Behind the Curtain: Therapeutic Drug Monitoring of Psychotropic Drugs from a Laboratory Analytical Perspective.

PURPOSE: Therapeutic drug monitoring (TDM) is a well-established tool for guiding psychopharmacotherapy and improving patient care. Despite their established roles in the prescription of psychotropic drugs, the "behind the curtain" processes of TDM requests are invariably obscure to clinicians, and literature addressing this topic is scarce. METHODS: In the present narrative review, we provide a comprehensive overview of the various steps, starting from requesting TDM to interpreting TDM findings, in routine clinical practice. Our goal was to improve clinicians' insights into the numerous factors that may explain the variations in TDM findings due to methodological issues. RESULTS: We discussed challenges throughout the TDM process, starting from the analyte and its major variation forms, through sampling procedures and pre-analytical conditions, time of blood sampling, sample matrices, and collection tubes, to analytical methods, their advantages and shortcomings, and the applied quality procedures. Additionally, we critically reviewed the current and future advances in the TDM of psychotropic drugs. CONCLUSIONS: The "behind the curtain" processes enabling TDM involve a multidisciplinary team, which faces numerous challenges in clinical routine. A better understanding of these processes will allow clinicians to join the efforts for achieving higher-quality TDM findings, which will in turn improve treatment effectiveness and safety outcomes of psychotropic agents.

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation.

BACKGROUND: Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians. METHODS: In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n = 41, matched out of n = 204). MEASUREMENTS AND MAIN RESULTS: PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5-190.2] vs. 189.1 [179.4-197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8-0.9] vs. 0.88 [0.8-0.9], p = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R = - 0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters. CONCLUSION: Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management. TRIAL REGISTRATION: This study was previously registered at ClinicalTrials ("All Eyes on PCS-Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome". NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552 ). Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com.

Fate After the Mustard Procedure for d-Transposition of the Great Arteries: Impact of Age, Complexity, and Atrial Tachyarrhythmias: A Single Center Experience.

Patients with dextro transposition of the great arteries (d-TGA) after atrial switch procedure are at risk to develop heart failure and arrhythmias during long-term follow-up. The present study aims to add knowledge on the fate of subjects after Mustard procedure during long-term follow-up into adulthood. A single center, retrospective chart review analysis was conducted. All subjects who had Mustard-type atrial switch procedure between 1969 and 1994 at our institution were included. A total of 92 subjects were included. Early postoperative death was reported in 2 subjects. Long-term follow-up was available in 49 survivors. Of those, 6 individuals died during further follow-up. Sudden cardiac death was the most prevalent cause for fatal outcome. Mortality during long-term follow-up was associated with the presence of additional cardiovascular malformations (complex d-TGA). Sinus node dysfunction was observed in 65% of the patients and atrial tachyarrhythmias were common in adult survivors (63%). Implantation of a pacemaker or a cardioverter defibrillator was required in 31% and 45% of those surviving into adulthood. Complications were frequently observed during follow-up after either pacemaker or cardioverter defibrillator implantation (43%) with lead failure being the most frequent complication. The aging population of patients after Mustard procedure is facing challenging problems mainly resulting from a failing systemic right ventricle, presence of associated cardiac malformations and the presence of atrial baffles associated with relevant atrial scars. Age, associated cardiac malformations, and atrial tachyarrhythmias seem to play a major role in determining the fate of patients with d-TGA after atrial switch procedures.

Contact force guided radiofrequency current application at developing myocardium.

