established cultures. CONCLUSIONS: SSTR-2 expression was highly sensitive and specific in all 148 meningiomas, regardless of WHO grade. According to TASC analysis, SSTR-2 is the most promising receptor for meningioma targeting. After establishing in vitro meningioma models, SSTR-2 cell membrane expression was confirmed in two of three meningioma cultures as well. This indicates that specific fluorescence in an experimental setting can be performed for the further development of targeted fluorescence guided meningioma surgery and near-infrared fluorescent tracers targeting SSTR-2.

NK cells in self-limited HCV infection exhibit a more extensively differentiated, but not memory-like, repertoire.

Natural killer (NK) cells have long been thought of as a purely innate immune cell population, but increasing reports have described developmental and functional qualities of NK cells that are commonly associated with cells of the adaptive immune system. Of these features, the ability of NK cells to acquire functional qualities associated with immunological memory and continuous differentiation resulting in the formation of specific NK cell repertoires has recently been highlighted in viral infection settings. By making use of a unique cohort of monitored, at-risk intravenous drug users in this study, we were able to dissect the phenotypic and functional parameters associated with NK cell differentiation and NK cell memory in patients 3 years after acute HCV infection and either the subsequent self-clearance or progression to chronicity. We observed increased expression of cytolytic mediators and markers CD56bright and NKp46+ of NK cells in patients with chronic, but not self-limited HCV infection. Patients with a self-limited infection expressed higher levels of differentiation-associated markers CD57 and KIRs, and lower levels of NKG2A. A more extensively differentiated NK cell phenotype is associated with self-clearance in HCV patients, while the NK cells of chronic patients exhibited more naïve and effector NK cell phenotypic and functional characteristics. The identification of these distinct NK cell repertoires may shed light on the role NK cells play in determining the outcome of acute HCV infections, and the underlying immunological defects that lead to chronicity.

Study protocol for a randomised controlled multicentre study: the Foraminotomy ACDF Cost-Effectiveness Trial (FACET) in patients with cervical radiculopathy.

INTRODUCTION: Cervical radiculopathy due to discogenic or spondylotic stenosis of the neuroforamen can be surgically treated by an anterior discectomy with fusion (ACDF) or a posterior foraminotomy (FOR). Most surgeons prefer ACDF, although there are indications that FOR is as effective as ACDF, has a lower complication rate and is less expensive. A head-to-head comparison of the 2 surgical techniques in a randomised controlled trial has not yet been performed. The study objectives of the Foraminotomy ACDF Cost-Effectiveness Trial (FACET) study are to compare clinical outcomes, complication rates and cost-effectiveness of FOR to ACDF. METHODS AND ANALYSIS: The FACET study is a prospective randomised controlled trial conducted in 7 medical centres in the Netherlands. The follow-up period is 2 years. The main inclusion criterion is a radiculopathy of the C4, C5, C6 or C7 nerve root, due to a single-level isolated cervical foraminal stenosis caused by a soft disc and/or osteophytic component, requiring operative decompression. A sample size of 308 patients is required to test the hypothesis of clinical non-inferiority of FOR versus ACDF. Primary outcomes are: 'operative success', the measured decrease in radiculopathy assessed by the visual analogue scale and 'patient success', assessed by the modified Odom's criteria. Secondary outcomes are: Work Ability Index (single-item WAI), quality of life (EuroQol 5 Dimensions 5 level Survey, EQ-5D-5L), Neck Disability Index (NDI) and complications. An economic evaluation will assess cost-effectiveness. In addition, a budget impact analysis will be performed. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Institutional Ethics Committee of the University Medical Center Groningen. Results of this study will be disseminated through national and international papers. The participants and relevant patient support groups will be informed about the results of the study. TRIAL REGISTRATION NUMBER: NTR5536, pre-results.

Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold-based xenograft model.

