Cardiovascular risk in patients with new gout diagnosis: is monosodium urate volume at ankles and feet on dual-energy computed tomography associated with previous cardiovascular events?

OBJECTIVES: Chronic inflammation associated with hyperuricaemia and urate deposition may contribute to an increased risk of developing cardiovascular (CV) events (CVE) in patients with gout. The aim of this study was to explore whether urate deposition on dual-energy CT (DECT) present at the diagnosis of gout is associated with a history of CVE. METHODS: Patients from a study on clinical value of DECT with mono or oligoarthritis who had gout according the 2015 EULAR/ACR classification criteria were included in this cross-sectional study. Urate volume on DECT was calculated. Patients underwent a structured CV consultation, including assessment of CVE-history and of CV risk factors, scored with the Dutch risk prediction SCORE and the Framingham score. The data were analysed using logistic regression analyses. RESULTS: Sixty-eight patients were included. In the multivariable model, -next to significant associations of age (OR per year 1.1, 95% CI 1.04 to 1.02, p=0.02), HDLc per mmol/l (OR 0.04, 95% CI 0.002 to 0.8, p=0.03), and diabetes yes/no (OR 4, 95% CI 0.8 to 20.9, p=0.09)-, urate volumes at ankles/feet on DECT in the third and fourth quartile with first quartile as reference showed a trend of association (OR 4.8, 95% CI 0.6 to 42, p=0.1 and 6.4, 0.7 to 63, 0.1, respectively) with past CVE events (yes/ no). This association could be bidirectional. Almost two-third of newly classified gout patients had a high or very high CV risk. CONCLUSIONS: CVE history probably is associated with urate volumes already present at the time of diagnosis of gout. Our data corroborate the need of assessing and treating CV risk factors when diagnosing gout.

The performance of dual-energy CT in the classification criteria of gout: a prospective study in subjects with unclassified arthritis.

OBJECTIVE: To establish the performance of (subsets of) the 2015 ACR/EULAR gout classification criteria in patients with unclassified arthritis, and to determine the value of dual-energy CT (DECT) herein. Reference was the MSU crystal detection result in SF at polarization microscopy. METHODS: We included subjects with acute, unclassified mono or oligoarthritis, who underwent SF analysis and DECT. Performance was assessed by calculating area under the receiver operating characteristic curve of (i) the clinical criteria subset, (ii) the clinical+serum urate subset and (iii) the full set (including DECT). RESULTS: Of the 89 subjects enrolled, 40 met the clinical+serum urate subset criteria, and 49 (55%) subjects did not. Of these 49, 30 had a negative microscopy result, of whom 15 had positive DECT; of these 15, 14 met the full set criteria only after adding the positive DECT result. For the clinical-only subset, the areas under the curves (AUCs) were 0.68 and 0.69 without and with DECT result, respectively, and for the clinical+serum urate subset without and with DECT, AUCs were 0.81 and 0.81, respectively (results not significant). CONCLUSION: Adding the serum urate results to the clinical subset improves the performance, but adding the DECT result does not, neither does adding the DECT results to the clinical+serum urate subset. However, DECT seems to have an additive value in gout classification, especially when microscopy of SF is negative; 14/89 of patients (16%) only met the classification criteria with the use of DECT. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT03038386.

Cardiovascular risk in patients with new gout: should we reclassify the risk?

