BACKGROUND: In populations with mild iodine deficiency, the serum level of thyrotropin (TSH) is negatively and the serum free thyroxine (FT4) is positively associated with age. An ongoing decrease of TSH and increase of FT4 can be found after iodine supplementation. The aim of this study was to investigate whether there are current differences in the relation between thyroid function and age in relation to differences in iodine intake in the past. METHODS: Eight medical laboratories in several regions of The Netherlands, which are all iodine sufficient at present but with a difference in iodine status in the past, provided the results of all TSH and FT4 measurements performed from 2006 until 2011, resulting in 330,802 TSH and 103,940 FT4 measurements. RESULTS: The negative association between TSH and age in the elderly is only present in areas with a historical iodine deficiency (regression coefficients [RC] -0.008, 95% confidence interval [CI] -0.009; -0.007).
In the historically iodine-sufficient population, TSH shows no obvious increase or decrease with age. In both the historically iodine-sufficient and iodine-deficient populations, FT4 levels were positively associated with age in the elderly (RC 0.009, 95% CI 0.008; 0.010 and RC 0.008, 95% CI 0.007; 0.010, respectively). CONCLUSIONS: There are differences in relation between thyroid function and age between populations with differences in iodine intake in the past, despite an adequate iodine status at present. This raises the question whether the present but also historical iodine status of a population should be taken into account when establishing the reference limits of TSH and FT4.
PMID: 25832305
Hamilton DW, Bins JE, McMeekin P, Pedersen A, Steen N, De Soyza A, Thomson R, Paleri V, Wilson JA. Quality compared to quantity of life in laryngeal cancer: A time trade-off study. Head Neck. 2016 Apr;38 Suppl 1:E631-7. doi: 10.1002/hed.24061.
BACKGROUND: The purpose of this study was to use time trade-off to assess the factors influencing patients’ decisions in advanced laryngeal cancer. Time trade-off is a well-established method of assessing how individuals value a particular health state. METHODS: We developed vignettes depicting life after chemoradiotherapy or laryngectomy. One hundred fourteen participants ranked them, assigned utility values, and rated the importance of survival on treatment choice. RE-SULTS: Chemoradiotherapy was preferred by 62% and laryngectomy by 38%. Chemoradiotherapy optimal outcome had the highest mean utility value (0.64) followed by total laryngectomy optimal outcome (0.56). Total laryngectomy poor outcome (0.33) was equivalent to chemoradiotherapy poor outcome (0.32).The average survival advantage required for a participant to change their preferred choice was 2.1 years. CONCLUSION: The functional treatment outcome had a greater effect on health state utility values than treatment modality. In many individuals, larynx conservation may not be the primary consi-deration in treatment preference. © 2015 Wiley Periodicals, Inc. Head Neck 38: E631-E637, 2016.
PMID: 25853764
Nieuwkamp DJ, Murk JL, van Oosten BW, Cremers CH, Killestein J, Viveen MC, Van Hecke W, Frijlink DW, Wattjes
MP; PML in Dutch MS Patients Consortium. PML in a patient without severe lymphocytopenia receiving dimethyl
fumarate. N Engl J Med. 2015 Apr 9;372(15):1474-6. doi: 10.1056/NEJMc1413724.
PMID: 25862010
de Lange MM, Hukkelhoven CW, Munster JM, Schneeberger PM, van der Hoek W. Nationwide registry-based ecological analysis of Q fever incidence and pregnancy outcome during an outbreak in the Netherlands.BMJ Open. 2015 Apr 10;5(4):e006821. doi: 10.1136/bmjopen-2014-006821.