INTRODUCTION: Catheter contact is a key determinant for lesion size in radiofrequency catheter ablation (RFA). Monitoring of contact force (CF) during RFA has been shown to improve efficacy of RFA in experimental settings as well as in adult patients. Coronary artery narrowing after RFA has been described in experimental settings as well as in children and adults and may be dependent from catheter contact. The value of CF monitoring concerning these issues has not been systematically studied yet. Value of high versus low CF during RFA in piglets was studied to assess lesion size and potential coronary artery involvement mimicking RFA in small children. METHODS: RFA with continuous CF monitoring was performed in 24 piglets (median weight 18.5 kg) using a 7 F TactiCath Quartz radiofrequency (RF) ablation catheter (Abbott). A total of 7 lesions were induced in each animal applying low (10-20 g) or high (40-60 g) CF. RF energy was delivered with a target temperature of 65°C at 30 W for 30 s. Coronary angiography was performed prior and immediately after RF application. Animals were assigned to repeat coronary angiography followed by heart removal after 48 h (n = 12) or 6 months (n = 12). Lesions with surrounding myocardium were excised, fixated, and stained. Lesion volumes were measured by microscopic planimetry. RESULTS: A total of 148 RF lesions were identified in the explanted hearts. Only in the subset of lesions at the AV annulus 6 month after ablation, lesion size and number of lesions exhibiting transmural extension were higher in the high CF group compared to low CF. In all other locations CF had no impact on lesion size and mural extension after 48 h as well as after 6 months. Additional parameters such as lesion size index and force time integral were also not related to lesion size. Coronary artery damage was present in two animals after 48 h and in one after 6 months and was not related to CF. CONCLUSION: In our experimental setting, lesion size in piglets was not related to catheter CF. Transmural extension of the RF lesions involving the layers of the coronary arteries was frequently noted irrespective of CF. Coronary artery narrowing was present in 3/24 animals and was not related to CF. In infants and toddlers, low CF (10-20 g) may be of adequate effect. Impact of CF monitoring during conventional RF ablation in children requires further investigation.

Repeat radiofrequency catheter ablation of atrial tachycardias in patients with congenital heart disease.

INTRODUCTION: Atrial tachycardias (AT) in patients with congenital heart disease (CHD) are significantly contributing to morbidity and mortality. Aim of this study was to evaluate the long-term course of CHD patients requiring repeat ablation procedures (RAP) of AT. PATIENTS AND METHODS: All 144 patients with CHD who had undergone ablation of AT at our center between January 2003 and October 2018 were enrolled. Patients were classified according to the complexity of CHD: complex CHD (cCHD), moderate CHD (mCHD), and simple CHD (sCHD). RESULTS: A total of 101 RAP were performed in 64 patients. One RAP was performed in n = 40, two in n = 13, three in n = 10, and five in n = 1. Acute success rate was 82% (83/101) and was not associated with the complexity of CHD (p = 1.0). Number of procedures was lower in patients with sCHD than in patients with mCHD and cCHD (sCHD 1.3 ± 0.6, mCHD 1.8 ± 1.0, and cCHD 1.8 ± 1.1, p = .04). RAP were most frequent in patients after Fontan palliation or Atrial switch procedure (2.0 ± 1.1 [n = 41] vs. 1.6 ± 0.9 all others, p = .016) and in patients with multiple unstable AT's (2.5 ± 1.1 [n = 11] vs. 1.7 ± 1.0, p = .008). Major complications occurred in 4/101 procedures. Complete follow-up was available in 125 patients. Since last RAP 73% of the patients were in sinus/atrial rhythm and 34/125 patients (27%) with AT recurrence did not require re-ablation with mean follow-up of 52 ± 40 months. CONCLUSIONS: Recurrences after ablation of AT in CHD patients were frequent. After RAP promising long-term results could be achieved. Data encourage repetitive ablation procedures in this patient population.

Quantification of Antibiotics in Patient Samples: State of the Art in Standardization and Proficiency Testing.

BACKGROUND: For many antibiotics, the convenient one-fits-all dosing regimen had to be abandoned. Owing to highly variable pharmacokinetics, therapeutic drug monitoring has become an indispensable prerequisite. It is based on a suitable measuring method, sample materials, and standardization. Appropriate quality control including external quality assessment (EQA) is essential. For many antibiotics, EQAs have been established for many decades, whereas others have only lately been introduced. This article gives an insight into the state of the art regarding the therapeutic drug monitoring of antibiotics regarding standardization, EQAs, and reference measurement procedures (RMPs). METHODS: An overview of the currently available international EQA schemes for antibiotics and a literature overview of available RMPs are given. EQAs including gentamicin and vancomycin have been offered by German providers for more than 25 years. The period 2000-2020 was selected for a detailed analysis. The experiences with a new EQA including linezolid, meropenem, and piperacillin are described. RESULTS: EQAs for gentamicin and vancomycin are provided in many countries. Those for linezolid, meropenem, and piperacillin do not seem to be very common. Most of the antibiotics monitored for decades are measured by commercially available assays. EQAs for linezolid, meropenem, and piperacillin introduced in 2018 were rapidly accepted in Germany. Methods reported in this study were HPLC based either with UV or mass spectrometric detection. The number of participants succeeding was comparable between UV and mass spectrometry. Candidate RMPs for gentamicin, vancomycin, and linezolid based on isotope dilution mass spectrometry were published. CONCLUSIONS: EQAs are offered regularly for many antibiotics worldwide. The results of EQAs in Germany generally compare well, but there is potential for improvement. Both immunoassays and HPLC-based methods work properly in EQAs evaluated in Germany. From a quality control perspective, fast and inexpensive methods may be selected without endangering the patient's health based on clinical needs.

