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The key to keep the rising slope of perovskite solar cell performances is to reduce non-radiative losses by minimizing defect density. To this end, a large variety of strategies have been adopted spanning from the use of interfacial layers, surface modifiers, to interface engineering. Although winning concepts have been demonstrated, they result from a mere trial and error approach, which is time consuming and operator-dependent. To face this challenge, in this work, we propose the use of a machine learning approach for an educated and rational material screening with optimal characteristics in terms of surface passivation. In particular, we applied Shapley additive explanation to extract the specific chemical features of the passivator, which directly impact the device parameters, specifically the open circuit voltage (Voc). By monitoring the different material parameters as input, we were able to list the most promising passivators and directly test them in working solar cells. By comparing the device performances with the results of the modeling and with additional optical and morphological characterization, we retrieved the most significant material properties linked to the highest efficiency, which are (i) the presence of chlorine and its strong binding capacity to positively charged defects on perovskite surface, reducing the non-radiative recombination and (ii) an increased flexibility of the molecule, resulting in better coverage of the surface. Finally, we tested the predictive power of the ML algorithm proposing a new passivator, which, implemented in a working device, leads to the predicted high Voc confirming the results of the modeling.

Abstract Background In 2018, our center started a program to offer genetic diagnosis to patients with kidney and liver monogenic rare conditions, potentially eligible for organ transplantation. We exploited a clinical exome sequencing approach, followed by analyses of in silico gene panels tailored to clinical suspicions, obtaining detection rates in line with what reported in literature. However, a percentage of patients remains without a definitive genetic diagnosis. This work aims to evaluate the utility of NGS data re-analysis for those patients with an inconclusive or negative genetic test at the time of first analysis considering that (i) the advance of alignment and variant calling processes progressively improve the detection rate, limiting false positives and false negatives; (ii) gene panels are periodically updated and (iii) variant annotation may change over time. Methods 114 patients, recruited between 2018 and 2020, with an inconclusive or negative NGS report at the time of first analysis, were included in the study. Re-alignment and variant calling of previously generated sequencing raw data were performed using the GenomSys Variant Analyzer software. Results 21 previously not reported potentially causative variants were identified in 20 patients. In most cases (n = 19), causal variants were retrieved out of the re-classification from likely benign to variants of unknown significance (VUS). In one case, the variant was included because of inclusion in the analysis of a newly disease-associated gene, not present in the original gene panel, and in another one due to the improved data alignment process. Whenever possible, variants were validated with Sanger sequencing and family segregation studies. As of now, 16 out of 20 patients have been analyzed and variants confirmed in 8 patients. Specifically, in two pediatric patients, causative variants were de novo mutations while in the others, the variant was present also in other affected relatives. In the remaining patients, variants were present also in non-affected parents, raising questions on their re-classification. Conclusions Overall, these data indicate that periodic and systematic re-analysis of negative or inconclusive NGS data reports can lead to new variant identification or reclassification in a small but significant proportion of cases, with benefits for patients’ management.

Hepatocellular adenomas (HAs) are tumors that can develop under different conditions, including in patients harboring a germline mutation in HNF1A. However, little is known about the pathogenesis of such disease. This work aims to better define what mechanisms lie under the development of this condition. Six HAs were sampled from the liver of a 17-year-old male affected by diabetes and multiple hepatic adenomatosis harboring the heterozygous pathogenic germline variant c.815G>A, p.(Arg272His) in HNF1A, which has a dominant negative effect. All HAs were molecularly characterized. Four of them were shown to harbor a second somatic HNF1A variant and one had a mutation in the ARID1A gene, while no additional somatic changes were found in the remaining HA and normal parenchyma. A transcriptomic profile of the same HA samples was also performed. HNF1A biallelic mutations were associated with the up-regulation of several pathways including the tricarboxylic acid cycle, the metabolism of fatty acids, and mTOR signaling while angiogenesis, endothelial and vascular proliferation, cell migration/adhesion, and immune response were down-regulated. Contrariwise, in the tumor harboring the ARID1A variant, angiogenesis was up-modulated while fatty acid metabolism was down-modulated. Histological analyses confirmed the molecular data. Independently of the second mutation, energetic processes and cholesterol metabolism were up-modulated, while the immune response was down-modulated. This work provides a complete molecular signature of HNF1A-associated HAs, analyzing the association between specific HNF1A variants and the development of HA while identifying potential new therapeutic targets for non-surgical treatment.

Summary: Reconstructive surgery of the medial canthus is among one of the most challenging due to its complex anatomy and aesthetic features. In this area even the slightest deformity or asymmetry is noticeable. Reconstructive surgery of this anatomical region aims to restore the tissue defect ensuring an appropriate aesthetic and functional feature, restoring colour, thickness and consistency of the replaced tissue. Orbicularis oculi myocutaneous flap is an option to reconstruct the medial canthal region; in this paper the authors present their experience with orbicularis oculi myocutaneous flap in 10 patients with medial canthal malignant lesions. The patients’ postoperative period was uneventful, the flaps usually showed some degree of temporary venous congestion during the first days after surgery, and any donor site morbidity was observed: no lid lag, ectropion, ptosis, or other eyelid deformity.This flap offers a similarity in texture, colour, and thickness to the recipient site and a negligible incidence of donor site morbidity, and it can be easily tailored to fit the shape of the soft tissue defect.

Current holographic approaches for neuronal stimulation have limitations in their temporal resolution and the number of targeted neurons. Here, the authors demonstrate an approach for ultra-fast holographic light targeting which, combined with optogenetics, enables sub-millisecond control of sequential neuronal activation and high throughput simultaneous multicell illumination.

Abstract The combination of noradrenergic (reboxetine) plus antimuscarinic (oxybutynin) drugs (reb-oxy) reduced obstructive sleep apnea (OSA) severity but no data are available on its effects on cardiac autonomic modulation. We sought to evaluate the impact of 1-week reb-oxy treatment on cardiovascular autonomic control in OSA patients. OSA patients were randomized to a double-blind, crossover trial comparing 4 mg reboxetine plus 5 mg oxybutynin to a placebo for OSA treatment. Heart rate (HR) variability (HRV), ambulatory blood pressure (BP) monitoring (ABPM) over 24 h baseline and after treatment were performed. Baroreflex sensitivity was tested over beat-to-beat BP recordings. 16 subjects with (median [interquartile range]) age 57 [51–61] years and body mass index 30 [26–36]kg/m2 completed the study. The median nocturnal HR was 65 [60–69] bpm at baseline and increased to 69 [64–77] bpm on reb-oxy vs 66 [59–70] bpm on placebo (p = 0.02). The mean 24 h HR from ABPM was not different among treatment groups. Reb-oxy administration was not associated with any modification in HRV or BP. Reb-oxy increased the baroreflex sensitivity and did not induce orthostatic hypotension. In conclusion, administration of reb-oxy did not induce clinically relevant sympathetic overactivity over 1-week and, together with a reduction in OSA severity, it improved the baroreflex function.

Abstract Purpose Inherited kidney diseases are among the leading causes of kidney failure in children, resulting in increased mortality, high healthcare costs and need for organ transplantation. Next-generation sequencing technologies can help in the diagnosis of rare monogenic conditions, allowing for optimized medical management and therapeutic choices. Methods Clinical exome sequencing (CES) was performed on a cohort of 191 pediatric patients from a single institution, followed by Sanger sequencing to confirm identified variants and for family segregation studies. Results All patients had a clinical diagnosis of kidney disease: the main disease categories were glomerular diseases (32.5%), ciliopathies (20.4%), CAKUT (17.8%), nephrolithiasis (11.5%) and tubular disease (10.5%). 7.3% of patients presented with other conditions. A conclusive genetic test, based on CES and Sanger validation, was obtained in 37.1% of patients. The highest detection rate was obtained for ciliopathies (74.4%), followed by nephrolithiasis (45.5%), tubular diseases (45%), while most glomerular diseases and CAKUT remained undiagnosed. Conclusions Results indicate that genetic testing consistently used in the diagnostic workflow of children with chronic kidney disease can (i) confirm clinical diagnosis, (ii) provide early diagnosis in the case of inherited conditions, (iii) find the genetic cause of previously unrecognized diseases and (iv) tailor transplantation programs.

