Diagnostic and societal impact of implementing the syncope guidelines of the European Society of Cardiology (SYNERGY study).

BACKGROUND: Syncope management is fraught with unnecessary tests and frequent failure to establish a diagnosis. We evaluated the potential of implementing the 2018 European Society of Cardiology (ESC) Syncope Guidelines regarding diagnostic yield, accuracy and costs. METHODS: A multicentre pre-post study in five Dutch hospitals comparing two groups of syncope patients visiting the emergency department: one before intervention (usual care; from March 2017 to February 2019) and one afterwards (from October 2017 to September 2019). The intervention consisted of the simultaneous implementation of the ESC Syncope Guidelines with quick referral routes to a syncope unit when indicated. The primary objective was to compare diagnostic accuracy using logistic regression analysis accounting for the study site. Secondary outcome measures included diagnostic yield, syncope-related healthcare and societal costs. One-year follow-up data were used to define a gold standard reference diagnosis by applying ESC criteria or, if not possible, evaluation by an expert committee. We determined the accuracy by comparing the treating physician's diagnosis with the reference diagnosis. RESULTS: We included 521 patients (usual care, n = 275; syncope guidelines intervention, n = 246). The syncope guidelines intervention resulted in a higher diagnostic accuracy in the syncope guidelines group than in the usual care group (86% vs.69%; risk ratio 1.15; 95% CI 1.07 to 1.23) and a higher diagnostic yield (89% vs. 76%, 95% CI of the difference 6 to 19%). Syncope-related healthcare costs did not differ between the groups, yet the syncope guideline implementation resulted in lower total syncope-related societal costs compared to usual care (saving €908 per patient; 95% CI €34 to €1782). CONCLUSIONS: ESC Syncope Guidelines implementation in the emergency department with quick referral routes to a syncope unit improved diagnostic yield and accuracy and lowered societal costs. TRIAL REGISTRATION: Netherlands Trial Register, NTR6268.

Cold extremities in migraine: a marker for vascular dysfunction in women.

BACKGROUND AND PURPOSE: Migraine is recognized as a vascular risk factor, especially in women. Presumably, migraine, stroke and cardiovascular events share pathophysiological mechanisms. Self-reported cold extremities were investigated as a marker for vascular dysfunction in migraine. Secondly, it was hypothesized that suffering from cold extremities affects sleep quality, possibly exacerbating migraine attack frequency. METHODS: In this case-control study, a random sample of 1084 migraine patients and 348 controls (aged 22-65 years) from the LUMINA migraine cohort were asked to complete questionnaires concerning cold extremities, sleep quality and migraine. RESULTS: A total of 594 migraine patients and 199 controls completed the questionnaires. In women, thermal discomfort and cold extremities (TDCE) were more often reported by migraineurs versus controls (odds ratio 2.3, 95% confidence interval 1.4-3.7; P < 0.001), but not significantly so in men (odds ratio 2.5, 95% confidence interval 0.9-6.9; P = 0.09). There was no difference in TDCE comparing migraine with or without aura. Female migraineurs who reported TDCE had higher attack frequencies compared to female migraineurs without TDCE (4 vs. 3 attacks per month; P = 0.003). The association between TDCE and attack frequency was mediated by the presence of difficulty initiating sleep (P = 0.02). CONCLUSION: Women with migraine more often reported cold extremities compared with controls, possibly indicating a sex-specific vascular vulnerability. Female migraineurs with cold extremities had higher attack frequencies, partly resulting from sleep disturbances. Future studies need to demonstrate whether cold extremities in female migraineurs are a predictor for cardiovascular and cerebrovascular events.

Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a monogenic small vessel disease.

BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a small vessel disease caused by C-terminal truncating TREX1 mutations. The disease is typically characterized by vascular retinopathy and focal and global brain dysfunction. Systemic manifestations have also been reported but not yet systematically investigated. METHODS: In a cross-sectional study, we compared the clinical characteristics of 33 TREX1 mutation carriers (MC+) from three Dutch RVCL-S families with those of 37 family members without TREX1 mutation (MC-). All participants were investigated using personal interviews, questionnaires, physical, neurological and neuropsychological examinations, blood and urine tests, and brain MRI. RESULTS: In MC+, vascular retinopathy and Raynaud's phenomenon were the earliest symptoms presenting from age 20 onwards. Kidney disease became manifest from around age 35, followed by liver disease, anaemia, markers of inflammation and, in some MC+, migraine and subclinical hypothyroidism, all from age 40. Cerebral deficits usually started mildly around age 50, associated with white matter and intracerebral mass lesions, and becoming severe around age 60-65. CONCLUSIONS: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations is a rare, but likely underdiagnosed, systemic small vessel disease typically starting with vascular retinopathy, followed by multiple internal organ disease, progressive brain dysfunction, and ultimately premature death.

Sensitivity of MG-ADL for generalized weakness in myasthenia gravis.

BACKGROUND AND PURPOSE: Myasthenia gravis activities of daily living (MG-ADL) is a commonly used questionnaire in MG trials. To investigate whether MG-ADL is equally sensitive to oculobulbar and generalized weakness, its correlation with the oculobulbar and generalized domain of the quantitative myasthenia gravis (QMG) score was analyzed (QMGob and QMGgen, respectively). To test whether the sensitivity of MG-ADL for generalized weakness could be improved, the additional value of ACTIVLIM on top of MG-ADL in the prediction QMGgen in was investigated. METHODS: MG-ADL, QMG and ACTIVLIM, an ADL questionnaire focusing on generalized weakness, were analyzed in a prospective cohort of 112 MG patients. A generalized linear model was used to calculate the correlation of MG-ADL with QMGob and QMGgen and to assess the additional value of ACTIVLIM on top of MG-ADL for its correlation with QMGgen. RESULTS: MG-ADL had a higher correlation with QMGob than with QMGgen (B = 0.68, P < 0.001, and B = 0.38, P < 0.001, respectively). A similar trend was found for changes in the scores (B = 0.68, P = 0.132, and B = 0.39, P = 0.492, respectively). ACTIVLIM had a significant additional value on top of MG-ADL in the prediction of QMGgen, both cross-sectionally (B = -0.61, P < 0.001) and for changes within individual patients (B = -0.93, P = 0.041). CONCLUSION: MG-ADL has a lower sensitivity for generalized weakness than for oculobulbar weakness. Adding questions on generalized weakness would improve the sensitivity of the MG-ADL for generalized weakness.

Fetuses with Isolated Congenital Heart Defects Show Normal Cerebral and Extracerebral Fluid Volume Growth: A 3D Sonographic Study in the Second and Third Trimester.

OBJECTIVE: The aim of our study is to explore whether the cerebral growth is delayed in fetuses with congenital heart defects (CHD) in the second and early third trimester. METHODS: A prospective cohort study was conducted in 77 CHD cases, with 75 healthy controls. 3D cerebral volume acquisition was performed sequentially. The volumes of the fetal hemicerebrum and extracerebral fluid were compared by linear regression analysis, and the Sylvian fissure was measured. RESULTS: Between 19 and 32 weeks of gestation, 158 measurements in cases and 183 measurements in controls were performed (mean 2.2/subject). The volume growth of the hemicerebrum (R2 = 0.95 vs. 0.95; p = 0.9) and the extracerebral fluid (R2 = 0.84 vs. 0.82, p = 0.9) were similar. Fetuses with abnormal oxygen delivery to the brain have a slightly smaller brain at 20 weeks of gestation (p = 0.02), but this difference disappeared with advancing gestation. CHD cases demonstrated a slightly shallower Sylvian fissure (mean ratio 0.146 vs. 0.153; p = 0.004). CONCLUSIONS: Our study shows no differences in cerebral growth, studied in an unselected cohort, with successive cases of isolated CHD. Even in the severest CHD cases, cerebral size is similar in the early third trimester. The cause and meaning of a shallower Sylvian fissure is unclear; possibly, it is a marker for delayed cerebral maturation or it might be an expression of decreasing amount of extracerebral fluid.

