The impact of treatment for childhood classical Hodgkin lymphoma according to the EuroNet-PHL-C2 protocol on serum anti-Müllerian Hormone.

STUDY QUESTION: What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)? SUMMARY ANSWER: Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL. WHAT IS KNOWN ALREADY: Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol. STUDY DESIGN, SIZE, DURATION: This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years. LIMITATIONS, REASONS FOR CAUTION: The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol. STUDY FUNDING/COMPETING INTEREST(S): The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Semen analysis and reproductive hormones in boys with classical Hodgkin lymphoma treated according to the EuroNet-PHL-C2 protocol.

STUDY QUESTION: What is the impact of the EuroNet-PHL-C2 treatment for boys with classical Hodgkin lymphoma (cHL) on semen parameters? SUMMARY ANSWER: More than half of the patients (52%, n = 16/31) had oligozoospermia or azoospermia at 2 years from cHL diagnosis; particularly boys treated for advanced-stage cHL had low sperm counts and motility. WHAT IS KNOWN ALREADY: Chemotherapy and radiotherapy to the inguinal region or testes can impair spermatogenesis and result in reduced fertility. The EuroNet-PHL-C2 trial aims to minimize radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. The present study aims to assess the (gonadotoxic) impact of this treatment protocol on semen parameters and reproductive hormones in boys aged ≤18 years. STUDY DESIGN, SIZE, DURATION: This international, prospective, multi-centre cohort study was an add-on study to the randomized phase-3 EuroNet-PHL-C2 trial, where the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) was compared to intensified OEPA-DECOPDAC-21 chemotherapy (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide). Patients were recruited between January 2017 and September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligibility criteria included male patients, diagnosed with classical HL before or at the age of 18 years, and treated according to the EuroNet-PHL-C2 protocol in any of the 18 participating sites in the Netherlands, Germany, Belgium, Czech Republic, and Austria. Sperm parameters (sperm concentration, progressive motility, sperm volume, and calculated total motile sperm count) were assessed at diagnosis and 2 years after diagnosis in (post)pubertal boys. Laboratory measurements (serum follicle-stimulating hormone (FSH) and inhibin B) were performed in samples drawn at diagnosis, during treatment (2-3 times), and at 2 years post-diagnosis, and (age-adjusted) analyses were conducted separately for pre-pubertal and (post)pubertal boys. Outcomes were compared between the treatment levels (TL1, TL2, and TL3) and consolidation treatment schemes (COPDAC-28 and DECOPDAC-21). MAIN RESULTS AND THE ROLE OF CHANCE: In total, 101 boys were included in the present analysis: 73 were (post)pubertal (median age 15.4 years, (IQR 14.4; 16.6), 10 TL1, 29 TL2, 34 TL3, 62% of TL2/3 patients received COPDAC-28) and 28 boys were pre-pubertal (median age 9.6 years (IQR 6.6; 11.4), 4 TL1, 7 TL2, 17 TL3, 38% of TL2/3 patients received COPDAC-28). The study included six boys who had received pelvic radiotherapy; none were irradiated in the inguinal or testicular area. At diagnosis, 48 (post)pubertal boys delivered semen for cryopreservation; 19 (40%) semen samples were oligospermic and 4 (8%) were azoospermic. Low sperm concentration (<15 mil/ml) appeared to be related to the HL disease itself, with a higher prevalence in boys who presented with B symptoms (76% vs 26%, aOR 2.3 (95% CI 1.0; 3.8), P = 0.001) compared to those without such symptoms. At 2 -years post-diagnosis, 31 boys provided semen samples for analysis, of whom 12 (39%) boys had oligozoospermia and 4 (13%) had azoospermia, while 22 boys (71%) had low total motile sperm counts (TMSC) (<20 mil). Specifically, the eight boys in the TL3 group treated with DECOPDAC-21 consolidation had low sperm counts and low progressive motility after 2 years (i.e. median sperm count 1.4 mil/ml (IQR <0.1; 5.3), n = 7 (88%), low sperm concentration, low median progressive motility 16.5% (IQR 0.0; 51.2), respectively). Age-adjusted serum FSH levels were significantly raised and inhibin B levels (and inhibin B:FSH ratios) were decreased during chemotherapy in (post)pubertal boys, with subsequent normalization in 80% (for FSH) and 60% (for inhibin B) of boys after 2 years. Only 4 out of the 14 (post)pubertal boys (29%) with low sperm concentrations after 2 years had elevated FSH (>7.6 IU/l), while 7 (50%) had low inhibin B levels (<100 ng/l). In pre-pubertal boys, reproductive hormones were low overall and remained relatively stable during chemotherapy. LIMITATIONS, REASONS FOR CAUTION: The present analyses included sperm and laboratory measurements up to 2 years post-diagnosis. Long-term reproductive outcomes and potential recovery of spermatogenesis remain unknown, while recovery was reported up to 5- or even 10-year post-chemotherapy in previous studies.Boys who were pre-pubertal at diagnosis were still too young and/or physically not able to deliver semen after 2 years and we could not assess a potential difference in gonadotoxicity according to pubertal state at the time of treatment. Overall, the statistical power of the analyses on sperm concentration and quality after 2 years was limited. WIDER IMPLICATIONS OF THE FINDINGS: Results of the semen analyses conducted among the 31 boys who had provided a semen sample at 2 years post-treatment were generally poor. However, additional long-term and adequately powered data are crucial to assess the potential recovery and clinical impact on fertility. The participating boys will be invited to deliver a semen sample after 5 years. Until these data become available, benefits of intensified chemotherapy in cHL treatment to reduce radiotherapy and lower risk for development of secondary tumours should be carefully weighed against potentially increased risk of other late effects, such as diminished fertility due to the increased chemotherapy burden. Boys with newly diagnosed cHL should be encouraged to deliver sperm for cryopreservation whenever possible. However, patients and clinicians should also realize that the overall state of disease and inflammatory milieu of cHL can negatively affect sperm quality and thereby reduce chance of successful fertility preservation. Furthermore, the measurement of FSH and inhibin B appears to be of low value in predicting low sperm quality at two years from cHL treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M.-K., D.K., W.H.W., D.H., MC, A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors declare no potential conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Low vision aids provision in an urban setting in Germany between 2014 and 2017: a regional population based study with healthcare claims data.

