Longitudinal associations between alcohol use, smoking, genetic risk scoring and symptoms of depression in the general population: a prospective 6-year cohort study.

BACKGROUND: Alcohol consumption, smoking and mood disorders are leading contributors to the global burden of disease and are highly comorbid. Yet, their interrelationships have remained elusive. The aim of this study was to examine the multi-cross-sectional and longitudinal associations between (change in) smoking and alcohol use and (change in) number of depressive symptoms. METHODS: In this prospective, longitudinal study, 6646 adults from the general population were included with follow-up measurements after 3 and 6 years. Linear mixed-effects models were used to test multi-cross-sectional and longitudinal associations, with smoking behaviour, alcohol use and genetic risk scores for smoking and alcohol use as independent variables and depressive symptoms as dependent variables. RESULTS: In the multi-cross-sectional analysis, smoking status and number of cigarettes per day were positively associated with depressive symptoms (p < 0.001). Moderate drinking was associated with less symptoms of depression compared to non-use (p = 0.011). Longitudinally, decreases in the numbers of cigarettes per day and alcoholic drinks per week as well as alcohol cessation were associated with a reduction of depressive symptoms (p = 0.001-0.028). Results of genetic risk score analyses aligned with these findings. CONCLUSIONS: While cross-sectionally smoking and moderate alcohol use show opposing associations with depressive symptoms, decreases in smoking behaviour as well as alcohol consumption are associated with improvements in depressive symptoms over time. Although we cannot infer causality, these results open avenues to further investigate interventions targeting smoking and alcohol behaviours in people suffering from depressive symptoms.

Cost-effectiveness of on-demand removal of syndesmotic screws.

PURPOSE: Syndesmotic screw removal following acute syndesmotic injury is a commonly performed procedure. However, recent studies suggest that the removal does not result in improved patient reported outcome, while the procedure has proved not to be without complications. The aim of this study was to present a health-economic evaluation of on-demand removal (ODR) compared to routine removal (RR) of the syndesmotic screw. METHODS: Data were collected from the RODEO trial, a randomized controlled non-inferiority trial comparing functional outcome of ODR with RR. Economic evaluation resulted in total costs, costs (in Euro) per quality adjusted life year (QALY) and costs per point improvement on the Olerud Molander Ankle Score (OMAS). This included both direct and indirect costs. RESULTS: Total costs for ODR were significantly lower with a mean difference of 3160 euro compared to RR (p < 0.001). The difference in QALY was not significant. The difference in OMAS at 12 months was 1.79 with an incremental cost-effectiveness ratio (ICER) of €-1763 (p = 0.512). The ICER was well below the willingness to pay. Although unit costs might vary between hospitals and countries, these results provide relevant data of cost-effectiveness. CONCLUSION: The clinical effectiveness of both ODR and RR can be considered equal. The costs are lower for patients treated with ODR, which leads to the conclusion that ODR is cost-effective.

Pediatric medulloblastoma express immune checkpoint B7-H3.

PURPOSE: Medulloblastomas (MB) are highly malignant brain tumors that predominantly occur in young infants. Immunotherapy to boost the immune system is emerging as a novel promising approach, but is often hampered by inhibitory immune checkpoints. In the present study, we have studied immune checkpoint B7-H3 expression in a tissue cohort of human pediatric MB. METHODS: Expression of B7-H3 was detected by immunohistochemistry and classified via B7-H3 staining intensity and percentage of B7-H3 positive tumor cells. Subsequently, B7-H3 protein expression was distinguished in MB molecular subtypes and correlated to immune cell infiltrates, patient characteristics, and survival. RESULTS: B7-H3 protein expression was found in 23 out of 24 (96%) human pediatric MB cases and in 17 out of 24 (71%) MB cases > 25% of tumor cells had any level of B7-H3 expression. B7-H3 protein expression was more frequent on Group-4 MB as compared with other molecular subtypes (p = 0.02). Tumors with high B7-H3 expression showed less influx of γδT cells (p = 0.002) and CD3+ T cells (p = 0.041). CONCLUSION: Immune checkpoint B7-H3 is differentially expressed by the large majority of pediatric MB. This further warrants the development of novel B7-H3-directed (immuno)therapeutic methods for children with incurable, metastatic, or chemo-resistant MB.