OBJECTIVES: Chronic inflammation, as seen in gout, may contribute to an increased risk of developing cardiovascular (CV) events (CVE). The aim of the study was to explore the effect of adding gout as a chronic inflammatory disease to the Dutch SCORE, a tool predicting 10-year CV mortality and morbidity. METHODS: This was a cross-sectional substudy including new patients with gout according the 2015 EULAR/ACR classification criteria who had participated in a trial on diagnostic accuracy of DECT with mono or oligoarthritis. Patients underwent a structured CV consultation, including assessment of CVE-history and of CV risk factors with the Dutch risk prediction SCORE. Chi-square test for trends was used to test for significance reclassification of the CV risk before and after adding gout to the Dutch SCORE. RESULTS: Seventy-six gout patients were included. SCORE was applied in 60 patients; 16 patients had experienced a prior CVE. The 10-year risk scores without gout as risk factor were high in 29 patients (48.3%), moderate in 6 (10%) and low in 25 (41.7%); with gout, the risk of 23/60 patients (38.3%) was reclassified from low to moderate in 6 patients (10%), from low to high in 11 (18.3%) and from moderate to high in 6 (10%), p<0.001 for trend. CONCLUSIONS: Adding gout to the risk prediction tools led to significant and clinically relevant reclassification of CV risk in new gout patients. Studies with large follow-up are warranted to validate these findings.

Learning curve of robot-assisted laparoscopic sacrocolpo(recto)pexy: a cumulative sum analysis.

BACKGROUND: Determination of the learning curve of new techniques is essential to improve safety and efficiency. Limited information is available regarding learning curves in robot-assisted laparoscopic pelvic floor surgery. OBJECTIVE: The purpose of this study was to assess the learning curve in robot-assisted laparoscopic pelvic floor surgery. STUDY DESIGN: We conducted a prospective cohort study. Consecutive patients who underwent robot-assisted laparoscopic sacrocolpopexy or sacrocolporectopexy were included (n=372). Patients were treated in a teaching hospital with a tertiary referral function for gynecologic/multicompartment prolapse. Procedures were performed by 2 experienced conventional laparoscopic surgeons (surgeons A and B). Baseline demographics were scored per groups of 25 consecutive patients. The primary outcome was the determination of proficiency, which was based on intraoperative complications. Cumulative sum control chart analysis allowed us to detect small shifts in a surgeon's performance. Proficiency was obtained when the first acceptable boundary line of cumulative sum control chart analysis was crossed. Secondary outcomes that were examined were shortening and/or stabilization of surgery time (measured with the use of cumulative sum control chart analysis and the moving average method). RESULTS: Surgeon A performed 242 surgeries; surgeon B performed 137 surgeries (n=7 surgeries were performed by both surgeons). Intraoperative complications occurred in 1.9% of the procedures. The learning curve never fell below the unacceptable failure limits and stabilized after 23 of 41 cases. Proficiency was obtained after 78 cases for both surgeons. Surgery time decreased after 24-29 cases in robot-assisted sacrocolpopexy (no distinct pattern for robot-assisted sacrocolporectopexy). Limitations were the inclusion of 2 interventions and concomitant procedures, which limited homogeneity. Furthermore, analyses treated all complications in cumulative sum as equal weight, although there are differences in the clinical relevance of complications. CONCLUSION: After 78 cases, proficiency was obtained. After 24-29 cases, surgery time stabilized for robot-assisted sacrocolpopexy. In this age of rapidly changing surgical techniques, it can be difficult to determine the learning curve of each procedure. Cumulative sum control chart analysis can assist with this determination and prove to be a valuable tool. Training programs could be individualized to improve both surgical performance and patient benefits.

Utility of zinc protoporphyrin in management of whole blood donors.

BACKGROUND: Deferral for low hemoglobin (Hb) increases the likelihood that donors do not return for future donations. Zinc protoporphyrin (ZPP) has been described as a sensitive marker of iron-deficient erythropoiesis, before Hb decreases. It is a relatively cheap, rapid, and easy-to-perform measurement in a drop of whole blood. To assess the utility of ZPP measurement in donor management we examined whether ZPP and Hb levels among first-time donors differ from repeat donors. We further explored whether ZPP increases over subsequent donations at a donor population level and whether increasing ZPP levels coincide with decreasing Hb levels and donor deferral. STUDY DESIGN AND METHODS: We included first-time (n = 4983) and repeat (n = 3533) whole blood donors from the ZPP and Iron in the Netherlands Cohort (ZINC) study. ZPP and Hb were measured at each subsequent donation during a 4-year period after inclusion in the study. RESULTS: Median ZPP levels were higher in repeat than in first-time donors. In first-time donors, especially women, ZPP levels were increased with a corresponding decline in Hb levels over subsequent donations. ZPP levels were increased among first-time donors deferred for low Hb. CONCLUSION: Our results suggest that adding ZPP to Hb measurements in the daily blood collection setting, especially for first-time donors and first-time female donors may add to the identification of a donor subpopulation with low functional iron stores.