OBJECTIVE: Whether areas affected by Q fever during a large outbreak (2008-2010) had higher rates of adverse pregnancy outcomes than areas not affected by Q fever. DESIGN: Nationwide registry-based ecological study. SETTING: Pregnant wo-men in areas affected and not affected by Q fever in the Netherlands, 2003-2004 and 2008-2010. PARTICIPANTS: Index group (N=58,737): pregnant women in 307 areas with more than two Q fever notifications. Reference group (N=310,635):
pregnant women in 921 areas without Q fever notifications. As a baseline, pregnant women in index and reference areas in the years 2003-2004 were also included in the reference group to estimate the effect of Q fever in 2008-2010, and not the already existing differences before the outbreak. MAIN OUTCOME MEASURES: Preterm delivery, small for gestational age, perinatal mortality. RESULTS: In 2008-2010, there was no association between residing in a Q fever-affected area and both preterm delivery (adjusted OR 1.01 (95% CI 0.94 to 1.08)), and perinatal mortality (adjusted OR 0.87 (95% CI 0.72 to 1.05)). In contrast, we found a weak significant association between residing in a Q fever-affected area in 2008-2010 and small for gestational age (adjusted OR 1.06 (95% CI 1.01 to 1.12)), with a population-attributable fraction of 0.70% (95% CI 0.07% to 1.34%). We observed no dose-response relation for this outcome with increasing Q fever notifications, and we did not find a stronger association for women who were in their first trimester of pregnancy during the months of high human Q fever incidence. CONCLUSIONS: This study found a weak association between residing in a Q fever-affected area and the pregnancy outcome small for gestational age. Early detection of infection would require mass screening of pregnant women;
this does not seem to be justified considering these results, and the uncertainties about its efficacy and the adverse effects of antibiotic treatment.
PMID: 25862517
Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. doi: 10.1016/S0140-6736(14)62004-3. Epub 2015 Apr 7.
BACKGROUND: The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. METHODS: In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study’s primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637. FINDINGS: Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279).
147 BIJLAGE WETENSCHAPPELIJKE PUBLICATIES 2013-2014 OPGENOMEN IN PUBMED
Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8•5 months in the observation group and 11•7 months in the maintenance group (HR 0•67, 95% CI 0•56-0•81, p<0•0001). This difference remained significant when any treatment after PFS1 was conside-red. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 [23%]
patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups. INTERPRETATION: Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life. FUNDING: Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis.
PMID: 25867514
Ballak D, van Asseldonk EJP, van Diepen JA, Jansen HJ, Hijmans A, Joosten A, Tack CJ, Netea MG, Stienstra R.
TLR-3 is present in human adipocytes, but its signalling is not required for obesity-induced inflammation in adipose tissue in vivo. Plos One. E0123152, 2015.
Innate immunity plays a pivotal role in obesity-induced low-grade inflammation originating from adipose tissue. Key recep-tors of the innate immune system including Toll-like receprecep-tors-2 and -4 (TLRs) are triggered by nutrient excess to promote inflammation. The role of other TLRs in this process is largely unknown. In addition to double-stranded viral mRNA, TLR-3 can also recognize mRNA from dying endogenous cells, a process that is frequently observed within obese adipose tissue.
Here, we identified profound expression of TLR-3 in adipocytes and investigated its role during diet-induced obesity. Human adipose tissue biopsies (n=80) and an adipocyte cell-line were used to study TLR-3 expression and function. TLR-3-/- and WT animals were exposed to a high-fat diet (HFD) for 16 weeks to induce obesity. Expression of TLR-3 was significantly higher in human adipocytes compared to the non-adipocyte cells part of the adipose tissue. In vitro, TLR-3 expression was induced during differentiation of adipocytes and stimulation of the receptor led to elevated expression of pro-inflammatory cytokines. In vivo, TLR-3 deficiency did not significantly influence HFD-induced obesity, insulin sensitivity or inflammation.
In humans, TLR-3 expression in adipose tissue did not correlate with BMI or insulin sensitivity (HOMA-IR). Together, our results demonstrate that TLR-3 is highly expressed in adipocytes and functionally active. However, TLR-3 appears to play a redundant role in obesity-induced inflammation and insulin resistance.
