Search Results (19)

Background/Objectives: P2X3 receptor antagonists have been suggested as a potential treatment for urogenital, respiratory and pain conditions. This first-in-human (FiH) study evaluated filapixant, a new P2X3 receptor antagonist with high receptor selectivity. It was anticipated that filapixant would cause fewer taste-related side effects compared to the unselective P2X3/P2X2/3 antagonist gefapixant and the less selective P2X3 antagonist eliapixant. This study assessed the tolerability, safety and PK of filapixant, the effect of food on PK and relative BA of a tablet vs. solution. Methods: This study (NCT03212586) followed a randomized, double-blind single-ascending-dose design. A total of 72 healthy male subjects received a solution (6–60 mg) or immediate-release tablets (120–1250 mg) of filapixant or corresponding placebo in fasted state. The subjects at 60 mg were re-dosed with 60 mg tablets in both fasted and fed states. The endpoints included PK parameters, dose proportionality, adverse events, and taste assessments (taste strips; dysgeusia questionnaire). Results: Filapixant showed dose-proportional PK with a half-life (about 10–15 h), supporting once-daily dosing. Food minimally affected PK and BA was comparable between tablet and solution. Filapixant was well tolerated; however, the number of taste side effects was unexpectedly high. Comparing the results observed across clinical filapixant studies, the threshold for such side effects seems to be well below the in vitro IC₅₀ for P2X2/3. Conclusions: Treatment with filapixant was safe and well tolerated. Filapixant showed dose-proportional PK, bioavailability similar to that of a solution and a tablet, and a minor effect of food on PK. The number of taste side effects was unexpectedly high considering the high in vitro P2X3 receptor selectivity. Factors other than selectivity are needed to explain taste profile differences between P2X3 antagonists. Full article

Background: Early post-operative airway management after laryngo-tracheal surgery is crucial. Acute respiratory failure due to glottis’ edema may occur, requiring reintubation. This can prolong ventilatory assistance, jeopardizing anastomosis. To date, only judicious steroid administration and fluid management are available to avoid more invasive procedures. High-flow oxygen therapy (HFOT) is a noninvasive O₂ support method providing humidification, warmed air, and Positive End-Expiratory Pressure (AIRVO2). No data about HFOT use to prevent early complications after laryngo-tracheal surgery are reported in the literature. Methods: Between September 2020 and September 2022, 107 consecutive patients who underwent laryngo-tracheal surgery received HFOT (Group A). Data and long-term results were compared with those of 80 patients operated between September 2018 and August 2020 (Group B), when HFOT was not available. All patients were operated in a single center. No pre- or post-operative settings changed, except for HFOT introduction. We analyzed and compared the risk for “delayed” reintubation (unexpected reintubation within the first 24–48 h after extubating/laryngeal mask removal) in the two groups. Results: No patients reported HFOT-related adverse events. The control group (B) presented “delayed” reintubation in 37% (p = 0.027), intensive care unit admission in 67% (p = 0.005) and longer hospital stay (p = 0.001) compared to the HFOT group (A). The minor complications’ rate was 3% in both group and overall mortality was 0%. Re-stenosis was described in 4.6% of the HFOT group, without a statistically significant difference (p = 0.7006). Conclusions: Our study is the first to investigate HFOT use in patients undergoing laryngo-tracheal surgery, potentially representing a consistent innovation in the peri-operative management of these patients. With the limitation of a retrospective series, we would suggest HFOT use for preventing post-operative reintubation rate, possibly reducing ICU admissions and hospital stays. Full article

