Invasive Mode Research Articles

Clinical outcomes of moderate to severe COVID-19 patients receiving invasive vs. non-invasive ventilation

Objective: To evaluate the in-hospital outcome of moderate to severe COVID-19 patients admitted in High Dependency Unit (HDU) in relation to invasive vs. non-invasive mode of ventilation. Methods: In this study, the patients required either non-invasive [oxygen ≤10 L/min or >10 L/min through mask or nasal prongs, rebreather masks and bilevel positive airway pressure (BiPAP)] or invasive ventilation. For analysis of 30-day in hospital mortality in relation to use of different modes of oxygen, Kaplan Meier and log rank analyses were used. In the end, independent predictors of survival were determined by Cox regression analysis. Results: Invasive ventilation was required by 15.1% patients while 84.9% patients needed non-invasive ventilation. Patients with evidence of thromboembolism, high inflammatory markers and hypoxemia mainly required invasive ventilation. The 30-day in hospital mortality was 72.7% for the invasive group and 12.9% for the non-invasive group (1.8% oxygen <10 L/min, 0.9% oxygen >10 L/min, 3.6% rebreather mask and 4.5% BiPAP). The median time from hospital admission to outcome was 7 days for the invasive group and 18 days for the non-invasive group (P<0.05). Age, presence of co-morbidities, number of days requiring oxygen, rebreather, BiPAP and invasive ventilation were independent predictors of outcome. Conclusions: Invasive mechanical ventilation is associated with adverse outcomes possibly due to ventilator associated lung injury. Thus, protective non-invasive ventilation remains the necessary and safe treatment for severely hypoxic COVID-19 patients.

Assessment of pulmonary artery hypertension by Doppler echocardiography and its correlation with right heart catheterization

Background: Definitive diagnosis of pulmonary artery hypertension (PH) requires an elevated mean pulmonary arterial pressure (MPAP) of 25 mmHg at rest measured by right heart catheterization (RHC). As it is invasive mode of investigation, it is declined by many patients, echocardiography was thought to be an acceptable substitute to assess pulmonary arterial pressures. Whether there is a correlation between these measurements is controversial. The aim of this study was to assess PH by echocardiography and its correlation with RHC.Methods: Twenty-six patients aged ≥18 years with pulmonary artery hypertension with or without tricuspid regurgitation (TR) were included in this cross-sectional study. All the patients underwent a transthoracic echocardiography evaluation and were taken for RHC study within an hour.Results: The correlation between pulmonary artery acceleration time (PAAT) and pulmonary artery systolic pressure (PASP) and PAAT and MPAP was significant in all degrees of PH. In contrast, correlation between TR jet maximum velocity (TR Vmax) derived estimated pulmonary artery systolic pressure (EPASP) and PASP was significant in moderate and severe PH, while it did not correlate in mild PH.Conclusions: PAAT is easily measurable parameter and strongly correlates with the values of PASP and the MPAP obtained by right heart catheterization. Implementation of a novel method of determining EPASP from PAAT shall increase significantly the number of patients in whom TTE can be used for the assessment of pulmonary hemodynamic non-invasively.

SPINAL MUSCULAR ATROPHY – THE NEEDS OF CHILDREN UNDERGOING PHARMA - COLOGICAL TREATMENT AND THEIR FAMILIES AS PART OF THE COMPREHENSIVE CARE SYSTEM IN POLAND

Introduction There is no coordinated care system for patients with rare diseases in Poland. Aim The aim of the study was to define the most important aspects of medical, social and professional care under the project titled “Education in a new reality: a comprehensive and long-term model of physiotherapeutic treatment in spinal muscular atrophy” developed by Stowarzyszenie Lwie Serca (Lion Hearts Association). Material and methods The study included 27 children with SMA1 and SMA2 treated pharmacologically. Motor development was checked using the CHOP INTEND and HFMSE scales; the body posture was measured with the Bunnell scoliometer and the Rippstein plurimeter, and the range of motion in the joints of the upper and lower limbs was measured. Respiratory and neurologopedic problems were assessed. The social, professional and financial situation of the families was analyzed. Psychological data was collected based on an interview with parents. Results Nineteen children were diagnosed with type 1 SMA and 8 with type 2. On the CHOP INTEND scale, the mean number of points was 30.8; in HFMSE 21.7. Disorders in the shape of the chest, spine, hip joints and reduced range of motion were found. 18 children (66.7%) used a ventilator in the invasive and non-invasive mode. Most children had symptoms of dysarthria and stomatognathic disorders. The main psychological problems among parents were severe stress, low mood, and a sense of loneliness. Conclusion In Poland, it is necessary to introduce a system of comprehensive, coordinated care for children with spinal muscular atrophy. Keywords: spinal muscular atrophy, body posture, developmental scales

