Preventive effects of early immunosuppressive treatment on the development of interstitial lung disease in systemic sclerosis.

BACKGROUND: Hypothesizing that early treatment yields improved prognosis, we aimed to investigate how the timing of immunosuppressive treatment relates to interstitial lung disease (ILD) development and the course of pulmonary function in systemic sclerosis (SSc). METHODS: A cohort was created using data from the EUSTAR database and Nijmegen Systemic Sclerosis cohort, including adult patients who started their first immunosuppressive treatment (ie mycophenolate mofetil, methotrexate, cyclophosphamide, tocilizumab or rituximab) after SSc diagnosis, and no signs of ILD on high-resolution CT. ILD-free survival and the course of forced vital capacity % predicted (ppFVC) were assessed for up to 5 years follow-up comparing patients who started early (disease duration ≤ 3 years) vs late with immunosuppression. RESULTS: 1052 patients met the eligibility criteria. The early treatment group (n = 547, 52%) showed a higher prevalence of male sex, diffuse cutaneous subtype (53.1% vs 36.5%), and anti-topoisomerase-I antibody (ATA, 51.1% vs 42.7%). Most patients were treated with methotrexate (60.1%), whereas only a few patients were treated with biologicals (1.7%). The incidence of ILD was 46.6% after mean (SD) 3.6(1.4) years; the hazards ratio for ILD in the early treatment group was 1.13 (95% CI: 0.93-1.38) after adjustment for confounders. PpFVC trajectories were comparable between groups. CONCLUSION: Our findings did not confirm a preventive role of early initiation of immunosuppressive therapy vs late initiation on ILD development. However, our findings should be interpreted with caution, considering the high inflammatory, ATA-positive enriched nature of the cohort, confounding by indication, and very few patients were treated with biologicals.

Fragmentomic analysis of circulating tumor DNA-targeted cancer panels.

BACKGROUND: The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA), and multiple cfDNA-targeted sequencing panels are now commercially available for Food and Drug Administration (FDA)-approved biomarker indications to guide treatment. More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner. PATIENTS AND METHODS: We used machine learning models of fragmentation patterns at the first coding exon in standard targeted cancer gene cfDNA sequencing panels to distinguish between cancer and non-cancer patients, as well as the specific tumor type and subtype. We assessed this approach in two independent cohorts: a published cohort from GRAIL (breast, lung, and prostate cancers, non-cancer, n = 198) and an institutional cohort from the University of Wisconsin (UW; breast, lung, prostate, bladder cancers, n = 320). Each cohort was split 70%/30% into training and validation sets. RESULTS: In the UW cohort, training cross-validated accuracy was 82.1%, and accuracy in the independent validation cohort was 86.6% despite a median ctDNA fraction of only 0.06. In the GRAIL cohort, to assess how this approach performs in very low ctDNA fractions, training and independent validation were split based on ctDNA fraction. Training cross-validated accuracy was 80.6%, and accuracy in the independent validation cohort was 76.3%. In the validation cohort where the ctDNA fractions were all <0.05 and as low as 0.0003, the cancer versus non-cancer area under the curve was 0.99. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that sequencing from targeted cfDNA panels can be utilized to analyze fragmentation patterns to classify cancer types, dramatically expanding the potential capabilities of existing clinically used panels at minimal additional cost.

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.

A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects.

BACKGROUND: Mutations in the myosin heavy chain 7 (MYH7) gene commonly cause cardiomyopathy but are less frequently associated with congenital heart defects. METHODS: In this study, we describe a mutation in the MYH7 gene, c. 5754C > G; p. (Asn1918Lys), present in 15 probands and 65 family members. RESULTS: Of the 80 carriers (age range 0-88 years), 46 (57.5%) had cardiomyopathy (mainly dilated cardiomyopathy (DCM)) and seven (8.8%) had a congenital heart defect. Childhood onset of cardiomyopathy was present in almost 10% of carriers. However, in only a slight majority (53.7%) was the left ventricular ejection fraction reduced and almost no arrhythmias or conduction disorders were noted. Moreover, only one carrier required heart transplantation and nine (11.3%) an implantable cardioverter defibrillator. In addition, the standardised mortality ratio for MYH7 carriers was not significantly increased. Whole exome sequencing in several cases with paediatric onset of DCM and one with isolated congenital heart defects did not reveal additional known disease-causing variants. Haplotype analysis suggests that the MYH7 variant is a founder mutation, and is therefore the first Dutch founder mutation identified in the MYH7 gene. The mutation appears to have originated in the western region of the province of South Holland between 500 and 900 years ago. CONCLUSION: Clinically, the p. (Asn1918Lys) mutation is associated with congenital heart defects and/or cardiomyopathy at young age but with a relatively benign course.