Serum concentrations of psychotropic drugs in neonates as a PROgnOstic Factor for admission to the neonatology ward and withdrawal symptoms: PROOF-1.

The aim is to determine whether serum drug concentrations obtained from the neonate's umbilical cord can be used as a prognostic factor for admission to the neonatology ward and the occurrence of withdrawal symptoms. A retrospective observational monocenter cohort study was carried out among pregnant women using psychotropic drugs and their baby. Binary logistic regression was used for the multivariate analysis. Of the 186 neonates included, 22.6% (n=42) were admitted to the neonatology ward, 6.5% (n=12) because of withdrawal. Among women with therapeutic concentrations of psychotropic medication, 22.0% (n=5) of the neonates had withdrawal symptoms. When comparing neonates with therapeutic versus undetectable drug concentrations, an odds ratio of 3.1 (95% confidence interval: 1.1-8.6) was found for admission to the neonatology ward and an odds ratio of 20.5 (95% confidence interval: 2.2-186.1) for the occurrence of withdrawal symptoms. Therapeutic concentrations of psychotropic drugs in neonates' umbilical cord blood correspond with higher odds for admission to the neonatology ward and the occurrence of withdrawal symptoms compared with neonates with undetectable drug concentrations. The measurement of drug concentrations in the neonate may contribute toward the general clinical assessment of the physician to predict the necessity of admission to the neonatology ward and the risk of withdrawal symptoms.

Blood donors' physical characteristics are associated with pre- and post-donation symptoms - Donor InSight.

BACKGROUND: Observational data suggest that some donors might benefit from donating while others may be harmed. The aim of this study was to investigate the prevalence and potential, routinely measured, determinants of pre- and post-donation symptoms. MATERIALS AND METHODS: In Donor InSight, questionnaire data from 23,064 whole blood donors (53% female) were linked to routinely measured data on donors' physical characteristics (haemoglobin, blood pressure, body mass index and estimated blood volume) from the Dutch donor database. Absolute and relative associations between donors' physical donor and the presence of pre- and post-donation symptoms were studied using multivariable logistic regression. RESULTS: Pre-donation symptoms (lack of energy, headaches) were reported by 3% of men and 3% of women. Five percent of men and 4% of women reported positive post-donation symptoms (feeling fit, fewer headaches). Negative symptoms (fatigue, dizziness) were more common, occurring in 8% of men and 19% of women. All the studied donors' physical characteristics were positively associated with pre- and positive post-donation symptoms and negatively associated with negative symptoms. Body mass index was most consistently and independently associated with symptoms. DISCUSSION: Donors' physical characteristics, in particular body mass index, were consistently associated with pre- and post-donation symptoms. This indicates that subgroups of donors more and less tolerant to donation might be identifiable using routinely measured data. Further research is warranted to study underlying mechanisms and potential strategies to predict and prevent donor reactions.

Treatment of painful bone metastases in prostate and breast cancer patients with the therapeutic radiopharmaceutical rhenium-188-HEDP. Clinical benefit in a real-world study.