Cyclin-dependent kinase 6 is a chromatin-bound cofactor for NF-κB-dependent gene expression.

Given the intimate link between inflammation and dysregulated cell proliferation in cancer, we investigated cytokine-triggered gene expression in different cell cycle stages. Transcriptome analysis revealed that G1 release through cyclin-dependent kinase 6 (CDK6) and CDK4 primes and cooperates with the cytokine-driven gene response. CDK6 physically and functionally interacts with the NF-κB subunit p65 in the nucleus and is found at promoters of many transcriptionally active NF-κB target genes. CDK6 recruitment to distinct chromatin regions of inflammatory genes was essential for proper loading of p65 to its cognate binding sites and for the function of p65 coactivators, such as TRIP6. Furthermore, cytokine-inducible nuclear translocation and chromatin association of CDK6 depends on the kinase activity of TAK1 and p38. These results have widespread biological implications, as aberrant CDK6 expression or activation that is frequently observed in human tumors modulates NF-κB to shape the cytokine and chemokine repertoires in chronic inflammation and cancer.

A Detailed View on the Proanthocyanidins in Ginkgo Extract EGb 761.

The Ginkgo extract EGb 761® manufactured with leaves of Ginkgo biloba has been continuously produced over decades at a large scale and is used as a clinically proven remedy for, among other things, the improvement of age-associated cognitive impairment and quality of life in patients with mild dementia. It belongs to the class of extracts addressed as quantified extracts according to the European Pharmacopeia. Accordingly, several compounds (e.g., flavone glycosides and terpene trilactones) are acknowledged to contribute to its clinical efficacy. Covering only about 30% of the mass balance, these characterized compounds are accompanied by a larger fraction of additional compounds, which might also contribute to the clinical efficacy and safety of the extract. As part of our systematic research to fully characterize the constituents of Ginkgo extract EGb 761, we focus on the structural class of proanthocyanidins in the present study. Structural insights into the proanthocyanidins present in EGb 761 and a quantitative method for their determination using HPLC are shown. The proanthocyanidins were found to be of oligomeric to polymeric structure, which yield delphinidin and cyanidin as main building blocks after acidic hydrolysis. A validated HPLC method for quantification of the anthocyanidins was developed in which delphinidin and cyanidin were detected after hydrolysis of the proanthocyanidins. The content of proanthocyanidins in Ginkgo extract EGb 761 was found to be approximately 7%.

Motor excitability in bilateral moyamoya vasculopathy and the impact of revascularization.

OBJECTIVE: Motor cortical dysfunction has been shown to be reversible in patients with unilateral atherosclerotic disease after cerebral revascularization. Moyamoya vasculopathy (MMV) is a rare bilateral stenoocclusive cerebrovascular disease. The aim of this study was to analyze the corticospinal excitability and the role of bypass surgery in restoring cortical motor function in patients by using navigated transcranial magnetic stimulation (nTMS). METHODS: Patients with bilateral MMV who met the criteria for cerebral revascularization were prospectively included. Corticospinal excitability, cortical representation area, and intracortical inhibition and facilitation were assessed by nTMS for a small hand muscle (first dorsal interosseous) before and after revascularization. The clinically and/or hemodynamically more severely affected hemisphere was operated first as the leading hemisphere. Intra- and interhemispheric differences were analyzed before and after direct or combined revascularization. RESULTS: A total of 30 patients with bilateral MMV were examined by nTMS prior to and after revascularization surgery. The corticospinal excitability was higher in the leading hemisphere compared with the non-leading hemisphere prior to revascularization. This hyperexcitability was normalized after revascularization as demonstrated in the resting motor threshold ratio of the hemispheres (preoperative median 0.97 [IQR 0.89-1.08], postoperative median 1.02 [IQR 0.94-1.22]; relative effect = 0.61, p = 0.03). In paired-pulse paradigms, a tendency for a weaker inhibition of the leading hemisphere was observed compared with the non-leading hemisphere. Importantly, the paired paradigm also demonstrated approximation of excitability patterns between the two hemispheres after surgery. CONCLUSIONS: The study results suggested that, in the case of a bilateral chronic ischemia, a compensation mechanism between both hemispheres seemed to exist that normalized after revascularization surgery. A potential role of nTMS in predicting the efficacy of revascularization must be further assessed.

