Plasma C24:0- and C26:0-lysophosphatidylcholines are reliable biomarkers for the diagnosis of peroxisomal ß-oxidation disorders.

The gold-standard diagnostic test for peroxisomal disorders (PDs) is plasma concentration analysis of very long-chain fatty acids (VLCFAs). However, this method's time-consuming nature and limitations in cases which present normal VLCFA levels necessitates alternative approaches. The analysis of C26:0-lysophosphatydylcholine (C26:0-LPC) in dried blood spot samples by tandem-mass spectrometry (MS/MS) has successfully been implemented in certain newborn screening programs to diagnose X-linked adrenoleukodystrophy (ALD). However, the diagnostic potential of very long-chain LPCs concentrations in plasma remains poorly understood. This study sought to evaluate the diagnostic performance of C26:0-LPC and other very long-chain LPCs, comparing them to VLCFA analysis in plasma. The study, which included 330 individuals affected by a peroxisomal ß-oxidation deficiency and 407 control individuals, revealed that C26:0- and C24:0-LPC concentrations demonstrated the highest diagnostic accuracy (98.8% and 98.4%, respectively), outperforming VLCFA when C26:0/C22:0 and C24:0/C22:0 ratios were combined (98.1%). Combining C24:0- and C26:0-LPC gave the highest sensitivity (99.7%), with ALD females exhibiting notably higher sensitivity compared with the VLCFA ratio combination (98.7% vs. 93.5%, respectively). In contrast, C22:0-LPC exhibited suboptimal performance, primarily due to its low sensitivity (75%), but we identified a potential use to help distinguish between ALD and Zellweger spectrum disorders. In summary, MS/MS analysis of plasma C24:0- and C26:0-LPC concentrations represents a rapid and straightforward approach to diagnose PDs, demonstrating superior diagnostic accuracy, particularly in ALD females, compared with conventional VLCFA biomarkers. We strongly recommend integrating very-long chain LPC plasma analysis in the diagnostic evaluation of individuals suspected of having a PD.

CSF neopterin and beta-2-microglobulin as inflammation biomarkers in newborns with hypoxic-ischemic encephalopathy.

BACKGROUND: Inflammation plays a crucial role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE). The aim of this study was to measure inflammation in HIE through an analysis of CSF neopterin and ß2-microglobulin and to study the association with brain injury as shown by MRI findings and neurodevelopmental outcomes. METHODS: CSF biomarkers were measured in study patients at 12 and 72 h. Brain injury was evaluated by MRI, and neurodevelopmental outcomes were assessed at 2-3 years of life. An adverse outcome was defined as the presence of motor or cognitive impairment. RESULTS: Sixty-nine HIE infants were included. Median values of neopterin and ß2-microglobulin paralleled the severity of HIE. Adverse outcomes were associated with early neopterin and ß2-microglobulin values, late neopterin values, and the neopterin percentage change between the two samples. A cutoff value of 75% neopterin change predicted adverse outcomes with a specificity of 0.9 and a sensitivity of 0.75. CONCLUSIONS: CSF neopterin and ß2-microglobulin are elevated in HIE, indicating the activation of inflammation processes. Infants with adverse neurodevelopmental outcomes show higher levels of CSF neopterin and ß2-microglobulin. The evolution of neopterin levels provides a better predictive capacity than a single determination. IMPACT: Brain inflammation in newborns with HIE could be measurable through the analysis of CSF neopterin and ß2-microglobulin, both of which are associated with neurodevelopmental outcomes. Our study introduces two inflammatory biomarkers for infants with HIE that seem to show a more stable profile and are easier to interpret than cytokines. CSF neopterin and ß2-m may become clinical tools to monitor inflammation in HIE and might eventually be helpful in measuring the response to emerging therapies.

COVID-19 in chronic hemodialysis patients: A report of 9 cases in Madrid, Spain.