[Implementation of a stop-smoking support program for patients and employees in a psychiatric hospital: First results]. / Implementatie van een stoppen-met-rokenprogramma in een psychiatrisch ziekenhuis: eerste resultaten.

BACKGROUND: In contrast to several other countries, smoking is not an integral part of treatment during admission to a psychiatric hospital in The Netherlands.
AIM: Implementation of a smoking cessation program for patients and employees of a psychiatric ward of an academic medical center in The Netherlands.
METHOD: Prospective, mixed-method study of implementation of a smoking cessation program for patients and employees of a psychiatric academic hospital in Amsterdam. The program consisted of 7 weekly group meetings by certified smoking cessation coaches. Nicotine replacement therapy was provided for free, if necessary.
RESULTS: During 14 months, 65 individuals were seeking help to stop smoking: 39 patients and 26 employees. Of these, 29 patients and 16 employees participated in group meetings with an average of 2.6 times per person. There were 20 individuals who visited the group meetings or received individual coaching at least 3 times (6 patients and 14 employees). Fifty-five percent of these individuals reported to be smoke-free at 3 months after joining the first meeting. Employees were much more likely to quit than patients. From interviews with 20 participants, it was noticed that combining patients and employees in one group was perceived as a barrier due to a gap in processing speed.
CONCLUSION: On the psychiatric ward of an academic hospital in The Netherlands, there was a positive experience with providing smoking cessation treatment. A small number of employees and patients participated in a smoking cessation program and quitting smoking was reached by only a few patients. Supporting smoking cessation in a psychiatric hospital asks for intensive screening, diagnosing, treatment and smoke-free policies.

[Smoke-free psychiatric hospitals and the role of aggression: a systematic review]. / Is er een risico op toename van agressie bij een rookvrije ggz? Een literatuurstudie.

AIM: To provide an overview of the literature on transitions towards smoke-free psychiatric hospitals and the risk of aggression.
METHOD: A systematic search was made in medline, Embase and Psycinfo. Studies were included if they reported data on: a smoke-free intervention in a psychiatric hospital or ward, the number of aggressive incidents, and seclusions or prn drugs.
RESULTS: A total of 17 studies matched the inclusion/exclusion criteria; 5 reported a decrease in the number of aggressive incidents after implementation of a smoke-free ward, 7 showed an increase in the number of incidents, and 5 studies reported no differences. Heterogeneity between the studies was high with respect to the definition and implementation of the intervention, the definition and measurement of aggression, study design, length of follow-up, and the sample size.
CONCLUSION: These findings suggest that, after changing the policy towards a smoke-free psychiatric hospital, the risk of aggression is limited. However, several precautions related to the preparation and implementation of this transition seem to be essential. The results support further investment in the implementation of smoke-free psychiatric hospitals in the Netherlands, while maintaining safety.

Functional outcome of implant removal following fracture fixation below the level of the knee: a prospective cohort study.

AIMS: The aim of this study was to evaluate the functional outcome in patients undergoing implant removal (IR) after fracture fixation below the level of the knee. PATIENTS AND METHODS: All adult patients (18 to 75 years) undergoing IR after fracture fixation below the level of the knee between November 2014 and September 2016 were included as part of the WIFI (Wound Infections Following Implant Removal Below the Knee) trial, performed in 17 teaching hospitals and two university hospitals in The Netherlands. In this multicentre prospective cohort, the primary outcome was the difference in functional status before and after IR, measured by the Lower Extremity Functional Scale (LEFS), with a minimal clinically important difference of nine points. RESULTS: A total of 179 patients were included with a median age of 50 years (interquartile range (IQR) 37 to 60), of whom 71 patients (39.7%) were male. With a median score of 60 before IR (IQR 45 to 72) and 66 after IR (IQR 51 to 76) on the LEFS, there was a statistically significant improvement in functional outcome (p < 0 .001). A total of 31 surgical site infections (17.3%) occurred. CONCLUSION: Although IR led to a statistically significant improvement of functional outcome, the minimal clinically important difference was not reached. In conclusion, this study shows that IR does not result in a clinically relevant improvement in functional outcome. These results, in combination with the high complication rate, highlight the importance of carefully reviewing the indication for IR. Cite this article: Bone Joint J 2019;101-B:447-453.

Non- or Minimally Displaced Distal Radial Fractures in Adult Patients: Three Weeks versus Five Weeks of Cast Immobilization-A Randomized Controlled Trial.