PURPOSE: Little is known about the utilization of low vision services (LVS) in Germany. To understand which persons and how often these services would be utilized, this study aimed to investigate low vision aids (LVAs) provision in an urban setting and to describe user characteristics and trends in their characteristics. METHODS: A retrospective study based on a population-based healthcare claims database in Cologne (N = ~ 500,000), Germany. The study population comprised individuals, who were continuously insured at four large statutory health insurers and who redeemed a prescription for visual aids or aids for blindness between January 2014 and December 2017. We examined their socio-demographic and clinical characteristics. Trends in characteristics were examined with logistic and linear regression models over time. RESULTS: Out of ~ 500,000 persons, 781 unique individuals (~ 0.2%) redeemed an LVA prescription. They were mainly female (68.7%), 60 years or older (75.3%) and had macular degeneration (50.6%) and/or glaucoma (25.9%). In the working-age subgroup, 33.8% were employed. Visual aids were most often prescribed (74.1%) and of all types of LVAs, individuals most commonly redeemed a prescription for magnifiers (35.8%), screen readers (34.3%) and/or canes (17.1%). Of the entire study population, 75.4% received their prescription from an ophthalmologist, 5.3% from a general practitioner and 7.1% from other medical specialists. Significant trends in characteristics of individuals who redeemed an LVA prescription were not found. CONCLUSIONS: Between 2014 and 2017, 781 individuals in Cologne redeemed an LVA prescription. They had characteristics which mostly can be explained by the epidemiology of VI. Results indicate that individuals that redeemed LVAs have a magnification requirement of ≥ 1.5-fold and ≥ 6-fold. Furthermore, next to ophthalmologists, general practitioners and other medical specialists seem to play a role in LVA provision as well, which should be taken into account by policy makers when planning interventions for increasing LVS provision. Our findings provide a starting point to examine LVS provision in Germany.

Effectiveness of a Comprehensive School-Based Sex Education Program for Young Adolescents in the Netherlands.

Most sexual education programs traditionally focused on providing sexual information regarding the risks of sex. However, current studies on sexual behavior in youth show a need for truly comprehensive sex education approaches with a sex-positive focus on sexuality, that effectively improve sexual competence. Therefore, in the current study the effectiveness of "Love is…", a four lesson school-based program based on the Sexual Interactional Competence model and Attitude-Social-Influence-Self-Efficacy-model was studied. A cluster-randomized controlled trial on the effectiveness of "Love is…" was conducted in 2018-2020. The sample consisted of 1160 adolescents in grades 8 and 9 from nine schools in the Netherlands. The sample was 48% female, 34% Dutch/Caucasian, 41% none-religious and 50% higher educated. They were randomized at class level into a program group [n = 32 classes; 567 students (Mage = 13.74 (SD = 0.74))] and a control group [n = 31 classes; 593 students (Mage = 13.86 (SD = 0.73))]. Results showed that "Love is…" increased sexual knowledge, that adolescents in the program group showed less cyber victim blaming attitudes and increased in communications skills after the program. In conclusion, the current study shows that "Love is…" was effective not only on the knowledge level, but also regarding sexual attitudes and competences. However, due to the developmental process of sexuality, there is a necessity to continue lessons in following grades through booster sessions by reinforcing competences as communicating comfortably about sexuality.On 12 November 2019 the study design and hypotheses were registered in the Dutch Trial Registration, number NL8150. ( https://onderzoekmetmensen.nl/nl/trial/26676 ).