Emerging and re-emerging viruses periodically cause outbreaks and epidemics around the world, which ultimately lead to global events such as the COVID-19 pandemic. Thus, the urgent need for new antiviral drugs is obvious. Over more than a century of antiviral development, nucleoside analogs have proven to be promising agents against diversified DNA and RNA viruses. Here, we present the synthesis and evaluation of the antiviral activity of nucleoside analogs and their deglycosylated derivatives based on a hydroxybenzo[4,5]imidazo[1,2-c]pyrimidin-1(2H)-one scaffold. The antiviral activity was evaluated against a panel of structurally and phylogenetically diverse RNA and DNA viruses. The leader compound showed micromolar activity against representatives of the family Coronaviridae, including SARS-CoV-2, as well as against respiratory syncytial virus in a submicromolar range without noticeable toxicity for the host cells. Surprisingly, methylation of the aromatic hydroxyl group of the leader compound resulted in micromolar activity against the varicella-zoster virus without any significant impact on cell viability. The leader compound was shown to be a weak inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase. It also inhibited biocondensate formation important for SARS-CoV-2 replication. The active compounds may be considered as a good starting point for further structure optimization and mechanistic and preclinical studies. Full article

Introduction: Patients receiving bariatric surgery are at risk for sleep apnea (OSA) and need extensive surveillance in the postoperative period. There is evidence of respiratory events (RE) several hours after leaving PACU. We analyzed the late onset of RE in patients recovering from bariatric surgery and their opiate requirements through the first night after surgery. Methods: We studied 52 patients with OSA and 38 non-OSA patients. Preoperative studies comprised meticulous OSA evaluation for all patients and computing the predictive score PRODIGY to stratify for the risk of RE. All patients received intraoperative multimodal non-opioid anesthesia. After PACU recovery, patients were admitted to a ward and continuously monitored for pulse oximetry, heart rate, and acoustic respiratory rate for up to 18 h using MASIMO RAD-97 and TRACE software (Masimo, USA). Results: All patients showed a progressing reduction in the frequency of RE after admission to the floor. Desaturations and bradypnea, however, increased significantly for a second peak between 14 and 16 h in the OSA group. The opiate doses administered to OSA and non-OSA patients were not different and remained low during the increases in RE. Discussion: After bariatric surgery, patients with OSA show significant late-desaturation and bradypnea events. Opiate administration cannot be invoked as the cause. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in humans in late 2019 and spread rapidly, becoming a global pandemic. A zoonotic spillover event from animal to human was identified as the presumed origin. Subsequently, reports began emerging regarding spillback events resulting in SARS-CoV-2 infections in multiple animal species. These events highlighted critical links between animal and human health while also raising concerns about the development of new reservoir hosts and potential viral mutations that could alter the virulence and transmission or evade immune responses. Characterizing susceptibility, prevalence, and transmission between animal species became a priority to help protect animal and human health. In this study, we coalesced a large team of investigators and community partners to surveil for SARS-CoV-2 in domestic and free-ranging animals around Ohio between May 2020 and August 2021. We focused on species with known or predicted susceptibility to SARS-CoV-2 infection, highly congregated or medically compromised animals (e.g., shelters, barns, veterinary hospitals), and animals that had frequent contact with humans (e.g., pets, agricultural animals, zoo animals, or animals in wildlife hospitals). This included free-ranging deer (n = 76 individuals), free-ranging mink (n = 57), multiple species of bats (n = 59), and other wildlife in addition to domestic cats (n = 275) and pigs (n = 184). In total, we tested 792 individual animals (34 species) via rRT-PCR for SARS-CoV-2 RNA. SARS-CoV-2 viral RNA was not detected in any of the tested animals despite a major peak in human SARS-CoV-2 cases that occurred in Ohio subsequent to the peak of animal samplings. Importantly, we did not test for SARS-CoV-2 antibodies in this study, which limited our ability to assess exposure. While the results of this study were negative, the surveillance effort was critical and remains key to understanding, predicting, and preventing the re-emergence of SARS-CoV-2 in humans or animals. Full article

Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality worldwide. Hospitalization due to acute exacerbations of COPD (AECOPD) is a relevant health problem both for its impact on disease outcomes and on health system resources. Severe AECOPD causing acute respiratory failure (ARF) often requires admission to an intensive care unit (ICU) with endotracheal intubation and invasive mechanical ventilation. AECOPD also acts as comorbidity in critically ill patients; this condition is associated with poorer prognoses. The prevalence reported in the literature on ICU admission rates ranges from 2 to 19% for AECOPD requiring hospitalization, with an in-hospital mortality rate of 20–40% and a re-hospitalization rate for a new severe event being 18% of the AECOPD cases admitted to ICUs. The prevalence of AECOPD in ICUs is not properly known due to an underestimation of COPD diagnoses and COPD misclassifications in administrative data. Non-invasive ventilation in acute and chronic respiratory failure may prevent AECOPD, reducing ICU admissions and disease mortality, especially when associated with a life-threating episode of hypercapnic ARF. In this review, we report on up to date evidence from the literature, showing how improving the knowledge and management of AECOPD is still a current research issue and clinical need. Full article