AIM: Rhenium-188-HEDP ((188)Re-HEDP) is an effective radiopharmaceutical for the palliative treatment of osteoblastic bone metastases. However, only limited data on its routine use are available and its effect on quality of life (QoL) has not been studied. Therefore, we evaluated the clinical benefit of (188)Re-HEDP in routine clinical care. PATIENTS AND METHODS: Prostate or breast cancer patients with painful bone metastases receiving (188)Re-HEDP as a routine clinical procedure were eligible for evaluation. Clinical benefit was assessed in terms of efficacy and toxicity. Pain palliation and QoL were monitored using the visual analogue scale (VAS), corrected for opioid intake, and the EORTC QLQ-C30 Global health status/QoL-scale. Thrombocyte and leukocyte nadirs were used to assess haematological toxicity. RESULTS: 45 and 47 patients were evaluable for pain palliation and QoL, respectively. After a single injection of (188)Re-HEDP, the overall pain response rate was 69% and mean VAS-scores decreased relevantly and significantly (p < 0.05). Repeated treatment resulted in similar pain response. The overall QoL response rate was 68% and mean Global health status/QoL-scores increased relevantly and significantly. Haematological side effects were mild and transient. CONCLUSION: The clinically relevant response on pain and quality of life and the limited adverse events prove clinical benefit of treatment with (188)Re-HEDP and support its use in routine clinical care. Its effectiveness appears comparable to that of external beam radiotherapy.

Hemoglobin assessment: precision and practicability evaluated in the Netherlands-the HAPPEN study.

BACKGROUND: Most donors do not like the invasive hemoglobin (Hb) measurement in fingerstick capillary samples. Alternative noninvasive devices have recently become available. In this study we assessed the precision and practicability of noninvasive devices and compared them with measurements in capillary and venous samples. STUDY DESIGN AND METHODS: A total of 2589 blood donors were included in the study. Hb levels were measured with the noninvasive devices NBM 200 or Haemospect and compared with values obtained with the invasive devices HemoCue 201 and HemoCue 301 and with venous values. Precision was evaluated in terms of sensitivity and specificity for detection of Hb levels below the cutoff level for donation, taking venous values as "reference values." RESULTS: Hb levels measured with both invasive and noninvasive devices differed significantly from venous measurements. Measurements with invasive devices correlated stronger with venous values and were more precise. Sensitivity ranged from 30.1% (HemoCue 201) to 3.5% (Haemospect) in men and from 36.6% (HemoCue 201) to 10.8% (Haemospect) in women. Specificity ranged from 99.8% (HemoCue 201) to 95.5% (Haemospect) in men and from 98.9% (HemoCue 201) to 94.6% (NBM 200) in women. Most donors preferred the noninvasive measurement. CONCLUSION: Measurements with invasive devices showed stronger correlation and better agreement with venous values than noninvasive devices. Sensitivity was low for all measurement devices, particularly the noninvasive ones. In terms of precision invasive measurement would be preferred for donor screening, although a majority of donors preferred the noninvasive measurement.

Centralisation of epithelial ovarian cancer surgery: results on survival from a peripheral teaching hospital.

OBJECTIVE: The objective of this retrospective descriptive study was to assess overall survival and disease free survival of patients treated for epithelial ovarian cancer by a gynaecologic-oncologist in a single Dutch peripheral teaching hospital and to identify independent prognostic factors. STUDY DESIGN: A retrospective series of 242 patients treated for epithelial ovarian cancer between 1999 and 2011 at Meander Medical Centre was reviewed. Data on patient, tumour and treatment characteristics were collected. Outcomes were overall survival and progression free survival. Data were analysed using the Kaplan-Meier method, log-rank test and Cox regression analysis. RESULTS: Median follow-up was 35 months (range 1-203). Staging procedures were performed in 81 patients of which 63% were complete. 61% of patients had advanced stage disease. In 46%, debulking surgery was complete. Five-year overall survival and progression free survival for all patients was 52% and 47%, respectively. Multivariate analysis identified performance status [HR=1.89 and 1.92 for performance status 2, HR=7.01 and 2.69 for performance status 3], FIGO stage [HR=3.59 for stage II, HR=5.43 and 5.64 for stage III, HR=12.17 and 10.21 for stage IV] and residual disease after debulking surgery [HR=2.01 and 1.72 for incomplete debulking] as independent prognostic factors for overall survival and progression free survival respectively. CONCLUSION: Survival after surgery for epithelial ovarian cancer in this cohort is comparable to survival in centralised clinics presented in literature. Partial concentration of cancer care by recruitment of specialised gynaecologic-oncologists in teaching hospitals might be an alternative to complete centralisation of epithelial ovarian cancer treatment in larger cancer centres.