A Comparative study on the efficacy of topical anaesthetic creams for fractional microneedling in acne scars

Acne scars are one of the commonest skin diseases encountered in clinical practice. Management of acne scars ranges from simple subcision to laser resurfacing. Topical anaesthetics can provide, non invasive mode of adequate analgesia for the management of acne scars. In a properly selected patient setting, this can even replace the need of lignocaine infiltration. Commonly available local anaesthetics creams are Eutectic mixture of local anaesthetics (EMLA) (2.5% Lignocaine and 2.5% Prilocaine) and Lignocaine Tetracaine cream (LT) (7%Lignoaine and & 7% Tetracaine). To compare the anaesthetic efficacy of topical creams in the management of acne scars. This study enrolled 20 cases of acne scars planned for Microneedling, of which 10 patients received EMLA cream (group A) and 10 patients received LT cream (group B). Pain perception was recorded with Visual Analog Scale (VAS) at 30 minutes after application of the cream and during the procedure (60 minutes after cream application). Patient preference about the topical creams was asked for the next procedure. The mean pain score after 30 minutes was 3.1 for group A and 2.1 for group B. The pain score recorded during the procedure was 2.1 for group A and 0.6 for group B. Patients had minimal and transient side effects. LT cream provided adequate and long lasting analgesia when compared to EMLA cream.

Oral administration of eugenol oleate cures experimental visceral leishmaniasis through cytokines abundance

Visceral leishmaniasis (VL) is an endemic fatal infectious disease in tropical and subtropical nations. The limited treatment options, long treatment regimens, invasive mode of administration of drugs, and lack of effective vaccination are the main reasons for the search of new alternative therapeutics against VL. On this quest, from a series of eugenol derivatives, we had demonstrated eugenol oleate as a lead immunomodulatory anti-VL molecule earlier. In this report, the oral efficacy and mechanism of eugenol oleate in inducing immunomodulatory anti-VL activity has been studied in BALB/c mice model. The plasma pharmacokinetic and acute toxicity studies suggested that the eugenol oleate is safe with an appreciable pharmacokinetic profile. Eugenol oleate (30 mg/kg B.W.) showed 86.5% of hepatic and 84.1% of splenic parasite clearance. The increased Th1 cytokine profile and decreased Th2 cytokine profile observed from ELISA and qRTPCR suggested that the eugenol oleate induced the parasite clearance through the activation of the host immune system. Subsequently, the mechanistic insights behind the anti-leishmanial activity of eugenol oleate were studied in peritoneal macrophages in vitro by inhibitor response study and immunoblotting. The results inferred that eugenol oleate activated the PKC-βII–p38 MAPK and produced IL-12 and IFN-γ which intern activated the iNOS2 to produce NO free radicals that cleared the intracellular parasite.

