If you were a policymaker, which treatment would you disinvest? A participatory value evaluation on public preferences for active disinvestment of health care interventions in the Netherlands.

INTRODUCTION: Currently, it is not known what attributes of health care interventions citizens consider important in disinvestment decision-making (i.e. decisions to discontinue reimbursement). Therefore, this study aims to investigate the preferences of citizens of the Netherlands toward the relative importance of attributes of health care interventions in the context of disinvestment. METHODS: A participatory value evaluation (PVE) was conducted in April and May 2020. In this PVE, 1143 Dutch citizens were asked to save at least €100 million by selecting health care interventions for disinvestment from a list of eight unlabeled health care interventions, described solely with attributes. A portfolio choice model was used to analyze participants' choices. RESULTS: Participants preferred to disinvest health care interventions resulting in smaller gains in quality of life and life expectancy that are provided to older patient groups. Portfolios (i.e. combinations of health care interventions) resulting in smaller savings were preferred for disinvestment over portfolios with larger savings. CONCLUSION: The disinvestment of health care interventions resulting in smaller health gains and that are targeted at older patient groups is likely to receive most public support. By incorporating this information in the selection of candidate interventions for disinvestment and the communication on disinvestment decisions, policymakers may increase public support for disinvestment.

Societal views in the Netherlands on active disinvestment of publicly funded healthcare interventions.

OBJECTIVES: To obtain public support for the active disinvestment (i.e. policy decision to stop reimbursement) of healthcare interventions, it is important to have insight in what the public thinks about disinvestment and which considerations they find relevant in this context. Currently, evidence on relevant considerations in the disinvestment context is limited. Therefore, this study aimed to explore the societal views in the Netherlands on the active disinvestment of healthcare interventions and obtain insight into the considerations that are relevant for those holding the different views. METHODS: A Q-methodology study was conducted among a purposively selected sample of citizens (n = 43). Data were collected in June and July 2019. Participants individually ranked a set of 43 statements broadly covering the issues that participants could consider relevant in the disinvestment context, from 'least agree' to 'most agree'. Qualitative feedback on the statement ranking was collected from each participant using a questionnaire. Principal component analysis followed by oblimin rotation was used to identify clusters of participants with similar statement rankings. These clusters/factors were interpreted as distinct viewpoints using the factor arrays and qualitative questionnaire responses of participants. RESULTS: Four viewpoints were identified. People holding viewpoint I believe that reimbursement of necessary healthcare should be maintained, irrespective of its costs. People holding viewpoint II agree with viewpoint I, although they believe that necessity should be objectively determined. People holding viewpoint III think that unnecessary, ineffective and inefficient healthcare should be disinvested. People holding viewpoint IV, consider it most important that disinvestment decision-making processes are transparent and consistent. CONCLUSION: Insight in the distinct viewpoints identified in this study contributes to a better understanding of why it has been considered difficult to obtain public support for disinvestment of healthcare interventions, and can help policymakers to change their approach to disinvestment to increase public support.

Sacral neuromodulation versus personalized conservative treatment in patients with idiopathic slow-transit constipation: study protocol of the No.2-trial, a multicenter open-label randomized controlled trial and cost-effectiveness analysis.

PURPOSE: The evidence regarding the (cost-)effectiveness of sacral neuromodulation (SNM) in patients with therapy-resistant idiopathic slow-transit constipation is of suboptimal quality. The Dutch Ministry of Health, Welfare and Sports has granted conditional reimbursement for SNM treatment. The objective is to assess the effectiveness, cost-effectiveness, and budget impact of SNM compared to personalized conservative treatment (PCT) in patients with idiopathic slow-transit constipation refractory to conservative treatment. METHODS: This study is an open-label, multicenter randomized controlled trial. Patients aged 14 to 80 with slow-transit constipation, a defecation frequency (DF) < 3 per week and meeting at least one other Rome-IV criterion, are eligible. Patients with obstructed outlet, irritable bowel syndrome, bowel pathology, or rectal prolapse are excluded. Patients are randomized to SNM or PCT. The primary outcome is success at 6 months (DF ≥ 3 a week), requiring a sample size of 64 (α = 0.05, ß = 0.80, 30% difference in success). Secondary outcomes are straining, sense of incomplete evacuation, constipation severity, fatigue, constipation specific and generic quality of life, and costs at 6 months. Long-term costs and effectiveness will be estimated by a decision analytic model. The time frame is 57 months, starting October 2016. SNM treatment costs are funded by the Dutch conditional reimbursement program, research costs by Medtronic. CONCLUSIONS: The results of this trial will be used to make a final decision regarding reimbursement of SNM from the Dutch Health Care Package in this patient group. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov , identifier NCT02961582, on 12 October 2016.