Lone Atrial Flutter in Children and Adolescents: Is It Really "Lone"?

Atrial flutter (AFL) in children and adolescents beyond the neonatal period in the absence of any underlying myocardial disease ("lone AFL") is rare and data is limited. Our study aims to present clinical and electrophysiological data of presumed "lone AFL" in pediatric patients and discuss the role of endomyocardial biopsy (EMB) and further follow-up. Since July 2005, eight consecutive patients at a median age of 12.7 (range 10.4-16.7) years presenting with presumed "lone AFL" after negative non-invasive diagnostic work-up had electrophysiological study (EPS) and induction of cavotricuspid isthmus (CTI) conduction block by radiofrequency (RF) current application. In 6/8 patients EMB could be taken. Induction of CTI conduction block was achieved in all patients. Histopathological examination of EMB from the right ventricular septum exhibited myocarditis or cardiomyopathy in 4/6 patients, respectively. During follow-up, 4/8 patients had recurrent arrhythmia (AFL n = 2, wide QRS complex tachycardia n = 1, monomorphic premature ventricular contractions n = 1) after the ablation procedure. 3/4 patients with recurrent arrhythmia had pathological EMB results. The remaining patient with recurrent arrhythmia had a negative EMB but was diagnosed with Brugada syndrome during further follow-up. Taking together results of EMB and further clinical course, only 3/8 patients finally turned out to have true "lone AFL". Our study demonstrates that true "lone AFL" in children and adolescents is rare. EMB and clinical course revealed an underlying cardiac pathology in the majority of the individuals studied. EMB was very helpful in order to timely establish the diagnosis of myocarditis or cardiomyopathy.

Safety of Transseptal Puncture for Access to the Left Atrium in Infants and Children.

Transseptal puncture (TSP) is a standard procedure to obtain access to the left heart. However, data on TSP in infants and children particularly with congenital heart defects (CHD) is sparse. Safety and efficacy of TSP in infants and children < 18 years with normal cardiac anatomy and with CHD were assessed. 327 TSP were performed in a total of 300 individuals < 18 years from 10/2002 to 09/2018 in our tertiary pediatric referral center. Median age at TSP was 11.9 years (IQR 7.8-15; range: first day of life to 17.9 years). 13 subjects were < 1 year. Median body weight was 43.8 kg (IQR 26.9-60; range: 1.8-121 kg). CHD was present in 28/327 (8.6%) procedures. TSP could be successfully performed in 323/327 (98.8%) procedures and was abandoned in 4 procedures due to imminent or incurred complications. Major complications occurred in 4 patients. 3 of these 4 subjects were ≤ 1 year of age and required TSP for enlargement of a restrictive atrial septal defect in complex CHD. Two of these babies deceased within 48 h after TSP attempt. The third baby needed urgent surgery in the cath lab. Pericardial effusion requiring drainage was noted in the forth patient (> 1 year) who was discharged well later. Minor complications emerged in 5 patients. The youngest of these individuals (0.3 years, 5.8 kg) developed small pericardial effusion after anterograde ballon valvuloplasty for critical aortic stenosis. The remaining 4/5 patients developed small pericardial effusion after ablation of a left-sided accessory atrioventricular pathway (6.1-12.2 years, 15.6-34.0 kg). TSP for access to the left heart was safe and effective in children and adolescents > 1 year of age. However, TSP was a high-risk procedure in small infants with a restrictive interatrial septum with need for enlargement of interatrial communication.

Value of defibrillation threshold testing in children with nontransvenous implantable cardioverter defibrillators: Are routine DFT tests indicated?