Risk factors and outcome of Klebsiella sepsis in neonates

Background: Klebsiella is the most common organism isolated in early onset sepsis and causes outbreaks in neonatal intensive care unit (NICU). No clear risk factors for Klebsiella sepsis have been documented. Objective: The objective of the study was to study the risk factors, clinical profile, and outcome of Klebsiella in neonatal sepsis. Materials and Methods: A retrospective observational study was done at an extramural tertiary care center from January to December 2017. After getting Institutional Ethics Committee approval, data were collected from hospital records of admitted neonates whose blood culture was positive for Klebsiella. Detailed antenatal and natal history including birth weight, Apgar score, sex, and age was taken. Data on ventilator support, continuous positive airway pressure, intravenous fluids, enteral and parenteral nutrition, central line, and surgical procedure were collected. Results: Of the total of 1852 blood cultures sent, 308 (16.63%) showed growth. Altogether, 63 (20.45%) cases with Klebsiella growth were included in the study, of which 40 were male and 23 were female (1.7:1). Klebsiella was isolated in 25 (62.5%) who died. Birth weight was 2.152±0.752 g for babies who died and 2.613±0.525 g among discharged. Mortality was high in males 18 (72%) as compared to females 7 (28%), in low birth weight babies 32 (63.69 %), with thrombocytopenia 18 (80%), and those on invasive mode of ventilation. By regression analysis, it was found that duration of days of NICU stay, shock, invasive ventilation, umbilical venous, and arterial catheterization were identified as the factors that influence outcome in Klebsiella sepsis. Conclusion: High index of suspicion, initiating early and appropriate antibiotic therapy, antibiotic stewardship, and environmental cleaning improve the outcome. With emerging drug resistance, prevention of sepsis by infection control measures is needed.

Critical Obstetric Patients During the Coronavirus Disease 2019 Pandemic: Operationalizing an Obstetric Intensive Care Unit.

Critical Obstetric Patients During the Coronavirus Disease 2019 Pandemic: Operationalizing an Obstetric Intensive Care Unit.

Superior breast cancer metastasis risk stratification using an epithelial-mesenchymal-amoeboid transition gene signature

BackgroundCancer cells are known to display varying degrees of metastatic propensity, but the molecular basis underlying such heterogeneity remains unclear. Our aims in this study were to (i) elucidate prognostic subtypes in primary tumors based on an epithelial-to-mesenchymal-to-amoeboid transition (EMAT) continuum that captures the heterogeneity of metastatic propensity and (ii) to more comprehensively define biologically informed subtypes predictive of breast cancer metastasis and survival in lymph node-negative (LNN) patients.MethodsWe constructed a novel metastasis biology-based gene signature (EMAT) derived exclusively from cancer cells induced to undergo either epithelial-to-mesenchymal transition (EMT) or mesenchymal-to-amoeboid transition (MAT) to gauge their metastatic potential. Genome-wide gene expression data obtained from 913 primary tumors of lymph node-negative breast cancer (LNNBC) patients were analyzed. EMAT gene signature-based prognostic stratification of patients was performed to identify biologically relevant subtypes associated with distinct metastatic propensity.ResultsDelineated EMAT subtypes display a biologic range from less stem-like to more stem-like cell states and from less invasive to more invasive modes of cancer progression. Consideration of EMAT subtypes in combination with standard clinical parameters significantly improved survival prediction. EMAT subtypes outperformed prognosis accuracy of receptor or PAM50-based BC intrinsic subtypes even after adjusting for treatment variables in 3 independent, LNNBC cohorts including a treatment-naïve patient cohort.ConclusionsEMAT classification is a biologically informed method that provides prognostic information beyond that which can be provided by traditional cancer staging or PAM50 molecular subtype status and may improve metastasis risk assessment in early stage, LNNBC patients, who may otherwise be perceived to be at low metastasis risk.

Non-invasive Respiratory Support of the Premature Neonate: From Physics to Bench to Practice.

Premature births continue to rise globally with a corresponding increase in various morbidities among this population. Rates of respiratory distress syndrome and the consequent development of Bronchopulmonary Dysplasia (BPD) are highest among the extremely preterm infants. The majority of extremely low birth weight premature neonates need some form of respiratory support during their early days of life. Invasive modes of respiratory assistance have been popular amongst care providers for many years. However, the practice of prolonged invasive mechanical ventilation is associated with an increased likelihood of developing BPD along with other comorbidities. Due to the improved understanding of the pathophysiology of BPD, and technological advances, non-invasive respiratory support is gaining popularity; whether as an initial mode of support, or for post-extubation of extremely preterm infants with respiratory insufficiency. Due to availability of a wide range of modalities, wide variations in practice exist among care providers. This review article aims to address the physical and biological basis for providing non-invasive respiratory support, the current clinical evidence, and the most recent developments in this field of Neonatology.