The response of spermatogonia and spermatocytes of the Northern vole Microtus oeconomus to the induction of sex-chromosome nondisjunction, diploidy and chromosome breakage by X-rays and fast fission neutrons.

Microtus males were exposed to different doses of 250 kV X-rays or fast fission neutrons of 1 MeV mean energy. Early (= round) spermatids were analyzed for the presence of extra sex chromosomes, diploidy and micronuclei at different time intervals corresponding with treated differentiating spermatogonia and spermatocytes. Induction of nondisjunction of sex chromosomes could not be detected. In contrast, induction of diploids by both types of radiation was statistically significant at all sampling times. Dose-effect relationships for most of the sampling times were linear and sometimes linear-quadratic concave upward or downward. There were pronounced stage-specific differences in sensitivity as reflected by differences in doubling doses that ranged from 4 to 22 cGy for X-rays and from 0.4 to 4 cGy for neutrons. Spermatocytes at pachytene were the most sensitive cells and proliferating spermatogonia the least sensitive ones. The relative biological effectiveness (RBE) of neutrons depended on the cell stage treated and fluctuated between 1.4 and 9.2. Evidence for radiation-induced chromosomal breakage events was obtained via detection of micronuclei. Induction of micronuclei by X-rays or neutrons was statistically significant at all spermatocyte stages tested. There was no effect in spermatogonia. With a few exceptions dose-effect relationships were linear. Differences in stage sensitivity were clearly present as evidenced by doubling dose which ranged from 5 to 29 cGy for X-rays and from 1 to 3 cGy for neutrons. RBE values varied from 5.2 to 12.7. Maximum sensitivity was detected in spermatocytes at diakinesis, MI and MII. Resting primary spermatocytes (G1 and S phase) were somewhat less sensitive and actively proliferating spermatogonia were the least sensitive cells. The pattern of stage sensitivity for induction of diploids was distinctly different from that for induction of chromosomal breakage.

Influence of incorporated 5-bromodeoxyuridine on the frequencies of spontaneous and induced sister-chromatid exchanges, detected by immunological methods.

We have utilized monoclonal antibody against BrdUrd to detect sister-chromatid exchanges in CHO cells. This technique allows detection of SCEs at very low levels of BrdUrd incorporation. At incorporation level of 0.5%, a frequency of about 2 SCEs/cell/cycle was found. In a UV-sensitive mutant (43-3B) which has an increased spontaneous frequency of SCEs, it is found that this increase is due to incorporated BrdUrd. In MMS- and MMC-treated cells, an influence of BrdUrd on the frequencies of induced SCEs was found only when high concentrations of mutagens were employed.

Persistence of preclastogenic damage in hepatocytes of rats exposed to ethylnitrosourea, diethylnitrosamine, dimethylnitrosamine and methyl methanesulphonate. Correlation with DNA O-alkylation.

Male Wistar rats received a single injection of ethylnitrosourea (ENU; 140 mg/kg), dimethylnitrosamine (DMN; 10 mg/kg) or methyl methanesulphonate (MMS; 80 mg/kg). After 1, 6, 28 and 56 days liver cells were assayed for the presence of preclastogenic lesions. This was done by analysis of micronuclei in hepatocytes isolated at 2, 3 and 4 days after partial hepatectomy. Treatment with MMS did not give rise to a statistically significant increased micronucleus frequency after the two time intervals tested (1 and 6 days). In contrast, frequencies of micronuclei were significantly enhanced at all time intervals after treatment with either ENU or DMN. These results support our previous conclusion that only those alkylating agents which give rise to substantial DNA O-alkylation are able to induce long-lived preclastogenic damage in rat liver cells. Both after ENU and DMN treatment, frequencies of micronuclei were significantly higher at day 6 than at days 1, 28 and 56. It is postulated that part of the primary preclastogenic lesions (supposed to be DNA adducts) are converted into secondary preclastogenic lesions during the first period after exposure to the chemicals. Apparently, both primary and secondary preclastogenic lesions are gradually lost after day 6. This loss is rather low (less than 25%) after ENU, but more impressive after DMN (approximately 60%). The persistent nature of preclastogenic damage induced by diethylnitrosamine was demonstrated in an experiment which showed that a single dose of this agent (50 mg/kg) had the same clastogenic effect as a fractionated dose (five weekly injections of 10 mg/kg). This result also implies that a threshold dose for induction of micronuclei, if present, must be very low, appreciably below 10 mg/kg.