Mitral annular disjunction in idiopathic ventricular fibrillation patients: just a bystander or a potential cause?

AIMS: Previously, we demonstrated that inferolateral mitral annular disjunction (MAD) is more prevalent in patients with idiopathic ventricular fibrillation (IVF) than in healthy controls. In the present study, we advanced the insights into the prevalence and ventricular arrhythmogenicity by inferolateral MAD in an even larger IVF cohort. METHODS AND RESULTS: This retrospective multi-centre study included 185 IVF patients [median age 39 (27, 52) years, 40% female]. Cardiac magnetic resonance images were analyzed for mitral valve and annular abnormalities and late gadolinium enhancement. Clinical characteristics were compared between patients with and without MAD. MAD in any of the 4 locations was present in 112 (61%) IVF patients and inferolateral MAD was identified in 24 (13%) IVF patients. Mitral valve prolapse (MVP) was found in 13 (7%) IVF patients. MVP was more prevalent in patients with inferolateral MAD compared with patients without inferolateral MAD (42 vs. 2%, P < 0.001). Pro-arrhythmic characteristics in terms of a high burden of premature ventricular complexes (PVCs) and non-sustained ventricular tachycardia (VT) were more prevalent in patients with inferolateral MAD compared to patients without inferolateral MAD (67 vs. 23%, P < 0.001 and 63 vs. 41%, P = 0.046, respectively). Appropriate implantable cardioverter defibrillator therapy during follow-up was comparable for IVF patients with or without inferolateral MAD (13 vs. 18%, P = 0.579). CONCLUSION: A high prevalence of inferolateral MAD and MVP is a consistent finding in this large IVF cohort. The presence of inferolateral MAD is associated with a higher PVC burden and non-sustained VTs. Further research is needed to explain this potential interplay.

Separable mixing: The general formulation and a particular example focusing on mask efficiency.

The aim of this short note is twofold. First, we formulate the general Kermack-McKendrick epidemic model incorporating static heterogeneity and show how it simplifies to a scalar Renewal Equation (RE) when separable mixing is assumed. A key general feature is that all information about the heterogeneity is encoded in one nonlinear real valued function of a real variable. Next, we specialize the model ingredients so that we can study the efficiency of mask wearing as a non-pharmaceutical intervention to reduce the spread of an infectious disease. Our main result affirms that the best way to protect the population as a whole is to protect yourself. This qualitative insight was recently derived in the context of an SIR network model. Here, we extend the conclusion to proportionate mixing models incorporating a general function describing expected infectiousness as a function of time since infection.

Modeling non-inherited antibiotic resistance.

A mathematical model is presented for the increase and decrease of non-inherited antibiotic resistance levels in bacteria. The model is applied to experimental data on E. coli exposed to amoxicillin or tetracyclin in different concentrations. The parameters of the model are estimated using a Monte Carlo Markov Chain method. The model accurately describes build-up and decline of antibiotic resistance caused by physiological adaptations as long as no genetic changes have occurred. The main conclusion of the analysis is that short time periods are sufficient to re-obtain low MIC-values after long-lasting exposure to these antibiotics.

Quantifying within-household transmission of extended-spectrum ß-lactamase-producing bacteria.