PMID: 25894620
Wassenaar A, van den Boogaard M, van Achterberg T, Slooter AJ, Kuiper MA, Hoogendoorn ME, Simons KS, Maseda E, Pinto N, Jones C, Luetz A, Schandl A, Verbrugghe W, Aitken LM, van Haren FM, Donders AR,
Schoonhoven L, Pickkers P. Multinational development and validation of an early prediction model for delirium in ICU patients. Intensive Care Med. 2015 Jun;41(6):1048-56
RATIONALE: Delirium incidence in intensive care unit (ICU) patients is high and associated with poor outcome. Identification of high-risk patients may facilitate its prevention. PURPOSE: To develop and validate a model based on data available at ICU admission to predict delirium development during a patient’s complete ICU stay and to determine the predictive value of this model in relation to the time of delirium development. METHODS: Prospective cohort study in 13 ICUs from seven coun-tries. Multiple logistic regression analysis was used to develop the early prediction (E-PRE-DELIRIC) model on data of the first two-thirds and validated on data of the last one-third of the patients from every participating ICU. RESULTS: In total, 2914 patients were included. Delirium incidence was 23.6%. The E-PRE-DELIRIC model consists of nine predictors assessed at ICU admission: age, history of cognitive impairment, history of alcohol abuse, blood urea nitrogen, admission category, urgent admission, mean arterial blood pressure, use of corticosteroids, and respiratory failure. The area under the receiver operating characteristic curve (AUROC) was 0.76 [95% confidence interval (CI) 0.73-0.77] in the development dataset and
0.75 (95% CI 0.71-0.79) in the validation dataset. The model was well calibrated. AUROC increased from 0.70 (95% CI 0.67-0.74), for delirium that developed <2 days, to 0.81 (95% CI 0.78-0.84), for delirium that developed >6 days. CONCLUSION:
Patients’ delirium risk for the complete ICU length of stay can be predicted at admission using the E-PRE-DELIRIC model, allowing early preventive interventions aimed to reduce incidence and severity of ICU delirium.
PMID: 25900905
Moolenaar LM, Cissen M, de Bruin JP, Hompes PG, Repping S, van der Veen F, Mol BW. Cost-effectiveness of assisted conception for male subfertility. Reprod Biomed Online. 2015 Feb 24. pii: S1472-6483(15)00093-0.
doi: 10.1016/j.rbmo.2015.02.006. [Epub ahead of print]
Intrauterine insemination (IUI), with or without ovarian stimulation, IVF and intracytoplasmatic sperm injection (ICSI) are frequently used treatments for couples with male subfertility. No consensus has been reached on specific cut-off values for semen parameters, at which IVF would be advocated over IUI and ICSI over IVF. The aim of this study was to evaluate the cost-effectiveness of interventions for male subfertility according to total motile sperm count (TMSC). A computer-simulated cohort of subfertile women aged 30 years with a partner was analysed with a pre-wash TMSC of 0 to 10 million. Three tre-atments were evaluated: IUI with and without controlled ovarian stimulation; IVF; and ICSI. Main outcome was expected live birth; secondary outcomes were cost per couple and the incremental cost-effectiveness ratio. The choice of IVF over IUI with ovarian stimulation and ICSI over IVF depends on the willingness to pay for an extra live birth. If only cost per live birth is considered for each treatment, above a pre-wash TMSC of 3 million, IUI is less costly than IVF and, below a pre-wash, TMSC of 3 million ICSI is less costly. Effectiveness needs to be confirmed in a large randomized controlled trial.
PMID: 25908965
Van de Sande-Bruinsma N, Leverstein van Hall MA, Janssen M, Nagtzaam N, Leenders S, de Greeff SC, Schneeberger PM. Impact of livestock-associated MRSA in a hospital setting. Antimicrob Resist Infect Control.