Continuous adaptations of the movement system to changing environments or task demands rely on superposed fractal processes exhibiting power laws, that is, multifractality. The estimators of the multifractal spectrum potentially reflect the adaptive use of perception, cognition, and action. To observe time-specific behavior in multifractal dynamics, a multiscale multifractal analysis based on DFA (MFMS-DFA) has been recently proposed and applied to cardiovascular dynamics. Here we aimed at evaluating whether MFMS-DFA allows identifying multiscale structures in the dynamics of human movements. Thirty-six (12 females) participants pedaled freely, after a metronomic initiation of the cadence at 60 rpm, against a light workload for 10 min: in reference to cycling (C), cycling while playing “Tetris” on a computer, alone (CT) or collaboratively (CTC) with another pedaling participant. Pedal revolution periods (PRP) series were examined with MFMS-DFA and compared to linearized surrogates, which attested to a presence of multifractality at almost all scales. A marked alteration in multifractality when playing Tetris was evidenced at two scales, τ ≈ 16 and τ ≈ 64 s, yet less marked at τ ≈ 16 s when playing collaboratively. Playing Tetris in collaboration attenuated these alterations, especially in the best Tetris players. This observation suggests the high sensitivity to cognitive demand of MFMS-DFA estimators, extending to the assessment of skill/demand interplay from individual behavior. So, by identifying scale-dependent multifractal structures in movement dynamics, MFMS-DFA has obvious potential for examining brain-movement coordinative structures, likely with sufficient sensitivity to find echo in diagnosing disorders and monitoring the progress of diseases that affect cognition and movement control.

Background Pulmonary artery wedge pressure (PAWP) during exercise, as a surrogate for left ventricular (LV) end-diastolic pressure (EDP), is used to diagnose heart failure with preserved ejection fraction (HFpEF). However, LVEDP is the gold standard to assess LV filling, end-diastolic PAWP (PAWPED) is supposed to coincide with LVEDP and mean PAWP throughout the cardiac cycle (PAWPM) better reflects the haemodynamic load imposed on the pulmonary circulation. The objective of the present study was to determine precision and accuracy of PAWP estimates for LVEDP during exercise, as well as the rate of agreement between these measures. Methods 46 individuals underwent simultaneous right and left heart catheterisation, at rest and during exercise, to confirm/exclude HFpEF. We evaluated: linear regression between LVEDP and PAWP, Bland–Altman graphs, and the rate of concordance of dichotomised LVEDP and PAWP ≥ or < diagnostic thresholds for HFpEF. Results At peak exercise, PAWPM and LVEDP, as well as PAWPED and LVEDP, were fairly correlated (R2>0.69, p2 mmHg·L−1·min−1. Conclusions During exercise, PAWP is accurate but not precise for the estimation of LVEDP. Despite a good rate of concordance, these two measures might occasionally disagree.

Introduction Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking.Methods and analysis The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners’ offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed.Ethics and dissemination This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study’s course and findings through regular meetings.Trial registration number NCT05339841.

There is a growing interest in photoplethysmography (PPG) for the continuous monitoring of cardio-respiratory signals by portable instrumentation aimed at the early diagnosis of cardiovascular diseases. In this context, it is conceivable that PPG sensors working at different wavelengths simultaneously can optimize the identification of apneas and the quantification of the associated heart-rate changes or other parameters that depend on the PPG shape (e.g., systematic vascular resistance and pressure), when evaluating the severity of breathing disorders during sleep and in general for health monitoring. Therefore, the objective of this work is to present a novel pulse oximeter that provides synchronous data logging related to three light wavelengths (green, red, and infrared) in transmission mode to optimize both heart rate measurements and a reliable and continuous assessment of oxygen saturation. The transmission mode is considered more robust over motion artifacts than reflection mode, but current pulse oximeters cannot employ green light in transmission mode due to the high absorbance of body tissues at this wavelength. For this reason, our device is based on a Single-Photon Avalanche Diode (SPAD) with very short deadtime (less than 1 ns) to have, at the same time, the single photon sensitivity and high-count rate that allows acquiring all the wavelengths of interest on the same site and in transmission mode. Previous studies have shown that SPAD cameras can be used for measuring the heart rate through remote PPG, but oxygen saturation and heart-rate measures through contact SPAD-based PPG sensors have never been addressed so far. The results of the preliminary validation on six healthy volunteers reflect the expected physiological phenomena, providing rms errors in the Inter Beat Interval estimation smaller than 70 ms (with green light) and a maximum error in the oxygen saturation smaller than 1% during the apneas. Our prototype demonstrates the reliability of SPAD-based devices for continuous long-term monitoring of cardio-respiratory variables as an alternative to photodiodes especially when minimal area and optical power are required.

Background: While vagus nerve stimulation (VNS) has been in use for over two decades, little professional guidance exists to describe dosing and titration of therapy which is the consequence of a limited amount of evidence developed during the pre-market phase of therapy development. Post-market surveillance of dosing practice has revealed significant deviations from dosing and titration guidance offered by professional societies as well as the manufacturer. Objective: This analysis aims to identify a target dose for VNS Therapy in Epilepsy. Methods: Herein, VNS clinical outcomes are linked to the patient-specific dosing parameters for each study visit (n = 1178 patients). A generalized linear mixed model was built to ascertain the relationship between key stimulation parameters (i.e., Output Current, Pulse Width, Signal Frequency, and Duty Cycle) and clinical response, defined as a 50% or greater reduction in seizure frequency from baseline. Other demographic parameters of interest, such as duration of epilepsy and age at implant, were also explored. Results: A population level target output current and duty cycle for VNS therapy for epilepsy was identified as 1.61 mA and 17.1% duty cycle. Patients with shorter duration of epilepsy were identified to have a higher likelihood to respond to VNS therapy (p

Tanzania reported its first COVID-19 case on 16 March 2020. We conducted event-based surveillance of COVID-19 suspect cases among pharmacy clients presenting with respiratory symptoms and influenza-like illness to increase early and rapid detection of COVID-19 cases and mitigate transmission. We conveniently sampled 103 pharmacies from Dar es Salaam, the epicentre for the COVID-19 pandemic in Tanzania at the time. Between 23 April 2020 and 18 May 2020, 67% of the pharmacies (69/103) reported an observed increase in the number of clients presenting with respiratory symptoms and influenza-like illness compared with the 1 month before the COVID-19 outbreak. In the 1-month surveillance period, the participating pharmacies recorded 75 alerts of COVID-19 suspect cases and referred all suspected COVID-19 cases to rapid response teams for additional symptomatic screening and SARS-CoV-2 testing. A key implementation challenge was that some clients identified as COVID-19 suspected cases were hesitant to provide follow-up information for linkage to rapid response teams. Addressing concerns among drug dispensers in the participating pharmacies and informing them of the benefits of the surveillance activity were important implementation components. Our approach demonstrates the overall feasibility of rapidly implementing an event-based surveillance system for an emerging health threat through an existing network of pharmacies within the community. The approach and tools used in this surveillance activity could be adapted in similar settings to detect and generate alerts of disease outbreaks in the community that other surveillance systems may otherwise miss.