OBJECTIVES: Patients can acquire extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae during hospitalization, and colonized patients may transmit these bacteria after discharge, most likely to household contacts. In this study, ESBL transmission was quantified in households. METHODS: Faecal samples were longitudinally collected from hospitalized patients colonized with ESBL-producing bacteria and from their household members during hospitalization of the index patient and at 3, 6, 12 and 18 months. A mathematical household model was developed, which allowed for person-to-person transmission, acquisition from other sources (background transmission), and losing carriage. Next, a deterministic population model with a household structure was created, informed by parameter values found in the household model. RESULTS: In all, 74 index patients and 84 household members were included. In more than half of the household members ESBL-producing bacteria were demonstrated at some time during follow up. Person-to-person transmission occurred at a rate of 0.0053/colonized person/day (0.0025-0.011), background transmission at 0.00015/day (95% CI 0.00002-0.00039), and decolonization at 0.0026/day (0.0016-0.0040) for index patients and 0.0090/day (0.0046-0.018) for household members. The estimated probability of transmission from an index patient to a household contact was 67% and 37% vice versa. CONCLUSION: There is frequent transmission of ESBL-producing bacteria in households, which may contribute to the observed endemicity of ESBL carriage in the Netherlands. However, the population model suggests that there is not a single dominant acquisition route in the community.

Potential confounding in evaluating infection-control interventions in hospital settings: changing antibiotic prescription.

The colonization dynamics of antibiotic-resistant pathogens in hospital settings are complex, with multiple and continuously interacting variables (e.g., introduction of resistance, infection-control practices, antibiotic use). Quantification of these variables is indispensable in the evaluation of intervention studies, because these variables represent potential confounders. In this article, the complexity of colonization dynamics is described. Through a systematic review, we identified studies that evaluated the modification of antibiotic prescription to reduce antibiotic resistance in intensive care units (n=19), and the extent of confounding-control was determined. Most studies evaluated antimicrobial restriction/substitution (n=12) or antibiotic rotation (n=4). Sixteen studies had a prospective cohort design (before-after), of which 12 were without a control group. Introduction of antibiotic resistance was determined in 10 studies. The relative importance of colonization routes and adherence to infection-control measures were not determined in any study. Therefore, it remains uncertain whether observed changes in the prevalence of antibiotic resistance after intervention were causally related to the intervention. Appropriate choices of study design, primary end point (colonization rates rather than infection rates) and statistical tests, determination of colonization routes, and control of potential confounders are needed to increase validity of intervention studies.

Epidemic potential of Escherichia coli ST131 and Klebsiella pneumoniae ST258: a systematic review and meta-analysis.

OBJECTIVES: Observational studies have suggested that Escherichia coli sequence type (ST) 131 and Klebsiella pneumoniae ST258 have hyperendemic properties. This would be obvious from continuously high incidence and/or prevalence of carriage or infection with these bacteria in specific patient populations. Hyperendemicity could result from increased transmissibility, longer duration of infectiousness, and/or higher pathogenic potential as compared with other lineages of the same species. The aim of our research is to quantitatively estimate these critical parameters for E. coli ST131 and K. pneumoniae ST258, in order to investigate whether E. coli ST131 and K. pneumoniae ST258 are truly hyperendemic clones. PRIMARY OUTCOME MEASURES: A systematic literature search was performed to assess the evidence of transmissibility, duration of infectiousness, and pathogenicity for E. coli ST131 and K. pneumoniae ST258. Meta-regression was performed to quantify these characteristics. RESULTS: The systematic literature search yielded 639 articles, of which 19 data sources provided information on transmissibility (E. coli ST131 n=9; K. pneumoniae ST258 n=10)), 2 on duration of infectiousness (E. coli ST131 n=2), and 324 on pathogenicity (E. coli ST131 n=285; K. pneumoniae ST258 n=39). Available data on duration of carriage and on transmissibility were insufficient for quantitative assessment. In multivariable meta-regression E. coli isolates causing infection were associated with ST131, compared to isolates only causing colonisation, suggesting that E. coli ST131 can be considered more pathogenic than non-ST131 isolates. Date of isolation, location and resistance mechanism also influenced the prevalence of ST131. E. coli ST131 was 3.2 (95% CI 2.0 to 5.0) times more pathogenic than non-ST131. For K. pneumoniae ST258 there were not enough data for meta-regression assessing the influence of colonisation versus infection on ST258 prevalence. CONCLUSIONS: With the currently available data, it cannot be confirmed nor rejected, that E. coli ST131 or K. pneumoniae ST258 are hyperendemic clones.