2015 Apr 17;4:11. doi: 10.1186/s13756-015-0053-8. eCollection 2015.
OBJECTIVES: The Netherlands is known for a stringent search and destroy policy to prevent spread of MRSA. In the hospital setting, livestock-associated MRSA (LA-MRSA) is frequently found in patients coming from the high density farming area in the south of the Netherlands. The aim of the study was to determine the contribution of LA-MRSA in the epidemiology of MRSA in cases found following the Dutch search and destroy policy. PATIENTS AND METHODS: From two hospitals serving a population of 550,000 persons all data on MRSA cultures and subsequent control measures from 2008 and 2009 were re-trospectively collected and analyzed. RESULTS: A total of 3856 potential index patients were screened for MRSA, 373 (9.7%) were found to be positive, 292 ( 78%) LA-MRSA and 81 (22%) non-LA-MRSA respectively. No secondary cases were found among contact research in persons exposed to LA-MRSA (0/416), whereas similar contact research for non-LA-MRSA resulted in 83 (2.5%) secondary cases. LA-MRSA were rarely found to cause infections. CONCLUSIONS: LA-MRSA is more prevalent than non-LA-MRSA in Dutch Hospitals in the South of the Netherlands. However, retrospectively studied cases show that the transmission rate for LA-MRSA was much lower than for non-LA-MRSA. This suggest that infection control practices for LA-MRSA may possibly be less stringent than for non-LA-MRSA.
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PMID: 25916606
Vogelaar FJ, Abegg R, van der Linden JC, Cornelisse HG, van Dorsten FR, Lemmens VE, Bosscha K. Epidural analgesia associated with better survival in colon cancer. Int J Colorectal Dis. 2015 Aug;30(8):1103-7. doi:
10.1007/s00384-015-2224-8.
PURPOSE: Surgery remains the mainstay of treatment for potentially curable colon cancer. Otherwise, the surgical stress response might increase the likelihood of cancer dissemination during and after cancer surgery. There is growing evidence that the type of anaesthesia during cancer surgery plays a role in the metastatic process. Therefore, we assessed if the method of anaesthesia is associated with long-term survival after colon cancer surgery. METHOD: A retrospective single-centre study was conducted including 588 patients who underwent colorectal cancer surgery, TNM stage I-IV, in the Jeroen Bosch Hospital between 1995 and 2003. The Cox proportional hazard model was used for statistical analysis. Adjustments were made for age, sex, comorbidity, TNM stage, chemotherapy, emergency surgery status and year of incidence. RESULTS:
Of the 588 primary colon cancer patients with a median age of 70 years, 399 (68 %) patients underwent colon surgery with epidural anaesthesia, whilst 189 (32 %) patients were operated without epidural anaesthesia. Five-year survival for patients not receiving epidural analgesia was 42 % versus 51 % for patients receiving epidural analgesia (p = 0.03). This effect remained after adjustment for relevant patient, tumour, and treatment characteristics (hazard ratio (HR) 1.30 (95 % confidence interval (CI) 1.05-1.59), p = 0.01). Subgroup analysis in patients of 80 years and older (n = 100) showed also a better overall survival after receiving epidural analgesia (HR 1.74 (95 % CI 1.11-2.72), p = 0.01). CONCLUSION: Epidural analgesia during colon cancer surgery was associated with a better overall survival. Prospective trials evaluating the effects of locoregional analgesia on colon cancer recurrence are warranted.
PMID: 25923503
Knol W, Verduijn MM, Lelie-van der Zande AC, van Marum RJ, Brouwers JR, van der Cammen TJ, Petrovic M, Jansen PA. Detecting inappropriate medication in older people: the revised STOPP/START criteria. Ned Tijdschr Geneeskd. 2015;159:A8904. Review. Dutch.
The use of potentially inappropriate medications (PIMs) by older people and potential prescribing omissions (PPOs) repre-sent a serious problem. It increases the risk of adverse drug reactions (ADRs), however it is susceptible to influence in a substantial number of cases. Use of the STOPP/START criteria developed in Ireland to optimise pharmacotherapy of older people reduces the number of ADRs and medication errors. Licensing of new drugs, the increased number of potentially inappropriate drugs, and the availability of new literature were grounds for an update of the first version of the STOPP/
START criteria which was published in 2008. In order to develop a screening tool with a broader application, a consensus panel of experts in the field of pharmacotherapy of older people was selected from 14 European countries for the second version of the STOPP/START criteria, including two from the Netherlands. The translation of the second version of the STOPP/START criteria has been adapted to the situation in the Netherlands, partly by omitting drugs that are not licensed in the Netherlands.