INTRODUCTION: In December 2019, a new respiratory disease, named COVID-19, caused by a novel coronavirus, emerged in Wuhan and since then spread rapidly throughout China and worldwide. Hemodialysis patients are an especially vulnerable subgroup of the general population. However, there are only a few reports on the course of COVID-19 in maintenance hemodialysis patients. CASE REPORT: We describe in depth the clinical, analytical, and radiological details of 9 hemodialysis patients from a single center in Madrid (Spain) diagnosed with COVID-19. Furthermore, we describe and discuss the therapeutic aspects and the patients' outcomes. DISCUSSION: We present one of the first case series of chronic hemodialysis patients with COVID-19. Between March 14 and April 8, 2020, out of 76 prevalent patients in our hemodialysis unit, 9 (11.8%) patients were diagnosed with COVID-19. The most common symptoms were fever (77.8%), asthenia (77.8%), cough (55.6%), and dyspnea (33.3%). A total of 3 patients developed severe pneumonia, whereas 4 patients developed mild pneumonia. In 2 patients, no pathologic changes were found on chest radiography. All patients presented lymphopenia. While 6 (66.7%) patients required hospitalization, none of them was admitted to intensive care unit. The most common treatments used were azithromycin (100%), hydroxychloroquine (66.7%), lopinavir/ritonavir (55.6%) and ß-interferon (22.2%). In general, we observed a mild to moderate severity of disease in our case series. One patient died, however due to a cause not related to COVID-19.

Impact of routine right parasternal electrocardiographic screening in assessing eligibility for subcutaneous implantable cardioverter-defibrillator.

INTRODUCTION: Between 7% and 15% of patients with an indication for an implantable cardioverter-defibrillator (ICD) are not eligible for implantation of a subcutaneous implantable cardioverter-defibrillator (S-ICD) on the basis of the result of the conventional left parasternal electrocardiographic screening (LPES). Our objective was to determine the impact of systematically performing right parasternal electrocardiographic screening (RPES) in addition to conventional LPES, in terms of increasing both the total percentage of potentially eligible patients for S-ICD implantation and the number of suitable vectors per patient. METHODS AND RESULTS: Consecutive patients from the outpatient device clinic who already had an implanted ICD, and no requirement for pacing were enrolled. Conventional left parasternal electrode position and right parasternal electrode positions were used. The automatic screening tool was used to analyze the recordings. Screenings were performed in the supine and standing positions. Overall, 209 patients were included. The mean age was 63.4 ± 13 years, 59.8% had ischemic heart disease, mean QRS duration was 100 ± 31 ms, and 69.9% had a primary prevention ICD indication. Based on conventional isolated LPES, 12.9% of patients were not eligible for S-ICD compared with 11.5% based on RPES alone (P = .664). Considering LPES and RPES together, only 7.2% of patients were not eligible for S-ICD (P < .001). Moreover, the number of patients with more than one suitable vector increased from 66.5% with isolated LPES to 82.3% (23.7% absolute increase [P < .001]). CONCLUSION: Adding an automated RPES to the conventional automated LPES increased patient eligibility for the S-ICD significantly. Moreover, combined screening increased the number of suitable vectors per eligible patient.

A regular wide QRS complex tachycardia: What is the mechanism?

A 14-year-old girl with a history of recurrent palpitations and documented wide QRS complex tachycardia was referred for electrophysiologic study and catheter ablation.

A scoring algorithm for the accurate differential diagnosis of regular wide QRS complex tachycardia.

BACKGROUND: The differential diagnosis of regular wide QRS complex tachycardia (RWQRST) remains the subject of numerous publications, all of which aim at diagnosis during the acute phase. Although an accurate diagnosis is necessary to make long-term decisions, it often leads to invasive testing. METHODS: Criteria with high positive predictive values (PPVs) for diagnosis can be obtained by analyzing the electrocardiogram (ECG) data during RWQRST and comparing them with these data at baseline. By assigning points to these criteria, a scoring algorithm to accurately diagnose numerous patients can be obtained. A total of 352 consecutive patients with RWQRST were included. Two electrophysiologists blind to patient condition analyzed the 16 criteria considered as having high PPVs. RESULTS: A total of 149 (42.3%) cases were supraventricular tachycardia (SVT), and 203 (57.7%) cases were ventricular tachycardia (VT). A higher percentage of patients with VT had structural heart disease (86.7% vs 16.1%). Seven of the 16 criteria analyzed had PPVs > 95%, and each criterion was assigned a score. A final score of -1 was indicative of SVT (PPV 98%); a score of 1 was indicative of VT (PPV 98%); and a score of ≥2 was indicative of VT (PPV 100%). A score of ≠0 was obtained for 51.7% of all cases of tachycardia, making it possible to reach a highly accurate diagnosis in approximately half of all cases. No cases of VT scored -1, and no cases of SVT scored ≥2. CONCLUSIONS: The current scoring system stands out for its high PPV (98%) and specificity (98%), enabling an accurate diagnosis for more than half of the patients.

