Improved Sleep Correlates with Improved Quality of Life and Motor Symptoms with Foslevodopa/Foscarbidopa.

BACKGROUND: Foslevodopa/foscarbidopa is a subcutaneous infusion of levodopa/carbidopa prodrugs. OBJECTIVES: Assess correlations between sleep and efficacy from interim data of a phase 3 trial of foslevodopa/foscarbidopa (NCT03781167). METHODS: Pearson correlations between sleep (Parkinson's Disease Sleep Scale-2 [PDSS-2]) and quality of life (QoL; Parkinson's Disease Questionnaire-39), motor experiences of daily living (m-EDL; Movement Disorder Society-Unified Parkinson's Disease Scale Part II), and "Off"/"On" times were calculated for baseline and week 26 improvements. Regression analyses were adjusted for baseline PDSS-2 score. RESULTS: Baseline sleep correlated moderately with QoL (r = 0.44, P < 0.001) and weakly with m-EDL (r = 0.28; P < 0.001). Sleep improvement weakly correlated with improved "Off" time (r = 0.37; P < 0.001) and QoL (r = 0.36; P < 0.001). Regression analyses demonstrated significant positive associations for improved sleep, "Off" time, QoL, and m-EDL. CONCLUSIONS: Improved sleep with foslevodopa/foscarbidopa was associated with improved QoL and "Off" time.

Continuous subcutaneous foslevodopa/foscarbidopa infusion for the treatment of motor fluctuations in Parkinson's disease: Considerations for initiation and maintenance.

Background: As Parkinson's disease (PD) advances, management is challenged by an increasingly variable and inconsistent response to oral dopaminergic therapy, requiring special considerations by the provider. Continuous 24 h/day subcutaneous infusion of foslevodopa/foscarbidopa (LDp/CDp) provides steady dopaminergic stimulation that can reduce symptom fluctuation. Objective: Our aim is to review the initiation, optimization, and maintenance of LDp/CDp therapy, identify possible challenges, and share potential mitigations. Methods: Review available LDp/CDp clinical trial data for practical considerations regarding the management of patients during LDp/CDp therapy initiation, optimization, and maintenance based on investigator clinical trial experience. Results: LDp/CDp initiation, optimization, and maintenance can be done without hospitalization in the clinic setting. Continuous 24 h/day LDp/CDp infusion can offer more precise symptom control than oral medications, showing improvements in motor fluctuations during both daytime and nighttime hours. Challenges include infusion-site adverse events for which early detection and prompt management may be required, as well as systemic adverse events (eg, hallucinations) that may require adjustment of the infusion rate or other interventions. A learning curve should be anticipated with initiation of therapy, and expectation setting with patients and care partners is key to successful initiation and maintenance of therapy. Conclusion: Continuous subcutaneous infusion of LDp/CDp represents a promising therapeutic option for individuals with PD. Individualized dose optimization during both daytime and nighttime hours, coupled with patient education, and early recognition of certain adverse events (plus their appropriate management) are required for the success of this minimally invasive and highly efficacious therapy.

Ruthenium(II)-Arene Curcuminoid Complexes as Photosensitizer Agents for Antineoplastic and Antimicrobial Photodynamic Therapy: In Vitro and In Vivo Insights.

Photodynamic therapy (PDT) is an anticancer/antibacterial strategy in which photosensitizers (PSs), light, and molecular oxygen generate reactive oxygen species and induce cell death. PDT presents greater selectivity towards tumor cells than conventional chemotherapy; however, PSs have limitations that have prompted the search for new molecules featuring more favorable chemical-physical characteristics. Curcumin and its derivatives have been used in PDT. However, low water solubility, rapid metabolism, interference with other drugs, and low stability limit curcumin use. Chemical modifications have been proposed to improve curcumin activity, and metal-based PSs, especially ruthenium(II) complexes, have attracted considerable attention. This study aimed to characterize six Ru(II)-arene curcuminoids for anticancer and/or antibacterial PDT. The hydrophilicity, photodegradation rates, and singlet oxygen generation of the compounds were evaluated. The photodynamic effects on human colorectal cancer cell lines were also assessed, along with the ability of the compounds to induce ROS production, apoptotic, necrotic, and/or autophagic cell death. Overall, our encouraging results indicate that the Ru(II)-arene curcuminoid derivatives are worthy of further investigation and could represent an interesting option for cancer PDT. Additionally, the lack of significant in vivo toxicity on the larvae of Galleria mellonella is an important finding. Finally, the photoantimicrobial activity of HCurc I against Gram-positive bacteria is indeed promising.

Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study.

INTRODUCTION: Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD. METHODS: Male and female patients with levodopa-responsive PD and ≥ 2.5 hours of "Off" time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700-4250 mg of LD per 24 hours) for 52 weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale-2 (PDSS-2), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L). RESULTS: Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, "On" time without troublesome dyskinesia and "Off" time were improved from baseline (mean [standard deviation (SD)] change in normalized "On" time without troublesome dyskinesia, 3.8 [3.3] hours; normalized "Off" time, -3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved. CONCLUSION: Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03781167.

Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson's disease: a randomised, double-blind, active-controlled, phase 3 trial.

BACKGROUND: Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. METHODS: A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. FINDINGS: Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (-2·75 [0·50] vs -0·96 [0·49] h; difference -1·79 h, -3·03 to -0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild-moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. INTERPRETATION: Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. FUNDING: AbbVie.

Foslevodopa/foscarbidopa subcutaneous infusion maintains equivalent levodopa exposure to levodopa-carbidopa intestinal gel delivered to the jejunum.

INTRODUCTION: The objective of this study was to compare the pharmacokinetics (PK) of levodopa (LD) from 24-h continuous subcutaneous infusion of foslevodopa/foscarbidopa to the LD pharmacokinetics from 16-h levodopa-carbidopa intestinal gel (LCIG) followed by night-time oral LD/carbidopa (CD) doses. METHODS: This was a Phase 1, open-label, randomized, 2-period crossover study conducted in 25 male and female healthy volunteers. RESULTS: The LD exposures (Cmax0-16, AUC0-16 and AUC∞) following subcutaneous infusion of 700/35 mg foslevodopa/foscarbidopa over 24 h were similar (<8% difference) to those of LCIG 350/87.5 mg LD/CD administered over 16 h followed by two 100/25 mg LD/CD oral doses at 18 and 21 h after the start of LCIG delivery. CONCLUSION: Foslevodopa/foscarbidopa subcutaneous infusion provides levodopa exposures comparable to LCIG throughout the day. GOV IDENTIFIER: Not Applicable.

177Lu-Dotatate plus long-acting octreotide versus high­dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results. METHODS: This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous 177Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg (177Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). The primary endpoint of progression-free survival has been previously reported; here, we report the key secondary endpoint of overall survival in the intention-to-treat population. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the 177Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239. FINDINGS: From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assigned for treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months (range 0·4-95·0) in the 177Lu-Dotatate group and 76·5 months (0·1-92·3) in the control group. The secondary endpoint of overall survival was not met: median overall survival was 48·0 months (95% CI 37·4-55·2) in the 177Lu-Dotatate group and 36·3 months (25·9-51·7) in the control group (HR 0·84 [95% CI 0·60-1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the 177Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given 177Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported 177Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up. INTERPRETATION: 177Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11·7 month difference in median overall survival with 177Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up. FUNDING: Advanced Accelerator Applications, a Novartis company.

Respiratory mechanics and mortality in coronavirus disease 2019 acute respiratory distress syndrome: A retrospective cohort study.

BACKGROUND: The association between commonly monitored respiratory parameters, including compliance and oxygenation and clinical outcomes in acute respiratory distress syndrome (ARDS) from coronavirus disease 2019 (COVID-19) remains unclear, limiting prognostication and the delivery of targeted treatments. Our project aim was to identify if any such associations exist between clinical outcomes and respiratory parameters. METHODS: We performed a retrospective observational cohort study of confirmed COVID-19 positive patients admitted to a single dedicated intensive care unit at a university hospital from March 27 to April 26, 2020. We collected information on baseline clinical and demographic characteristics and initial respiratory parameters. Our primary outcome was in-hospital mortality. RESULTS: A total of 22 patients met criteria for ARDS and were included in our study. Nine of the 22 (40.9%) patients with ARDS died during hospitalization. The initial static respiratory system compliance of survivors was 39 (interquartile range [IQR] 34, 55) and nonsurvivors was 27 (IQR 24, 33, P < 0.01). A lower respiratory system compliance was associated with an increased adjusted odd of in-hospital mortality (odds ratio 1.2, 95% confidence interval 1.01, 1.45 P = 0.04). CONCLUSION: In our cohort of 22 patients mechanically ventilated with ARDS from COVID-19, having lower respiratory system compliance after intubation was associated with an increased risk of in-hospital mortality, consistent with ARDS from non-COVID etiologies.

Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion.

BACKGROUND: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson's disease (aPD). OBJECTIVE: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. METHODS: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. RESULTS: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. CONCLUSION: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.

Epidemiology of skin event rates among users of pumps for the subcutaneous administration of drugs for chronic conditions.

OBJECTIVE: To provide the epidemiology of skin events occurring during long-term administration of medications delivered by continuous subcutaneous infusion pump (CSIP) systems as background rates for the development of novel CSIP treatments to use in community-based settings. METHODS: Using a United Kingdom general practice database, we conducted a study to assess the rates of skin events among new users of apomorphine and insulin delivered by CSIP in patients with Parkinson's disease or diabetes, respectively. Skin events included skin infections, skin nodules/localized swelling, dermatitis/eczema, urticaria/erythema, and rash/other non-specific skin eruptions. RESULTS: Five hundred and fifty-seven adults (age 30+) were included in this descriptive cohort. The median duration of CSIP use was 17 months among 255 apomorphine users and 41 months among 302 insulin users. By 60 months, ∼40% of both cohorts experienced skin events. Repeated skin events occurred in 11% of the apomorphine cohort and 14% of the insulin cohort at any time during follow-up. The overall skin event rate in the apomorphine cohort was 17 per 1000 person-months (PM) and 13 per 1000 PM in the insulin cohort. The most common skin events in both cohorts were infection and rash/unspecified skin eruptions. The highest rates of skin events occurred soon after apomorphine CSIP initiation (36 per 1000 PM in weeks 1-2 and 50 per 1000 PM in weeks 3-4), with lower rates after 4 weeks. Insulin CSIP users' skin event rates were consistent over the treatment duration. CONCLUSIONS: Clinically important skin events are common during long-term administration of medications by CSIP.

Susceptibility of Drosophila suzukii larvae to the combined administration of the entomopathogens Bacillus thuringiensis and Steinernema carpocapsae.

Non-native pests are often responsible for serious crop damage. Since Drosophila suzukii has invaded North America and Europe, the global production of soft, thin-skinned fruits has suffered severe losses. The control of this dipteran by pesticides, although commonly used, is not recommended because of the negative impact on the environment and human health. A possible alternative is the use of bio-insecticides, including Bacillus thuringiensis and entomopathogenic nematodes, such as Steinernema carpocapsae. These biological control agents have a fair effectiveness when used individually on D. suzukii, but both have limits related to different environmental, methodological, and physiological factors. In this work, we tested various concentrations of B. thuringiensis and S. carpocapsae to evaluate their efficacy on D. suzukii larvae, when administered individually or in combination by using agar traps. In the combined trials, we added the nematodes after 16 h or concurrently to the bacteria, and assessed larvae lethality from 16 to 48 h. The assays demonstrated a higher efficacy of the combined administration, both time-shifted and concurrent; the obtained data also showed a relevant decrease of the time needed to kill the larvae. Particularly, the maximum mortality rate, corresponding to 79% already at 16 h, was observed with the highest concentrations (0.564 µg/mL of B. thuringiensis and 8 × 102 IJs of S. carpocapsae) in the concurrent trials. This study, conducted by laboratory tests under controlled conditions, is a good starting point to develop a further application step through field studies for the control of D. suzukii.

Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease.

OBJECTIVE: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication. METHODS: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study. RESULTS: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated. INTERPRETATION: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.

Characteristics, Outcomes, and Trends of Patients With COVID-19-Related Critical Illness at a Learning Health System in the United States.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally. OBJECTIVE: To describe the epidemiology of COVID-19-related critical illness, including trends in outcomes and care delivery. DESIGN: Single-health system, multihospital retrospective cohort study. SETTING: 5 hospitals within the University of Pennsylvania Health System. PATIENTS: Adults with COVID-19-related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic. MEASUREMENTS: The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions. RESULTS: Among 468 patients with COVID-19-related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change. LIMITATIONS: Single-health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications. CONCLUSION: Among patients with COVID-19-related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Outcomes After Tracheostomy in COVID-19 Patients.