Interactive Dynamics of Reaction-Diffusion and Adhesion Predict Diverse Invasion Strategies of Cancer Cells in Matrix-Like Microenvironments

The metastasis of malignant epithelial tumors begins with the egress of transformed cells from the confines of their basement membrane to their surrounding collagenous stroma. The invasion can be morphologically diverse, ranging from that of dispersed mesenchymal cells to multicellular collectives. When cancer cells are cultured within basement membrane-like matrix (BM), or Type 1 collagen, or a combination of both, they show collective-, dispersed mesenchymal-, and hybrid collective-dispersed (multiscale) invasion respectively. Here, we ask how distinct these invasive modes are with respect to the cellular and microenvironmental cues that drive them, and how can cancer cells transition between such states. A rigorous exploration of invasion was performed within an experimentally motivated Cellular Potts-based computational modeling environment. The model comprises of adhesive interactions between cancer cells, BM- and collagen-like extracellular matrix (ECM), and reaction-diffusion-based remodeling of ECM. The model output consisted of metrics cognate to dispersed- and collective- invasion. An exhaustive combination of input values gave rise to a spatial output distribution that comprised dispersed-, collective- and multiscale- invasion. K-means clustering of the output distribution followed by silhouette analysis revealed three optimal clusters: one signifying indolent invasion and two representing multiscale invasions, each of which encompass the purer dispersed- and collective invasions respectively. Principal component analyses of phenotypic outputs close to the separation of these two multiscale modes established specific input signatures: perturbing such signatures revealed the cues that can allow phenotypic transitions among these three clusters. Our systems-level analysis provides quantitative insights into the biases and constraints cancer cells face during their invasion through tissue microenvironments with distinct physicochemical properties.

Delineating the role of membrane blebs in a hybrid mode of cancer cell invasion in three-dimensional environments.

The study of cancer cell invasion in 3D environments in vitro has revealed a variety of invasive modes, including amoeboid migration, characterized by primarily round cells that invade in a protease- and adhesion-independent manner. Here, we delineate a contractility-dependent migratory mode of primarily round breast cancer cells that is associated with extensive integrin-mediated extracellular matrix (ECM) reorganization that occurs at membrane blebs, with bleb necks sites of integrin clustering and integrin-dependent ECM alignment. We show that the spatiotemporal distribution of blebs and their utilization for ECM reorganization is mediated by functional β1 integrin receptors and other components of focal adhesions. Taken together, the work presented here characterizes a migratory mode of primarily round cancer cells in complex 3D environments and reveals a fundamentally new function for membrane blebs in cancer cell invasion.

Neuromodulation for Cognitive Disorders: In Search of Lazarus?

Alzheimer's disease (AD) and other forms of dementia can have a large impact on patients, their families, and for the society as a whole. Current medical treatments have not shown enough potential in treating or altering the course of the disease. Deep brain stimulation (DBS) has shown great neuromodulatory potential in Parkinson's disease, and there is a growing body of evidence for justifying its use in cognitive disorders. At the same time there is mounting interest at less invasive and alternative modes of neuromodulation for the treatment of AD. This manuscript is a brief review of the infrastructure of memory, the current understanding of the pathophysiology of AD, and the body of preclinical and clinical evidence for noninvasive and invasive neuromodulation modalities for the treatment of cognitive disorders and AD in particular.

Chitosan coated liposomes (CCL) containing triamcinolone acetonide for sustained delivery: A potential topical treatment for posterior segment diseases

Drug delivery to the posterior eye is limited by epithelial and mucosal barriers limiting the topical administration of drugs leading to invasive modes of repeated long-term painful administration of drugs. Several constructs of liposomes have been prepared to counter this challenge yet are often limited by size and surface charge resulting in poor encapsulation efficiency, low retention time, and poor permeability. In the present study, chitosan coated liposomes (CCL) were prepared to address these challenges. Conventional liposomes encapsulating Triamcinolone Acetonide (TA) were compared with their chitosan coated counterpart for drug loading and release studies. CCL showed a higher encapsulation efficiency (74%), and a highly positive surface charge (+41.1Mv), increased retention time and sustained release. Choroidal neovascularization (CNV) rat models were generated to assess the efficiency of CCLs as nanocarriers in drug delivery. Significant amount of TA was found to be present and retaining in the eye after fifteen days of treatment with CCL, as shown by HPLC analysis. The results showed successful penetration of the construct via corneal mucosal barrier and its accumulation in vitreous body. The analysis shows that this chitosan based liposomal construct can be employed as a potential topical delivery system for treating posterior segment diseases.

