A Novel Broadband Forcecardiography Sensor for Simultaneous Monitoring of Respiration, Infrasonic Cardiac Vibrations and Heart Sounds

The precordial mechanical vibrations generated by cardiac contractions have a rich frequency spectrum. While the lowest frequencies can be palpated, the higher infrasonic frequencies are usually captured by the seismocardiogram (SCG) signal and the audible ones correspond to heart sounds. Forcecardiography (FCG) is a non-invasive technique that measures these vibrations via force sensing resistors (FSR). This study presents a new piezoelectric sensor able to record all heart vibrations simultaneously, as well as a respiration signal. The new sensor was compared to the FSR-based one to assess its suitability for FCG. An electrocardiogram (ECG) lead and a signal from an electro-resistive respiration band (ERB) were synchronously acquired as references on six healthy volunteers (4 males, 2 females) at rest. The raw signals from the piezoelectric and the FSR-based sensors turned out to be very similar. The raw signals were divided into four components: Forcerespirogram (FRG), Low-Frequency FCG (LF-FCG), High-Frequency FCG (HF-FCG) and heart sounds (HS-FCG). A beat-by-beat comparison of FCG and ECG signals was carried out by means of regression, correlation and Bland–Altman analyses, and similarly for respiration signals (FRG and ERB). The results showed that the infrasonic FCG components are strongly related to the cardiac cycle (R2 > 0.999, null bias and Limits of Agreement (LoA) of ± 4.9 ms for HF-FCG; R2 > 0.99, null bias and LoA of ± 26.9 ms for LF-FCG) and the FRG inter-breath intervals are consistent with ERB ones (R2 > 0.99, non-significant bias and LoA of ± 0.46 s). Furthermore, the piezoelectric sensor was tested against an accelerometer and an electronic stethoscope: synchronous acquisitions were performed to quantify the similarity between the signals. ECG-triggered ensemble averages (synchronized with R-peaks) of HF-FCG and SCG showed a correlation greater than 0.81, while those of HS-FCG and PCG scored a correlation greater than 0.85. The piezoelectric sensor demonstrated superior performances as compared to the FSR, providing more accurate, beat-by-beat measurements. This is the first time that a single piezoelectric sensor demonstrated the ability to simultaneously capture respiration, heart sounds, an SCG-like signal (i.e., HF-FCG) and the LF-FCG signal, which may provide information on ventricular emptying and filling events. According to these preliminary results the novel piezoelectric FCG sensor stands as a promising device for accurate, unobtrusive, long-term monitoring of cardiorespiratory functions and paves the way for a wide range of potential applications, both in the research and clinical fields. However, these results should be confirmed by further analyses on a larger cohort of subjects, possibly including also pathological patients

6-Methylquinazolin-4(3H)-one Based Compounds as BRD9 Epigenetic Reader Binders: A Rational Combination of in silico Studies and Chemical Synthesis

6-methylquinazolin-4(3H)-one-based compounds were here identified and synthesized as novel binders of bromodomain-containing protein 9 (BRD9) epigenetic reader. Accounting a fast and efficient synthetic route aimed to easily obtain differently 2- and 8-disubstituted 6-methylquinazolin-4(3H)-one derivatives, a virtual library of synthesizable items was built and submitted to molecular docking experiments. Based on two 3D structure-based pharmacophore models recently developed by us on BRD9, 16 compounds were selected and synthesized, using mild conditions with good yields in relatively short reaction times. Among them, 14, 16, 18, 22, and 26 emerged as the most potent compounds of these series, able to bind BRD9 at the low micromolar range of concentrations. These molecules also showed a promising selective behavior when tested against BRD4 bromodomain. These results highlighted the quinazolin-4(3H)-one chemical core as a valuable scaffold for developing promising BRD9 binders

A General Stochastic Process for Day-to-Day Dynamic Traffic Assignment: Formulation, Asymptotic Behaviour, and Stability Analysis

This paper presents a general modelling approach to day-to-day dynamic assignment to a congested network through discrete-time stochastic and deterministic process models including an explicit modelling of users’ habit as a part of route choice behaviour, through an exponential smoothing filter, and of their memory of network conditions on past days, through a moving average or an exponentially smoothing filter. An asymptotic analysis of the mean process is carried out to provide a better insight. Results of such analyses are also used for deriving conditions, about values of the system parameters, assuring that the mean process is dissipative and/or converges to some kind of attractor. Numerical small examples are also provided in order to illustrate the theoretical results obtained

Tracing day-zero and forecasting the COVID-19 outbreak in Lombardy, Italy: A compartmental modelling and numerical optimization approach