BACKGROUND: Nontransvenous implanted cardioverter defibrillators (NT-ICD) are used in infants and small children with life-threatening ventricular tachyarrhythmias. With growth, shock vector shift may result in increase of defibrillation threshold (DFT) and fatal ICD failure. OBJECTIVES: To date, the only way to verify ICD function in children with NT-ICD is repetitive DFT testing, which is potentially harmful and may even be life threatening. The aim of the study was to analyze data from NT-ICD DFT testing to prospectively predict individual DFT. PATIENTS AND METHODS: Data from all pediatric patients with NT-ICD implanted in our center from July 2004 to August 2019 were collected. Postoperative DFT testing was scheduled according to individual DFT but at least annually. Surgical revision of NT-ICD was performed if DFT was > 25 J. Selected noninvasive parameters from DFT testing were analyzed as predictors for DFT using a logistic regression model. RESULTS: A total of 46 children with NT-ICD underwent a total of 402 DFT tests. Mean age at implantation had been 5.4 ± 3.3 years, mean follow-up was 5.6 ± 3.7 years in 5 (1%) DFT testing, maximum device output failed, and external defibrillation was necessary. A retrospective multiple mixed logistic regression model was able to predict a DFT ≥25 J (area under the curve [AUC] = 0.836). However, when prospectively validated the model showed moderate performance only (AUC = 0.70). CONCLUSION: A significant number of NT-ICD failures were detected by serial DFT testing. Serial DFT testing was safe in pediatric patients with an NT-ICD as all induced arrhythmia could be terminated. Prediction of DFT with noninvasive markers remains difficult and might help to schedule intervals for routine DFT tests to avoid unnecessary tests.

NTMS mapping of non-primary motor areas in brain tumour patients and healthy volunteers.

OBJECTIVE: Navigated transcranial magnetic stimulation (nTMS) has been increasingly used for presurgical cortical mapping of the primary motor cortex (M1) but remains controversial for the evaluation of non-primary motor areas (NPMA). This study investigates clinical and neurophysiological parameters in brain tumour patients and healthy volunteers to decide whether single-pulse biphasic nTMS allows to reliably elicite MEP outside from M1 or not. MATERIALS AND METHODS: Twelve brain tumour patients and six healthy volunteers underwent M1 nTMS mapping. NPMA nTMS mapping followed using 120% and 150% M1 resting motor threshold (RMT) stimulation intensity. Spearman's correlation analysis tested the association of clinical and neurophysiological parameters between M1 and NPMA mapping. RESULTS: A total of 88.81% of nTMS stimulations in NPMA in patients/83.87% in healthy volunteers in patients/83.87% in healthy volunteers did not result in MEPs ≥ 50 µV. Positive nTMS mapping in NPMA correlated with higher stimulation intensity and larger M1 areas in patients (120% M1 RMT SI p = 0.005/150% M1 RMT SI p = 0.198). CONCLUSION: Our findings indicate that in case of positive nTMS mapping in NPMA, MEPs originate mostly from M1. For future studies, MEP parameters and TMS coil rotation should be studied closely to assess the risk for postoperative motor deterioration.

Acute and midterm outcomes of the post-approval MELODY Registry: a multicentre registry of transcatheter pulmonary valve implantation.

AIMS: The post-approval MELODY Registry aimed to obtain multicentre registry data after transcatheter pulmonary valve implantation (TPVI) with the Melody™ valve (Medtronic plc.) in a large-scale cohort of patients with congenital heart disease (CHD). METHODS AND RESULTS: Retrospective analysis of multicentre registry data after TPVI with the Melody™ valve. Eight hundred and forty-five patients (mean age: 21.0 ± 11.1 years) underwent TPVI in 42 centres between December 2006 and September 2013 and were followed-up for a median of 5.9 years (range: 0-11.0 years). The composite endpoint of TPVI-related events during follow-up (i.e. death, reoperation, or reintervention >48 h after TPVI) showed an incidence rate of 4.2% per person per year [95% confidence interval (CI) 3.7-4.9]. Transcatheter pulmonary valve implantation infective endocarditis (I.E.) showed an incidence rate of 2.3% per person per year (95% CI 1.9-2.8) and resulted in significant morbidity and in nine deaths. In multivariable Cox proportional hazard models, the invasively measured residual right ventricle (RV)-to-pulmonary artery (PA) pressure gradient (per 5 mmHg) was associated with the risk of the composite endpoint (adjusted hazard ratio: 1.21, 95% CI 1.12-1.30; P < 0.0001) and the risk of TPVI I.E. (adjusted hazard ratio: 1.19, 95% CI 1.07-1.32; P = 0.002). Major procedural complications (death, surgical, or interventional treatment requirement) occurred in 0.5%, 1.2%, and 2.0%, respectively. Acutely, the RV-to-PA pressure gradient and the percentage of patients with pulmonary regurgitation grade >2 improved significantly from 36 [interquartile range (IQR) 24-47] to 12 (IQR 7-17) mmHg and 47 to 1%, respectively (P < 0.001 for each). CONCLUSION: The post-approval MELODY Registry confirms the efficacy of TPVI with the Melody™ valve in a large-scale cohort of CHD patients. The residual invasively measured RV-to-PA pressure gradient may serve as a target for further improvement in the composite endpoint and TPVI I.E. However, TPVI I.E. remains a significant concern causing significant morbidity and mortality.

