Gene editing: a near future for the treatment of genetic kidney diseases.

The study by Chen et al. is the first to apply the revolutionary genetic engineering tool, base editing, in a rat model for the treatment of primary hyperoxaluria type 1, a disease that originates in the liver but in which the kidney is the main organ affected. This commentary contextualizes and describes the gene-editing technology applied by the authors, provides an interpretation and opinion of their results, and indicates possible future applications.

Estimation of liver fibrosis using elastography in cholestatic diseases: systematic review and meta-analysis.

INTRODUCTION: staging fibrosis extent in liver disease is highly relevant for appropriate management. Liver biopsy remains the reference standard for assessment, but noninvasive methods such as elastography are becoming increasingly accurate and relevant. However, evidence regarding elastography in cholestatic diseases is lower than in other etiologies. METHODS: we searched MEDLINE, EMBASE and Web of Science for publications on the diagnostic accuracy of transient elastography and sonoelastography in cholestatic diseases (PBC and PSC) using biopsy as the reference standard. A systematic review and meta-analysis of the results was then carried out. RESULTS: a total of 13 studies were included. Using transient elastography in PBC sensitivity and specificity were estimated to be 0.76 and 0.93; 0.88 and 0.9; and 0.91 and 0.95 for ≥ F2, ≥ F3 and = F4, respectively. For sonoelastography in PBC sensitivity and specificity estimates were 0.79 and 0.82; 0.95 and 0.86; and 0.94 and 0.85 for ≥ F2, ≥ F3 y = F4, respectively. In PSC, transient elastography had a sensivity and specificity of 0.76 and 0.88; 0.91 and 0.86; and 0.71 and 0.93 for ≥ F2, ≥ F3 and = F4, respectively. CONCLUSION: elastography has adequate diagnostic accuracy in the assessment of fibrosis stages in cholestatic liver diseases.

Hepatic splenosis, description of an unusual behavior at contrast-enhanced ultrasonography (CEUS).

The case was a 47-year-old male, asymptomatic, with a personal history of splenectomy in childhood. He was referred to our outpatient clinic to complete the study of space-occupying liver lesion. The initial diagnostic suspicion was liver adenoma, given its behavior on magnetic resonance imaging and the absence of previous liver disease. We performed an intravascular contrast-enhanced ultrasound (CEUS) (SonoVue©). The lesion showed rapid centripetal enhancement, remaining enhanced in the portal phase with dim washout in the late venous phase. Given the therapeutic implications of the diagnosis of a hepatic adenoma, an ultrasound-guided percutaneous biopsy with an 18-gauge core needle was performed. The anatomopathological study confirmed the presence of hepatic splenosis. Hepatic splenosis can present as isolated or multiple foci (1). There is little published information on the behavior of hepatic splenosis in CEUS (2, 3, 4), which prevents any behavior from being generalized. The most frequently described behavior is hyperenhancement in the arterial phase without subsequent washout, not a specific behavior that can lead to the misdiagnosis of other entities such as hemangioma. In our case, it was caused by an isolated focus of splenosis that did not show the most frequent described behavior at CEUS, since it presented a faint washout in the venous phase, making it necessary to rule out malignancy.

Sildenafil prevents right ventricular hypertrophy and improves heart rate variability in rats with pulmonary hypertension secondary to experimental diabetes.

Chronic treatment with sildenafil (SILD) is an effective protector on the development of cardiovascular complications of pulmonary hypertension (PH) and diabetes. However, to date, no studies have evaluated the effect of SILD on cardiopulmonary pathophysiology during PH secondary to type 1 diabetes. AIM: The present study aimed to evaluate the beneficial effects of chronic SILD treatment on pulmonary arterial pressure, right ventricular hypertrophy (RVH) and cardiac autonomic dysfunction in rats with PH secondary to diabetes. METODOLOGY: Male Sprague Dawley rats were randomly distributed into the control group (saline), diabetic group (60 mg/kg with streptozotocin), SILD-treated control group (20 mg/kg) and SILD-treated diabetic group. RESULTS: After 8 weeks the type 1 diabetic animals presented PH, endothelial dysfunction of the pulmonary arteries, electrocardiographic alterations, RVH and overexpression of phosphodiesterase type 5 in the heart. In type 1 diabetic animals, SILD treatment prevented the development of PH, endothelial dysfunction and RVH. SILD treatment also prevented alterations in the corrected QT period and heart rate variability and prevented overexpression of phosphodiesterase type 5. CONCLUSION: Our results indicate for the first time that SILD treatment prevents pulmonary arterial endothelial dysfunction, pulmonary hypertension, right ventricular hypertrophy and improves heart rate variability in type 1 diabetic rats.

TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. METHODS: To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. RESULTS: Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-related MAPK signaling, decreased NF-κB pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. CONCLUSIONS: This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.

Long-term outcome of omalizumab-assisted desensitisation to cow's milk and eggs in patients refractory to conventional oral immunotherapy: real-life study.

BACKGROUND: Oral immunotherapy (OIT) is a promising approach to cow's milk and egg allergies, but reactions are frequent and some patients cannot be desensitized. OBJECTIVE: To evaluate long-term OIT outcomes with omalizumab (OMZ) in paediatric patients with severe egg and/or milk allergies. METHODS: This retrospective real-life study analysed findings in children with Immunoglobulin E-mediated allergy to cow's milk and/or hen eggs refractory to conventional OIT, who underwent OIT with OMZ in our department between 1 January 2010 and 31 December 2015. RESULTS: In all, 41 patients were included (median age: 7 years; interquartile range [IQR]: 5.5-9.5); 26/41 (63.4%) underwent OIT for milk, 8/41 (19.5%) for egg and 7/41 (17.1%) for both. The median time between initiation of OMZ and OIT was 27 weeks (IQR: 22-33). Forty (97.56%) patients reached the maintenance phase (200 mL of cow's milk and 30 mL of raw egg or 1 cooked egg) in a median time of 27 weeks (IQR: 18-37). The median total time with OMZ was 117 weeks (IQR: 88-144). During the OMZ period, 2.44% (1/41) of patients presented anaphylaxis. After discontinuation of OMZ, 29.3% (12/41) presented anaphylaxis, 50% of them had a poor adherence to daily ingestion. One patient (2.44%) was diagnosed with eosinophilic esophagitis after 2 years of discontinuation of OMZ. Currently, after a median time of 9 years (IQR: 7-10) since the initiation of OMZ, 75.6% (31/41) are desensitized (27/31 without OMZ). CONCLUSIONS: Omalizumab allows desensitisation of children with severe allergies to cow's milk and/or egg without developing severe reactions while receiving this treatment. However, discontinuation of OMZ leads to severe allergic reactions, and hence must be monitored carefully.

Characteristics and outcome of incidental hepatocellular carcinoma after liver transplantation: a cohort study.

INTRODUCTION: despite advances in imaging diagnostic modalities, hepatocellular carcinoma is sometimes incidentally diagnosed on histological examination of the liver explant. The objectives of the study were: a) to compare the characteristics between incidental and known hepatocellular carcinoma; and b) to estimate survival and tumor recurrence after liver transplantation. MATERIAL AND METHODS: a retrospective, single-center study was performed. The inclusion criteria were: a) cirrhotic patients, age ≥ 18 years; b) liver transplantation between 1998 and 2018; and c) hepatocellular carcinoma diagnosed via histopathologic examination of the explanted liver. Cholangiocarcinoma and patients with early retransplantation were excluded. Multivariate analysis was performed using binomial logistic regression to assess the factors associated with incidental hepatocellular carcinoma. Kaplan-Meier curves were plotted to explore the impact on overall survival and recurrence free survival. RESULTS: two hundred and sixty-nine patients were enrolled. The prevalence of incidental hepatocellular carcinoma was 4.18 % (95 % CI: 2.89-6.01 %) of all liver transplants performed in cirrhotic patients. The median diameter of the main nodule was smaller in incidental hepatocellular carcinoma (20 vs 27 mm, p = 0.004), although they were more likely to be beyond the Up-to-Seven criteria on explant examination (22.2 % vs 7.5 %, p = 0.001), with no differences in any other histological features. No differences were found in overall survival rates (incidental 70.2 % vs 70.4 %, p = 0.87) or recurrence-free survival (incidental 100 % vs 83.8 %, p = 0.07) at five years. CONCLUSION: incidental hepatocellular carcinoma are smaller in size and are more frequently found to be beyond the Up-to-Seven criteria. However, no differences were found in overall survival rates or recurrence-free survival, although there was no tumor recurrence in the incidental hepatocellular carcinoma group.

Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study.

BACKGROUND AND AIM: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain. METHODS: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels ≤ 5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated. RESULTS: in the EVR + rTAC group (n = 105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73 m2 to 86.1 [27.9] mL/min/1.73 m2) whereas it decreased in the MMF + TAC (n = 106) group (88.4 [34.3] mL/min/1.73 m2 to 83.2 [25.2] mL/min/1.73 m2), with significant (p < 0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups. CONCLUSION: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation.