ACTR-28. A CALL FOR INCREASED ROLE OF NEUROSURGEONS IN SURGICAL TRIALS FOR NON-GLIOMATOUS PRIMARY CNS TUMORS: A SYSTEMATIC REVIEW OF THE CLINICALTRIALS.GOV DATABASE

Abstract BACKGROUND Surgery continues to be part of the mainstay of therapy for most primary CNS tumors. However, neurosurgical innovations advancing treatment options have stagnated. An understanding of past and current investigational trends is necessary to catalyze innovation in surgical trials. OBJECTIVE To evaluate the landscape of surgical clinical trials for non-diffusely infiltrating primary CNS tumors. METHODS ClinicalTrials.gov was searched on May 14th, 2019 for surgical/procedural trials based on non-diffusely infiltrating primary CNS tumors, with a focus on meningiomas, ependymomas, medulloblastomas, pituitary adenomas, vestibular scwhannomas, and chordomas. Key trial design parameters were extracted. Purely surgical interventions were classified as “technical” while fluorescence-guided and other intraoperative imaging modalities were classified as image-guided surgery. Any invasive mode of drug delivery (e.g. intra-arterial or intra-ventricular, local chemotherapy wafers, and oncolytic virus injection) was considered. RESULTS Among 944 total trial records (257 medulloblastomas, 254 ependymomas, 179 meningiomas, 156 pituitary adenomas, 56 vestibular schwannomas, and 48 chordomas) only 54 (5.7%) were procedural in nature. Ependymomas had the highest absolute number (18/254, 7%) while vestibular schwannomas had the highest percentage (6/56, 10.7%) of surgical trials. The majority of records were not randomized (41/54, 75.9%), not industry-funded (45/54, 83.3%), and were early Phase (30/54, 55.6%); there were only three Phase III trials. The relative number of new surgical trial registrations has not changed significantly over time (1990s: 5, 2000s: 19, and 2010s: 30). Approaches integrated with other disciplines, such as image-guided surgery (16/54, 29.6%) and local drug delivery (16/24, 29.6%), were among the leading categories of trials. CONCLUSIONS Despite the clinical role of surgery in management of non-diffusely infiltrating primary CNS tumors, a paucity of innovative surgical trials has been put forth. Multi-disciplinary approaches appear to be necessary for pushing the therapeutic envelope for individuals affected by these tumors, with imaging and drug development at the forefront.

The use of continuous Flow Ventilatory Support for Hypercapnic Respiratory Failure

Our aim was to assess the effectivity of continuous flow ventilatory support (CFVS) in those COPD patients undergoing cardiac surgery who developed hypercapnic respiratory failure.Materials and methods. CFVS was applied in 11 COPD (Stage 2.55±0.52 on average) patients undergoing cardiac surgery, after weaning from «conventional» pressure controlled (PCV) or pressure support ventilation (PSV) mode. All of these patients had hypercapnea with respiratory failure that has been manifested after 15±10 hours after postoperative weaning from ventilator. CFVS was applied using nasotracheal catheter (diameter 5–6 mm) with average inspiratory flow Qin = 26±2,3 l/min while using FiO2 of 0.3–0.35.Results. Only one out of 11 patients failed to recover from hypercapnic respiratory failure using CFVS and had to be intubated instead. Spontaneous ventilation frequency was gradually decreasing from 24.8±3.6 breaths/min to 16±2 breaths/min after initiation of CFVS (P<0.01). Average value of PaO2 before CFVS was 59±7.5 mmHg and rose to 99.6±4.5 mmHg just before CFVS was terminated (P<0.01). PaCO2 before CFVS was measured to be 73.2±7.5 mmHg and dropped to 45.7±4.3 mmHg (P<0.01). CO2 drop was fast in the first 18 hours from CFVS application. Average time for application of CFVS was 3.09±0.9 day.Conclusion. CFVS is an effective and minimally invasive mode of ventilation support that can be used in patients suffering from hypercapnic respiratory failure to avoid the need to intubate trachea and connect the patient to conventional ventilator.