Outcome of Carpal Tunnel Release and the Relation With Depression.

PURPOSE: To examine the relation between depressive symptoms and outcome of carpal tunnel release (CTR). METHODS: Prospective study in a general hospital with data collection at baseline and 3 and 12 months after CTR. We quantified depressive symptoms using the Center for Epidemiologic Studies Depression (CES-D) scale and performed multivariable analyses on 2 outcome measures: (1) carpal tunnel syndrome (CTS) symptoms (Boston Carpal Tunnel Questionnaire [BCTQ]) and (2) palmar pain, focusing on preoperative CES-D and BCTQ score, sex, age, alcohol use, diabetes, and severity of nerve conduction abnormalities. RESULTS: We included 227 patients. Before surgery, patients with depression had a higher BCTQ score than patients without depression. After 1 year, depressed patients had a higher BCTQ score and more palmar pain. The CES-D decreased by a median of 2 points from baseline to 1 year. This correlated with the decrease in BCTQ score. Multivariable analyses showed that preoperative depression had a small but statistically significant influence on palmar pain, but not on postoperative BCTQ score. CONCLUSIONS: Depression is not an independent predictor of residual CTS symptoms 1 year after CTR. Depressive symptoms in patients with CTS decrease after CTR, along with a decrease in CTS symptoms. The nature of this relationship is unknown. Patients with CTS and depression may expect a somewhat higher degree of palmar pain after CTR, the clinical relevance of which is small. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Pretransplantation Donor-Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation.

Kidney transplant donors are not currently implicated in predicting BK polyomavirus (BKPyV) infection in kidney transplant recipients. It has been postulated, however, that BKPyV infection originates from the kidney allograft. Because BKPyV seroreactivity correlates with BKPyV replication and thus might mirror the infectious load, we investigated whether BKPyV seroreactivity of the donor predicts viremia and BKPyV-associated nephropathy (BKPyVAN) in the recipient. In a retrospective cohort of 407 living kidney donor-recipient pairs, pretransplantation donor and recipient sera were tested for BKPyV IgG levels and correlated with the occurrence of recipient BKPyV viremia and BKPyVAN within 1 year after transplantation. Donor BKPyV IgG level was strongly associated with BKPyV viremia and BKPyVAN (p < 0.001), whereas recipient BKPyV seroreactivity showed a nonsignificant inverse trend. Pairing of high-BKPyV-seroreactive donors with low-seroreactive recipients resulted in a 10-fold increased risk of BKPyV viremia (hazard ratio 10.1, 95% CI 3.5-29.0, p < 0.001). In multivariate analysis, donor BKPyV seroreactivity was the strongest pretransplantation factor associated with viremia (p < 0.001) and BKPyVAN (p = 0.007). The proportional relationship between donor BKPyV seroreactivity and recipient infection suggests that donor BKPyV seroreactivity reflects the infectious load of the kidney allograft and calls for the use of pretransplantation BKPyV serological testing of (potential) donors and recipients.

Adjusted Hospital Outcomes of Abdominal Aortic Aneurysm Surgery Reported in the Dutch Surgical Aneurysm Audit.