Travel behavior and deferral of Dutch blood donors: consequences for donor availability.

BACKGROUND: Donors returning from areas with outbreaks of infectious diseases may donate infectious blood back home. Geographic donor deferral is an effective measure to ensure the blood safety, but donor deferral may pose a threat for the blood supply especially after holiday seasons. Insight into the travel behavior of blood donors is a first step to define appropriate deferral strategies. This study describes the travel behavior of Dutch donors, the actual deferral, and the consequences of deferral strategies on donor availability. STUDY DESIGN AND METHODS: A questionnaire designed to assess travel behavior (destination, frequency, and duration of travels) was sent to 2000 Dutch donors. The impact of travel deferral policies on donor availability was calculated, expressed as proportionate decrease in donor availability. The deferral policies considered were 1) deferral based on entire countries instead of affected regions where an infection is prevalent and 2) deferral after any travel outside Europe ("universal deferral"). RESULTS: Of the 1340 respondents, 790 (58.9%) donors traveled within Europe only, 61 (4.6%) outside Europe only, and 250 (18.7%) within and outside Europe. The deferral for entire countries and universal deferral would lead to 11.1 and 11.4% decrease in donor availability, respectively. CONCLUSION: Most Dutch donors traveled outside the Netherlands, while 23.2% traveled outside Europe. Universal deferral resulted in an additional decrease in donor availability of 0.3% compared with deferral for entire countries instead of affected regions where an infection is prevalent. Thus, the universal deferral could be considered as a simpler and safer measure.

Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial.

AIM: The disturbed circadian rhythm in haemodialysis patients results in perturbed sleep. Short term melatonin supplementation has alleviated these sleep problems. Our aim was to investigate the effects of long-term melatonin supplementation on quality of life and sleep. METHODS: In this randomized double-blind placebo-controlled trial haemodialysis patients suffering from subjective sleep problems received melatonin 3 mg day(-1) vs. placebo during 12 months. The primary endpoint quality of life parameter 'vitality' was measured with Medical Outcomes Study Short Form-36. Secondary outcomes were improvement of three sleep parameters measured by actigraphy and nighttime salivary melatonin concentrations. RESULTS: Sixty-seven patients were randomized. Forty-two patients completed the trial. With melatonin, no beneficial effect on vitality was seen. Other quality of life parameters showed both advantageous and disadvantageous effects of melatonin. Considering sleep, at 3 months sleep efficiency and actual sleep time had improved with melatonin compared with placebo on haemodialysis days (difference 7.6%, 95% CI 0.77, 14.4 and 49 min, 95% CI 2.1, 95.9, respectively). At 12 months none of the sleep parameters differed significantly from placebo. Melatonin salivary concentrations at 6 months had significantly increased in the melatonin group compared with the placebo group. CONCLUSIONS: The high drop-out rate limits the strength of our conclusions. However, although a previous study reported beneficial short term effects of melatonin on sleep in haemodialysis patients, in this long-term study the positive effects disappeared during follow up (6-12 months). Also the quality of life parameter, vitality, did not improve. Efforts should be made to elucidate the mechanism responsible for the loss of effect with chronic use.

Preemptive dosage reduction of nadroparin in patients with renal failure: a retrospective case series.