Systemic and cardiac neuroendocrine activation and severity of myocardial ischemia in humans.

OBJECTIVES: The purpose of this study was to assess the effect of different degrees of ischemia on circulating and cardiac neurohormones and vasotone. BACKGROUND: Neuroendocrine activation and subsequent systemic vasoconstriction may complicate ischemia. Whether this relates to severity of ischemia and subsequent cardiac dysfunction, and whether neurohormonal balance in the ischemic area changes, is unknown. METHODS: Fifty-six normotensive patients with coronary artery disease were evaluated during incremental atrial pacing. On the basis of ST segment changes, patients were classified in a nonischemic (n = 11) or ischemic group (n = 45), the latter patients were subsequently classified as lactate (n = 28) or nonlactate (n = 17) producing, to identify neurohormonal changes in the effluent of the ischemic myocardium. RESULTS: Angina occurred in 55%, 82% and 82% of patients in the nonischemic, lactate- and nonlactate-producing groups, respectively. Baseline hemodynamic variables and neurohormones were comparable in all groups, as were heart rate, rate-pressure product and coronary hemodynamic variables during pacing. In lactate producers, contractility did not improve, relaxation deteriorated, left ventricular filling pressure increased and cardiac output decreased during pacing, indicating more severe ischemia compared with that in nonlactate producers. Neurohormones did not change in the nonischemic group. In contrast, arterial and coronary venous catecholamines increased significantly more in lactate producers than in nonlactate producers (arterial norepinephrine by 68% vs. 36%, respectively). Moreover, arterial angiotensin II increased in lactate producers from a baseline mean +/- SEM of 6.8 +/- 0.9 to 9.7 +/- 1.6 pmol/liter (p < 0.05), accompanied by a sustained 23% increase in systemic resistance and arterial pressures. In lactate producers, baseline net cardiac norepinephrine release changed to net uptake during pacing (-0.05 +/- 0.02 vs. 0.06 +/- 0.05 nmol/min, p < 0.05). Epinephrine uptake increased in all patients with ischemia, albeit more in lactate producers. CONCLUSIONS: Circulating catecholamines and renin-angiotensin levels are activated, and systemic vasotone is increased in relation to the degree of ischemia. Cardiac epinephrine uptake increases, whereas net baseline norepinephrine release from the ischemic myocardium changes to net uptake. Modulation of this neurohormonal activation may provide an alternative mode to limit ischemia.

[Radiofrequency catheter ablation for treating children with cardiac arrhythmias: favourable results after a mean of 4 years]. / Katheterablatie met radiofrequente energie ter behandeling van kinderen met hartritmestoornissen: gunstige resultaten na gemiddeld 4 jaar.

OBJECTIVE: Analysis of long-term results with radiofrequency catheter ablation (RF ablation) in children. DESIGN: Retrospective. METHOD: Data were analysed from all 118 paediatric patients < or =18 years old who underwent RF ablation at the Leiden University Medical Centre (LUMC), the Netherlands, during the period 1 December 1992-31 May 2004. RESULTS: The group consisted of 6o boys and 58 girls with a mean age of 12.7 years (SD: 4.6). They underwent 140 RF ablation procedures for 122 disorders. Indications for RF ablation were: failure or side-effects of antiarrhythmic medication (45%), patient/parent choice (45%), cardiomyopathy or life-threatening arrhythmia (8%), and impending surgery for a congenital heart defect (2%). The mean follow-up interval was 4 years (SD: 3.2; range: 1.2 months-11.3 years). The final total success rate for RF was 93% (n = 110). 19 patients (16%) underwent a total of 22 repeat procedures. Recurrences occurred after a mean period of 2.3 months (SD: 2.5) following successful RF ablation. Major complications (2nd degree AV block) occurred in 2 patients. During follow-up, no evidence was found of new arrhythmias or of coronary artery lesion development as the result ofRF ablation. There was no difference between the < 10 years of age group and the > or = 10 years of age group in terms of final success rate (93% vs. 93%; p = 0.914) and complication rate (3% vs. 7%, p = 0.680). CONCLUSION: The long-term outcome of paediatric patients who underwent RF ablation was good. RF ablation in young children (< 10 years) was found to be safe and effective. These results demonstrate that it is also possible to curatively treat this group of patients with RF ablation in specialized centres.