OBJECTIVE/BACKGROUND: The Dutch Surgical Aneurysm Audit (DSAA) is mandatory for all patients with primary abdominal aortic aneurysms (AAAs) in the Netherlands. The aims are to present the observed outcomes of AAA surgery against the predicted outcomes by means of V-POSSUM (Vascular-Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity). Adjusted mortality was calculated by the original and re-estimated V(physiology)-POSSUM for hospital comparisons. METHODS: All patients operated on from January 2013 to December 2014 were included for analysis. Calibration and discrimination of V-POSSUM and V(p)-POSSUM was analysed. Mortality was benchmarked by means of the original V(p)-POSSUM formula and risk-adjusted by the re-estimated V(p)-POSSUM on the DSAA. RESULTS: In total, 5898 patients were included for analysis: 4579 with elective AAA (EAAA) and 1319 with acute abdominal aortic aneurysm (AAAA), acute symptomatic (SAAA; n = 371) or ruptured (RAAA; n = 948). The percentage of endovascular aneurysm repair (EVAR) varied between hospitals but showed no relation to hospital volume (EAAA: p = .12; AAAA: p = .07). EAAA, SAAA, and RAAA mortality was, respectively, 1.9%, 7.5%, and 28.7%. Elective mortality was 0.9% after EVAR and 5.0% after open surgical repair versus 15.6% and 27.4%, respectively, after AAAA. V-POSSUM overestimated mortality in most EAAA risk groups (p < .01). The discriminative ability of V-POSSUM in EAAA was moderate (C-statistic: .719) and poor for V(p)-POSSUM (C-statistic: .665). V-POSSUM in AAAA repair overestimated in high risk groups, and underestimated in low risk groups (p < .01). The discriminative ability in AAAA of V-POSSUM was moderate (.713) and of V(p)-POSSUM poor (.688). Risk adjustment by the re-estimated V(p)-POSSUM did not have any effect on hospital variation in EAAA but did in AAAA. CONCLUSION: Mortality in the DSAA was in line with the literature but is not discriminative for hospital comparisons in EAAA. Adjusting for V(p)-POSSUM, revealed no association between hospital volume and treatment or outcome. Risk adjustment for case mix by V(p)-POSSUM in patients with AAAA has been shown to be important.

Detoxification in medication-overuse headache, a retrospective controlled follow-up study: Does care by a headache nurse lead to cure?

AIM: J.A.P. and M.A.L. contributed equally to this manuscript.The aim of this article is to determine whether support by a headache nurse in the treatment of medication-overuse headache (MOH) increases successful withdrawal, and to study determinants of response to withdrawal therapy. METHODS: A retrospective, controlled follow-up study was performed with 416 MOH patients. All patients were treated with outpatient withdrawal therapy, with two treatment arms: with or without the support of a specialised headache nurse. The outcome measures were: i) successful withdrawal, defined as discontinuation of all headache medication according to the study protocol; and ii) the responder rate, defined as the percentage of patients with ≥ 50% reduction in headache days after successful withdrawal and iii) relative reduction in headache days after successful withdrawal. RESULTS: Successful withdrawal percentages were significantly higher in the group supported by the headache nurse than in the group without support (73.1% vs. 60.7%; p = 0.008), which was confirmed in multivariate analysis (OR 1.73, 95% CI 1.11-2.71, p = 0.016). Support by a headache nurse was not associated with response. The underlying primary headache diagnosis, determined after withdrawal, was significantly correlated with response. CONCLUSION: The support by a headache nurse results in an increased adherence to detoxification.

Head growth in fetuses with isolated congenital heart defects: lack of influence of aortic arch flow and ascending aorta oxygen saturation.

OBJECTIVES: Congenital heart defects (CHDs) are reported to be associated with a smaller fetal head circumference (HC) and neurodevelopmental delay. Recent studies suggest that altered intrauterine brain hemodynamics may explain these findings. Our objectives were to evaluate the pattern of head growth in a large cohort of fetuses with various types of CHD, analyze these patterns according to the type of CHD and estimate the effect of cerebral hemodynamics with advancing gestation in the second and third trimesters. METHODS: Singleton fetuses with an isolated CHD were selected from three fetal medicine units (n = 436). Cases with placental insufficiency or genetic syndromes were excluded. CHD types were clustered according to the flow and oxygen saturation in the aorta. Z-scores of biometric data were constructed using growth charts of a normal population. HC at different gestational ages was evaluated and univariate and multivariate mixed regression analyses were performed to examine the patterns of prenatal HC growth. RESULTS: Fetuses with severe and less severe types of CHD demonstrated statistically significant HC growth restriction with increasing gestational age (slope of -0.017/day); however, there was no statistically significant effect of fetal hemodynamics on HC growth. Fetuses with CHD but normal brain oxygenation and normal aortic flow showed a significant decrease in HC growth (slope of -0.024/day). Only fetuses with isolated tetralogy of Fallot demonstrated a smaller HC z-score at 20 weeks of gestation (-0.67 (95% CI, -1.16 to -0.18)). CONCLUSIONS: Despite the decline in head growth in fetuses with a prenatally detected isolated CHD, HC values were within the normal range, raising the question of its clinical significance. Furthermore, in contrast to other studies, this large cohort did not establish a significant correlation between aortic flow or oxygen saturation and HC growth. Factors other than altered fetal cerebral hemodynamics may contribute to HC growth restriction with increasing gestational age, such as (epi)genetic or placental factors. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Early-onset thrombocytopenia in near-term and term infants with perinatal asphyxia.