The recent advances of quantum biology suggest a potential role in biomedical research. Studies related to electromagnetic fields, proton pumping in mitochondrial respiratory chain, quantum theory of T-cell receptor (TCR)-degeneracy, theories on biophotons, pyrophosphates or tubulin as possible carriers for neural information, and quantum properties of ions and protons, might be useful for understanding mechanisms of some serious immune, cardiovascular, and neural pathologies for which classic biomedical research, based on biochemical approach, is struggling to find new therapeutic strategies. A breakthrough in medical knowledge is therefore needed in order to improve the understanding of the complex interactions among various systems and organs typical of such pathologies. In particular, problems related to immune system over-activation, to the role of autonomic nervous system (ANS) dysfunction in the obstructive sleep apnea (OSA) syndrome, to the clinical consequences of ion channels dysfunction and inherited cardiac diseases, could benefit from the new perspective provided by quantum biology advancement. Overall, quantum biology might provide a promising biophysical theoretic system, on which to base pathophysiology understanding and hopefully therapeutic strategies. With the present work, authors hope to open a constructive and multidisciplinary debate on this important topic.

Extracellular vesicles (EVs) are emerging as a promising field of research in liver disease. EVs are small, membrane-bound vesicles that contain various bioactive molecules, such as proteins, lipids, and nucleic acids and are involved in intercellular communication. They have been implicated in numerous physiological and pathological processes, including immune modulation and tissue repair, which make their use appealing in liver transplantation (LT). This review summarizes the current state of knowledge regarding the role of EVs in LT, including their potential use as biomarkers and therapeutic agents and their role in graft rejection. By providing a comprehensive insight into this emerging topic, this research lays the groundwork for the potential application of EVs in LT.

Abstract The target of human flight in space has changed from permanence on the International Space Station to missions beyond low earth orbit and the Lunar Gateway for deep space exploration and Missions to Mars. Several conditions affecting space missions had to be considered: for example the effect of weightlessness and radiations on the human body, behavioral health decrements or communication latency, and consumable resupply. Telemedicine and telerobotic applications, robot-assisted surgery with some hints on experimental surgical procedures carried out in previous missions, had to be considered as well. The need for greater crew autonomy in health issues is related to the increasing severity of medical and surgical interventions that could occur in these missions, and the presence of a highly trained surgeon on board would be recommended. A surgical robot could be a valuable aid but only inasfar as it is provided with multiple functions, including the capability to perform certain procedures autonomously. Space missions in deep space or on other planets present new challenges for crew health. Providing a multi-function surgical robot is the new frontier. Research in this field shall be paving the way for the development of new structured plans for human health in space, as well as providing new suggestions for clinical applications on Earth.

Background: Sleep disordered breathing (SDB) may trigger nocturnal cardiac arrhythmias (NCA) in patients with heart failure with reduced ejection fraction (HFrEF). The NCA ancillary study of the ADVENT-HF trial will test whether, in HFrEF-patients with SDB, peak-flow-triggered adaptive servo-ventilation (ASVpf) reduces NCA. To this end, accurate scoring of NCA from polysomnography (PSG) is required. Objective: To develop a method to detect NCA accurately from a single-lead electrocardiogram (ECG) recorded during PSG and assess inter-observer agreement for NCA detection. Methods: Quality assurance of ECG analysis included training of the investigators, development of standardized technical quality, guideline-conforming semi-automated NCA-scoring via Holter-ECG software and implementation of an arrhythmia adjudication committee. To assess inter-observer agreement, the ECG was analysed by two independent investigators and compared for agreement on premature ventricular complexes (PVC) /h, premature atrial complexes/h (PAC) as well as for other NCA in 62 patients from two centers of the ADVENT-HF trial. Results: The intraclass correlation coefficients for PVC/h and PAC/h were excellent: 0.99 (95%- confidence interval [CI]: 0.99–0.99) and 0.99 (95%-CI: 0.97–0.99), respectively. No clinically relevant difference in inter-observer classification of other NCA was found. The detection of non-sustained ventricular tachycardia (18% versus 19%) and atrial fibrillation (10% versus 11%) was similar between the two investigators. No sustained ventricular tachycardia was detected. Conclusion: These findings indicate that our methods are very reliable for scoring NCAs and are adequate to apply for the entire PSG data set of the ADVENT-HF trial.

BackgroundNovel smartwatch-based cuffless blood pressure (BP) measuring devices are coming to market and receive FDA and CE labels. These devices are often insufficiently validated for clinical use. This study aims to investigate a recently CE-cleared smartwatch using cuffless BP measurement in a population with normotensive and hypertensive individuals scheduled for 24-h BP measurement.MethodsPatients that were scheduled for 24-h ambulatory blood pressure monitoring (ABPM) were recruited and received an additional Samsung Galaxy Watch Active 2 smartwatch for simultaneous BP measurement on their opposite arm. After calibration, patients were asked to measure as much as possible in a 24-h period. Manual activation of the smartwatch is necessary to measure the BP. Accuracy was calculated using sensitivity, specificity, positive and negative predictive values and ROC curves. Bland-Altman method and Taffé methods were used for bias and precision assessment. BP variability was calculated using average real variability, standard deviation and coefficient of variation.ResultsForty patients were included. Bland-Altman and Taffé methods demonstrated a proportional bias, in which low systolic BPs are overestimated, and high BPs are underestimated. Diastolic BPs were all overestimated, with increasing bias toward lower BPs. Sensitivity and specificity for detecting systolic and/or diastolic hypertension were 83 and 41%, respectively. ROC curves demonstrate an area under the curve (AUC) of 0.78 for systolic hypertension and of 0.93 for diastolic hypertension. BP variability was systematically higher in the ABPM measurements compared to the smartwatch measurements.ConclusionThis study demonstrates that the BP measurements by the Samsung Galaxy Watch Active 2 show a systematic bias toward a calibration point, overestimating low BPs and underestimating high BPs, when investigated in both normotensive and hypertensive patients. Standards for traditional non-invasive sphygmomanometers are not met, but these standards are not fully applicable to cuffless devices, emphasizing the urgent need for new standards for cuffless devices. The smartwatch-based BP measurement is not yet ready for clinical usage. Future studies are needed to further validate wearable devices, and also to demonstrate new possibilities of non-invasive, high-frequency BP monitoring.

Type 1 diabetes mellitus (T1DM) has an important impact on morbidity and mortality because it may start early in life. Therefore, the early detection of cardiovascular autonomic neuropathy (DCAN) in T1DM patients is important to intervene quickly and prevent further deterioration. Traditional autonomic function tests detect abnormalities in severely symptomatic patients but they are difficult to be standardized, require the patient’s active participation and their sensitivity to the early disease is limited. In comparison, heart rate variability (HRV) is easier to be measured and standardized. Therefore, we aim to find the HRV indexes that better identify DCAN at an early stage in T1DM patients, and evaluate if HRV is a valid alternative to traditional tests. For this aim, we administered the SCOPA-AUT questionnaire on symptoms of autonomic dysfunction as well as deep breathing, Valsalva, handgrip, head-up tilt (HUT), and cold-pressor tests, to 52 T1DM patients and 27 controls. We calculated HRV indexes during supine rest (SUP) and HUT, assessing differences between groups and postures by a linear mixed-effect model for repeated measures. Receiver Operating Characteristic (ROC) analysis quantified how each HRV index and autonomic test distinguishes between patients and controls. We found that the SCOPA-AUT score was slightly but significantly (p < 0.05) greater in patients, indicating an early DCAN. T1DM patients preserved the HRV response to changing posture but in SUP they showed significantly lower standard deviation and vagal indexes of HRV than controls. The area under the ROC curve of these HRV indexes was not lower than 0.68. By contrast, traditional autonomic tests did not differ between groups. Therefore, early DCAN initially causes an impairment of the cardiac vagal control manifest in conditions of elevated vagal tone, as in SUP. Compensatory adjustments of the sympathetic control might explain the unaltered response to traditional autonomic tests. In conclusion, vagal HRV indexes in SUP help to identify early DCAN better than traditional tests, potentially allowing rapid interventions.