Background Patients with non- or minimally displaced distal radial fractures, that do not need repositioning, are mostly treated by a short-arm cast for a period of 4 to 6 weeks. A shorter period of immobilization may lead to a better functional outcome. Purpose We conducted a randomized controlled trial to evaluate whether the duration of cast immobilization for patients with non- or minimally displaced distal radial fractures can be safely shortened toward 3 weeks. Materials and Methods The primary outcomes were patient-reported outcomes measured by the Patient-Related Wrist Evaluation (PRWE) and Quick Disability of Arm, Shoulder and Hand (QuickDASH) score after 1-year follow-up. Secondary outcome measures were: PRWE and QuickDASH earlier in follow-up, pain (Visual Analog Scale), and complications like secondary displacement. Results Seventy-two patients (male/female, 23/49; median age, 55 years) were included and randomized. Sixty-five patients completed the 1-year follow-up. After 1-year follow up, patients in the 3 weeks immobilization group had significantly better PRWE (5.0 vs. 8.8 points, p = 0.045) and QuickDASH scores (0.0 vs. 12.5, p = 0.026). Secondary displacement occurred once in each group. Pain did not differ between groups ( p = 0.46). Conclusion Shortening the period of immobilization in adult patients with a non- or minimally displaced distal radial fractures seems to lead to equal patient-reported outcomes for both the cast immobilization groups. Also, there are no negative side effects of a shorter period of cast immobilization. Therefore, we recommend a period of 3 weeks of immobilization in patients with distal radial fractures that do not need repositioning.

Understanding the impact of supervision on reducing medication risks: an interview study in long-term elderly care.

BACKGROUND: In 2009, the Dutch Health Care Inspectorate (IGZ) observed several serious risks to safety involving medication within elderly care facilities. However, by 2011, high risks had been reduced in almost all the organisations we visited. And yet the IGZ analysed too the alarming increase in the number of incidents arising in the self-reported national indicator of medication safety between 2009 and 2010. The aim of this study was to understand the factors that can explain this contradiction between the increase in self-reported medication incidents and the observation of the IGZ in reducing the risks to medication safety through supervision. METHODS: We interviewed health care professionals of ten care facilities, visited by the IGZ, who were involved in, or responsible for, the improvement of medication safety in their institutions. As outcome measures we used the rate of medication safety risk per facility; the perceptions of the participant with regard to the reports of medication incidents; the level of medication safety of the facility; the measures used to improve medication safety; and the supervision of medication safety. This was a mixed methods study, qualitative in that we used semi-structured interviews, and quantitative, by calculating risks for the different organisations we visited. The findings from both study methods resulted in a comprehensive view and an in-depth understanding of this contradiction. RESULTS: The contradiction between the increase in self-reported medication incidents and the observation of reduced risks was explained by three themes: activities designed to improve medication safety, the reporting of medication incidents, and, lastly, the impact of supervision. The focus of the IGZ on issues of medication safety stimulated most elderly care facilities to reduce medication risks. Also, a change in the culture of reporting incidents caused an increase in the number of reported incidents. CONCLUSIONS: Supervision contributed to an improvement in actions geared towards reducing the risks associated with the safety of medication. It also increased a willingness to report such incidents. The more incidents reported are therefore not necessarily a sign of an increase in the risks, but can also be considered as a sign of a safer culture.

Rare complication of pediatric inguinal hernia repair: case report of transection of the femoral vein.

INTRODUCTION: The incidence of pediatric inguinal hernias ranges up to 13 %. Currently, many different techniques are being used to successfully perform herniotomy and risks of complications are minor. CASE REPORT: This case report describes a 4-year-old male patient who underwent routine herniotomy during which the femoral vein was mistaken for hernial sac and thereby the femoral vein was transected. Postoperative vascular duplex ultrasonography revealed a complete transection of the right common femoral vein. Multiple treatment options such as venous reconstruction and interposition were considered, but a conservative treatment was chosen. At 6 months postoperative, the patient only shows minor complaints. Long-term results remain uncertain, especially since no similar case has previously been described in the current literature.

Treatment of rectal war wounds.

Treatment strategies for penetrating rectal injuries (PRI) in civilian settings are still not uniformly agreed, in part since high-energy transfer PRI, such as is frequently seen in military settings, are not taken into account. Here, we describe three cases of PRI, treated in a deployed combat environment, and outline the management strategies successfully employed. We also discuss the literature regarding PRI management. Where there is a major soft tissue component, repetitive debridement and vacuum therapy is useful. A loop or end colostomy should be used, depending on the degree of damage to the anal sphincter complex.