Study of clincial profile and outcome of Klebsiella sepsis in neonates at a tertiary care centre

Background: Objective of the study is to study clinical profile and outcome of Klebsiella sepsis in neonates.Methods: A retrospective observational study from January 2018 to Sep 2018. After getting approval of institute ethics committee, admitted neonates whose blood culture showed Klebsiella growth were enrolled. A detailed history, birth weight, sex , age, APGAR, need for resuscitation at birth, distress at birth, ventilator support, CPAP, central line, blood products, species of Klebsiella and drug sensitivity and outcome-discharge or death were taken. Data were entered into Microsoft excel data sheet and was analyzed using SPSS 23 version software.Results: Out of the total 252 positive blood culture, 110 (43%) grew Klebsiella in blood culture. 92 cases were included in the study. Male to female ratio was 1.24:1. Mean age at admission was 1.22 days. 40 (43.5%) died and 52(56.5%) were discharged. Birth weight was 1.635±802 gm for babies who died and 2211±939 gm among discharged. Mean gestational age were 32.5 weeks in died and 34.8 weeks among discharged. Mortality was 23(57.5%) in males, low birth weight babies 23(59%), thrombocytopenia 28 (78%), invasive mode of ventilation 19(67%). By Univariate analysis, it was found that pregnancy induced hypertension (PIH), premature rupture of membrane (PROM), abnormal APGAR, Birth weight, shock, invasive ventilation, DIC, inotropes, blood products, abnormal total count, thrombocytopenia, umbilical venous catheterization were factors which influenced outcome. Regression analysis identified only thrombocytopenia and umbilical venous catheterization as factors that influenced outcome in Klebsiella sepsis. Klebsiella isolated was uniformly sensitive to Meropenam.Conclusions: No single risk factor was ascertained but thrombocytopenia and umbilical venous catheterization possibly influence the outcome of Klebsiella sepsis. Mortality is high in neonates.

Influence of invasive ventilation modes on weaning and extubation evolution of critical patients

The aim of this research was to analyze the influence of invasive ventilation modes on weaning and extubation process. It is a prospective cohort study that assessed patients admitted to the Intensive Care Unit (ICU) using Invasive Mechanical Ventilation (IMV). The following aspects were considered: ventilation mode used, days until evolution to weaning and extubation, its success/failure, hospitalization period, and ICU outcome (discharge/death). Sixty patients were assessed, 48 of which were admitted on volume-controlled ventilation (VCV), three on pressure-controlled ventilation (PCV), and nine on spontaneous mode. A total of 79% of VCV individuals and 67% of PCV went into spontaneous mode. There was no significant difference between modes for time until evolution to spontaneous breathing, neither between that and weaning and extubation. Among possible factors responsible for weaning and extubation success, only days on spontaneous mode influenced these outcomes, so individuals who breathed spontaneously for more days were 1.5% more likely to succeed at weaning and 1.3% more likely to succeed at extubation. The ventilation mode used at admission did not influence weaning and extubation process. Longer time on spontaneous breathing mode predicted the patients’ greater chances of weaning and extubation success.

Abstract 1117: The molecular basis of LIF-mediated NPC metastasis

Abstract Distant metastasis and local recurrence are frequently observed in nasopharyngeal carcinoma (NPC) but the mechanisms remain largely unclear. Here, we report that higher levels of leukemia inhibitory factor (LIF) and LIF receptor (LIFR) are correlated with poorer metastasis/recurrence-free survival. LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically, both in vitro and in vivo, through modulation of LIFR-YAP1-focal adhesion signaling. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer progression, targeting of this pathway presents a promising opportunity to block metastasis. Citation Format: Shu-Chen Liu. The molecular basis of LIF-mediated NPC metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1117.