Introduction: Benign subglottic/tracheal stenosis (SG/TS) is a life-threatening condition commonly caused by prolonged endotracheal intubation or tracheostomy. Invasive mechanical ventilation was frequently used to manage severe COVID-19, resulting in an increased number of patients with various degrees of residual stenosis following respiratory weaning. The aim of this study was to compare demographics, radiological characteristics, and surgical outcomes between COVID-19 and non-COVID patients treated for tracheal stenosis and investigate the potential differences between the groups. Materials and methods: We retrospectively retrieved electronical medical records of patients managed at two referral centers for airways diseases (IRCCS Humanitas Research Hospital and Avicenne Hospital) with tracheal stenosis between March 2020 and May 2022 and grouped according to SAR-CoV-2 infection status. All patients underwent a radiological and endoscopic evaluation followed by multidisciplinary team consultation. Follow-up was performed through quarterly outpatient consultation. Clinical findings and outcomes were analyzed by using SPPS software. A significance level of 5% (p < 0.05) was adopted for comparisons. Results: A total of 59 patients with a mean age of 56.4 (±13.4) years were surgically managed. Tracheal stenosis was COVID related in 36 (61%) patients. Obesity was frequent in the COVID-19 group (29.7 ± 5.4 vs. 26.9 ± 3, p = 0.043) while no difference was found regarding age, sex, number, and types of comorbidities between the two groups. In the COVID-19 group, orotracheal intubation lasted longer (17.7 ± 14.5 vs. 9.7 ± 5.8 days, p = 0.001), tracheotomy (80%, p = 0.003) as well as re-tracheotomy (6% of cases, p = 0.025) were more frequent and tracheotomy maintenance was longer (21.5 ± 11.9 days, p = 0.006) when compared to the non-COVID group. COVID-19 stenosis was located more distal from vocal folds (3.0 ± 1.86 vs. 1.8 ± 2.03 cm) yet without evidence of a difference (p = 0.07). The number of tracheal rings involved was lower in the non-COVID group (1.7 ± 1 vs. 2.6 ± 0.8 p = 0.001) and stenosis were more frequently managed by rigid bronchoscopy (74% vs. 47%, p = 0.04) when compared to the COVID-19 group. Finally, no difference in recurrence rate was detected between the groups (35% vs. 15%, p = 0.18). Conclusions: Obesity, a longer time of intubation, tracheostomy, re-tracheostomy, and longer decannulation time occurred more frequently in COVID-related tracheal stenosis. These events may explain the higher number of tracheal rings involved, although we cannot exclude the direct role of SARS-CoV-2 infection in the genesis of tracheal stenosis. Further studies with in vitro/in vivo models will be helpful to better understand the role of inflammatory status caused by SARS-CoV-2 in upper airways. Full article

Among prematurely born infants and newborns with chronic conditions, a respiratory syncytial virus (RSV) infection may cause (re-)admission and later respiratory complications. Therapeutic protection is possible with monthly injections of a specific monoclonal antibody, palivizumab, during RSV season. Standard care is giving up to five injections in clinic-based settings. Immunization at home could be an alternative to standard care for vulnerable infants to reduce the number of revisits and associated risk of RSV infection. The aim of this randomized pilot trial was to evaluate safety aspects and explore parents’ preferences of home versus hospital immunization with palivizumab during one RSV season. Immediate adverse events (AEs) were observed and registered by a pediatric specialist nurse. Late-onset AEs were reported by parents. Parents’ perceptions were collected through a questionnaire and analyzed using content analysis. The study population consisted of 43 infants in 38 families. No immediate AEs occurred. Three late-onset AEs were reported in two infants in the intervention group. Three categories emerged in the content analysis: (1) protect and watch over the infant, (2) optimal health and well-being for the whole family, and (3) avoid suffering for the infant. The study results show that home immunization with palivizumab is feasible if safety aspects are considered and that parental involvement in the choice of place for immunization after a neonatal intensive care experience can be important. Full article