Introduction Italy became the second epicenter of the novel coronavirus disease 2019 (COVID-19) pandemic after China, surpassing by far China’s death toll. The disease swept through Lombardy, which remained in lockdown for about two months, starting from the 8th of March. As of that day, the isolation measures taken in Lombardy were extended to the entire country. Here, assuming that effectively there was one case “zero” that introduced the virus to the region, we provide estimates for: (a) the day-zero of the outbreak in Lombardy, Italy; (b) the actual number of asymptomatic infected cases in the total population until March 8; (c) the basic (R0)and the effective reproduction number (Re) based on the estimation of the actual number of infected cases. To demonstrate the efficiency of the model and approach, we also provide a tentative forecast two months ahead of time, i.e. until May 4, the date on which relaxation of the measures commenced, on the basis of the COVID-19 Community Mobility Reports released by Google on March 29. Methods To deal with the uncertainty in the number of the actual asymptomatic infected cases in the total population Volpert et al. (2020), we address a modified compartmental Susceptible/ Exposed/ Infectious Asymptomatic/ Infected Symptomatic/ Recovered/ Dead (SEIIRD) model with two compartments of infectious persons: one modelling the cases in the population that are asymptomatic or experience very mild symptoms and another modelling the infected cases with mild to severe symptoms. The parameters of the model corresponding to the recovery period, the time from the onset of symptoms to death and the time from exposure to the time that an individual starts to be infectious, have been set as reported from clinical studies on COVID-19. For the estimation of the day-zero of the outbreak in Lombardy, as well as of the “effective” per-day transmission rate for which no clinical data are available, we have used the proposed SEIIRD simulator to fit the numbers of new daily cases from February 21 to the 8th of March. This was accomplished by solving a mixed-integer optimization problem. Based on the computed parameters, we also provide an estimation of the basic reproduction number R0 and the evolution of the effective reproduction number Re. To examine the efficiency of the model and approach, we ran the simulator to “forecast” the epidemic two months ahead of time, i.e. from March 8 to May 4. For this purpose, we considered the reduction in mobility in Lombardy as released on March 29 by Google COVID-19 Community Mobility Reports, and the effects of social distancing and of the very strict measures taken by the government on March 20 and March 21, 2020. Results Based on the proposed methodological procedure, we estimated that the expected day-zero was January 14 (min-max rage: January 5 to January 23, interquartile range: January 11 to January 18). The actual cumulative number of asymptomatic infected cases in the total population in Lombardy on March 8 was of the order of 15 times the confirmed cumulative number of infected cases, while the expected value of the basic reproduction number R0 was found to be 4.53 (min-max range: 4.40- 4.65). On May 4, the date on which relaxation of the measures commenced the effective reproduction number was found to be 0.987 (interquartiles: 0.857, 1.133). The model approximated adequately two months ahead of time the evolution of reported cases of infected until May 4, the day on which the phase I of the relaxation of measures was implemented over all of Italy. Furthermore the model predicted that until May 4, around 20% of the population in Lombardy has recovered (interquartile range: *10% to *30%)

First-in-human pharmacokinetics of tamoxifen and its metabolites in the milk of a lactating mother. A case study

Background Breast cancer represents the most frequent neoplasm diagnosed in women of childbearing age. When the tumour is oestrogen receptor-positive, tamoxifen is among the recommended endocrine treatments. Lactating women are advised not to breastfeed while receiving tamoxifen. However, information about tamoxifen transfer into breast milk is lacking. Methods We measured the concentration of tamoxifen and its metabolites by liquid chromatography-tandem mass spectrometry in the milk of a nursing mother that was treated for pregnancy-associated breast cancer diagnosed a few months after delivery. She was advised not to breastfeed her child and she collected milk samples for 23 days while the baby was fed with formula. Results Tamoxifen concentrations in milk increased reaching a maximum of 214 nM. The two active metabolitesZ-4-hydroxy-tamoxifen and Z-endoxifen, could not be quantified in milk the first days after tamoxifen intake, but increased over time and reached clinically significant levels after day 18. Conclusion This study demonstrates for the first time in human that tamoxifen and its metabolites transfer into milk. Since tamoxifen has a complete oral bioavailability, a long half-life (>7 days) and may interfere with the normal development of the infant, mothers should not breastfeed during tamoxifen treatment

Wearable Bluetooth Triage Healthcare Monitoring System.

Triage is the first interaction between a patient and a nurse/paramedic. This assessment, usually performed at Emergency departments, is a highly dynamic process and there are international grading systems that according to the patient condition initiate the patient journey. Triage requires an initial rapid assessment followed by routine checks of the patients' vitals, including respiratory rate, temperature, and pulse rate. Ideally, these checks should be performed continuously and remotely to reduce the workload on triage nurses; optimizing tools and monitoring systems can be introduced and include a wearable patient monitoring system that is not at the expense of the patient's comfort and can be remotely monitored through wireless connectivity. In this study, we assessed the suitability of a small ceramic piezoelectric disk submerged in a skin-safe silicone dome that enhances contact with skin, to detect wirelessly both respiration and cardiac events at several positions on the human body. For the purposes of this evaluation, we fitted the sensor with a respiratory belt as well as a single lead ECG, all acquired simultaneously. To complete Triage parameter collection, we also included a medical-grade contact thermometer. Performances of cardiac and respiratory events detection were assessed. The instantaneous heart and respiratory rates provided by the proposed sensor, the ECG and the respiratory belt were compared via statistical analyses. In all considered sensor positions, very high performances were achieved for the detection of both cardiac and respiratory events, except for the wrist, which provided lower performances for respiratory rates. These promising yet preliminary results suggest the proposed wireless sensor could be used as a wearable, hands-free monitoring device for triage assessment within emergency departments. Further tests are foreseen to assess sensor performances in real operating environments