Similar orthostatic defense in active, healthy young adult and late middle-aged men.

Orthostatic defense is commonly validated with a 60 degrees to 80 degrees head-up tilt test, addressing the step response rather than the response to permanent orthostatis. During the initial phase of tilt, neural factors predominate, while later, the slower humoral factors fade in. It has been demonstrated that, during adaptation of the circulatory system to the standing conditions, overshoot and undershoot occur. These oscillations hamper straight-forward interpretation of a tilt test, and may contribute to the inconclusiveness of current studies regarding the aging of orthostatic defense. Gradual, progressive, orthostatic load testing seems a valuable alternative. We used a novel, incremental, head-up tilt protocol (0 degrees to 80 degrees, 13 increments) to impose graded orthostatic stress on 46 healthy young adult men (mean age +/- SD 25 +/- 3 years), and on 16 healthy late middle-aged men (60 +/- 4 years), while recording the electrocardiogram and the blood pressure. A first-order estimate of the heart rate range associated with the sympathovagal transition was made by combined analysis of heart rate and heart rate variability trends. We observed similar responses in heart rate, heart rate variability, and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic neurohumoral activation and vasoconstriction during pacing-induced acute myocardial ischemia in patients with stable angina pectoris.

To identify the effect of myocardial ischemia on systemic neurohormones and vascular resistance, 32 untreated, normotensive patients with coronary artery disease underwent incremental atrial pacing until angina. Arterial and coronary venous lactate and arterial values of catecholamines and angiotensin II were determined at control, at maximal pacing rates, and at 1, 2, 5 and 30 minutes after pacing. Based on pacing-induced ST-segment depression (greater than or equal to 0.1 mV) or myocardial lactate production, or both, patients were selected as ischemic (n = 25) or nonischemic (n = 7). Baseline clinical and hemodynamic data were comparable. During pacing, chest pain was similar (20 ischemic vs 7 nonischemic patients). Also, hemodynamic measurements were comparable, except for contractility, which did not improve, and left ventricular end-diastolic pressure, which significantly increased in ischemic patients. Moreover, during ischemia arterial pressures increased significantly (13%) and systemic resistance increased from 1,470 +/- 60 (control) to 1,632 +/- 76 dynes.s.cm-5 5 minutes after pacing (p less than 0.05) in ischemic but not in nonischemic patients. Pacing did not affect neurohormones in nonischemic patients. In contrast, norepinephrine in ischemic patients increased significantly from 1.7 +/- 0.2 (control) to 2.6 +/- 0.3 (maximal pacing) and to 3.0 +/- 0.4 nmol/liter (1 minute after pacing), whereas angiotensin II levels increased from 6.2 +/- 1.4 (control) to 9.3 +/- 2.1 pmol/liter (1 minute after pacing, p less than 0.05). Epinephrine only increased during maximal rates (0.9 +/- 0.1 vs 0.6 +/- 0.1 nmol/liter at control, p less than 0.05). Thus, myocardial ischemia activates circulating catecholamines and angiotensin II, accompanied by systemic vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Heart rate variability during repeated incremental head-up tilt discloses time dependence of individual autonomic dynamics.