CystAnalyser: A new software tool for the automatic detection and quantification of cysts in Polycystic Kidney and Liver Disease, and other cystic disorders.

The Polycystic Kidney Disease (PKD) is characterized by progressive renal cyst development and other extrarenal manifestation including Polycystic Liver Disease (PLD). Phenotypical characterization of animal models mimicking human diseases are commonly used, in order to, study new molecular mechanisms and identify new therapeutic approaches. The main biomarker of disease progression is total volume of kidney and liver in both human and mouse, which correlates with organ function. For this reason, the estimation of the number and area of the tissue occupied by cysts, is critical for the understanding of physiological mechanisms underlying the disease. In this regard, cystic index is a robust parameter commonly used to quantify the severity of the disease. To date, the vast majority of biomedical researchers use ImageJ as a software tool to estimate the cystic index by quantifying the cystic areas of histological images after thresholding. This tool has imitations of being inaccurate, largely due to incorrectly identifying non-cystic regions. We have developed a new software, named CystAnalyser (register by Universidade de Santiago de Compostela-USC, and Fundación Investigación Sanitaria de Santiago-FIDIS), that combines automatic image processing with a graphical user friendly interface that allows investigators to oversee and easily correct the image processing before quantification. CystAnalyser was able to generate a cystic profile including cystic index, number of cysts and cyst size. In order to test the CystAnalyser software, 795 cystic kidney, and liver histological images were analyzed. Using CystAnalyser there were no differences calculating cystic index automatically versus user input, except in specific circumstances where it was necessary for the user to distinguish between mildly cystic from non-cystic regions. The sensitivity and specificity of the number of cysts detected by the automatic quantification depends on the type of organ and cystic severity, with values 76.84-78.59% and 76.96-89.66% for the kidney and 87.29-93.80% and 63.42-86.07% for the liver. CystAnalyser, in addition, provides a new tool for estimating the number of cysts and a more specific measure of the cystic index than ImageJ. This study proposes CystAnalyser is a new robust and freely downloadable software tool for analyzing the severity of disease by quantifying histological images of cystic organs for routine biomedical research. CystAnalyser can be downloaded from https://citius.usc.es/transferencia/software/cystanalyser (for Windows and Linux) for research purposes.

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Bartter and Gitelman Syndromes: A Primer for Clinicians.

Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies.

Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. Here, we review the clinics, treatment, genetics, and molecular basis of ARPKD, highlighting the most recent findings in the field.

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Alport Syndrome: A Primer for Clinicians.

Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes COL4A3, COL4A4 and COL4A5, that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin-angiotensin-aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it.

Resuming ultrasound activity after the acute phase of the COVID-19 pandemic.

Recently, Dr. Crespo et al. published in your Journal a paper recommending the use of ultrasonography during the current phase of the COVID-19 pandemic whilst wearing only a facial mask for protection, which we deem inadequate. Prevention is key when performing an ultrasound test, since this virus is highly contagious. During the pandemic, every patient should be considered as potentially infected and the procedure requires a close proximity. Therefore, extreme hygiene and a sonographer equipped with the appropriate personal protection (mask, cap, gown, gloves, shoe covers and goggles, with a facial screen and high-efficacy mask for confirmed or highly suspect cases) are of the utmost importance to prevent viral transmission.

Autosomal Dominant Tubulointerstitial Kidney Disease: Clinical Presentation of Patients With ADTKD-UMOD and ADTKD-MUC1.