Illness perceptions; exploring mediators and/or moderators in disabling persistent low back pain. Multiple baseline single-case experimental design.

INTRODUCTION: Illness Perceptions (IPs) may play a role in the management of persistent low back pain. The mediation and/or moderation effect of IPs on primary outcomes in physiotherapy treatment is unknown. METHODS: A multiple single-case experimental design, using a matched care physiotherapy intervention, with three phases (phases A-B-A') was used including a 3 month follow up (phase A'). Primary outcomes: pain intensity, physical functioning and pain interference in daily life. Analyzes: linear mixed models, adjusted for fear of movement, catastrophizing, avoidance, sombreness and sleep. RESULTS: Nine patients were included by six different primary care physiotherapists. Repeated measures on 196 data points showed that IPs Consequences, Personal control, Identity, Concern and Emotional response had a mediation effect on all three primary outcomes. The IP Personal control acted as a moderator for all primary outcomes, with clinically relevant improvements at 3 month follow up. CONCLUSION: Our study might indicate that some IPs have a mediating or a moderating effect on the outcome of a matched care physiotherapy treatment. Assessing Personal control at baseline, as a relevant moderator for the outcome prognosis of successful physiotherapy management of persistent low back pain, should be further eplored.

[Suicide prevention training for youth care professionals]. / Suïcidepreventietraining voor jeugdzorgprofessionals.

BACKGROUND: Suicidality is common in youth care and has a major impact on young people, parents and professionals. The number of suicides among young people (10-25 years) in the Netherlands has risen in recent years from 103 suicides in 2008 to 159 suicides in 2019, with a high of 169 suicides in 2017. Many youth care professionals experience timidity in dealing with suicidal behaviour. AIM: To investigate whether suicide prevention training leads to an improvement in knowledge, skills and self-confidence in dealing with suicidal behavior in young people. METHOD: Professionals working at a national youth care institution participated in suicide prevention training. Before and immediately after the training they completed questionnaires to measure their knowledge, skills and self-confidence in the field of suicide prevention. RESULTS: There was an improvement in knowledge, skills and self-confidence of youth care professionals after the training. In particular, more knowledge about suicide prevention led to more self-confidence. The change was equal in the different forms of care. Scientifically trained and higher educated professionals showed a less strong change in their competencies than secondary educated professionals. The change in knowledge and skills was less pronounced the older the professionals were. CONCLUSION: Participation in suicide prevention training led to more knowledge, skills and self-confidence of youth care professionals in dealing with suicidal behaviour.

Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE).

STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.

Reduced pregnancy and live birth rates after in vitro fertilization in women with previous Caesarean section: a retrospective cohort study.