PMID: 25924761
Pennings JL, Kremers MN, Hodemaekers HM, Hagenaars JC, Koning OH, Renders NH, Hermans MH, de Klerk A, Notermans DW, Wever PC, Janssen R. Dysregulation of serum gamma interferon levels in vascular chronic Q Fever patients provides insights into disease pathogenesis. Clin Vaccine Immunol. 2015 Jun;22(6):664-71.
A large community outbreak of Q fever occurred in the Netherlands in the period 2007 to 2010. Some of the infected patients developed chronic Q fever, which typically includes pathogen dissemination to predisposed cardiovascular sites, with potentially fatal consequences. To identify the immune mechanisms responsible for ineffective clearance of Coxiella burnetii
in patients who developed chronic Q fever, we compared serum concentrations of 47 inflammation-associated markers among patients with acute Q fever, vascular chronic Q fever, and past resolved Q fever. Serum levels of gamma interferon were strongly increased in acute but not in vascular chronic Q fever patients, compared to past resolved Q fever patients. In-terleukin-18 levels showed a comparable increase in acute as well as vascular chronic Q fever patients. Additionally, vascular chronic Q fever patients had lower serum levels of gamma interferon-inducible protein 10 (IP-10) and transforming growth factor κ (TGF-κ) than did acute Q fever patients. Serum responses for these and other markers indicate that type I immune responses to C. burnetii are affected in chronic Q fever patients. This may be attributed to an affected immune system in cardiovascular patients, which enables local C. burnetii replication at affected cardiovascular sites.
PMID: 25924761
Pennings JL, Kremers MN, Hodemaekers HM, Hagenaars JC, Koning OH, Renders NH, Hermans MH, de Klerk A, Notermans DW, Wever PC, Janssen R. Dysregulation of serum gamma interferon levels in vascular chronic Q Fever patients provides insights into disease pathogenesis. Clin Vaccine Immunol. 2015 Jun;22(6):664-71. doi:
10.1128/CVI.00078-15. Epub 2015 Apr 29.
A large community outbreak of Q fever occurred in the Netherlands in the period 2007 to 2010. Some of the infected patients developed chronic Q fever, which typically includes pathogen dissemination to predisposed cardiovascular sites, with potentially fatal consequences. To identify the immune mechanisms responsible for ineffective clearance of Coxiella burnetii in patients who developed chronic Q fever, we compared serum concentrations of 47 inflammation-associated markers among patients with acute Q fever, vascular chronic Q fever, and past resolved Q fever. Serum levels of gamma interferon were strongly increased in acute but not in vascular chronic Q fever patients, compared to past resolved Q fever patients. In-terleukin-18 levels showed a comparable increase in acute as well as vascular chronic Q fever patients. Additionally, vascular chronic Q fever patients had lower serum levels of gamma interferon-inducible protein 10 (IP-10) and transforming growth factor κ (TGF-κ) than did acute Q fever patients. Serum responses for these and other markers indicate that type I immune responses to C. burnetii are affected in chronic Q fever patients. This may be attributed to an affected immune system in cardiovascular patients, which enables local C. burnetii replication at affected cardiovascular sites.
A large community outbreak of Q fever occurred in the Netherlands in the period 2007 to 2010. Some of the infected patients developed chronic Q fever, which typically includes pathogen dissemination to predisposed cardiovascular sites, with potentially fatal consequences. To identify the immune mechanisms responsible for ineffective clearance of Coxiella burnetii in patients who developed chronic Q fever, we compared serum concentrations of 47 inflammation-associated markers among patients with acute Q fever, vascular chronic Q fever, and past resolved Q fever. Serum levels of gamma interferon were strongly increased in acute but not in vascular chronic Q fever patients, compared to past resolved Q fever patients. In-terleukin-18 levels showed a comparable increase in acute as well as vascular chronic Q fever patients. Additionally, vascular chronic Q fever patients had lower serum levels of gamma interferon-inducible protein 10 (IP-10) and transforming growth factor κ (TGF-κ) than did acute Q fever patients. Serum responses for these and other markers indicate that type I immune responses to C. burnetii are affected in chronic Q fever patients. This may be attributed to an affected immune system in cardiovascular patients, which enables local C. burnetii replication at affected cardiovascular sites.