Mobile-health solutions based on heart rate variability often require electrocardiogram (ECG) recordings by inexperienced operators or real-time automatic analyses of long-term recordings by wearable devices in free-moving individuals. In this context, it is useful to associate a quality index with the ECG, scoring the adequacy of the recording for heart rate variability to identify noise or arrhythmias. Therefore, this work aims to propose and validate a computational method for assessing the adequacy of single-lead ECGs for heart rate variability analysis that may run in real time on wearable systems with low computational power. The method quantifies the ECG pseudo-periodic structure employing cepstral analysis. The cepstrum (spectrum of log-spectrum) is estimated on a running ECG window of 10 s before and after “liftering” (filtering in the cepstral domain) to remove slower noise components. The ECG periodicity generates a dominant peak in the liftered cepstrum at the “quefrency” of the mean cardiac interval. The Cepstral Quality Index (CQI) is the ratio between the cepstral-peak power and the total power of the unliftered cepstrum. Noises and arrhythmias reduce the relative power of the cepstral peak decreasing CQI. We analyzed a public dataset of 6072 single-lead ECGs manually classified in normal rhythm or inadequate for heart rate variability analysis because of noise or atrial fibrillation, and the CQI = 47% cut-off identified the inadequate recordings with 79% sensitivity and 85% specificity. We showed that the performance is independent of the lead considering a public dataset of 1,000 12-lead recordings with quality classified as “acceptable” or “unacceptable” by visual inspection. Thus, the cepstrum describes the ECG periodic structure effectively and concisely and CQI appears to be a robust score of the adequacy of ECG recording for heart rate variability analysis, evaluable in real-time on wearable devices.

Distribution Entropy (DistEn) has been introduced as an alternative to Sample Entropy (SampEn) to assess the heart rate variability (HRV) on much shorter series without the arbitrary definition of distance thresholds. However, DistEn, considered a measure of cardiovascular complexity, differs substantially from SampEn or Fuzzy Entropy (FuzzyEn), both measures of HRV randomness. This work aims to compare DistEn, SampEn, and FuzzyEn analyzing postural changes (expected to modify the HRV randomness through a sympatho/vagal shift without affecting the cardiovascular complexity) and low-level spinal cord injuries (SCI, whose impaired integrative regulation may alter the system complexity without affecting the HRV spectrum). We recorded RR intervals in able-bodied (AB) and SCI participants in supine and sitting postures, evaluating DistEn, SampEn, and FuzzyEn over 512 beats. The significance of “case” (AB vs. SCI) and “posture” (supine vs. sitting) was assessed by longitudinal analysis. Multiscale DistEn (mDE), SampEn (mSE), and FuzzyEn (mFE) compared postures and cases at each scale between 2 and 20 beats. Unlike SampEn and FuzzyEn, DistEn is affected by the spinal lesion but not by the postural sympatho/vagal shift. The multiscale approach shows differences between AB and SCI sitting participants at the largest mFE scales and between postures in AB participants at the shortest mSE scales. Thus, our results support the hypothesis that DistEn measures cardiovascular complexity while SampEn/FuzzyEn measure HRV randomness, highlighting that together these methods integrate the information each of them provides.

Abstract Background High number of unintended pregnancies—often leading to induced abortions—are reported among female sex workers (FSWs), highlighting a major unmet need for contraception. To better understand barriers to contraceptive use, we explored FSW’s pregnancy perceptions and experiences of unintended pregnancy. We hypothesized that sex work exacerbates barriers to contraceptive use and that FSW’s pregnancy perceptions and experiences of unintended pregnancy influence future commitment to contraceptive use. Methods We conducted in-depth interviews with 11 FSWs (January–June 2019) in Dar es Salaam, Tanzania. We purposively sampled FSWs with a positive pregnancy test from those participating in a HIV vaccine preparedness cohort. We used open ended questions to explore how FSWs make decisions when facing barriers to contraceptive use, dealing with unintended pregnancy and adhering to contraceptive use after experiencing unintended pregnancy. All interviews were conducted in Kiswahili, audio-recorded, transcribed and translated into English. Grounded theory approach was used to analyse transcripts. Open and selective coding was performed using Nvivo software. Results FSWs reported that sex work impedes good contraceptive behaviour because sex workers felt unable to negotiate consistent condom use, avoided health services due to stigma, missed monthly contraceptive supplies because of inconvenient clinic operating hours or skipped contraceptive pills when intoxicated after taking alcohol. FSWs who perceived pregnancy to be a burden terminated the pregnancy because of fear of loss of income during pregnancy or child rearing expenses in case child support was not assured by their partners. FSWs who perceived pregnancy to be a blessing decided to keep the pregnancy because they desired motherhood and hoped that children would bring prosperity. Family planning counselling and availability of contraceptives during postpartum care influenced the initiation of contraception among FSWs. Financial hardships related to childrearing or painful abortion experiences influenced FSWs’ commitment to good contraceptive practices. Conclusion Our results demonstrate that FSWs face barriers to initiating and adhering to contraceptive use because of sex work stigma, inability to negotiate condoms and failure to access medical services at their convenience. Our findings underscore the need to integrate contraceptive services with HIV programs serving FSWs in their areas of work.

Abstract Background Prevalence of HIV infection among people who inject drugs (PWID) has been reported to be higher than that of the general population. The present study aimed to estimate the prevalence of HIV infection and associated risk factors among PWID in Dar es Salaam, Tanzania, following the introduction of a comprehensive HIV intervention package (CHIP) for PWID in the country in 2014. Methods We conducted an integrated bio-behavioral survey (IBBS) among PWID using respondent-driven sampling (RDS) in Dar es Salaam, Tanzania, between October and December 2017. Data on socio-demographic characteristics and risky behaviors were collected through face-to-face interviews. Blood samples were collected and tested for HIV infection. We accounted for weighting in the analyses, and logistic regression was performed to assess risk factors for HIV infection. Results A total of 611 PWID (94.4% males and 5.6% females) with a median age of 34 years (IQR 29–38) were recruited. The overall prevalence of HIV infection was 8.7% (95% CI 6.5–10.9). The prevalence of HIV infections for males and females were 6.8% (95% CI 4.7–8.9%) and 41.2% (95% CI 23.7–58.6%) respectively. Adjusted weighted logistic regression analysis (WLRA) showed that being a female (aOR 19.1; 95% CI 5.9–61.8), injecting drugs for more than 10 years (aOR = 7.32; 95% CI 2.1–25.5) compared to 1 year or less and being 45 years or older (aOR = 34.22; 95% CI 2.4–489.5) compared to being 25 years or younger were associated with increased odds of HIV infection. Use of a sterile needle at last injection decreased odds of HIV infection (aOR = 0.3; 95% CI 0.1–0.8). Conclusions The present study observed a decline in prevalence of HIV infections among PWID in Dar es Salaam (8.7%) compared to a previous estimate of 15.5% from an IBBS conducted in 2013. Despite the decrease, HIV prevalence remains high among PWID compared to the general population, and women are disproportionally affected. The decline may be possibly attributed to the on-going implementation of CHIP for PWID, highlighting the need for strengthening the existing harm reduction interventions by incorporating access to sterile needle/syringe and addressing the layered risks for women.