STUDY QUESTION: Does a previous Caesarean section affect reproductive outcomes, including live birth, in women after IVF or ICSI? SUMMARY ANSWER: A previous Caesarean section impairs live birth rates after IVF or ICSI compared to a previous vaginal delivery. WHAT IS KNOWN ALREADY: Rates of Caesarean sections are rising worldwide. Late sequelae of a Caesarean section related to a niche (Caesarean scar defect) include gynaecological symptoms and obstetric complications. A systematic review reported a lower pregnancy rate after a previous Caesarean section (RR 0.91 CI 0.87-0.95) compared to a previous vaginal delivery. So far, studies have been unable to causally differentiate between problems with fertilisation, and the transportation or implantation of an embryo. Studying an IVF population allows us to identify the effect of a previous Caesarean section on the implantation of embryos in relation to a previous vaginal delivery. STUDY DESIGN, SIZE, DURATION: We retrospectively studied the live birth rate in women who had an IVF or ICSI treatment at the IVF Centre, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands, between 2006 and 2016 with one previous delivery. In total, 1317 women were included, of whom 334 had a previous caesarean section and 983 had previously delivered vaginally. PARTICIPANTS/MATERIALS, SETTING, METHODS: All secondary infertile women, with only one previous delivery either by caesarean section or vaginal delivery, were included. If applicable, only the first fresh embryo transfer was included in the analyses. Patients who did not intend to undergo embryo transfer were excluded. The primary outcome was live birth. Multivariate logistic regression analyses were used with adjustment for possible confounders ((i) age; (ii) pre-pregnancy BMI; (iii) pre-pregnancy smoking; (iv) previous fertility treatment; (v) indication for current fertility treatment: (a) tubal, (b) male factor and (c) endometriosis; (vi) embryo quality; and (vii) endometrial thickness), if applicable. Analysis was by intention to treat (ITT). MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics of both groups were comparable. Live birth rates were significantly lower in women with a previous caesarean section than in women with a previous vaginal delivery, 15.9% (51/320) versus 23.3% (219/941) (OR 0.63 95% CI 0.45-0.87) in the ITT analyses. The rates were also lower for ongoing pregnancy (20.1 versus 28.1% (OR 0.64 95% CI 0.48-0.87)), clinical pregnancy (25.7 versus 33.8% (OR 0.68 95% CI 0.52-0.90)) and biochemical test (36.2 versus 45.5% (OR 0.68 95% CI 0.53-0.88)). The per protocol analyses showed the same differences (live birth rate OR 0.66 95% CI 0.47-0.93 and clinical pregnancy rate OR 0.72 95% CI 0.54-0.96). LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design. Furthermore, 56 (16.3%) cases lacked data regarding delivery outcomes, but these were equally distributed between the two groups. WIDER IMPLICATIONS OF THE FINDINGS: The lower clinical pregnancy rates per embryo transfer indicate that implantation is hampered after a caesarean section. Its relation with a possible niche (caesarean scar defect) in the uterine caesarean scar needs further study. Our results should be discussed with clinicians and patients who consider an elective caesarean section. STUDY FUNDING/COMPETING INTEREST(S): Not applicable. TRIAL REGISTRATION NUMBER: This study has been registered in the Dutch Trial Register (Ref. No. NL7631 http://www.trialregister.nl).

Predicting return to work among patients with colorectal cancer.

BACKGROUND: The increase in prevalence of colorectal cancer among young patients coupled with an older retirement age in developed countries means that more patients are being diagnosed with colorectal cancer while still at work. The aim of this study was to develop prediction models for return to work by 1 and 2 years after the start of sick leave. METHODS: This was a retrospective registry-based cohort study of data from a nationwide occupational health service in the Netherlands. Only employed patients with colonic or rectal cancer treated with curative intent were included. Two predictor variable models were developed using multivariable logistic regression with backward selection. Calibration, discrimination and explained variance were used to assess model performance, and internal validation by bootstrapping was performed. RESULTS: Median time to return to work for 317 included patients was 423 (95 per cent c.i. 379 to 467) days. Two-thirds of patients had returned to work by 2 years after the start of the sick leave. Presence of metastases, adjuvant treatment, stoma, emotional distress and postoperative complications were predictors of not returning to work in the 1-year model. In the 2-year model, presence of metastases, emotional distress, postoperative complications, company size and the trajectory of the return-to-work process were predictors. CONCLUSION: Almost 70 per cent of patients with colorectal cancer in this population returned to work within 2 years after the start of sick leave. The models can be used to guide patients early in colorectal cancer treatment about the likelihood of returning to work, and to identify and modify barriers that could facilitate this.

ANTECEDENTES: El aumento de la prevalencia del cáncer colorrectal (colorectal cancer, CCR) en pacientes jóvenes, junto con una edad de jubilación más avanzada en los países desarrollados, significa un mayor número de pacientes en edad laboral diagnosticados de CCR. El objetivo de este estudio fue desarrollar modelos de predicción del regreso al trabajo uno y dos años después del inicio de la baja por enfermedad para el tratamiento de CCR. MÉTODOS: Se trata de un estudio de cohortes retrospectivo basado en el registro de datos nacionales de salud laboral en los Países Bajos. Solo se incluyeron pacientes con cáncer de colon o recto tratados con intención curativa. Se desarrollaron dos modelos de variables de predicción utilizando regresión logística multivariante con selección de variables hacia atrás. Para evaluar el rendimiento del modelo se utilizaron la calibración, la discriminación y la varianza explicada y se realizó la validación interna mediante bootstrap. RESULTADOS: La mediana de tiempo de regreso al trabajo de 317 pacientes incluidos fue de 423 días (i.c. del 95%: 378,6-467,4). Dos tercios de los pacientes habían regresado al trabajo dos años después del inicio del período de baja por enfermedad. La presencia de metástasis, el tratamiento adyuvante, el estoma, la angustia emocional y las complicaciones postoperatorias fueron factores predictivos de no volver a trabajar en el modelo de un año. En el modelo de dos años, la presencia de metástasis, la angustia emocional, las complicaciones postoperatorias, el tamaño de la empresa y la trayectoria del proceso de retorno al trabajo fueron factores predictores del regreso laboral. CONCLUSIÓN: Casi el 70% de los pacientes con CCR en esta población volvieron a trabajar dentro de los dos años posteriores al inicio del periodo de baja por enfermedad. Los modelos se pueden usar para guiar a los pacientes con CCR al inicio de su tratamiento sobre su probabilidad de regresar al trabajo, así como para identificar y modificar las barreras que podrían facilitarlo.