BACKGROUND: Neonates after perinatal asphyxia are at increased risk of thrombocytopenia. The correlation between perinatal asphyxia and the risk and severity of early-onset thrombocytopenia is not well known. OBJECTIVE: To estimate the incidence, severity and risk factors for early-onset thrombocytopenia in neonates after perinatal asphyxia. METHODS: We included all newborns (gestational age ≥ 36 weeks) admitted to our neonatal nursery due to perinatal asphyxia in this retrospective study. We collected platelet counts that were obtained within the first 48 h of life to estimate the incidence and severity of early-onset thrombocytopenia. RESULTS: A total number of 171 neonates with perinatal asphyxia were included in the study. The incidence of early-onset thrombocytopenia (platelet count < 150 × 109/l) was 51% (87/171). Several factors were associated with increased risk of early-onset thrombocytopenia, including prolonged prothrombin time (PT) [odds ratio (OR) 1·18, 95% confidence interval (CI) 1·08­1·30, P < 0·01], prolonged activated partial thromboplastin time (APTT) (OR 1·07, 95% CI 1·03­1·11, P < 0·01), low Apgar score at 10 min (OR 1·25, 95% CI 1·08­1·45, P < 0·01) and high serum lactate (OR 1·12, 95% CI 1·06­1·19, P < 0·01). After multiple logistic regression analysis, we found an independent association between early-onset thrombocytopenia and prolonged PT (OR 1·15, 95% CI 1·00­1·33, P = 0·045) and higher lactate level (OR 1·15, 95% CI 1·03­1·28, P = 0·01). CONCLUSIONS: Early-onset thrombocytopenia occurs frequently in neonates after perinatal asphyxia and is independently associated with PT and lactate level.

Laser surgery as a management option for twin anemia-polycythemia sequence.

OBJECTIVE: To evaluate the effectiveness of laser treatment for antenatally detected twin anemia-polycythemia sequence (TAPS) compared with intrauterine transfusion or expectant management. METHODS: All monochorionic twin pregnancies with TAPS managed between 2005 and 2013 in two European fetal therapy centers were evaluated. The outcomes of TAPS cases treated primarily with laser surgery were compared with the outcomes of cases managed expectantly or treated with intrauterine transfusion. RESULTS: In this retrospective study 52 cases of TAPS were detected antenatally and were managed with either laser surgery (n=8; 15%) or intrauterine blood transfusion (n=17; 33%) or expectantly (n=27; 52%). Perinatal survival in the laser group was 94% (15/16) vs 85% (29/34) in the intrauterine-transfusion group and 83% (45/54) in the expectant-management group (P=0.30). The rates of severe neonatal morbidity in liveborn neonates in the laser, intrauterine-transfusion and expectant-management groups were 7% (1/15), 38% (12/32) and 24% (12/50), respectively (P=0.17). There was a significant reduction in respiratory distress syndrome in cases treated by laser. No severe postnatal hematological complications were detected in the laser group compared with 72% (23/32) in the intrauterine-transfusion group and 52% (26/50) in the expectant-management group (P<0.01). Median time between diagnosis and birth was 11 weeks in the laser group compared to 5 weeks after intrauterine transfusion and 8 weeks after expectant management (P<0.01). After injection of colored dye no residual anastomoses were found in the laser group. CONCLUSIONS: Laser surgery for TAPS appears to improve perinatal outcome by prolonging pregnancy and reducing respiratory distress syndrome. Larger, adequately controlled studies are needed to reach firm conclusions on the optimal management of TAPS.