A targeted metabolomic procedure for amino acid analysis in different biological specimens by ultra-high-performance liquid chromatography-tandem mass spectrometry.

INTRODUCTION: Amino acid analysis in biological fluids is essential for the study of inborn errors of metabolism (IEM) and other diseases. OBJECTIVES: Our aim was to develop a UPLC-MS/MS procedure for the analysis of 25 amino acids and identification of 17 related compounds. METHODS: Sample treatment conditions were optimized for plasma, urine, cerebrospinal fluid (CSF) and dried blood spots. Amino acids and related compounds were analyzed on a Waters ACQUITY UPLC H-class instrument with a reversed-phase C-18 column using water and acetonitrile with 0.1% formic acid as the mobile phases (run time = 9 min). The detection was performed with a Waters Xevo TQD triple-quadrupole mass spectrometer using positive electrospray ionization in the multiple reaction monitoring mode. RESULTS: The method linearity, intra-assay and inter-assay precision, detection limit, quantification limit and trueness analysis displayed adequate results in both physiological and pathological conditions. Method comparison was performed between UPLC-MS/MS and ion exchange chromatography (IEC) with ninhydrin derivatization, and the methods showed good agreement, except for 4-hydroxyproline, aspartate and citrulline. Paediatrics age-related reference values in plasma, urine and CSF were established and patients with different IEM were easily identified. CONCLUSION: We report a modified UPLC-MS/MS procedure for the analysis of 42 amino acids and related compounds in different specimens. The method is fast, sensitive and robust, and it has been validated to be an alternative to the traditional IEC procedure as the routine method used in metabolic laboratories. The method greatly decreases the run time of the analysis while displaying good metrological results.

Cerebrospinal fluid monoamines, pterins, and folate in patients with mitochondrial diseases: systematic review and hospital experience.

Mitochondrial diseases are a group of genetic disorders leading to the dysfunction of mitochondrial energy metabolism pathways. We aimed to assess the clinical phenotype and the biochemical cerebrospinal fluid (CSF) biogenic amine profiles of patients with different diagnoses of genetic mitochondrial diseases. We recruited 29 patients with genetically confirmed mitochondrial diseases harboring mutations in either nuclear or mitochondrial DNA (mtDNA) genes. Signs and symptoms of impaired neurotransmission and neuroradiological data were recorded. CSF monoamines, pterins, and 5-methyltetrahydrofolate (5MTHF) concentrations were analyzed using high-performance liquid chromatography with electrochemical and fluorescence detection procedures. The mtDNA mutations were studied by Sanger sequencing, Southern blot, and real-time PCR, and nuclear DNA was assessed either by Sanger or next-generation sequencing. Five out of 29 cases showed predominant dopaminergic signs not attributable to basal ganglia involvement, harboring mutations in different nuclear genes. A chi-square test showed a statistically significant association between high homovanillic acid (HVA) values and low CSF 5-MTHF values (chi-square = 10.916; p = 0.001). Seven out of the eight patients with high CSF HVA values showed cerebral folate deficiency. Five of them harbored mtDNA deletions associated with Kearns-Sayre syndrome (KSS), one had a mitochondrial point mutation at the mtDNA ATPase6 gene, and one had a POLG mutation. In conclusion, dopamine deficiency clinical signs were present in some patients with mitochondrial diseases with different genetic backgrounds. High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes.

Estimation of the effects of multipoint pacing on battery longevity in routine clinical practice.