Evaluating Benefit-risk Decision-making in Spinal Muscular Atrophy: A First-ever Study to Assess Risk Tolerance in the SMA Patient Community

PurposePatients’ perceptions of benefit–risk are essential to informing the regulatory process and the context in which potential therapies are evaluated. To bring this critical information to regulators, Cure SMA launched a first-ever Benefit-Risk Survey for spinal muscular atrophy (SMA) to characterize decision-making and benefit–risk trade-offs in SMA associated with a potential therapy. We hypothesized that risk tolerance would be correlated with SMA type/severity and disease progression. This article presents the results of a benefit–risk survey to enhance understanding of how patients with SMA and caregivers evaluate specific benefits and risks associated with potential therapies. MethodsAffected adults, representing all SMA types (I–IV) within the Cure SMA database, and caregivers of affected individuals of all ages/types were invited via e-mail to participate. Best–worst scaling (BWS) was used to assess participants’ priorities on benefit–risk trade-offs, as it provides higher discrimination and importance scaling among tested attributes. Twelve potentially clinically meaningful treatment benefits and 11 potential risks (ranging in severity and immediacy) were tested. Multiple factors were correlated with individual responses, including: SMA type/disease severity, stage of disease, respondent type, sex, and quality of life/level of independence (current and expected). Survey respondents were also evaluated for "risk-taking attitudes." FindingsA total of 298 responses were evaluated (28% affected adults and 72% caregivers, mostly parents). Most respondents were diagnosed >5 years ago (67.3%), with 22.1% SMA type I, 45.6% SMA type II, and 27.9% SMA type III. No strong correlation was found between risk tolerance and SMA type, stage of disease progression, respondent type, sex, quality of life assessment, or rated levels of independence. Irrespective of SMA type, respondents consistently rated the following risks, associated with a potential treatment, as "least tolerable": life-threatening allergic reactions; 1 in 1000 risk of life-threatening side effects leading to possible organ failure; or worsening quality of life. Furthermore, all SMA type respondents rated these risks as "most tolerable": invasive mode of treatment administration (including need for general anesthesia); side effect of dizziness; and other common side effects such as nausea, vomiting, loss of appetite, headaches, back pain, or fatigue. ImplicationsWith the approval of the first SMA treatment, these findings offer a unique opportunity to assess and characterize baseline risk-tolerance in SMA against which to evaluate future SMA treatment options. Although differences had been expected in risk tolerance among respondents based on disease baseline and certain patient attributes, this was not observed. Survey results should inform future SMA drug development and benefit–risk assessments.

Humidification in Very-High-Flow Nasal-Cannula Therapy in an Adult Lung Model.

High-flow nasal cannula (HFNC) therapy is used for patients with respiratory failure. Recently, HFNC therapy with very high gas flows (ie, gas flows of 60-100 L/min) was reported to generate higher positive airway pressure and an associated decrease in breathing frequency. However, the humidification of HFNC therapy with very high gas flow remains to be clarified. We evaluated 3 heated humidifier systems: a single MR850, the Hummax2, and parallel MR850s. The MR850 is a pass-over humidifier system, and the Hummax2 works with a porous hollow polyethylene fiber membrane. The parallel MR850 system included 2 MR850s connected in parallel to the lung with a 22 mm Y-piece. Gas flow was set at 40-90 L/min in increments of 10 L/min, and FIO2 was set at 0.21. Heated humidifiers in the MR850 systems were set in invasive mode (40°C/-3), and with the Hummax2 the vapor temperature was set at 39°C. The simulated external nares were connected to a test lung via a standard ventilator circuit. One-way valves prevented mixing of inspired and expired gases. Compliance of the test lung was 0.05 L/cm H2O and resistance 5 cm H2O/L/s. Simulated tidal volumes (VT) were 300, 500, and 700 mL, with a breathing frequency of 10 or 20 breaths/min and an inspiratory time of 1.0 s. Temperature, relative humidity, and absolute humidity (AH) of inspired gas downstream of the external nares were measured using a hygrometer for 1 min, and results for the last 3 breaths were extracted. With the single MR850, when gas flow was > 80 L/min, AH decreased as gas flow increased (P < .001). With the Hummax2, as gas flow increased, AH decreased (P < .001). With the parallel MR850s, regardless of gas flow, AH was constant. As breathing frequency increased, AH increased in all systems. During HFNC therapy with very high gas flows in this bench study, conventional heated humidifiers did not provide adequate humidification. Caution is advised when using HFNC therapy with very high gas flows with conventional heated humidifiers.