Mastery and self-esteem mediate the association between visual acuity and mental health: a population-based longitudinal cohort study.

BACKGROUND: With deteriorating eyesight, people often become dependent on others for many aspects of their daily lives. As a result, they feel less 'in control' and experience lower self-esteem. Lower sense of mastery and self-esteem are known to predict depression, but their roles in people with visual impairment have only marginally been investigated. Therefore, this study aimed to determine the influence of mastery and self-esteem on the relationship between visual acuity and mental health. METHODS: A longitudinal cohort study was performed using data from the Longitudinal Aging Study Amsterdam (LASA), collected between 2001 and 2012. A community-based population of 2599 older adults were included, who were randomly selected from population registers. Outcomes of interest were the Pearlin Mastery Scale, Rosenberg Self-Esteem Scale, Center for Epidemiologic Studies - Depression scale and the Hospital Anxiety Depression Scale - Anxiety subscale. Linear mixed models were used to establish the association between visual acuity and mental health over time. RESULTS: Mean age was 72 years, 56% was female and 1.2% qualified as having low vision. Visual impairment was associated with a lower sense of mastery (ß = - 0.477, p < 0.001), lower self-esteem (ß = - 0.166, p = 0.008) and more depression (ß = 0.235, p < 0.001). No significant association between visual acuity and anxiety was found. The relationship between visual acuity and depression was mediated by self-esteem (25%) and sense of mastery (79%). CONCLUSIONS: Vision loss was associated with depression. This association was mediated by self-esteem and sense of mastery. This provides us with new possibilities to identify, support and treat those at risk for developing depression by aiming to increase their self-esteem and sense of mastery.

Short-term cost-effectiveness of one-stage implant-based breast reconstruction with an acellular dermal matrix versus two-stage expander-implant reconstruction from a multicentre randomized clinical trial.

BACKGROUND: Implant-based breast reconstruction (IBBR) is the most commonly performed reconstructive procedure and its economic impact is significant. This study aimed to analyse whether a direct one-stage IBBR with use of an acellular dermal matrix (ADM) is more cost-effective than two-stage (expander-implant) breast reconstruction. METHODS: The BRIOS (Breast Reconstruction In One Stage) study was an open-label multicentre RCT in which women scheduled for skin-sparing mastectomy and immediate IBBR were randomized between one-stage IBBR with ADM or two-stage IBBR. Duration of surgery and hospital stay, and visits for the primary surgery, unplanned and cosmetic procedures were recorded. Costs were estimated at an institutional level. Health status was assessed by means of the EuroQol Five Dimensions 5L questionnaire. RESULTS: Fifty-nine patients (91 breasts) underwent one-stage IBBR with ADM and 62 patients (92 breasts) two-stage IBBR. The mean(s.d.) duration of surgery in the one-stage group was significantly longer than that for two-stage IBBR for unilateral (2·52(0·55) versus 2·02(0·35) h; P < 0·001) and bilateral (4·03(1·00) versus 3·25(0·58) h; P = 0·017) reconstructions. Costs were higher for one-stage compared with two-stage IBBR for both unilateral (€12 448 (95 per cent c.i. 10 722 to 14 387) versus €9871 (9373 to 10 445) respectively; P = 0·025) and bilateral (€16 939 (14 887 to 19 360) versus €13 383 (12 414 to 14 669); P = 0·002) reconstructions. This was partly related to the use of relatively expensive ADM. There was no difference in postoperative health status between the groups. CONCLUSION: One-stage IBBR with ADM was associated with higher costs, but similar health status, compared with conventional two-stage IBBR. Registration number: NTR5446 ( http://www.trialregister.nl).

Diagnostic accuracy of preoperative ultrasonography in predicting contralateral inguinal hernia in children: a systematic review and meta-analysis.