RtcB enzymes are RNA ligases that play essential roles in tRNA splicing, unfolded protein response, and RNA repair. In metazoa, RtcB functions as part of a five-subunit tRNA ligase complex (tRNA-LC) along with Ddx1, Cgi-99, Fam98B, and Ashwin. The human tRNA-LC or its individual subunits have been implicated in additional cellular processes including microRNA maturation, viral replication, DNA double-strand break repair, and mRNA transport. Here, we present a biochemical analysis of the inter-subunit interactions within the human tRNA-LC along with crystal structures of the catalytic subunit RTCB and the N-terminal domain of CGI-99. We show that the core of the human tRNA-LC is assembled from RTCB and the C-terminal alpha-helical regions of DDX1, CGI-99, and FAM98B, all of which are required for complex integrity. The N-terminal domain of CGI-99 displays structural homology to calponin-homology domains, and CGI-99 and FAM98B associate via their N-terminal domains to form a stable subcomplex. The crystal structure of GMP-bound RTCB reveals divalent metal coordination geometry in the active site, providing insights into its catalytic mechanism. Collectively, these findings shed light on the molecular architecture and mechanism of the human tRNA ligase complex and provide a structural framework for understanding its functions in cellular RNA metabolism.

Introduction: Limited information is available on blood pressure (BP) behavior in workers exposed to chronic intermittent hypoxia (CIH), and even less is known regarding effects of CIH on 24-h ambulatory BP in those affected by arterial hypertension at sea level (SL). The aims of this study were to assess clinic and 24-h ambulatory BP at SL and at high altitude (HA; 3,870 m above SL) in workers exposed to CIH, and to compare BP response to HA exposure between normotensive and hypertensive workers.Methods: Nineteen normotensive and 18 pharmacologically treated hypertensive miners acclimatized to CIH were included, whose work was organized according to a “7 days-on−7 days-off” shift pattern between SL and HA. All measurements were performed on the second and seventh day of their HA shift and after the second day of SL sojourn.Results: Compared to SL, 24-h systolic BP (SBP) and diastolic BP (DBP) increased at HA [+14.7 ± 12.6 mmHg (p < 0.001) and +8.7 ± 7.2 mmHg (p < 0.001), respectively], and SBP nocturnal fall decreased consistently (−4.1 ± 9.8%; p < 0.05) in all participants, with hypertensives showing higher nocturnal DBP than normotensives (p < 0.05) despite the current therapy. Also, heart rate (HR) nocturnal fall tended to be reduced at HA. In addition, the 24-h SBP/DBP hypertension threshold of ≥130/80 mmHg was exceeded by 39% of workers at SL and by 89% at HA. Clinic HR, SBP, and DBP were significantly higher on the second day of work at HA compared with SL, the increase being more pronounced for SBP in hypertensives (p < 0.05) and accompanied by, on average, mild altitude sickness in both groups. These symptoms and the values of all cardiovascular variables decreased on the seventh day at HA (p < 0.05) regardless of CIH exposure duration.Conclusion: Long history of work at HA according to scheduled CIH did not prevent the occurrence of acute cardiovascular changes at HA during the first days of exposure. The BP response to HA tended to be more pronounced in hypertensive than in normotensive workers despite being already treated; the BP changes were more evident for 24-h ambulatory BP. Twenty-four-hour ABP monitoring is a useful tool for an appropriate evaluation of BP in CIH workers.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy but there is limited literature characterizing the disease burden despite this being crucial for disease management strategies, and for designing and interpreting clinical trials. We searched the Vagus Nerve Stimulation (VNS) Therapy Patient Outcome Registry including over 7000 patients with drug‑resistant epilepsy (DRE). Propensity Score Matching (PSM) matched LGS-DRE patients and non-LGS-DRE patients and frequencies of individual seizure types were assessed. The PSM population included 705 and 1410 DRE patients with and without LGS. 40% of the LGS-DRE group had polypharmacy with 3 antiseizure medications (ASM) while 42% in non-LGS-DRE had polypharmacy with 2 ASMs. Median total monthly seizure frequency was over double in the LGS group: 90 (IQR, 28–312) versus 40 (IQR, 10–150); p

Background The higher cardiovascular variability and the increased prevalence of arrhythmias in patients with obstructive sleep apneas may contribute to their higher rate of fatal events during sleep. In this regard, the use of beta blockers (BB) is debated because they may induce bradyarrhythmias and alter the pattern of heart rate changes induced by apneas. Thus, the aim of our study is to quantify peri‐apneic heart‐rate swings and prevalence of nocturnal bradyarrhythmias in BB‐treated and BB‐naïve patients with obstructive sleep apnea. Methods and Results Our real‐life, retrospective, cohort study analyzed data from patients with obstructive sleep apnea after a basal cardiorespiratory polysomnography. Among 228 eligible participants, we enrolled 78 BB‐treated and 88 BB‐naïve patients excluding those treated with antiarrhythmic drugs or pacemakers, or with uninterpretable ECG traces during polysomnography. In each patient, type and frequency of arrhythmias were identified and peri‐apneic changes of RR intervals were evaluated for each apnea. BB‐treated patients were older and with more comorbidities than BB‐naïve patients, but had similar obstructive sleep apnea severity, similar frequency of arrhythmic episodes, and similar prevalence of bradyarrhythmias. Apnea‐induced heart‐rate swings, unadjusted for age, showed lower RR interval changes in BB‐treated (133.5±63.8 ms) than BB‐naïve patients (171.3±87.7 ms, P=0.01), lower RR interval increases during apneas (58.5±28.5 versus 74.6±40.2 ms, P=0.01), and lower RR interval decreases after apneas (75.0±42.4 versus 96.7±55.5 ms, P

The interest in photoplethysmography (PPG) for sleep monitoring is increasing because PPG may allow assessing heart rate variability (HRV), which is particularly important in breathing disorders. Thus, we aimed to evaluate how PPG wearable systems measure HRV during sleep at high altitudes, where hypobaric hypoxia induces respiratory disturbances. We considered PPG and electrocardiographic recordings in 21 volunteers sleeping at 4554 m a.s.l. (as a model of sleep breathing disorder), and five alpine guides sleeping at sea level, 6000 m and 6800 m a.s.l. Power spectra, multiscale entropy, and self-similarity were calculated for PPG tachograms and electrocardiography R–R intervals (RRI). Results demonstrated that wearable PPG devices provide HRV measures even at extremely high altitudes. However, the comparison between PPG tachograms and RRI showed discrepancies in the faster spectral components and at the shorter scales of self-similarity and entropy. Furthermore, the changes in sleep HRV from sea level to extremely high altitudes quantified by RRI and PPG tachograms in the five alpine guides tended to be different at the faster frequencies and shorter scales. Discrepancies may be explained by modulations of pulse wave velocity and should be considered to interpret correctly autonomic alterations during sleep from HRV analysis.

IntroductionRisk reduction towards safer behaviour is promoted after enrolment in HIV prevention trials. We evaluated sexual behaviour, changes in sexual behaviour and factors associated with risky behaviour after one-year of follow-up among women enrolled in HIV prevention trials in Northern Tanzania.MethodsSelf-reported information from 1378 HIV-negative women aged 18-44 enrolled in microbicide and vaccine feasibility studies between 2008-2010,was used to assess changes in behaviour during a 12-month follow-up period. Logistic regression with random intercepts was used to estimate odds ratios for trends in each behaviour over time. A behavioural risk score was derived from coefficients of three behavioural variables in a Poisson regression model for HIV incidence and thereafter, dichotomized to risky vs less-risky behaviour. Logistic regression was then used to identify factors associated with risky behaviour at 12 months.ResultsAt baseline, 22% reported multiple partners, 28% were involved in transactional sex and only 22% consistently used condoms with non-regular partners. The proportion of women reporting multiple partners, transactional sex and high-risk sex practices reduced at each 3-monthly visit (33%, 43% and 47% reduction in odds per visit respectively, p for linear trend ConclusionAn overall reduction in risky behaviours over time was observed in HIV prevention cohorts. Risk reduction counselling was associated with decreased risk behaviour but was insufficient to change behaviours of all those at highest risk. Biological HIV prevention interventions such as PrEP for individuals at highest risk, should complement risk reduction counselling so as to minimize HIV acquisition risk.