Double cryoenergy application (freeze-thaw-freeze) at growing myocardium: Lesion volume and effects on coronary arteries late after energy application. Implications for efficacy and safety in pediatric patients.

INTRODUCTION: Cryoenergy is accepted as an alternative to radiofrequency ablation (RFA) in childen for ablation of supraventricular tachycardia substrates. Single cryoenergy application has been shown to be inferior to RFA. Double cryoenergy application has therefore been introduced into clinical practice, but experience concerning efficacy is limited. Coronary artery stenosis has been reported as serious complication after RFA for arrhythmia substrates but not after single cryoablation. The purpose of the study was to assess lesion volume (efficacy) and risk of coronary artery damage (safety), late, that is, 6 months, after double cryoenergy application in a piglet model. METHODS: Two sequential cycles of cryoenergy were delivered at -75°C for 4 minutes at the atrioventricular groove in five piglets. Animals were restudied after 6 months by coronary angiography and intracoronary ultrasound (ICUS). Ablation lesions were examined histologically and lesion volume was determined by three-dimensional morphometric analysis. RESULTS: Cryolesion volume was 174.04 ± 67.18 mm3 for atrial and 238.69 ± 112.1 mm3 for ventricular lesions (P > .05). Ventricular lesions, 4.06 ± 1.05 mm, were significantly deeper than atrial lesions, 3.58 ± 0.78 mm, (P < .05). In two of the 29 lesions, cryoenergy induced minor coronary artery injury with mild medial and adventitial thickening as well as minimal intimal proliferation, which had neither been detected by coronary angiography nor by ICUS. CONCLUSION: Late after double cryoenergy application at growing myocardium, subclinical minor affection of the coronary artery wall could be detected with minimal intimal proliferation. As lifetime sequelae of this finding remains unknown, further studies are warranted to address safety of repeated cycles of cryoenergy application for tachycardia substrates in children.

Serum Vitamin D Levels in Patients with Myelodysplastic Syndromes: A Retrospective Single-Center Analysis.

BACKGROUND/AIMS: There is growing evidence supporting the role of innate immune deregulation and inflammation in the pathogenesis of myelodysplastic syndromes (MDS). Vitamin D (VD) is known to be involved in various immune and epigenetic processes. This analysis aimed to evaluate serum VD levels in patients with MDS and to analyze associations between serum VD levels and disease characteristics. METHODS: Serum levels of 25-hydroxyvitamin D3 (25(OH)-D3), the major form of VD in human serum, were measured by chemiluminescence immunoassay in 62 unselected patients with MDS. Associations between serum 25(OH)-D3 levels and disease characteristics were analyzed using Kendall's tau and two-sided p values. RESULTS: The median serum 25(OH)-D3 level was markedly reduced (17.5 ng/mL). Patients with lower-risk disease features had lower serum 25(OH)-D3 levels than patients with higher-risk disease features with regard to medullary blast counts (16 vs. 31 ng/mL, p < 0.001), the revised international prognostic scoring system (13 vs. 30.5 ng/mL, p = 0.001), and blood counts. CONCLUSIONS: We show that patients with lower-risk disease characteristics exhibit lower serum VD levels than patients with higher-risk disease characteristics. Whether these findings might reflect innate immune deregulation has to be investigated in further studies.