OBJECTIVES: The incidence of children developing metachronous contralateral inguinal hernia (MCIH) is 7-15%. Contralateral groin exploration during unilateral hernia repair can prevent MCIH development and subsequent second surgery and anaesthesia. Preoperative ultrasonography is a less invasive strategy and potentially able to detect contralateral patent processus vaginalis (CPPV) prior to MCIH development. METHODS: We queried MEDLINE, Embase and Cochrane library to identify studies regarding children aged < 18 years diagnosed with unilateral inguinal hernia without clinical signs of contralateral hernia, who underwent preoperative ultrasonography of the contralateral groin. We assessed heterogeneity and used a random-effects model to obtain pooled estimates of sensitivity, specificity and area under the receiver operating characteristic curve (AUC). RESULTS: Fourteen studies (2120 patients) were included, seven (1013 patients) in the meta-analysis. In studies using surgical exploration as reference test (n = 4, 494 patients), pooled sensitivity and specificity were 93% and 88% respectively. In studies using contralateral exploration as reference test following positive and clinical follow-up after negative ultrasonographic test results (n = 3, 519 patients), pooled sensitivity was 86% and specificity 98%. The AUC (0.984) shows high diagnostic accuracy of preoperative ultrasonography for detecting CPPV, although diagnostic ultrasonographic criteria largely differ and large heterogeneity exists. Reported inguinal canal diameters in children with CPPV were 2.70 ± 1.17 mm, 6.8 ± 1.3 mm and 9.0 ± 1.9 mm. CONCLUSION: Diagnostic accuracy of preoperative ultrasonography to detect CPPV seems promising, though may result in an overestimation of MCIH prevalence, since CPPV does not invariably lead to MCIH. Unequivocal ultrasonographic criteria are mandatory for proper diagnosis of CPPV and subsequent prediction of MCIH. KEY POINTS: • Diagnostic accuracy of preoperative ultrasonography for detection of CPPV in children with unilateral inguinal hernia is high. • Preoperative ultrasonographic evaluation of the contralateral groin assumedly results in an overestimation of MCIH prevalence. • Unequivocal ultrasonographic criteria are mandatory for proper diagnosis of CPPV and risk factor identification is needed to predict whether CPPV develops into clinically apparent MCIH.

Guideline compliance for bridging anticoagulation use in vitamin-K antagonist patients; practice variation and factors associated with non-compliance.

BACKGROUND: Bridging anticoagulation is used in vitamin-K antagonist (VKA) patients undergoing invasive procedures and involves complex risk assessment in order to prevent thromboembolic and bleeding outcomes. OBJECTIVES: Our aim was to assess guideline compliance and identify factors associated with bridging and especially, non-compliant bridging. METHODS: A retrospective review of 256 patient records in 13 Dutch hospitals was performed. Demographic, clinical, surgical and care delivery characteristics were collected. Compliance to the American College of Chest Physicians ninth edition guideline (AT9) was assessed. Multilevel regression models were built to explain bridging use and predict non-compliance. RESULTS: Bridging use varied from 15.0 to 83.3% (mean = 41.8%) of patients per hospital, whereas guideline compliance varied from 20.0 to 88.2% (mean = 68.5%) per hospital. Both established thromboembolic risk factors and characteristics outside thromboembolic risk assessment were associated with bridging use. Predictors for overuse were gastrointestinal surgery (OR 14.85, 95% CI 2.69-81.99), vascular surgery (OR 13.01, 95% CI 1.83-92.30), non-elective surgery (OR 8.67, 95% CI 1.67-45.14), lowest 25th percentile socioeconomic status (OR 0.33, 95% CI 0.11-1.02) and use of VKA reversal agents (OR 0.22, 95% CI 0.04-1.16). CONCLUSION: Bridging anticoagulation practice was not compliant with the AT9 in 31.5% of patients. The aggregated AT9 thromboembolic risk was inferior to individual thromboembolic risk factors and other characteristics in explaining bridging use. Therefor the AT9 risk seems less important for the decision making in everyday practice. Additionally, a heterogeneous implementation of the guideline between hospitals was found. Further research and interventions are needed to improve bridging anticoagulation practice in VKA patients.

Predicting quality of life during and post detention in incarcerated juveniles.

PURPOSE: Besides reducing recidivism, juvenile justice institutions aim to rehabilitate juvenile delinquents, in order for them to reintegrate in society. As such, improving quality of life (QoL), especially post detention, is an important treatment goal. However, research is primarily focused on recidivism as an outcome measure for juvenile detention. The aim of the current study is therefore to describe and predict QoL of detained young offenders up to 1 year after an initial assessment, and to examine whether QoL differs between youth who are still detained versus released. METHODS: A sample of 186 juveniles admitted to juvenile justice institutions in the Netherlands was assessed within the institution (initial assessment/T0), using psychosocial and neurobiological factors as predictors (self-control, treatment motivation, trauma, mental health problems, respiratory sinus arrhythmia). QoL (MANSA), as well as substance use (alcohol, cannabis) and daily activities (education, work) were assessed at first, second, and third follow-up (respectively 2.5 months, 4.5 months, and 12 months after T0). RESULTS: QoL increased from first to third follow-up, and was higher for individuals who were no longer detained. The model that best predicted higher QoL upon follow-up consisted of lower trauma and stronger parasympathetic nervous system reactivity. The effects of the predictors did not differ between the various follow-ups, nor between individuals who were or were not detained. CONCLUSION: Methods incorporating trauma-sensitive focus and relaxation techniques in treatment protocols in juvenile justice institutions may be of added value in improving the general functioning of these individuals.

Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve.

STUDY QUESTION: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? SUMMARY ANSWER: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. WHAT IS KNOWN ALREADY: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. STUDY DESIGN, SIZE, DURATION: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. LIMITATIONS, REASONS FOR CAUTION: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922.

Predictors of complications after direct-to-implant breast reconstruction with an acellular dermal matrix from a multicentre randomized clinical trial.

BACKGROUND: In the multicentre randomized trial BRIOS (Breast Reconstruction In One Stage), direct-to-implant (DTI) breast reconstruction with an acellular dermal matrix (ADM) was associated with a markedly higher postoperative complication rate compared with two-stage tissue expander/implant breast reconstruction. This study aimed to identify factors that contribute to the occurrence of complications after DTI ADM-assisted breast reconstruction. METHODS: Data were obtained from the BRIOS study, including all patients treated with DTI ADM-assisted breast reconstruction. Logistic regression analyses were performed to identify factors predictive of postoperative complications. RESULTS: Fifty-nine patients (91 breasts) were included, of whom 27 (35 breasts) developed a surgical complication. Reoperations were performed in 29 breasts (32 per cent), with prosthesis removal in 22 (24 per cent). In multivariable analyses, mastectomy weight was associated with complications (odds ratio (OR) 1·94, 95 per cent c.i. 1·33 to 2·83), reoperations (OR 1·70, 1·12 to 2·59) and removal of the implant (OR 1·55, 1·11 to 2·17). Younger patients (OR 1·07, 1·01 to 1·13) and those who received adjuvant chemotherapy (OR 4·83, 1·15 to 20·24) more frequently required reoperation. In univariable analyses, adjuvant radiotherapy showed a trend towards more complications (OR 7·23, 0·75 to 69·95) and removal of the implant (OR 5·12, 0·76 to 34·44), without reaching statistical significance. CONCLUSION: Breast size appeared to be the most significant predictor of complications in DTI ADM-assisted breast reconstruction. The technique should preferably be performed in patients with small to moderate sized breasts. Registration number: NTR5446 ( http://www.trialregister.nl).

Does hypoglycaemia affect the improvement in QoL after the transition to insulin in people with type 2 diabetes?

PURPOSE: Quality of Life (QoL) of insulin-naïve people with type 2 diabetes mellitus (T2DM) improves after transition to insulin. Little is known about the role of hypoglycaemia in this context. Secondary analyses of the Study of the Psychological Impact in Real care of Initiating insulin glargine Treatment (SPIRIT) aimed to investigate the relationship between hypoglycaemia and QoL when transitioning to insulin. METHODS: Insulin-naïve Dutch people with T2DM in suboptimal glycaemic control (HbA1c >53 mmol/mol; 7.0%) on maximum dose of oral glucose-lowering medications were included from 363 primary care practices (n = 911). Participants started insulin glargine and completed QoL-questionnaires (WHO-5 Well-being Index (WHO-5; emotional well-being), Hypoglycaemia Fear Survey-worry scale (HFS-w; hypoglycaemia fear) and Diabetes Symptom Checklist-revised (DSC-r; diabetes symptom distress) at baseline, 3 and 6 months follow-up. Linear GEE analyses were used to investigate the association between symptomatic, nocturnal, severe hypoglycaemia (number of episodes during 3 months prior to visit) and QoL over time. RESULTS: 52.5% men participated, mean age 62.2 years (SD ± 10.92), and median HbA1c 67 mmol/mol (range 61-77) (8.3%). More symptomatic hypoglycaemic episodes were associated with higher HFS-w and DSC-r scores (P < 0.01). Experiencing multiple nocturnal or severe episodes was related to higher symptom distress as well, when compared to no episodes. These associations did not change significantly over time. CONCLUSIONS: Hypoglycaemia is associated with lower QoL in terms of hypoglycaemia fear and diabetes symptom distress. The transition to insulin does not affect this relationship, suggesting hypoglycaemia in itself has a detrimental effect on diabetes-related QoL independent of treatment regimen.

Lung ultrasound compared with chest X-ray in diagnosing postoperative pulmonary complications following cardiothoracic surgery: a prospective observational study.