BACKGROUND: Low-molecular-weight heparins (LMWHs) are frequently used to treat arterial and venous thrombo-embolic events. LMWHs accumulate with renal failure, but only limited clinical data regarding appropriate dosage adjustments are available. Nevertheless, LMWHs are routinely used in these patients worldwide. Although many clinics apply renal function-based dosage reductions, anti-factor Xa (anti-Xa) activity is not measured routinely. METHODS: We determined anti-Xa activity in 51 patients with MDRD-eGFR <60 mL/min/1.73 m(2), treated with therapeutic doses of nadroparin according to a standard, renal function-based guideline. RESULTS: An a priori dosage reduction resulted in anti-Xa activity within, below and above the reference range in 51, 30 and 19% of the measurements, respectively. Treatment resulted in different anti-Xa activities compared with dosages that were not given according to official advice (P < 0.001). Anti-Xa values increased with longer treatment duration (P = 0.038). CONCLUSIONS: A preemptive fixed reduction (25%) of the nadroparin dosage in all patients with renal failure seems appropriate. However, because target anti-Xa activities were reached in only half of the patients, we submit that the use of nadroparin, dosage reduction and monitoring of anti-Xa activity in combination with clinical outcome monitoring in this patient population urgently needs further investigation.

The effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer's pathology in animal models of Alzheimer's disease: a systematic review and meta-analysis.

To date, only a few randomized clinical trials (RCTs) have investigated the effects of omega-3 fatty acids (FA) on Alzheimer's disease (AD). Some of these studies demonstrated that patients with very mild AD or mild cognitive impairment benefit from omega-3 FA treatment, but none showed significant improvements in cognitive function in patients with moderate or advanced AD. All these RCTs had a relatively short duration of supplementation, however, and we hypothesized that this might be one of the reasons why no effects of omega-3 FA supplementation could be observed in patients with "moderate" or "advanced" AD. Animal studies offer better possibilities for controlled long-term supplementation than clinical studies. Therefore, we performed a systematic review (SR) and meta-analysis of the literature that focused on effects of the relatively long-term omega-3 FA supplementation (minimum period; 10% of average total lifespan) on cognitive impairment, amyloid-ß pathology, and neuronal loss in animal models of AD. This SR shows that long-term omega-3 FA supplementation decreased the omega-6/omega-3 FA ratio and reduced the amount of amyloid-ß in experimental animal models of AD. Omega-3 FA supplementation also improved cognitive function; this effect appeared larger in rats compared to mice, and in males compared to females. Moreover, omega-3 FA supplementation diminished the amount of neuronal loss, especially in female animals. The results of this SR indicate that it might be worthwhile to perform new clinical trials with long-term omega-3 FA supplementation in AD patients.

Mifepristone and misoprostol versus Dilapan and sulprostone for second trimester termination of pregnancy.

OBJECTIVE: To compare two methods for second trimester termination of pregnancy: mifepristone and misoprostol versus Dilapan and sulprostone. METHODS: This was a randomized study involving 16 patients with a singleton live fetus with congenital malformations or genetic disorders. Eight patients were treated with 200 mg mifepristone orally followed by 200 microg misoprostol vaginally 3 hourly and eight patients received a sulprostone infusion after cervical dilatation with Dilapan. RESULTS: Mifepristone and misoprostol had a mean induction interval of 17.8 hours and sulprostone and Dilapan 20.9 hours. The mean induction interval did not differ significantly. Mean hospital stay was shorter in the patients treated with misoprostol: 2.1 vs. 3.3 days (p = 0.02) with a 95% confidence interval of -2.1 to 0.3. CONCLUSION: Mifepristone and misoprostol did not reduce the induction interval significantly compared to the sulprostone and Dilapan treatment for second trimester pregnancy termination. Hospital admission was significantly shorter in patients treated with mifepristone and misoprostol.

Ethnic variation in infant-feeding practices in the Netherlands and weight gain at 4 months.