FER kinase promotes breast cancer metastasis by regulating α6- and ß1-integrin-dependent cell adhesion and anoikis resistance.

Metastatic breast cancer cannot be treated successfully. Currently, the targeted therapies for metastatic disease are limited to human epidermal growth factor receptor 2 and hormone receptor antagonists. Understanding the mechanisms of breast cancer growth and metastasis is therefore crucial for the development of new intervention strategies. Here, we show that FER kinase (FER) controls migration and metastasis of invasive human breast cancer cell lines by regulating α6- and ß1-integrin-dependent adhesion. Conversely, the overexpression of FER in non-metastatic breast cancer cells induces pro-invasive features. FER drives anoikis resistance, regulates tumour growth and is necessary for metastasis in a mouse model of human breast cancer. In human invasive breast cancer, high FER expression is an independent prognostic factor that correlates with high-grade basal/triple-negative tumours and worse overall survival, especially in lymph node-negative patients. These findings establish FER as a promising target for the prevention and inhibition of metastatic breast cancer.

Exon-level expression analyses identify MYCN and NTRK1 as major determinants of alternative exon usage and robustly predict primary neuroblastoma outcome.

BACKGROUND: Using mRNA expression-derived signatures as predictors of individual patient outcome has been a goal ever since the introduction of microarrays. Here, we addressed whether analyses of tumour mRNA at the exon level can improve on the predictive power and classification accuracy of gene-based expression profiles using neuroblastoma as a model. METHODS: In a patient cohort comprising 113 primary neuroblastoma specimens expression profiling using exon-level analyses was performed to define predictive signatures using various machine-learning techniques. Alternative transcript use was calculated from relative exon expression. Validation of alternative transcripts was achieved using qPCR- and cell-based approaches. RESULTS: Both predictors derived from the gene or the exon levels resulted in prediction accuracies >80% for both event-free and overall survival and proved as independent prognostic markers in multivariate analyses. Alternative transcript use was most prominently linked to the amplification status of the MYCN oncogene, expression of the TrkA/NTRK1 neurotrophin receptor and survival. CONCLUSION: As exon level-based prediction yields comparable, but not significantly better, prediction accuracy than gene expression-based predictors, gene-based assays seem to be sufficiently precise for predicting outcome of neuroblastoma patients. However, exon-level analyses provide added knowledge by identifying alternative transcript use, which should deepen the understanding of neuroblastoma biology.

Preoperative staging of perforated diverticulitis by computed tomography scanning.

BACKGROUND: Treatment of perforated diverticulitis depends on disease severity classified according to Hinchey's preoperative classification. This study assessed the accuracy of preoperative staging of perforated diverticulitis by computerized tomography (CT) scanning. METHODS: All patients who presented with perforated diverticulitis between 1999 and 2009 in two teaching hospitals of Rotterdam, the Netherlands, and in addition had a preoperative CT scan within 24 h before emergency surgery were included. Two radiologists reviewed all CT scans and were asked to classify the severity of the disease according to the Hinchey classification. The CT classification was compared to Hinchey's classification at surgery. RESULTS: Seventy-five patients were included, 48 of whom (64 %) were classified Hinchey 3 or 4 perforated diverticulitis during surgery. The positive predictive value of preoperative CT scanning for different stages of perforated diverticulitis ranged from 45 to 89 %, and accuracy was between 71 and 92 %. The combination of a large amount of free intra-abdominal air and fluid was strongly associated with Hinchey 3 or 4 and therefore represented a reliable indicator for required surgical treatment. CONCLUSIONS: The accuracy of predicting Hinchey's classification by preoperative CT scanning is not very high. Nonetheless, free intra-abdominal air in combination with diffuse fluid is a reliable indication for surgery as it is strongly associated with perforated diverticulitis with generalized peritonitis. In 42 % of cases, Hinchey 3 perforated diverticulitis is falsely classified as Hinchey 1 or 2 by CT scanning.

The influence of mechanical bowel preparation in elective colorectal surgery for diverticulitis.