Interview investigation of insecure attachment styles as mediators between poor childhood care and schizophrenia-spectrum phenomenology

Background Insecure attachment styles have received theoretical attention and some initial empirical support as mediators between childhood adverse experiences and psychotic phenomena; however, further specificity needs investigating. The present interview study aimed to examine (i) whether two forms of poor childhood care, namely parental antipathy and role reversal, were associated with subclinical positive and negative symptoms and schizophrenia-spectrum personality disorder (PD) traits, and (ii) whether such associations were mediated by specific insecure attachment styles. Method A total of 214 nonclinical young adults were interviewed for subclinical symptoms (Comprehensive Assessment of At-Risk Mental States), schizophrenia-spectrum PDs (Structured Clinical Interview for DSM-IV Axis II Disorders), poor childhood care (Childhood Experience of Care and Abuse Interview), and attachment style (Attachment Style Interview). Participants also completed the Beck Depression Inventory-II and all the analyses were conducted partialling out the effects of depressive symptoms. Results Both parental antipathy and role reversal were associated with subclinical positive symptoms and with paranoid and schizotypal PD traits. Role reversal was also associated with subclinical negative symptoms. Angry-dismissive attachment mediated associations between antipathy and subclinical positive symptoms and both angry-dismissive and enmeshed attachment mediated associations of antipathy with paranoid and schizotypal PD traits. Enmeshed attachment mediated associations of role reversal with paranoid and schizotypal PD traits. Conclusions Attachment theory can inform lifespan models of how adverse developmental environments may increase the risk for psychosis. Insecure attachment provides a promising mechanism for understanding the development of schizophrenia-spectrum phenomenology and may offer a useful target for prophylactic intervention

Fertility-sparing treatment for endometrial cancer and atypical endometrial hyperplasia in patients with Lynch Syndrome: Molecular diagnosis after immunohistochemistry of MMR proteins

Introduction: Lynch Syndrome (LS) represents the hereditary condition that is most frequently associated with endometrial cancer (EC). The aim of this study is to assess the presence of Lynch Syndrome (LS) in young women with mismatch repair (MMR)-deficient atypical endometrial hyperplasia (AEH) and non-myoinvasive FIGO G1 endometrioid EC and its possible impact on the outcome of conservative treatment. Methods: Six MMR-deficient cases identified from a previous cohort of 69 conservatively treated patients were selected to be screened for germline mutations in MMR genes. In each patient, the outcomes of conservative treatment for AEH and EEC, including response, relapse, progression, and pregnancy, were assessed. Results: Five out of 6 patients underwent genetic test for LS. Three out of these 5 patients showed a positive genetic test. Patient 1 showed the c.942 + 2 T>A heterozygous variant of MSH2 mutation; after 12 months of complete response, she had relapse and progression of disease. Patient 4 showed the c.2459-1G>C variant of MSH2 mutation; after complete response, she failed to achieve pregnancy; she had relapse after 24 months and underwent hysterectomy. Patient 6 showed the c.803 + 1 heterozygous variant of PMS2 mutation; she had relapse of disease after 18 months from the first complete response and then underwent hysterectomy. Conclusions: In this series, 3 out of 6 women with MMR-deficiency had LS. None of the patients achieved pregnancy, and those who responded to treatment had subsequent relapse of disease. Patients undergoing fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer should perform MMR immunohistochemical analysis in order to screen LS

Immuno-modulatory and anti-Inflammatory effects of dihydrogracilin A, a trpene derived from the marine sponge Dendrilla membranosa.

We assessed the immunomodulatory and anti-inflammatory effects of 9,11-dihydrogracilin A (DHG), a molecule derived from the Antarctic marine sponge Dendrilla membranosa. We used in vitro and in vivo approaches to establish DHG properties. Human peripheral blood mononuclear cells (PBMC) and human keratinocytes cell line (HaCaT cells) were used as in vitro system, whereas a model of murine cutaneous irritation was adopted for in vivo studies. We observed that DHG reduces dose dependently the proliferative response and viability of mitogen stimulated PBMC. In addition, DHG induces apoptosis as revealed by AnnexinV staining and downregulates the phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B), signal transducer and activator of transcription (STAT) and extracellular signal\u2013regulated kinase (ERK) at late time points. These effects were accompanied by down-regulation of interleukin 6 (IL-6) production, slight decrease of IL-10 and no inhibition of tumor necrosis factor-alpha (TNF-) secretion. To assess potential properties of DHG in epidermal inflammation we used HaCaT cells; this compound reduces cell growth, viability and migration. Finally, we adopted for the in vivo study the croton oil-induced ear dermatitis murine model of inflammation. Of note, topical use of DHG significantly decreased mouse ear edema. These results suggest that DHG exerts anti-inflammatory effects and its anti-edema activity in vivo strongly supports its potential therapeutic application in inflammatory cutaneous diseases