Left perisylvian tumor surgery aided by TMS language mapping in a 6-year-old boy: case report.

BACKGROUND: Awake surgery to preserve language function in young children is challenging, therefore reliable non-invasive work-up of language functional anatomy is needed to preserve language function at any cost. Furthermore, there are obvious limitations of an awake craniotomy with direct stimulation on a child. CASE REPORT: A 6-year-old boy with a low-grade glioma of the left temporal lobe suffering from epileptic seizures underwent surgery, guided by preoperative transcranial magnetic stimulation (TMS) language mapping and consecutive DTI fiber tracking. DISCUSSION AND CONCLUSION: We report successful surgery of a language eloquent brain tumor in a young child based on TMS mapping and DTI fiber tracking alone. Surgical treatment of left-sided perisylvian tumors in children is discussed.

Estimation of the resting motor threshold (RMT) in transcranial magnetic stimulation using relative-frequency and threshold-hunting methods in brain tumor patients.

BACKGROUND: Application of transcranial magnetic stimulation is often based on the resting motor threshold. The aim of this study was to validate recent findings on the advantage of resting motor threshold estimation using adaptive threshold-hunting algorithms over the Rossini-Rothwell method in a clinical sample and healthy subjects. METHODS: Resting motor thresholds in 115 patients with a brain tumor and 10 healthy subjects were assessed using the Rossini-Rothwell method and compared to an adaptive threshold-hunting algorithm. In healthy subjects, this measurement was repeated twice to capture test-retest reliability of both methods. Efficiency of both methods was assessed by comparing the number of pulses needed for resting motor threshold estimation. RESULTS: There was no significant difference between the Rossini-Rothwell method and the adaptive threshold-hunting algorithm in patients and healthy controls with limits of agreement between ± 12 V/m. There was a strong intraclass correlation and both methods showed a good test-retest reliability. However, the adaptive threshold-hunting algorithm was significantly faster. CONCLUSIONS: The adaptive threshold-hunting algorithm was more efficient in assessing the resting motor threshold, while reaching comparable results as the Rossini-Rothwell method. Thus, our results support the advantage of adaptive threshold-hunting algorithms to determine the resting motor threshold also in a clinical sample.

TMS motor mapping in brain tumor patients: more robust maps with an increased resting motor threshold.

OBJECTIVE: Navigated transcranial magnetic stimulation (nTMS) has found widespread usage across many clinical centers as part of their surgical planning routines. NTMS offers a non-invasive approach to delineation of the motor cortex, in which the region is outlined through electromagnetic stimulation and electromyographic recordings of target muscles. Several neurophysiological parameters such as the motor evoked potential (MEP) and its derivatives, the resting motor threshold (RMT) and motor latency, are collected. The present study investigates the clinical feasibility and reproducibility of increasing the MEP threshold in brain tumor patients, with the goal to improve the robustness of the procedure. MATERIALS AND METHODS: Twenty-three subjects with peri-motor cortex tumors underwent motor mapping with nTMS. RMT was calculated with both conventional 50-µV and experimental 500-µV MEP amplitude thresholds. Motor mapping was performed with 105% of both RMTs stimulator intensity using the FDI as the target muscle. RESULTS: Motor mapping was possible in 20 patients with both the conventional and experimental thresholds. No significant differences in area size were found between motor area maps generated with a conventional 50-µV threshold in comparison to those generated with the higher 500-µV threshold (50 µV 272.56 mm2 [170.47-434.31] vs. 500 µV 240.54 mm2 [169.77-362.84], P = 0.34). Latency time was significantly reduced in 500-µV recordings relative to 50-µV recordings (50 µV 23.38 ms [22.55-24.51] vs. 500 µV 22.57 ms [21.41-23.70], P < 0.001). Both electric field intensity (50 µV 63.81 V/m [54.26-76.11] vs. 500 µV 77.83 V/m [65.21-93.94], P < 0.001) and RMT (50 µV 33 MSO% [28-36] vs. 500 µV 39.5 MSO% [32-44], P < 0.001) were significantly greater with the higher 500-µV threshold. CONCLUSIONS: Our study demonstrates the feasibility of increasing the MEP detection threshold to 500 µV in brain tumor patients for RMT determination and motor area mapping with nTMS.