BACKGROUND: Mechanical bowel preparation (MBP) has been shown to have no influence on the incidence of anastomotic leakage in overall colorectal surgery. The role of MBP in elective surgery in combination with an inflammatory component such as diverticulitis is yet unclear. This study evaluates the effects of MBP on anastomotic leakage and other septic complications in 190 patients who underwent elective surgery for colonic diverticulitis. METHODS: A subgroup analysis was performed in a prior multicenter (13 hospitals) randomized trial comparing clinical outcome of MBP versus no MBP in elective colorectal surgery. Primary endpoint was the occurrence of anastomotic leakage in patients operated on for diverticulitis, and secondary endpoints were septic complications and mortality. RESULTS: Out of a total of 1,354 patients, 190 underwent elective colorectal surgery (resection with primary anastomosis) for (recurrent or stenotic) diverticulitis. One hundred and three patients underwent MBP prior to surgery and 87 did not. Anastomotic leakage occurred in 7.8 % of patients treated with MBP and in 5.7 % of patients not treated with MBP (p = 0.79). There were no significant differences between the groups in septic complications and mortality. CONCLUSION: Mechanical bowel preparation has no influence on the incidence of anastomotic leakage, or other septic complications, and may be safely omitted in case of elective colorectal surgery for diverticulitis.

Management of penetrating neck injuries.

BACKGROUND: Routine surgical exploration after penetrating neck injury (PNI) leads to a large number of negative neck explorations and potential iatrogenic injury. Selective non-operative management (SNOM) of PNI is gaining favour. The present study assessed the feasibility of SNOM in PNI. METHODS: Seventy-seven consecutive patients with PNI presenting to a tertiary trauma centre were included in this prospective study from September 2009 to December 2009. All patients were managed according to Advanced Trauma Life Support guidelines, and either underwent emergency surgery or were managed without surgery, based on clinical presentation and/or outcome of special investigations. RESULTS: Eight patients (10 per cent) were haemodynamically unstable at presentation. Foley catheter balloon tamponade (FCBT) was successful in stopping active bleeding in six of these patients, and diagnostic angiography revealed an arterial injury in five. The remaining 69 patients were managed using SNOM. Angiography or computed tomography was done in 41 patients (53 per cent), and showed arterial injury in 15. These injuries were treated surgically (7 patients), radiologically (stenting in 3) or conservatively. Contrast swallow and/or endoscopy were performed in 37 patients (48 per cent) for suspected oesophageal injury, but yielded no positive results. During follow-up no missed injuries were detected. CONCLUSION: FCBT was useful in patients with PNI and active bleeding. Stable patients should undergo additional investigation based on clinical findings only.

Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma.

Neuroblastoma tumors frequently show loss of heterozygosity of chromosome 11q with a shortest region of overlap in the 11q23 region. These deletions are thought to cause inactivation of tumor suppressor genes leading to haploinsufficiency. Alternatively, micro-deletions could lead to gene fusion products that are tumor driving. To identify such events we analyzed a series of neuroblastomas by comparative genomic hybridization and single-nucleotide polymorphism arrays and integrated these data with Affymetrix mRNA profiling data with the bioinformatic tool R2 (http://r2.amc.nl). We identified three neuroblastoma samples with small interstitial deletions at 11q23, upstream of the forkhead-box R1 transcription factor (FOXR1). Genes at the proximal side of the deletion were fused to FOXR1, resulting in fusion transcripts of MLL-FOXR1 and PAFAH1B2-FOXR1. FOXR1 expression has only been detected in early embryogenesis. Affymetrix microarray analysis showed high FOXR1 mRNA expression exclusively in the neuroblastomas with micro-deletions and rare cases of other tumor types, including osteosarcoma cell line HOS. RNAi silencing of FOXR1 strongly inhibited proliferation of HOS cells and triggered apoptosis. Expression profiling of these cells and reporter assays suggested that FOXR1 is a negative regulator of fork-head box factor-mediated transcription. The neural crest stem cell line JoMa1 proliferates in culture conditional to activity of a MYC-ER transgene. Over-expression of the wild-type FOXR1 could functionally replace MYC and drive proliferation of JoMa1. We conclude that FOXR1 is recurrently activated in neuroblastoma by intrachromosomal deletion/fusion events, resulting in overexpression of fusion transcripts. Forkhead-box transcription factors have not been previously implicated in neuroblastoma pathogenesis. Furthermore, this is the first identification of intrachromosomal fusion genes in neuroblastoma.