Cerebral injury in monochorionic twins with selective intrauterine growth restriction: a systematic review.

OBJECTIVE: To estimate incidence and risk factors of severe cerebral injury in survivors from monochorionic pregnancies with selective intrauterine growth restriction (sIUGR) and/or birth weight discordance (BWD). METHODS: Electronic databases were searched for studies describing perinatal and neurologic outcome in monochorionic twins with sIUGR and/or BWD. Exclusion criteria were twin-twin transfusion syndrome, twin anemia-polycythemia sequence, selective feticide or laser treatment. RESULTS: Eleven articles were included in the systematic review. Analysis was hampered by different methodology and definitions of cerebral injury. The incidence of severe cerebral injury varied from 0% to 33% (average 8%, 52/661), and was higher in studies including single intrauterine demise [odds ratio (OR) 2.92; 95% confidence interval (CI) 0.89-9.56] and studies with a median gestational age at birth of ≤32 weeks (OR 1.56; 95% CI 1.06-2.27). The risk of severe cerebral injury was higher in pregnancies with abnormal umbilical artery Doppler (13.5% vs 2.5%; OR 7.69; 95% CI 2.56-25.00) and in larger twins (9% vs 5%; OR 1.93; 95% CI 0.95-3.92). CONCLUSIONS: The incidence of severe cerebral injury in monochorionic twins with sIUGR and/or BWD is approximately 8% and is associated with abnormal umbilical artery Doppler, larger twins, intrauterine fetal demise and low gestational age at birth.

Intracorporeal knot tying in a box trainer: how proficient is in vitro evaluation in laparoscopic experts?

OBJECTIVE: To determine the applicability of motion analysis parameters of intracorporeal knot tying in box trainers in experts as predictors of surgical outcome. DESIGN: Consecutive series of 1534 advanced laparoscopic hysterectomies (Canadian Task Force classification II-2). INTERVENTION: Time, path length, and motion in depth of a standardized intracorporeal knot-tying task were compared with mean risk-adjusted primary clinical outcomes for each participant. RESULTS: Although a large variety in proficient knot tying and surgical skills factors was observed; after correction for patient mix in 50 expert surgeons, motion analysis of intracorporeal knot tying could not significantly determine surgical outcome skills in advanced laparoscopic surgery. CONCLUSION: Levels of proficiency in advanced laparoscopic surgery cannot be appropriately determined using motion analysis in box trainers. Therefore, box trainer assessments do not adequately differentiate proficient from suboptimal clinical performance.

Quantitative electroencephalography in cerebral amyloid angiopathy.

OBJECTIVE: We investigated whether quantitative electroencephalography (qEEG) correlates with cognition and cortical superficial siderosis (cSS) in cerebral amyloid angiopathy. METHODS: We included patients with sporadic (sCAA) and hereditary Dutch-type CAA (D-CAA). Spectral measures and the phase lag index (PLI) were analyzed on qEEG. Cognition was assessed with the MoCA and cSS presence was scored on 3T-MRI. Linear regression analyses were performed to investigate these qEEG measures and cognition. Independent samples T-tests were used to analyze the qEEG measure differences between participants with and without cSS. RESULTS: We included 92 participants (44 D-CAA; 48 sCAA). A lower average peak frequency (ß[95 %CI] = 0.986[0.252-1.721]; P = 0.009) and a higher spectral ratio (ß[95 %CI] = -0.918[-1.761--0.075]; P = 0.033) on qEEG correlated with a lower MoCA score, irrespective of a history of symptomatic intracerebral hemorrhage (sICH). The PLI showed no correlation to the MoCA. qEEG slowing was not different in those with or without cSS. CONCLUSIONS: Spectral qEEG (but not PLI) reflects cognitive performance in patients with CAA with and without a history of sICH. We found no association between qEEG slowing and cSS. SIGNIFICANCE: qEEG could be a valuable biomarker, especially in challenging cognitive testing situations in CAA, and a potential predictive tool in future studies.