Background and Objectives: Lymphedema is an important and underestimated condition, and this progressive chronic disease has serious implications on patients’ quality of life. The main goal of research would be to prevent lymphedema, instead of curing it. Patients receiving radiotherapy after lymph node dissection have a significantly higher risk of developing lymphedema. Through the prophylactic use of microsurgical lymphaticovenular anastomoses in selected patients, we could prevent the development of lymphedema. Materials and Methods: Six patients who underwent prophylactic lymphaticovenular anastomoses in a distal site to the axillary or groin region after axillary or inguinal complete lymph node dissection followed by radiotherapy were analyzed. Patients characteristics, comorbidities, operative details, postoperative complications and follow-up assessments were recorded. Results: Neither early nor late generic surgical complications were reported. We observed no lymphedema development throughout the post-surgical follow-up. In particular, we observed no increase in limb diameter measured at 1, 3, 6 and 12 months postoperatively. Conclusion: In our experience, performing LVA after axillary or groin lymphadenectomy and after adjuvant radiotherapy, and distally to the irradiated area, allows us to ensure the long-term patency of anastomoses in order to obtain the best results in terms of reducing the risk of iatrogenic lymphedema. This preliminary report is encouraging, and the adoption of our approach should be considered in selected patients.

Los accidentes por mordeduras de perros (AMP) constituyen un creciente problema en salud pública. La ciudad de Rosario es la más poblada de la provincia de Santa Fe y se encuentra organizada en seis distritos. OBJETIVOS: Caracterizar demográficamente la probabilidad de AMP en niños menores de 15 años durante 2012-2013 y caracterizar las zonas corporales de lesión. METODOS: Se realizó un estudio observacional analítico retrospectivo a partir de los registros provenientes del Instituto Antirrábico del Hospital Carrasco, centro de referencia regional para los AMP. Se determinaron las incidencias acumuladas de AMP en el período 2012-2013 cada 1000 niños (IA2012-2013/1000), atendiendo a grupos etarios y a los distritos de la ciudad de Rosario. Se calcularon las razones de IA2012-2013/1000 y se ajustaron según correspondiese. RESULTADOS: En comparación con las mujeres, los varones presentaron casi el doble de probabilidad de padecer un AMP. A medida que descendía el grupo etario, se incrementaba la chance de AMP. Los distritos de la ciudad de Rosario registraron diferencias marcadas en términos de probabilidad de AMP; el Oeste se mostró como el más vulnerable. Se encontró una correlación significativa entre los grupos etarios y las zonas corporales de lesión. CONCLUSIONES: Se encontraron diferencias subpoblacionales en las variables estudiadas para los AMP, que deberán atenderse para implementar estrategias de prevención.

Trisomy 21 (T21) is a major cause of Down syndrome but little is known about its impact on the cellular proteome. Here, the authors define the proteome of T21 fibroblasts and its turnover and also map proteomic differences in monozygotic T21-discordant twins, revealing extensive, organelle-specific changes caused by T21.

Closed-loop models of the interactions between blood pressure (BP) and heart rate variations allow for estimation of baroreflex sensitivity (feedback effects of BP changes on heart rate) while also considering the feedforward effects of heart rate on BP. Our study is aimed at comparing modulations of feedback and feedforward couplings over 24 h in normotensive and hypertensive subjects, by assessing closed-loop baroreflex models in ambulatory conditions. Continuous intra-arterial BP recordings were performed for 24 h in eight normotensive and eight hypertensive subjects. Systolic BP (SBP) and pulse interval (PI) beat-by-beat series were analyzed by an autoregressive moving average model over consecutive 6-min running windows, estimating closed-loop feedback and feedforward gains in each window. The open-loop feedback gain was estimated for comparison. Normotensive and hypertensive patients were compared during wake (18:00–22:00) and sleep (23:00–5:00) periods by a mixed-effect linear model at p < 0.05. In both groups feedback (feedforward) gain averaged values were higher (lower) in sleep than in wake. Moreover, the closed-loop feedback gain was higher in normotensive subjects both in wake and sleep, whereas the closed-loop feedforward gain was higher in hypertensive subjects during sleep. By contrast, no significant differences were found between the normotensive and hypertensive groups for the open-loop feedback gain. Therefore, the closed-loop SBP-PI model can detect circadian alterations in the feedforward gain of PI on SBP and derangements of spontaneous baroreflex sensitivity in hypertension not detectable with the open-loop approach. These findings may help to obtain a more comprehensive assessment of the autonomic dysfunction underlying hypertension and for the in-depth evaluation of the benefits of rehabilitation procedures on autonomic cardiovascular modulation.

Background Several devices have been proposed to assess arterial stiffness in clinical daily use over the past few years, by estimating aortic pulse wave velocity (PWV) from a single measurement of brachial oscillometric blood pressure, using patented algorithms. It is uncertain if these systems are able to provide additional elements, beyond the contribution carried by age and blood pressure levels, in the definition of early vascular damage expressed by the stiffening of the arterial wall. Methods and Results The aim of our study was to compare the estimated algorithm‐based PWV values, provided by the Mobil‐O‐Graph system, with the standard noninvasive assessment of aortic PWV in patients with Marfan syndrome (ie, in subjects characterized by premature aortic stiffening and low blood pressure values). Aortic stiffness was simultaneously evaluated by carotid‐femoral PWV with a validated arterial tonometer and estimated with an arm cuff–based ambulatory blood pressure monitoring Mobil‐O‐Graph device on 103 patients with Marfan syndrome (50 men; mean±SD age, 38±15 years). Aortic PWV, estimated by the Mobil‐O‐Graph, was significantly (P

Detrended fluctuation analysis (DFA) is a popular tool in physiological and medical studies for estimating the self-similarity coefficient, α, of time series. Recent researches extended its use for evaluating multifractality (where α is a function of the multifractal parameter q) at different scales n. In this way, the multifractal-multiscale DFA provides a bidimensional surface α(q,n) to quantify the level of multifractality at each scale separately. We recently showed that scale resolution and estimation variability of α(q,n) can be improved at each scale n by splitting the series into maximally overlapped blocks. This, however, increases the computational load making DFA estimations unfeasible in most applications. Our aim is to provide a DFA algorithm sufficiently fast to evaluate the multifractal DFA with maximally overlapped blocks even on long time series, as usually recorded in physiological or clinical settings, therefore improving the quality of the α(q,n) estimate. For this aim, we revise the analytic formulas for multifractal DFA with first- and second-order detrending polynomials (i.e., DFA1 and DFA2) and propose a faster algorithm than the currently available codes. Applying it on synthesized fractal/multifractal series we demonstrate its numerical stability and a computational time about 1% that required by traditional codes. Analyzing long physiological signals (heart-rate tachograms from a 24-h Holter recording and electroencephalographic traces from a sleep study), we illustrate its capability to provide high-resolution α(q,n) surfaces that better describe the multifractal/multiscale properties of time series in physiology. The proposed fast algorithm might, therefore, make it easier deriving richer information on the complex dynamics of clinical signals, possibly improving risk stratification or the assessment of medical interventions and rehabilitation protocols.