Postoperative pulmonary complications are common after cardiothoracic surgery and are associated with adverse outcomes. The ability to detect postoperative pulmonary complications using chest X-rays is limited, and this technique requires radiation exposure. Little is known about the diagnostic accuracy of lung ultrasound for the detection of postoperative pulmonary complications after cardiothoracic surgery, and we therefore aimed to compare lung ultrasound with chest X-ray to detect postoperative pulmonary complications in this group of patients. We performed this prospective, observational, single-centre study in a tertiary intensive care unit treating adult patients who had undergone cardiothoracic surgery. We recorded chest X-ray findings upon admission and on postoperative days 2 and 3, as well as rates of postoperative pulmonary complications and clinically-relevant postoperative pulmonary complications that required therapy according to the treating physician as part of their standard clinical practice. Lung ultrasound was performed by an independent researcher at the time of chest X-ray. We compared lung ultrasound with chest X-ray for the detection of postoperative pulmonary complications and clinically-relevant postoperative pulmonary complications. We also assessed inter-observer agreement for lung ultrasound, and the time to perform both imaging techniques. Subgroup analyses were performed to compare the time to detection of clinically-relevant postoperative pulmonary complications by both modalities. We recruited a total of 177 patients in whom both lung ultrasound and chest X-ray imaging were performed. Lung ultrasound identified 159 (90%) postoperative pulmonary complications on the day of admission compared with 107 (61%) identified with chest X-ray (p < 0.001). Lung ultrasound identified 11 out of 17 patients (65%) and chest X-ray 7 out of 17 patients (41%) with clinically-relevant postoperative pulmonary complications (p < 0.001). The clinically-relevant postoperative pulmonary complications were detected earlier using lung ultrasound compared with chest X-ray (p = 0.024). Overall inter-observer agreement for lung ultrasound was excellent (κ = 0.907, p < 0.001). Following cardiothoracic surgery, lung ultrasound detected more postoperative pulmonary complications and clinically-relevant postoperative pulmonary complications than chest X-ray, and at an earlier time-point. Our results suggest lung ultrasound may be used as the primary imaging technique to search for postoperative pulmonary complications after cardiothoracic surgery, and will enhance bedside decision making.

Preventing musculoskeletal complaints in music students: a randomized controlled trial.

BACKGROUND: Musculoskeletal complaints in music students are common. Little is known about effectiveness of interventions. AIMS: To assess whether a biopsychosocial prevention course is better at reducing disability due to musculoskeletal disorders compared with physical activity promotion. METHODS: This was a multicentre randomized controlled trial with intention-to-treat analysis. Participants were first- and second-year students from five conservatories, randomized to experimental or control groups. The experimental group participated in 11 classes on body posture playing the instrument according to postural exercise therapy, and performance-related psychosocial aspects. The control group participated in five classes promoting physical activity according to national guidelines. The primary outcome was disability using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, including the performing arts module. Secondary outcomes were pain, quality of life, playing-related musculoskeletal disorders and health behaviour. Outcomes were assessed at six points, from baseline until 2-year follow-up. RESULTS: One hundred and seventy participants were randomized to experimental (n = 84) or control (n = 86) groups. Loss to follow-up was 40% during the trial and 69% at 2-year follow-up. The dropout rate was equal in both groups. Overall, there were no significant differences between groups for any outcome adjusted for baseline characteristics: percentage disability, odds ratio was 1.31, 95% confidence interval (CI) 0.69-2.51; general DASH, ß = -0.57, 95% CI -3.23 to 2.09; and performing arts module, ß = -0.40, 95% CI 5.12-4.32. CONCLUSIONS: A biopsychosocial prevention course tailored for musicians was not superior to physical activity promotion in reducing disability. Large numbers lost to follow-up warrant cautious interpretation.

[The reliability of Delta-T]. / De betrouwbaarheid van Delta-T.

BACKGROUND: In Dutch mental health care there is an ongoing debate about the benefits of rom and utility of benchmarking. Opinions vary regarding the reliability and validity of performance indicators.
AIM: Investigation of the reliability of the main indicator of Foundation Benchmark Mental Health Care (sbg), Delta-T, the indicator of treatment outcome.
METHOD: The reliability was established with two indices: the intraclass correlation coefficient (icc) for the agreement between repeated assessments of average treatment outcome and the consistency in rank order of mental health care providers over time.
RESULTS: The reliability of Delta-T proved to be excellent.
CONCLUSION: Reliability is a basic requirement, but only the first step in establishing the utility of Delta-T. Further investigation of its validity is ongoing, especially on how robust treatment outcome is for bias due to instrumentation, selection, and confounding by casemix composition. Ultimately, the usefulness of treatment outcome as indicator of quality of care needs to be demonstrated in practice.