Increased metallothionein expression reflects steroid resistance in renal allograft recipients.

Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid-refractory acute rejection. Eighty-three kidney transplant recipients (1995-2005), who were treated with methylprednisolone during a first acute rejection episode, were included in this study. Gene expression patterns were investigated in a discovery cohort of 36 acute rejection biopsies, and verified in a validation cohort of 47 acute rejection biopsies. In the discovery set, expression of metallothioneins (MT) was significantly (p < 0.000001) associated with decreased response to steroid treatment. Multivariate analysis resulted in a predictive model containing MT-1 as an independent covariate (AUC = 0.88, p < 0.0000001). In the validation set, MT-1 expression was also significantly associated with steroid resistance (p = 0.029). Metallothionein expression was detected in macrophages and tubular epithelial cells. Parallel to the findings in patients, in vitro experiments of peripheral blood mononuclear cells from 11 donors showed that nonresponse to methylprednisolone treatment is related to highly elevated MT levels. High expression of metallothioneins in renal allografts is associated with resistance to steroid treatment. Metallothioneins regulate intracellular concentrations of zinc, through which they may diminish the zinc-requiring anti-inflammatory effect of the glucocorticoid receptor.

Increased perinatal loss after intrauterine transfusion for alloimmune anaemia before 20 weeks of gestation.

OBJECTIVES: To evaluate and compare perinatal outcome after intrauterine transfusions (IUT) performed before and after 20 weeks of gestation. To analyse contributing factors. DESIGN: Retrospective analysis. SETTING: The Dutch referral centre for fetal therapy. POPULATION: IUTs for fetal alloimmune anaemia. METHODS: Fetuses were divided into two groups: fetuses requiring the first IUT before 20 weeks of gestation (Group 1) and those in which the IUTs started after 20 weeks (Group 2). The cause of perinatal loss was classified as procedure-related (PR) or not procedure-related (NPR). The cohort was divided into two periods to describe the change of perinatal loss over time. MAIN OUTCOME MEASURES: Perinatal loss of fetuses requiring the first IUT before 20 weeks of gestation, compared with perinatal loss later in gestation. RESULTS: A total of 1422 IUTs were performed in 491 fetuses. Perinatal loss rate in Group 1 was higher (7/29 24% versus 35/462 8%, P = 0.002). Especially NPR was higher for IUTs performed before 20 weeks (4/37 11% versus 19/1385 1%, P < 0.001). Kell alloimmunisation was overrepresented in Group 1 (7/29 24% versus 52/462 11%, P = 0.04). In a multivariate regression analysis, only hydrops was independently associated with perinatal loss (P = 0.001). In recent years, a decline in total perinatal loss was found (36/224 16% versus 6/267 2%, P < 0.001), but perinatal loss in Group 1 did not decline (4/224 1.8% versus 3/267 1.1%, P = 0.5). CONCLUSIONS: Perinatal loss after IUT performed before 20 weeks of gestation is increased compared with loss after IUT performed later in gestation. In addition, we confirmed earlier observations that hydrops is a major contributor to adverse outcome. Early and timely detection and treatment may prevent hydrops and improve outcome.

Funnel plots a graphical instrument for the evaluation of population performance and quality of trauma care: a blueprint of implementation.