Law no. 281, enacted by the Italian Parliament in 1991, was the first that aimed at managing urban free-roaming cats living in colonies, without killing and/or moving them from their site. It had been anticipated by the Lazio Regional Law no. 63/1988 and subsequently refined by the Lazio Regional Law no. 34/1997. These laws introduced: (i) the cats' right to live free and safe; (ii) the compulsory neutering of cats by the Veterinary Services of the Local Health Unit; (iii) the institutionalization of cat caretakers. Within this context, this paper intends to evaluate the effects of the application of the Italian laws on management of urban free-roaming cats for the years 1988 to 2018. To this end, some indicators have been built and applied to our activity data: number of censused colonies and number of cats; number of stable colonies due to neutering; number of hygiene and sanitary notifications; number of notifications to check cat welfare; number of bites by unowned free-roaming cats; number of notifications of cat poisoning. The number of citizens' requests for institutional interventions by public veterinary services in cat colonies management and, accordingly, the detection of cat colonies yet unknown, seem to confirm the interest of people to control the cat colonies in Rome in a humanitarian way, as evidenced in our data. This fact/phenomenon should be analyzed in its multiple dimensions, also including the many changes and social unrests which have affected the human-cat relationship in the last 30 years.

Objective: To investigate if invasively measured aortic pulse wave velocity (PWV) is accurately estimated by non-invasive methods purporting to assess it. Methods: One-hundred and two patients (30% female, age 65 ± 13 years) planned to undertake coronary angiography were evaluated with the following non-invasive devices: BPLab (Petr Telegin, Russia), Complior Analyse (Alam Medical, France), Mobil-O-Graph (IEM, Germany), pOpmètre (Axelife, France), PulsePen-ET, PulsePen-ETT (Diatecne, Italy) and SphygmoCor (AtCor, Australia). Aortic PWV was measured by aortic catheterization and simultaneous measurement of pressure waves above the aortic valve and at the aortic bifurcation (FS-Stiffcath, Flag Vascular, Italy). Results: The devices evaluating carotid-femoral PWV showed a very strong agreement between each other (r2 > 0.65) and with invasive aortic PWV (mean difference ± SD with invasive PWV: −0.73 ± 2.83 m/s (r2 = 0.41) for Complior-Analyse; 0.20 ± 2.54 m/s (r2 = 0.51) for PulsePen-ETT; −0.04 ± 2.33 m/s (r2 = 0.61) for PulsePen-ET; −0.61 ± 2.57 m/s (r2 = 0.49) for SphygmoCor). The finger-toe PWV, evaluated by the pOpmètre, and the PWV measured by BPLab showed a weak relationship with invasive PWV (respectively r 2 =0.12, 0.05), with carotid-femoral PWV measurements (r 2 =0.11, 0.010) and with age (r 2 =0.10, 0.06). PWV estimated with Mobil-O-Graph through a proprietary algorithm showed a good agreement with invasive PWV (mean difference ± SD = −1.01 ± 2.54 m/s; r2 = 0.51) and appeared to be strictly dependent on age-squared and peripheral systolic blood pressure (r2 > 0.99). Conclusions: Methods estimating carotid-femoral PWV should be considered the only non-invasive approach to reliably assess aortic stiffness. Aortic PWV values estimated by Mobil-O-Graph algorithm are also significantly related to invasive PWV, but do not offer any additional information on top of what provided by age and systolic blood pressure levels.

In the neocortex, critical periods (CPs) of plasticity are closed following the accumulation of perineuronal nets (PNNs) around parvalbumin (PV)-positive inhibitory interneurons. However, how PNNs tune cortical function and plasticity is unknown. We found that PNNs modulated the gain of visual responses and γ-oscillations in the adult mouse visual cortex in vivo, consistent with increased interneuron function. Removal of PNNs in adult V1 did not affect GABAergic neurotransmission from PV cells, nor neuronal excitability in layer 4. Importantly, PNN degradation coupled to sensory input potentiated glutamatergic thalamic synapses selectively onto PV cells. In the absence of PNNs, increased thalamic PV-cell recruitment modulated feed-forward inhibition differently on PV cells and pyramidal neurons. These effects depended on visual input, as they were strongly attenuated by monocular deprivation in PNN-depleted adult mice. Thus, PNNs control visual processing and plasticity by selectively setting the strength of thalamic recruitment of PV cells.

The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies—all issues of clinical relevance.

Multiple myeloma (MM) is a hematological disease characterized by the proliferation and accumulation of malignant plasmacells (PCs) in the bone marrow (BM). Despite widespread use of high-dose chemotherapy in combination with autologous stem cell transplantation (ASCT) and the introduction of novel agents (immunomodulatory drugs, IMiDs, and proteasome inhibitors, PIs), the prognosis of MM patients is still poor. CD38 is a multifunctional cell-surface glycoprotein with receptor and ectoenzymatic activities. The very high and homogeneous expression of CD38 on myeloma PCs makes it an attractive target for novel therapeutic strategies. Several anti-CD38 monoclonal antibodies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab. Here we provide an in-depth look atCD38 biology, the role of CD38 in MM progression and its complex interactions with the BM microenvironment, the importance of anti-CD38 monoclonal antibodies, and the main mechanisms of antibody resistance. We then review a number of multiparametric flow cytometry techniques exploiting CD38 antigen expression on PCs to diagnose and monitor the response to treatment in MM patients.

Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma.

Recently, a multifractal-multiscale approach to detrended fluctuation analysis (DFA) was proposed to evaluate the cardiovascular fractal dynamics providing a surface of self-similarity coefficients α(q,τ), function of the scale τ, and moment order q. We hypothesize that this versatile DFA approach may reflect the cardiocirculatory adaptations in complexity and nonlinearity occurring during the day/night cycle. Our aim is, therefore, to quantify how α(q, τ) surfaces of cardiovascular series differ between daytime and night-time. We estimated α(q,τ) with −5 ≤ q ≤ 5 and 8 ≤ τ ≤ 2048 s for heart rate and blood pressure beat-to-beat series over periods of few hours during daytime wake and night-time sleep in 14 healthy participants. From the α(q,τ) surfaces, we estimated short-term (q. We found a long-term night/day modulation of α(q,τ) between 128 and 256 s affecting heart rate and blood pressure similarly, and multifractal short-term modulations at q < 0 for the heart rate and at q > 0 for the blood pressure. Consistent nonlinearity appeared at the shorter scales at night excluding q = 2. Long-term circadian modulations of the heart rate DFA were previously associated with the cardiac vulnerability period and our results may improve the risk stratification indicating the more relevant α(q,τ) area reflecting this rhythm. Furthermore, nonlinear components in the nocturnal α(q,τ) at q ≠ 2 suggest that DFA may effectively integrate the linear spectral information with complexity-domain information, possibly improving the monitoring of cardiac interventions and protocols of rehabilitation medicine.

Multiple myeloma (MM) derives from malignant transformation of plasma cells (PC), which accumulate in the bone marrow (BM), where microenvironment supports tumor growth and inhibits anti-tumor immune responses. Adenosine (ADO), an immunosuppressive molecule, is produced within MM patients' BM by adenosinergic ectoenzymes, starting from ATP (CD39/CD73) or NAD+ [CD38/CD203a(PC-1)/CD73]. These ectoenzymes form a discontinuous network expressed by different BM cells. We investigated the expression and function of ectoenzymes on microvesicles (MVs) isolated from BM plasma samples of patients with MM, using asymptomatic forms of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) as controls. The percentage of MVs expressing ectoenzymes at high levels was higher when derived from MM patients than controls. BM CD138+ PC from MM patients expressed high levels of all ectoenzymes. Paired MVs samples confirmed a higher percentage of MVs with high ectoenzymes expression in MM patients than controls. Pooled MVs from MM patients or controls were tested for ADO production. The catabolism of ATP, NAD+, ADPR and AMP to ADO was higher in MVs from MM patients than in those from controls. In conclusion, our results confirmed the hypothesis that MVs in MM niche are main contributor of ADO production. The ability of MVs to reach biological fluids strongly support the view that MVs may assume diagnostic and pathogenetic roles.