RATIONALE & OBJECTIVE: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare underdiagnosed cause of end-stage renal disease (ESRD). ADTKD is caused by mutations in at least 4 different genes: MUC1, UMOD, HNF1B, and REN. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 56 families (131 affected individuals) with ADTKD referred from different Spanish hospitals. Clinical, laboratory, radiologic, and pathologic data were collected, and genetic testing for UMOD, MUC1, REN, and HNF1B was performed. PREDICTORS: Hyperuricemia, ultrasound findings, renal histology, genetic mutations. OUTCOMES: Age at ESRD, rate of decline in estimated glomerular filtration rate. RESULTS: ADTKD was diagnosed in 25 families (45%), 9 carried UMOD pathogenic variants (41 affected members), and 16 carried the MUC1 pathogenic mutation c.(428)dupC (90 affected members). No pathogenic variants were identified in REN or HNF1B. Among the 77 individuals who developed ESRD, median age at onset of ESRD was 51 years for those with ADTKD-MUC1 versus 56 years (P=0.1) for those with ADTKD-UMOD. Individuals with the MUC1 duplication presented higher risk for developing ESRD (HR, 2.24; P=0.03). The slope of decline in estimated glomerular filtration rate showed no significant difference between groups (-3.0mL/min/1.73m2 per year in the ADTKD-UMOD group versus -3.9mL/min/1.73m2 per year in the ADTKD-MUC1 group; P=0.2). The prevalence of hyperuricemia was significantly higher in individuals with ADTKD-UMOD (87% vs 54%; P=0.006). Although gout occurred more frequently in this group, the difference was not statistically significant (24% vs 7%; P=0.07). LIMITATIONS: Relatively small Spanish cohort. MUC1 analysis limited to cytosine duplication. CONCLUSIONS: The main genetic cause of ADTKD in our Spanish cohort is the MUC1 pathogenic mutation c.(428)dupC. Renal survival may be worse in individuals with the MUC1 mutation than in those with UMOD mutations. Clinical presentation does not permit distinguishing between these variants. However, hyperuricemia and gout are more frequent in individuals with ADTKD-UMOD.

Efficacy and safety of daclatasvir-based antiviral therapy in hepatitis C virus recurrence after liver transplantation. Role of cirrhosis and genotype 3. A multicenter cohort study.

Direct-acting antiviral agents (DAA) combining daclatasvir (DCV) have reported good outcomes in the recurrence of hepatitis C virus (HCV) infection after liver transplant (LT). However, its effect on the severe recurrence and the risk of death remains controversial. We evaluated the efficacy, predictors of survival, and safety of DAC-based regimens in a large real-world cohort. A total of 331 patients received DCV-based therapy. Duration of therapy and ribavirin use were at the investigator's discretion. The primary end point was sustained virological response (SVR) at week 12. A multivariate analysis of predictive factors of mortality was performed. Intention-to-treat (ITT) and per-protocol SVR were 93.05% and 96.9%. ITT-SVR was lower in cirrhosis (n = 163) (96.4% vs. 89.6% P = 0.017); the SVR in genotype 3 (n = 91) was similar, even in advanced fibrosis (96.7% vs. 88%, P = 0.2). Ten patients (3%) experienced virological failure. Therapy was stopped in 18 patients (5.44%), and ten died during treatment. A total of 22 patients (6.6%) died. Albumin (HR = 0.376; 95% CI 0.155-0.910) and baseline MELD (HR = 1.137; 95% CI: 1.061-1.218) were predictors of death. DCV-based DAA treatment is efficacious and safe in patients with HCV infection after LT. Baseline MELD score and serum albumin are predictors of survival irrespective of viral response.

Effect of vibration frequency on agonist and antagonist arm muscle activity.

PURPOSE: This study aimed to assess the effect of vibration frequency (f out) on the electromyographic (EMG) activity of the biceps brachii (BB) and triceps brachii (TB) muscles when acting as agonist and antagonist during static exercises with different loads. METHODS: Fourteen healthy men were asked to hold a vibratory bar as steadily as possible for 10 s during lying row (pulling) and bench press (pushing) exercise at f out of 0 (non-vibration condition), 18, 31 and 42 Hz with loads of 20, 50, and 80 % of the maximum sustainable load (MSL). The root mean square of the EMG activity (EMGRMS) of the BB and TB muscles was expressed as a function of the maximal EMGRMS for respective muscles to characterize agonist activation and antagonist coactivation. RESULTS: We found that (1) agonist activation was greater during vibration (42 Hz) compared to non-vibration exercise for the TB but not for the BB muscle (p < 0.05); (2) antagonist activation was greater during vibration compared to non-vibration exercise for both BB (p < 0.01) and TB (p < 0.05) muscles; (3) the vibration-induced increase in antagonist coactivation was proportional to vibration f out in the range 18-42 Hz and (4) the vibration-induced increase in TB agonist activation and antagonist coactivation occurred at all loading conditions in the range 20-80 % MSL. CONCLUSION: The use of high vibration frequencies within the range of 18-42 Hz can maximize TB agonist activation and antagonist activation of both BB and TB muscles during upper limb vibration exercise.

The influence of preset frequency, loading condition, and exercise type on the mechanical behavior of a novel vibratory bar.