BACKGROUND: Using patient outcomes to monitor medical centre performance has become an essential part of modern health care. However, classic league tables generally inflict stigmatization on centres rated as "poor performers", which has a negative effect on public trust and professional morale. In the present study, we aim to illustrate that funnel plots, including trends over time, can be used as a method to control the quality of data and to monitor and assure the quality of trauma care. Moreover, we aimed to present a set of regulations on how to interpret and act on underperformance or overperformance trends presented in funnel plots. METHODS: A retrospective observational cohort study was performed using the Dutch National Trauma Registry (DNTR). Two separate datasets were created to assess the effects of healthy and multiple imputations to cope with missing values. Funnel plots displaying the performance of all trauma-receiving hospitals in 2020 were generated, and in-hospital mortality was used as the main indicator of centre performance. Indirect standardization was used to correct for differences in the types of cases. Comet plots were generated displaying the performance trends of two level-I trauma centres since 2017 and 2018. RESULTS: Funnel plots based on data using healthy imputation for missing values can highlight centres lacking good data quality. A comet plot illustrates the performance trend over multiple years, which is more indicative of a centre's performance compared to a single measurement. Trends analysis offers the opportunity to closely monitor an individual centres' performance and direct evaluation of initiated improvement strategies. CONCLUSION: This study describes the use of funnel and comet plots as a method to monitor and assure high-quality data and to evaluate trauma centre performance over multiple years. Moreover, this is the first study to provide a regulatory blueprint on how to interpret and act on the under- or overperformance of trauma centres. Further evaluations are needed to assess its functionality. LEVEL OF EVIDENCE: Retrospective study, level III.

Thrombocytopenia at birth in neonates with red cell alloimmune haemolytic disease.

OBJECTIVE: To evaluate the incidence and severity of and risk factors for thrombocytopenia at birth in neonates with red cell alloimmunization. STUDY DESIGN: All neonates with haemolytic disease of the foetus/newborn (HDFN) due to red cell alloimmunization admitted to our centre between January 2000 and September 2010 were included in this retrospective study. We measured platelet counts at birth and determined the incidence of thrombocytopenia (platelet count<150×10(9)/l) and severe thrombocytopenia (platelet count<50×10(9)/l). Risk factors for thrombocytopenia at birth were evaluated. RESULTS: Thrombocytopenia was present in 26% (94/362) of included neonates with HDFN at birth. Severe thrombocytopenia was found in 6% (20/362) of neonates. Three risk factors were found to be independently associated with thrombocytopenia at birth: treatment with intrauterine red cell transfusion (IUT) (OR 3·32, 95% CI 1·67-6·60, P=0·001), small for gestational age (SGA) below the 10th percentile (OR 3·32, 95% CI 1·25-8·80, P=0·016) and lower gestational age at birth (OR 1·22/week, 95% CI 1·02-1·44, P=0·025). CONCLUSIONS: Thrombocytopenia at birth occurs in 26% of neonates with HDFN due to red cell alloimmunization and is independently associated with IUT treatment, SGA and lower gestational age at birth.

Dysphagia, Fear of Choking and Preventive Measures in Patients with Huntington's Disease: The Perspectives of Patients and Caregivers in Long-Term Care.

OBJECTIVES: To explore the prevalence of dysphagia and fear of choking in patients with Huntington's disease (HD) as well as preventive measures, both those applied and those not included in managing dysphagia. Also, to investigate related problems encountered by their formal and informal caregivers. DESIGN: A multi-center observational cross-sectional study. SETTING AND PARTICIPANTS: 158 HD patients, recruited from six Dutch nursing homes specialized in HD, and their formal and informal caregivers. MEASUREMENTS: Patients were assessed by means of questionnaires enquiring about dysphagia, fear of choking and measures to manage dysphagia. Also, questionnaires were administered about awareness of dysphagia symptoms, cognition and anxiety. Because we expected individuals with greater care dependency to have a higher severity of dysphagia, we distinguished between a care-independent and a care-dependent group of HD patients. RESULTS: In the total group, 90.5% of HD patients had one or more dysphagia symptoms. The prevalence of FoC in HD patients and the formal and informal caregivers' fears about choking in HD patients was 45.7%, 19.0% and 59.5%, respectively, for care-independent patients and 58.7%, 50.1% and 77.5% for care-dependent patients. The score on the Huntington's Disease Dysphagia Scale was a predictor for fear of FoC in care-independent patients. Speech-language therapy, supervision during eating and drinking and adaptation of food and drink consistency were the most frequently applied measures to manage dysphagia, a combination was used in most HD patients. CONCLUSIONS: In HD patients, the prevalence of dysphagia is high and fear of choking is common among both patients and caregivers. A more severe degree of dysphagia is a predictor of FoC in care-independent HD patients. A combination of measures was used to manage dysphagia in most HD patients.