Background Acute exposure to high‐altitude hypobaric hypoxia induces a blood pressure rise in hypertensive humans, both at rest and during exercise. It is unclear whether this phenomenon reflects specific blood pressure hyperreactivity or rather an upward shift of blood pressure levels. We aimed at evaluating the extent and rate of blood pressure rise during exercise in hypertensive subjects acutely exposed to high altitude, and how these alterations can be counterbalanced by antihypertensive treatment. Methods and Results Fifty‐five subjects with mild hypertension, double‐blindly randomized to placebo or to a fixed‐dose combination of an angiotensin‐receptor blocker (telmisartan 80 mg) and a calcium‐channel blocker (nifedipine slow release 30 mg), performed a cardiopulmonary exercise test at sea level and after the first night's stay at 3260 m altitude. High‐altitude exposure caused both an 8 mm Hg upward shift (P

Introduction: The observed association between depressive symptoms and cognitive performances has not been previously clarified in patients with amyotrophic lateral sclerosis (pALS). In fact, the use of cognitive measures often not accommodating for motor disability has led to heterogeneous and not conclusive findings about this issue. The aim of the present study was to evaluate the relationship between cognitive and depressive/anxiety symptoms by means of the recently developed Edinburgh Cognitive and Behavioral ALS Screen (ECAS), a brief assessment specifically designed for pALS.Methods: Sample included 168 pALS (114 males, 54 females); they were administered two standard cognitive screening tools (FAB; MoCA) and the ECAS, assessing different cognitive domains, including ALS-specific (executive functions, verbal fluency, and language tests) and ALS non-specific subtests (memory and visuospatial tests). Two psychological questionnaires for depression and anxiety (BDI; STAI/Y) were also administered to patients. Pearson’s correlation coefficient was used to assess the degree of association between cognitive and psychological measures.Results: Depression assessment negatively correlated with the ECAS, more significantly with regard to the executive functions subdomain. In particular, Sentence Completion and Social Cognition subscores were negatively associated with depression levels measured by BDI total score and Somatic-Performance symptoms subscore. Conversely, no significant correlations were observed between depression level and cognitive functions as measured by traditional screening tools for frontal abilities (FAB) and global cognition (MoCA) assessment. Finally, no significant correlations were observed between state/trait anxiety and the ECAS.Discussion and conclusion: This represents the first study focusing on the relationship between cognitive and psychological components in pALS by means of the ECAS, the current gold standard for ALS cognitive-behavioral assessment. If confirmed by further investigations, the observed association between depression and executive functions suggests the need for a careful screening and treatment of depression, to avoid overestimation of cognitive involvement and possibly improve cognitive performances in ALS.

BACKGROUND:In pulmonary hypertension (PH), both wedge pressure elevation (PAWP) and a precapillary component may affect right ventricular (RV) afterload. These changes may contribute to RV failure and prognosis. We aimed at describing the different haemodynamic phenotypes of patients with PH due to left heart disease (LHD) and at characterizing the impact of pulmonary haemodynamics on RV function and outcome PH-LHD. METHODS:Patients with PH-LHD were compared with treatment-naïve idiopathic/heritable pulmonary arterial hypertension (PAH, n = 35). PH-LHD patients were subdivided in Isolated post-capillary PH (IpcPH: diastolic pressure gradient, DPG3 WU, n = 27), and "intermediate" PH-LHD (either DPG

Iron overload-related heart failure is the principal cause of death in transfusion dependent patients, including those with Thalassemia Major. Linking cardiac siderosis measured by T2* to therapy improves outcomes. T1 mapping can also measure iron; preliminary data suggests it may have higher sensitivity for iron, particularly for early overload (the conventional cut-point for no iron by T2* is 20ms, but this is believed insensitive). We compared T1 mapping to T2* in cardiac iron overload.In a prospectively large single centre study of 138 Thalassemia Major patients and 32 healthy controls, we compared T1 mapping to dark blood and bright blood T2* acquired at 1.5T. Linear regression analysis was used to assess the association of T2* and T1. A "moving window" approach was taken to understand the strength of the association at different levels of iron overload.The relationship between T2* (here dark blood) and T1 is described by a log-log linear regression, which can be split in three different slopes: 1) T2* low, 30ms, weak relationship. All subjects with T2*20ms, 38% had low T1 with most of the subjects in the T2* range 20-30ms having a low T1.In established cardiac iron overload, T1 and T2* are concordant. However, in the 20-30ms T2* range, T1 mapping appears to detect iron. These data support previous suggestions that T1 detects missed iron in 1 out of 3 subjects with normal T2*, and that T1 mapping is complementary to T2*. The clinical significance of a low T1 with normal T2* should be further investigated.

Detrended Fluctuation Analysis (DFA) is a popular method for assessing the fractal characteristics of biosignals, recently adapted for evaluating the heart-rate multifractal and/or multiscale characteristics. However, the existing methods do not consider the beat-by-beat sampling of heart rate and have relatively low scale resolutions and were not applied to cardiovascular signals other than heart rate. Therefore, aim of this work is to present a DFA-based method for joint multifractal/multiscale analysis designed to address the above critical points and to provide the first description of the multifractal/multiscale structure of interbeat intervals (IBI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in male and female volunteers separately. The method optimizes data splitting in blocks to reduce the DFA estimation variance and to evaluate scale coefficients with Taylor’s expansion formulas and maps the scales from beat domains to temporal domains. Applied to cardiovascular signals recorded in 42 female and 42 male volunteers, it showed that scale coefficients and degree of multifractality depend on the temporal scale, with marked differences between IBI, SBP, and DBP and with significant sex differences. Results may be interpreted considering the distinct physiological mechanisms regulating heart-rate and blood-pressure dynamics and the different autonomic profile of males and females.

BACKGROUND AND OBJECTIVE:The presence of executive deficits in patients with Amyotrophic Lateral Sclerosis is well established, even if standardized measures are difficult to obtain due to progressive physical disability of the patients. We present clinical data concerning a newly developed measure of cognitive flexibility, administered by means of Eye-Tracking (ET) technology in order to bypass verbal-motor limitations. METHODS:21 ALS patients and 21 age-and education-matched healthy subjects participated in an ET-based cognitive assessment, including a newly developed test of cognitive flexibility (Arrows and Colors Cognitive Test-ACCT) and other oculomotor-driven measures of cognitive functions. A standard screening of frontal and working memory abilities and global cognitive efficiency was administered to all subjects, in addition to a psychological self-rated assessment. For ALS patients, a clinical examination was also performed. RESULTS:ACCT successfully discriminated between patients and healthy controls, mainly concerning execution times obtained at different subtests. A qualitative analysis performed on error distributions in patients highlighted a lower prevalence of perseverative errors, with respect to other type of errors. Correlations between ACCT and other ET-based frontal-executive measures were significant and involved different frontal sub-domains. Limited correlations were observed between ACCT and standard 'paper and pencil' cognitive tests. CONCLUSIONS:The newly developed ET-based measure of cognitive flexibility could be a useful tool to detect slight frontal impairments in non-demented ALS patients by bypassing verbal-motor limitations through the oculomotor-driven administration. The findings reported in the present study represent the first contribution towards the development of a full verbal-motor free executive test for ALS patients.