This study aimed to analyze the influence of different vibration frequencies, loading conditions, and exercise types on the mechanical behavior of a novel vibratory bar (VB). Fourteen healthy men were asked to hold the VB during lying row (pulling) and bench press (pushing) static exercise as steadily as possible for 10 seconds with loads of 20, 50, and 80% of the maximum sustained load (MSL) and at preset vibration frequencies (f(in)) of 20, 35, and 50 Hz. Root mean square vibration acceleration (a(RMS)), peak-to-peak displacement (D), and frequency (f(out)) were gained from a 3-dimensional accelerometer fixed to the VB. Increasing vibration frequency (from 20 to 50 Hz) resulted in a progressive and sizeable increase in VB a(RMS) and f(out) (both p ≤ 0.001) with smaller variations of D (≤5.9%, p ≤ 0.001). Adding weight to the VB (progressive overload from 20 to 80% MSL) did not affect D and minimally altered a(RMS) (<4.2%, p = 0.014) and f(out) (<1.7%, p = 0.002). Altering the type of exercise (pulling vs. pushing) did not affect VB a(RMS), D, and f(out). In conclusion, this study establishes the validity of a novel VB and legitimates its use for effective and safe upper-body static exercise with a wide range of vibration frequencies and loading conditions in the context of physical training or rehabilitation.

On the use of fractional calculus to improve the pulse arrival time (PAT) detection when using photoplethysmography (PPG) and electrocardiography (ECG) signals.

The pulse arrival time (PAT) has been considered a surrogate measure for pulse wave velocity (PWV), although some studies have noted that this parameter is not accurate enough. Moreover, the inter-beat interval (IBI) time series obtained from successive pulse wave arrivals can be employed as a surrogate measure of the RR time series avoiding the use of electrocardiogram (ECG) signals. Pulse arrival detection is a procedure needed for both PAT and IBI measurements and depends on the proper fiducial points chosen. In this paper, a new set of fiducial points that can be tailored using several optimization criteria is proposed to improve the detection of successive pulse arrivals. This set is based on the location of local maxima and minima in the systolic rise of the pulse wave after fractional differintegration of the signal. Several optimization criteria have been proposed and applied to high-quality recordings of a database with subjects who were breathing at different rates while sitting or standing. When a proper fractional differintegration order is selected by using the RR time series as a reference, the agreement between the obtained IBI and RR is better than that for other state-of-the-art fiducial points. This work tested seven different traditional fiducial points. For the agreement analysis, the median standard deviation of the difference between the IBI and RR time series is 5.72 ms for the proposed fiducial point versus 6.20 ms for the best-performing traditional fiducial point, although it can reach as high as 9.93 ms for another traditional fiducial point. Other optimization criteria aim to reduce the standard deviation of the PAT (7.21 ms using the proposed fiducial point versus 8.22 ms to 15.4 ms for the best- and worst-performing traditional fiducial points) or to minimize the standard deviation of the PAT attributable to breathing (3.44 ms using the proposed fiducial point versus 4.40 ms to 5.12 ms for best- and worst-performing traditional fiducial points). The use of these fiducial points may help to better quantify the beat-to-beat PAT variability and IBI time series.

Impact of 1-Year Supplementation with High-Rich Docosahexaenoic Acid (DHA) on Clinical Variables and Inflammatory Biomarkers in Pediatric Cystic Fibrosis: A Randomized Double-Blind Controlled Trial.

A randomized, double-blind, and placebo-controlled study was conducted to assess the effect of dietary supplementation with high-rich docosahexaenoic acid (DHA) (Tridocosahexanoin-AOX® 70%) at 50 mg/kg/day in pediatric patients with cystic fibrosis (CF) as compared with placebo. The duration of supplementation was 12 months. A total of 22 patients were included, with 11 in the DHA group and 11 in the placebo group. The mean age was 11.7 years. The outcome variables were pulmonary function, exacerbations, sputum cellularity, inflammatory biomarkers in sputum and peripheral blood, and anthropometric variables. In the DHA group, there was a significant increase in FVC (p = 0.004) and FVE1 expressed in liters (p = 0.044) as compared with placebo, and a lower median number of exacerbations (1 vs. 2). Differences in sputum cellularity (predominantly neutrophilic), neutrophilic elastase, and sputum and serum concentrations of resolvin D1 (RvD1), interleukin (IL)-8 (IL-8), and tumor necrosis factor alpha (TNF-α) between the study groups were not found. Significant increases in weight and height were also observed among DHA-supplemented patients. The administration of the study product was safe and well tolerated. In summary, the use of a highly concentrated DHA supplement for 1 year as compared with placebo improved pulmonary function and reduced exacerbations in pediatric CF.