Introduction with Aim: Postoperative respiratory depression can complicate a patient’s recovery after surgery. A predictive score (PRODIGY) was recently proposed to evaluate the risk of opioid-induced postoperative respiratory depression. For the first time, we applied this score to a cohort of patients receiving bariatric surgery, stratified by Obstructive Sleep Apnea (OSA) status. In addition, we recorded continuous postoperative capnography to evaluate respiratory depression and apnea episodes (Respiratory Events, RE). Materials and Methods: The present study was approved by our IRB and comprised continuous surveillance of respiratory variables during postoperative recovery (in PACU) after robotic bariatric surgery. We utilized continuous capnography and pulse oximetry (Capnostream 35, Medtronic Inc., and Profox Respiratory Oximetry software). Preoperative preparation included OSA evaluation for all bariatric patients, additional sleep studies for severe OSA grades, and evaluation of risk for respiratory depression (low, intermediate, or high) using the published PRODIGY score. In addition, we evaluated patients by OSA status. All patients received multimodal intraoperative non-opioid anesthesia from the same team. After surgery, all patients received continuous respiratory surveillance in PACU (average duration exceeding 140 min). Respiratory depression events were scored using a modified list of the five standard published categories. Events were measured according to analysis of continuously recorded tracing of the compiled respiratory variables by observers kept blind from the study patient’s group. Results: Of the 80 patients evaluated (18 male), 56 had obstructive sleep apnea and were using CPAP at home (OSA); 24 did not. OSA patients received CPAP via an oronasal mask or a nasal pillow pressure support immediately after arriving in PACU, utilizing their at-home settings. We encountered 115 respiratory depression events across 48 patients. The most frequent respiratory event recorded was a transient desaturation (as low as 85%), which usually lasted 20–30 sec and resolved spontaneously in 3 to 5 min; most episodes followed small boluses of IV opioid analgesia administered during recovery, on demand. All episodes resolved spontaneously without any nursing or medical intervention. OSA patients had significantly more events than non-OSA patients (1.84 (1.78–1.9) mean events vs. 0.50 (0.43–0.57) for non-OSA, p = 0.0002). The level of PRODIGY score (low, intermediate, or high), instead, was not predictive of the number of events when we treated this variable as continuous (p = 0.39) or categorical (high vs. low, p = 0.65, and intermediate vs. low, p = 0.17). Conclusions: We attribute these novel results, showing a lack of respiratory events requiring intervention, to opioid-free anesthesia, early CPAP utilization, and head-up positioning on admission to PACU. Furthermore, all these patients had light postoperative narcotic requirements. Finally, an elevated PRODIGY score in our patients did not sufficiently predict respiratory events, but OSA status alone did. Key Points Summary: We investigated the incidence of Respiratory Events (RE) in Obstructive Sleep Apnea patients after surgery (56 patients) and compared them to similar patients without OSA (24 patients). All patients received identical robotic-assisted surgery and low- or no-opiate anesthesia. Patients were pre-screened with the standard published PRODIGY scores and were monitored after PACU arrival with continuous oximetry and capnography (Capnostream 35 and Profox analysis). OSA patients showed more RE than non-OSA (1.8 vs. 0.5, p = −0.0002). However, patients with elevated PRODIGY scores did not develop more frequent RE compared to patients with low scores. We attribute these novel results to opioid-sparing anesthesia/analgesia and immediate CPAP utilization on admission to PACU. Full article