Although NOD-SCID IL2Rγ-/- (NSG) xenograft mice are currently the most frequently used model to study human leukemia in vivo, the absence of a human niche severely hampers faithful recapitulation of the disease. We used NSG mice in which ceramic scaffolds seeded with human mesenchymal stromal cells were implanted to generate a human bone marrow (huBM-sc)-like niche. We observed that, in contrast to the murine bone marrow (mBM) niche, the expression of BCR-ABL or MLL-AF9 was sufficient to induce both primary acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). Stemness was preserved within the human niches as demonstrated by serial transplantation assays. Efficient engraftment of AML MLL-AF9 and blast-crisis chronic myeloid leukemia patient cells was also observed, whereby the immature blast-like phenotype was maintained in the huBM-sc niche but to a much lesser extent in mBM niches. We compared transcriptomes of leukemias derived from mBM niches versus leukemias from huBM-like scaffold-based niches, which revealed striking differences in the expression of genes associated with hypoxia, mitochondria and metabolism. Finally, we utilized the huBM-sc MLL-AF9 B-ALL model to evaluate the efficacy of the I-BET151 inhibitor in vivo. In conclusion, we have established human niche models in which the myeloid and lymphoid features of BCR-ABL+ and MLL-AF9+ leukemias can be studied in detail.

Psychotic experiences and risk of self-injurious behaviour in the general population: a systematic review and meta-analysis.

BACKGROUND: Recent studies suggest that psychotic experiences (PE) in the general population are associated with an increased risk of self-injurious behaviour. Both the magnitude of this association and the level of adjustment for confounders vary among studies. A meta-analysis was performed to integrate the available evidence. The influence of possible confounders, including variably defined depression, was assessed. METHOD: A systematic review and meta-analysis was conducted including general population studies reporting on the risk of self-injurious behaviour in individuals with PE. Studies were identified by a systematic search strategy in Pubmed, PsycINFO and Embase. Reported effect sizes were extracted and meta-analytically pooled. RESULTS: The risk of self-injurious behaviour was 3.20 times higher in individuals with PE compared with those without. Subanalyses showed that PE were associated with self-harm, suicidal ideation as well as suicidal attempts. All studies had scope for considerable residual confounding; effect sizes adjusted for depression were significantly smaller than effect sizes unadjusted for depression. In the longitudinal studies, adjustment for psychopathology resulted in a 74% reduction in excess risk. CONCLUSIONS: PE are associated with self-injurious behaviour, suggesting they have potential as passive markers of suicidality. However, the association is confounded and several methodological issues remain, particularly how to separate PE from the full range of connected psychopathology in determining any specific association with self-injurious behaviour. Given evidence that PE represent an indicator of severity of non-psychotic psychopathology, the association between PE and self-injurious behaviour probably reflects a greater likelihood of self-injurious behaviour in more severe states of mental distress.

Outcome after intracranial haemorrhage from dural arteriovenous fistulae; a systematic review and case-series.

Dural arteriovenous fistulae (DAVFs) are a rare cause of intracranial haemorrhage. We aimed to investigate outcome of patients with intracranial haemorrhage from a DAVF. We performed a systematic literature search for studies reporting outcome after intracranial haemorrhage caused by a DAVF. We used predefined selection criteria and assessed the quality of the studies. In addition, we studied outcome in all patients with DAVF who had presented with intracranial haemorrhage at two university centers in the Netherlands, between January 2007 and April 2012. We calculated case fatality and proportions of patients with poor outcome (defined as modified Rankin Scale ≥ 3 or Glasgow Outcome Scale ≤ 3) during follow-up. We investigated mean age, sex, mid-year of study and percentage of patients with parenchymal haemorrhage as determinants of case fatality and poor outcome. The literature search yielded 16 studies, all but two retrospective and all hospital-based. Combined with our cohort of 29 patients the total number of patients with DAVF-related intracranial haemorrhage was 326 (58% intracerebral haemorrhage). At a median follow-up of 12 months case fatality was 4.7% (95% CI 2.5-7.5; 17 cohorts) and the proportion of patients with poor outcome 8.3% (95% CI 3.1-15.7; nine cohorts). We found no effect of mean age, sex, mid-year of the cohorts and percentage of patients with parenchymal haemorrhage on either outcome. Hospital based case-series suggest a relatively low risk of death and poor outcome in patients with intracranial haemorrhage due to rupture of a DAVF. These risks may be underestimated because of bias.

Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab.

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.