Aims: Multipoint pacing (MPP) permits simultaneous multisite pacing of the left ventricle (LV); initial studies suggest haemodynamic and clinical benefits over conventional (single LV site) cardiac resynchronization therapy (CRT). The aim of this study was to estimate the impact of MPP activation on battery longevity in routine clinical practice. Methods and results: Patient (n = 46) and device data were collected from two centres at least 3 months after MPP-CRT device implantation. Multipoint pacing programming was based on the maximal possible anatomical LV1/LV2 separation according to three predefined LV pacing capture threshold (PCT) cut-offs (≤1.5 V; ≤4.0 V; and ≤6.5 V). Estimated battery longevity was calculated using the programmed lower rate limit, lead impedances, outputs, and pacing percentages. Relative to the longevity for conventional CRT using the lowest PCT (8.9 ± 1.2 years), MPP activation significantly shortened battery longevity for all three PCT cut-offs (≤1.5 V, -5.6%; ≤4.0 V, -16.9%; ≤6.5 V, -21.3%; P's <0.001). When compared with conventional CRT based on longest right ventricle-LV delay (8.3 ± 1.3 years), battery longevity was significantly shortened for the MPP ≤ 4.0 V and ≤6.5 V cut-offs (-10.8 and -15.7%, respectively; P's <0.001). Maximal LV1/LV2 spacing was possible in 23.9% (≤1.5 V), 56.5% (≤4.0 V), and 69.6% (≤6.5 V) of patients. Conclusion: Multipoint pacing activation significantly reduces battery longevity compared with that for conventional CRT configuration. When reasonable MPP LV vector PCTs (≤4.0 V) are achieved, the decrease in battery longevity is relatively small which may prompt the clinician to activate MPP.

Paradoxical preexcitation during cryoablation of a concealed parahisian accessory pathway.

A 16-year-old male presented with an orthodromic atrioventricular reentrant tachycardia over a concealed parahisian accessory pathway (AP). Cryoablation of the AP resulted in transient manifestation of a fully preexcited sinus rhythm of parahisian AP morphology. Potential causes for the paradoxical preexcitation include inadvertent atrioventricular nodal block, sourse-sink mismatch, as well as the activation of a dormant AP capable of anterograde conduction.

Reduction of mortality following better detection of hypertension and alcohol problems in primary health care in Spain. / Reducción de la mortalidad mediante una mejor detección de la hipertensión y los problemas con el alcohol en atención primaria de salud en España.

Through a simulation study, we estimated the potential effects of better detection of hypertension and improved screening for alcohol problems with subsequent interventions. Results showed that if 50% of Spanish males between 40 and 64 years of age who are currently unaware of their hypertension become aware of their condition and receive the usual treatment, and 50% of these males with hypertension are screened for alcohol and are treated for hazardous drinking or alcohol use disorders, then the percentage of uncontrolled hypertension among men with hypertension decreases from 61.2% to 55.9%, i.e. by 8.6%, with about 1/3 of the effect due to the alcohol intervention. For women, likewise, these interventions would decrease the percentage of women in the same age group with uncontrolled hypertension by 7.4% (about 40% due to the alcohol intervention). The reduction of blood pressure in the population would avoid 412 premature CVD deaths (346 in men, 66 in women) within one year. Therefore, better detection of hypertension and screening for alcohol with subsequent interventions would result in marked reductions of uncontrolled hypertension and CVD mortality.

Se estudian mediante una simulación los potenciales beneficios que puede comportar una mejora en la detección y tratamiento de la hipertensión y de los problemas relacionados con el alcohol. Los resultados muestran que si el 50% de los varones españoles entre 40 y 64 años que desconocen que padecen hipertensión fuesen detectados y recibiesen tratamiento; y si en el 50% de los varones hipertensos se realizase el cribado de consumo alcohólico y recibieran consejo para la reducción de consumos o tratamiento cuando procediera, el porcentaje de hipertensión no controlada descendería del 61,2% al 55,9% (una reducción del 8,6%). Un tercio del efecto es atribuible a la intervención sobre el alcohol. De forma similar, las mismas intervenciones en mujeres de los mismos grupos etarios implicarían una reducción del 7,4% de la hipertensión no controlada (40% debido a la intervención sobre alcohol). La reducción de la presión arterial en la población permitiría evitar 412 muertes prematuras por patología cardiovascular (346 varones y 66 mujeres) anualmente. Una mejor detección de la hipertensión y el cribado de consumos alcohólicos con las consiguientes intervenciones resultarían en una marcada reducción de la hipertensión no controlada y de las muertes de origen cardiovascular.

Towards new recommendations to reduce the burden of alcohol-induced hypertension in the European Union.