According to the Rosenblueth-Simeone model, the heart rate (HR) is proportional to the sympathovagal balance. The individual proportionality constant is the intrinsic HR, which can be determined only invasively. The percentage low-frequency spectral HR variability power, relative to the low- plus high-frequency spectral power (%LF) has been raised as a noninvasive alternative. We previously studied young healthy male subjects, in whom gradual autonomic changes were induced by incremental head-up tilt (0-10-20-30-40-45-50-55-60-65-70-75-80 degrees). At each tilt angle we computed HR and %LF. Linear regressions of %LF on HR, characterizing individual autonomic dynamics, confirmed that, within a subject, changes in %LF were proportional to changes in HR. For the current study, we made repeated measurements in 19 subjects after 1 to 8 months. In six subjects, the session 1 and session 2 regression lines differed significantly (t-test, p < 0.05), demonstrating the time dependence of the autonomic dynamics. In such cases, similar HR values on different days are to be associated with different %LF values. We also determined the reproducibility of the supine HR and %LF values. For all 19 subjects, the coefficients of variation were 7 and 22%, respectively: HR reproduces better than %LF. Hence, time-dependent autonomic dynamics contribute systematically to the inferior reproducibility of %LF.

[Risk of ventricular fibrillation in patients with Wolff-Parkinson White syndrome]. / Risico van het ontstaan van ventrikelfibrilleren bij patiënten met Wolff-Parkinson-White-syndroom.

A 16-year-old boy suddenly fell off his stool, a 26-year-old man had persistent palpitations and a 29-year-old man was reanimated without an incriminating anamnesis. The diagnosis 'Wolff-Parkinson-White(WPW)-syndrome' was made in all three cases. The boy died as a result of postanoxic neurological injury; in the two men, further cardiac rhythm disturbances were prevented by interrupting the accessory atrioventricular connection via radiofrequency catheter ablation. In ECG databases, a WPW-pattern is encountered in 1-3 of 1000 electrocardiograms. Atrial fibrillation with 1:1 conduction via the accessory pathway, leading to ventricular fibrillation, is the most common cause of sudden death in WPW-patients. In some cases, atrial fibrillation with a rapid ventricular response is the first sign of the syndrome. The risk of sudden death in these patients is estimated to be 0.0-0.6% per patient per year and cannot be predicted easily. Curative treatment is possible in the form of radiofrequency catheter ablation.

The impact of an implantable cardioverter defibrillator: the Leiden follow-up study of ICD patients and their partners.

OBJECTIVES: The goal of this study was to evaluate 1) the presence of psychosocial problems in both ICD patients and their partners, and 2) the relation between psychosocial problems and various clinical variables. METHODS: Questionnaires were sent to 219 ICD patients and their partners. RESULTS: Sixty-eight percent of the ICD patients, 122 (81%) male, aged 59±12 years, and 62% of their partners, 28 (21%) male, aged 58±11 years, returned the questionnaires. Anxiety, depression or nervousness was reported by 49%, 30% and 52% respectively of the patients and by 36%, 24% and 66% of the partners. In patients, mental health problems were associated with a lower left ventricular ejection fraction (p=0.006), younger age (p=0.029), employment (p=0.011), unpleasant experiences from ICD discharges (p=0.032), prior myocardial infarction (p=0.019) and a higher NYHA functional class (p=0.05). Nervousness was more often reported by partners of ICD patients with prior myocardial infarction (p=0.049). Sixty percent of the partners had a need for counselling or support groups. CONCLUSION: Psychosocial problems are present in ICD patients and their partners and are associated with a number of clinical variables. A specific ICD rehabilitation programme should therefore not only be offered to ICD patients but to their partners as well.

Heart rate variability and sympathovagal balance: pharmacological validation.