This prospective study of 4438 infants (0-4 months) examined differences in infant-feeding patterns in relation to the ethnic origin of their mothers, based on the mother's native language: Dutch (87%), Turkish (4%), Moroccan (3%), other European languages (3%), and various other languages (4%). Breastfeeding at birth varied between 75% and 94%. Dutch and Moroccan mothers breastfed for a shorter period (32% and 37% at 4 months, respectively) than did Turkish mothers and mothers with a native European language other than Dutch (47% and 51% at 4 months, respectively; P < .001). Of all mothers, 71% started exclusive breastfeeding at birth, and 21% continued exclusive breastfeeding for at least 4 months. The reasons why mothers discontinued breastfeeding (both exclusive breastfeeding and breastfeeding) were generally infant related. The average weight gain between birth and day 133 was 3.45, 3.87, and 3.69 kg for Dutch, Turkish, and Moroccan infants, respectively. Weight gain was influenced by ethnicity of the mothers and exclusive breastfeeding.

Systematic review of the effect of radiation dose on tumor control and morbidity in the treatment of prostate cancer by 3D-CRT.

PURPOSE: A higher radiation dose is believed to result in a larger probability of tumor control and a higher risk of side effects. To make an evidence-based choice of dose, the relation between dose and outcome needs to be known. This study focuses on the dose-response relation for prostate cancer. METHODS AND MATERIALS: A systematic review was carried out on the literature from 1990 to 2003. From the selected studies, the radiation dose, the associated 5-year survival, 5-year bNED (biochemical no evidence of disease), acute and late gastrointestinal (GI) and genitourinary (GU) morbidity Grade 2 or more, and sexual dysfunction were extracted. With logistic regression models, the relation between dose and outcome was described. RESULTS: Thirty-eight studies met our criteria, describing 87 subgroups and involving up to 3000 patients per outcome measure. Between the (equivalent) dose of 70 and 80 Gy, various models estimated an increase in 5-year survival (ranging from 10% to 11%), 5-year bNED for low-risk patients (5-7%), late GI complications (12-16%), late GU complications (8-10%), and erectile dysfunction (19-24%). Only for the overall 5-year bNED, results were inconclusive (range, 0-18%). CONCLUSIONS: The data suggest a relationship between dose and outcome measures, including survival. However, the strength of these conclusions is limited by the sometimes small number of studies, the incompleteness of the data, and above all, the correlational nature of the data. Unambiguous proof for the dose-response relationships can, therefore, only be obtained by conducting randomized trials.

Clinically relevant anterograde amnesia and its relationship with blood levels of benzodiazepines in suicide attempters who took an overdose.

The relationship between anterograde amnesia, sedation and plasma levels of benzodiazepines was studied prospectively in a group of 24 patients who took an overdose of benzodiazepines. Patients were tested on two sequential days after having taken an overdose. Anterograde amnesia was tested by using a verbal recall test and a photo recognition test. Sedation was scored on a visual analogue scale (VAS) by the patient and the interviewer. The concentration of benzodiazepines in plasma was measured by using a radioreceptor assay that adds benzodiazepines and their active metabolites. The cumulative amount of benzodiazepines was expressed as diazepam equivalents (DZE). Diazepam equivalents determined by this radioreceptor assay were significantly higher on the first day than on the second day. Ratings on the verbal recall test were significantly lower on the first day than on the second day. There was a significant relation between decrease of diazepam equivalents and increase of verbal recall: more than 30% of increase of verbal recall was explained by decrease of diazepam equivalents. There was not a strong relation between decrease of diazepam equivalents and reduction of level of sedation as scored by the patients. There was almost no relation between decrease of diazepam equivalents and reduction of level of sedation as scored by the interviewer. No relation was found between verbal recall, sedation and diazepam equivalents. There was no relation between diazepam equivalents and photo recognition. It was concluded that anterograde amnesia was strongly associated with benzodiazepines in patients who take benzodiazepines in an overdose. Sedation does not predict the degree of anterograde amnesia.