BACKGROUND: Hazardous and harmful alcohol use and high blood pressure are central risk factors related to premature non-communicable disease (NCD) mortality worldwide. A reduction in the prevalence of both risk factors has been suggested as a route to reach the global NCD targets. This study aims to highlight that screening and interventions for hypertension and hazardous and harmful alcohol use in primary healthcare can contribute substantially to achieving the NCD targets. METHODS: A consensus conference based on systematic reviews, meta-analyses, clinical guidelines, experimental studies, and statistical modelling which had been presented and discussed in five preparatory meetings, was undertaken. Specifically, we modelled changes in blood pressure distributions and potential lives saved for the five largest European countries if screening and appropriate intervention rates in primary healthcare settings were increased. Recommendations to handle alcohol-induced hypertension in primary healthcare settings were derived at the conference, and their degree of evidence was graded. RESULTS: Screening and appropriate interventions for hazardous alcohol use and use disorders could lower blood pressure levels, but there is a lack in implementing these measures in European primary healthcare. Recommendations included (1) an increase in screening for hypertension (evidence grade: high), (2) an increase in screening and brief advice on hazardous and harmful drinking for people with newly detected hypertension by physicians, nurses, and other healthcare professionals (evidence grade: high), (3) the conduct of clinical management of less severe alcohol use disorders for incident people with hypertension in primary healthcare (evidence grade: moderate), and (4) screening for alcohol use in hypertension that is not well controlled (evidence grade: moderate). The first three measures were estimated to result in a decreased hypertension prevalence and hundreds of saved lives annually in the examined countries. CONCLUSIONS: The implementation of the outlined recommendations could contribute to reducing the burden associated with hypertension and hazardous and harmful alcohol use and thus to achievement of the NCD targets. Implementation should be conducted in controlled settings with evaluation, including, but not limited to, economic evaluation.

Cuff-Based Oscillometric Central and Brachial Blood Pressures Obtained Through ABPM are Similarly Associated with Renal Organ Damage in Arterial Hypertension.

BACKGROUND/AIMS: Central blood pressure (BP) has been suggested to be a better estimator of hypertension-associated risks. We aimed to evaluate the association of 24-hour central BP, in comparison with 24-hour peripheral BP, with the presence of renal organ damage in hypertensive patients. METHODS: Brachial and central (calculated by an oscillometric system through brachial pulse wave analysis) office BP and ambulatory BP monitoring (ABPM) data and aortic pulse wave velocity (PWV) were measured in 208 hypertensive patients. Renal organ damage was evaluated by means of the albumin to creatinine ratio and the estimated glomerular filtration rate. RESULTS: Fifty-four patients (25.9%) were affected by renal organ damage, displaying either microalbuminuria (urinary albumin excretion ≥30 mg/g creatinine) or an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Compared to those without renal abnormalities, hypertensive patients with kidney damage had higher values of office brachial systolic BP (SBP) and pulse pressure (PP), and 24-h, daytime, and nighttime central and brachial SBP and PP. They also had a blunted nocturnal decrease in both central and brachial BP, and higher values of aortic PWV. After adjustment for age, gender, and antihypertensive treatment, only ABPM-derived BP estimates (both central and brachial) showed significant associations with the presence of renal damage. Odds ratios for central BP estimates were not significantly higher than those obtained for brachial BP. CONCLUSION: Compared with peripheral ABPM, cuff-based oscillometric central ABPM does not show a closer association with presence of renal organ damage in hypertensive patients. More studies, however, need to be done to better identify the role of central BP in clinical practice.

Analysis of cerebrospinal fluid γ-aminobutyric acid by capillary electrophoresis with laser-induced fluorescence detection.

The measurement of γ-aminobutyric acid (GABA) is suitable for investigating various neurological disorders. In this study, a sensitive and selective method for free GABA quantification in cerebrospinal fluid (CSF) has been standardised. This method is based on CE with LIF detection using 4-fluoro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-F) as a derivatisating agent. The reaction conditions (NBD-F concentration, pH, temperature and reaction time) and the electrophoretic parameters (run buffer composition and pH and separation voltage) were optimised to obtain the maximum derivatisation efficiency and electrophoretic resolution. The best resolution was obtained using 200 mM sodium borate, 10 mM SDS, 8.5 mM ß-CD, pH 10 and 20 kV voltage. The method was linear in the concentration range of 2.5-1000 nM with good inter- and intra-assay precision values. The effects of CSF handling on free GABA concentrations were also evaluated. Our results show that the time delay between CSF collection and freezing strongly increases the CSF GABA values. Age-related reference values were established in 55 paediatric controls. The influence of antiepileptic therapy on free CSF GABA was studied in 38 neuropaediatric patients. Significantly, higher GABA values were obtained in patients taking valproic acid or vigabatrin therapy, which are antiepileptic drugs that modulate GABA metabolism.