Artificial intelligence (AI) adopting deep learning technology has been widely used in the med-ical imaging domain in recent years. It realized the automatic judgment of benign and malig-nant solitary pulmonary nodules (SPNs) and even replaced the work of doctors to some extent. However, misdiagnoses can occur in certain cases. Only by determining the causes can AI play a larger role. A total of 21 Coronavirus disease 2019 (COVID-19) patients were diagnosed with SPN by CT imaging. Their Clinical data, including general condition, imaging features, AI re-ports, and outcomes were included in this retrospective study. Although they were confirmed COVID-19 by testing reverse transcription-polymerase chain reaction (RT-PCR) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), their CT imaging data were misjudged by AI to be high-risk nodules for lung cancer. Imaging characteristics included burr sign (76.2%), lobulated sign (61.9%), pleural indentation (42.9%), smooth edges (23.8%), and cavity (14.3%). The accuracy of AI was different from that of radiologists in judging the nature of be-nign SPNs (p < 0.001, κ = 0.036 < 0.4, means the two diagnosis methods poor fit). COVID-19 patients with SPN might have been misdiagnosed using the AI system, suggesting that the AI system needs to be further optimized, especially in the event of a new disease outbreak. Full article

Background: Takotsubo syndrome (TTS) is a syndrome with ambiguous pathophysiology. Impaired kidney function (KF) seems to impact the outcome of patients with TTS. We hypothesized that KF worsens the outcome among TTS patients and furthermore, TTS patients with concomitant KF experience more adverse events compared to myocardial infarction (MI) patients with concomitant KF. Methods and Results: This retrospective single-center study comprised two groups (cohorts) of patients including patients with TTS and concomitant KF (n = 61, 27.1%) and patients with MI and concomitant KF (n = 164, 72.9%). The clinical outcomes were delineated as short-term outcomes defined as in-hospital adverse events during index hospitalization and long-term outcomes defined as adverse events over five-year clinical follow-ups. All-cause mortality, stroke, cardiopulmonary resuscitation (CPR), life-threatening arrhythmias, need for respiratory support, and cardiogenic shock with subsequent use of inotropic agents during index hospitalization were denoted as in-hospital adverse events. All-cause mortality, rehospitalization due to heart failure, stroke, thromboembolic events, and the recurrence of primary pathology (TTS and MI) were analyzed during five-year follow-ups after index hospitalization. A higher mortality rate was noted among TTS patients with KF compared to TTS without KF. In addition, in-hospital event rates in patients with TTS and concomitant KF compared to MI and concomitant KF were comparable with the exception of a higher rate of respiratory support in TTS patients. The mortality rate was significantly higher among patients with TTS and KF at 4 years (29.5% vs. 15.9%, p = 0.02) and 5 years (34.4% vs. 20.7%, p = 0.03) in comparison to patients with MI and concomitant KF. In contrast, the rate of re-hospitalization related to heart failure was higher at 30 days, and at one-, four-, and five-year follow-ups in patients suffering from MI and KF compared to TTS and concomitant KF. Additionally, the recurrence of MI after 4 and 5 years was higher than the recurrence of TTS (4.9% vs. 15.2%; 4.9% vs. 16.5%). There were no differences in life-threatening arrhythmias and stroke in both groups. Conclusions: Patients with TTS and concomitant KF have higher all-cause mortality when compared to MI and concomitant KF. The mechanisms responsible remain to be determined. Full article

Obstructive sleep apnea (OSA) is a common sleep disorder characterized by repetitive upper airway obstruction, intermittent hypoxemia, and recurrent awakenings during sleep. The most used treatment for this syndrome is a device that generates a positive airway pressure—Continuous Positive Airway Pressure (CPAP), but it works continuously, whether or not there is apnea. An alternative consists on systems that detect apnea episodes and produce a stimulus that eliminates them. Article focuses on the development of a simple and autonomous processing system for the detection of obstructive sleep apneas, using polysomnography (PSG) signals: electroencephalography (EEG), electromyography (EMG), respiratory effort (RE), respiratory flow (RF), and oxygen saturation (SO₂). The system is evaluated using, as a gold standard, 20 PSG tests labeled by sleep experts and it performs two analyses. A first analysis detects awake/sleep stages and is based on the accumulated amplitude in a channel-dependent frequency range, according to the criteria of the American Academy of Sleep Medicine (AASM). The second analysis detects hypopneas and apneas, based on analysis of the breathing cycle and oxygen saturation. The results show a good estimation of sleep events, where for 75% of the cases of patients analyzed it is possible to determine the awake/asleep states with an effectiveness of >92% and apneas and hypopneas with an effectiveness of >55%, through a simple processing system that could be implemented in an electronic device to be used in possible OSA treatments. Full article