RATIONALE: We validated heart rate (HR) and six time and six frequency domain measures of heart rate variability (HRV) as estimators of autonomic outflow in 44 young healthy male subjects. Gold standards for autonomic outflow were the Rosenblueth-Simeone factors m (sympathetic tone) and n (vagal tone), and the sympathovagal balance m·n, determined by two-stage complete autonomic blockade. METHODS: Rank correlations were computed between HR and the HRV measures obtained before autonomic blockade, and m, n and m·n. Also, the maximal mean performances (averaged sensitivity and specificity) for HR and HRV as discriminators between low and high values of m, n or m·n were computed. RESULTS: The spectral HRV measures showed less good correlations and performances than the time domain HRV measures. Correlations with sympathetic tone were all below 0.31. Respiratory sinus arrhythmia during 15 cycles/min metronome breathing was superior in estimating vagal tone and sympathovagal balance (correlations -0.71/-0.73; both performances 0.82), heart rate scored similarly for assessing the sympathovagal balance (correlation 0.71; performance 0.82). CONCLUSIONS: It does not appear justified to evaluate HR or HRV in terms of sympathetic tone, vagal tone, or sympathovagal balance. HR and HRV are specifically weak in assessing sympathetic tone. Respiratory sinus arrhythmia during 15 cycles/min metronome breathing is superior in assessing vagal tone. Current HRV analysis techniques offer no advantages compared with HR in assessing the sympathovagal balance.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy: new avenues for diagnosis and treatment.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a heart muscle disorder of unknown course that is characterised pathologically by fatty or fibrofatty replacement of the right ventricular myocardium and electrical instability. Clinical manifestations include structural and functional malformations of the right ventricle, electrocardiographic abnormalities, and presentation of ventricular tachycardias with left bundle branch pattern or sudden death. The disease is often familial with an autosomal inheritance. In addition to right ventricular dilatation, right ventricular aneurysms are typical deformities of ARVD/C and they are distributed in the so-called 'triangle of dysplasia', i.e. the right ventricular outflow tract, apex and infundibulum. Ventricular aneurysms at these sites can be considered highly suggestive for ARVD/C. Another typical hallmark of ARVD/C is fatty or fibrofatty infiltration of the right ventricular free wall with potential extension to the left ventricle. These functional and morphological characteristics are relevant to clinical imaging investigations such as contrast angiography, echocardiography, radionuclide angiography, ultrafast-computed tomography and magnetic resonance (MR) imaging. Among these techniques, MR imaging allows the most comprehensive assessment of the heart, in particular because it provides functional and flow-dynamic information in addition to anatomic images. Furthermore, MR imaging offers the specific advantage of visualising adipose infiltration as a bright signal of the right ventricular myocardium. Non-pharmacological treatment by radio-frequency ablation and implantable defibrillators will play an increasing role in the treatment of patients with ARVD/C, especially in case of drug ineffectivity. Despite new diagnostic and therapeutic approaches in ARVD/C, there remain many unanswered issues since the current guidelines present criteria that are highly specific but lack sensitivity. Therefore, optimal assessment of diagnostic criteria would require a prospective evaluation from a large population obtained by an international registry.

The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses.

Variance between studies in a meta-analysis will exist. This heterogeneity may be of clinical, methodological or statistical origin. The last of these is quantified by the I(2) -statistic. We investigated, using simulated studies, the accuracy of I(2) in the assessment of heterogeneity and the effects of heterogeneity on the predictive value of meta-analyses. The relevance of quantifying I(2) was determined according to the likely presence of heterogeneity between studies (low, high, or unknown) and the calculated I(2) (low or high). The findings were illustrated by published meta-analyses of selective digestive decontamination and weaning protocols. As expected, I(2) increases and the likelihood of drawing correct inferences from a meta-analysis decreases with increasing heterogeneity. With low levels of heterogeneity, I(2) does not appear to be predictive of the accuracy of the meta-analysis result. With high levels of heterogeneity, even meta-analyses with low I(2) -values have low predictive values. Most commonly, the level of heterogeneity in a meta-analysis will be unknown. In these scenarios, I(2) determination may help to identify estimates with low predictive values (high I(2) ). In this situation, the results of a meta-analysis will be unreliable. With low I(2) -values and unknown levels of heterogeneity, predictive values of pooled estimates may range extensively, and findings should be interpreted with caution. In conclusion, quantifying statistical heterogeneity through I(2) -statistics is only helpful when the amount of clinical heterogeneity is unknown and I(2) is high. Objective methods to quantify the levels of clinical and methodological heterogeneity are urgently needed to allow reliable determination of the accuracy of meta-analyses.