The role of schools as a source of infection and driver in the coronavirus-pandemic has been controversial and is still not completely clarified. To prevent harm and disadvantages for children and adolescents, but also adults, detailed data on school outbreaks is needed, especially when talking about open schools employing evidence-based safety concepts. Here, we investigated the first significant COVID-19 school outbreak in Hamburg, Germany, after the re-opening of schools in 2020. Using clinical, laboratory, and contact data and spatial measures for epidemiological and environmental studies combined with whole-genome sequencing (WGS) analysis, we examined the causes and the course of the secondary school outbreak. The potential index case was identified by epidemiological tracking and the lessons in classrooms with presumably high virus spreading rates and further infection chains in the setting. Sequence analysis of samples detected one sample of a different virus lineage and 25 virus genomes with almost identical sequences, of which 21 showed 100% similarity. Most infections occurred in connection with two lesson units of the primary case. Likely, 31 students (12–14 years old), two staff members, and three family members were infected in the school or the typical household. Sequence analysis revealed an outbreak cluster with a single source that was epidemiologically identified as a member of the educational staff. In lesson units, two superspreading events of varying degrees with airborne transmission took place. These were influenced by several parameters including the exposure times, the use of respiratory masks while speaking and spatial or structural conditions at that time. Full article

Paediatric chronic diseases (CD) are characterised by their ongoing duration and the fact that they are often managed throughout the lifespan, with the need to adjust lifestyle and expectations with the limitations coming from the CD. The aim of the PENSAMI study is to not only cure the disease, but to also care for the person from a clinical and psychosocial perspective. Data will be collected from 150 paediatric patients affected by heart disease, diabetes, and asthma admitted during in-hospital stay or outpatient visits, and from 200 healthy control subjects. The protocol will consist of two phases. The first one will aim at elaborating the predictive model by detecting (clinical, anthropometric at birth, environmental, lifestyle, social context, emotional state, and mental abilities) in order to develop a model predictive of the events considered: (1) re-hospitalisation; (2) severity and progression of the disease; (3) adherence to therapy; (4) HRQoL; (5) obesity and metabolic syndrome; (6) illness-stress related; (7) school drop-out; (8) school performance. The second one will address validating the previous predictive model. This model will aim to: (1) understand, prevent, and halt the progression of childhood CD; (2) develop new and improved diagnostic tools; (3) pave the way for innovative treatments and additional therapies to traditional clinical practice; and (4) create truly personalised therapeutic and preventive strategies in various sectors, such as cardiology, diabetes, and respiratory diseases. Full article

Acute mesenteric ischemia, caused by an abrupt interruption of blood flow in the mesenteric vessels, is associated with high mortality. When treated with surgical interventions or drugs to re-open the vascular lumen, the reperfusion process itself can inflict damage to the intestinal wall. Ischemia and reperfusion injury comprise complex mechanisms involving disarrangement of the splanchnic microcirculatory flow and impairment of the mitochondrial respiratory chain due to initial hypoxemia and subsequent oxidative stress during the reperfusion phase. This pathophysiologic process results in the production of large amounts of reactive oxygen (ROS) and nitrogen (RNS) species, which damage deoxyribonucleic acid, protein, lipids, and carbohydrates by autophagy, mitoptosis, necrosis, necroptosis, and apoptosis. Fluorescence-based systems using molecular probes have emerged as highly effective tools to monitor the concentrations and locations of these often short-lived ROS and RNS. The timely and accurate detection of both ROS and RNS by such an approach would help to identify early injury events associated with ischemia and reperfusion and increase overall clinical diagnostic sensitivity. This abstract describes the pathophysiology of intestinal ischemia and reperfusion and the early biological laboratory diagnosis using fluorescent molecular probes anticipating clinical decisions in the face of an extremely morbid disease. Full article