OBJECTIVE: To determine the outcomes of patients undergoing tracheostomy for COVID-19 and of healthcare workers performing these procedures. BACKGROUND: Tracheostomy is often performed for prolonged endotracheal intubation in critically ill patients. However, in the context of COVID-19, tracheostomy placement pathways have been altered due to the poor prognosis of intubated patients and the risk of transmission to providers through this highly aerosolizing procedure. METHODS: A prospective single-system multi-center observational cohort study was performed on patients who underwent tracheostomy after acute respiratory failure secondary to COVID-19. RESULTS: Of the 53 patients who underwent tracheostomy, the average time from endotracheal intubation to tracheostomy was 19.7 days ±â€Š6.9 days. The most common indication for tracheostomy was acute respiratory distress syndrome, followed by failure to wean ventilation and post-extracorporeal membrane oxygenation decannulation. Thirty patients (56.6%) were liberated from the ventilator, 16 (30.2%) have been discharged alive, 7 (13.2%) have been decannulated, and 6 (11.3%) died. The average time from tracheostomy to ventilator liberation was 11.8 days ±â€Š6.9 days (range 2-32 days). Both open surgical and percutaneous dilational tracheostomy techniques were performed utilizing methods to mitigate aerosols. No healthcare worker transmissions resulted from performing the procedure. CONCLUSIONS: Alterations to tracheostomy practices and processes were successfully instituted. Following these steps, tracheostomy in COVID-19 intubated patients seems safe for both patients and healthcare workers performing the procedure.

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study.

PURPOSE: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. METHODS: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. RESULTS: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. CONCLUSIONS: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

In Vivo Effects of A Pro-PO System Inhibitor on the Phagocytosis of Xenorhabdus Nematophila in Galleria Mellonella Larvae.

Xenorhabdus nematophila is a Gram-negative bacterium symbiont of the entomopathogen nematode Steinernema carpocapsae whose immunosuppressive properties over host's immune response have been thoroughly investigated. In particular, live X. nematophila actively impairs phagocytosis in host's hemocytes through the secretion of inhibitors of eicosanoids synthesis. In this article we have investigated the cell surface structural features of X. nematophila responsible for the elusion from phagocytosis. To this end we have studied the uptake of heat-killed (hk), fluorescein isothiocyanate (FITC)-labeled X. nematophila by phagocytes from both a host insect and a mammalian species. In vitro dead X. nematophila passively resists engulfment by insect hemocytes without impairing the phagocytosis machinery whereas, unexpectedly, in vivo a significant phagocytosis of dead X. nematophila was observed. X. nematophila in vivo phagocytosis was increased by the co-injection of the specific inhibitor of pro-phenoloxidase (PO) system phenylthiourea (PTU), even if these effects were not observed in in vitro tests. Furthermore, biochemical modifications of X. nematophila cell wall implement in vivo phagocytosis, suggesting that this bacterium avoid phagocytosis because the ligand of phagocytic receptors is somehow buried or disguised in the cell wall. Finally, dead X. nematophila escapes engulfment even by human phagocytes suggesting that X. nematophila could be a useful model to investigate escape from phagocytosis by mammalian macrophages.

Measurement of Regional 2D Gas Transport Efficiency in Rabbit Lung Using Hyperpolarized 129Xe MRI.

While hyperpolarized xenon-129 (HXe) MRI offers a wide array of tools for assessing functional aspects of the lung, existing techniques provide only limited quantitative information about the impact of an observed pathology on overall lung function. By selectively destroying the alveolar HXe gas phase magnetization in a volume of interest and monitoring the subsequent decrease in the signal from xenon dissolved in the blood inside the left ventricle of the heart, it is possible to directly measure the contribution of that saturated lung volume to the gas transport capacity of the entire lung. In mechanically ventilated rabbits, we found that both xenon gas transport and transport efficiency exhibited a gravitation-induced anterior-to-posterior gradient that disappeared or reversed direction, respectively, when the animal was turned from supine to prone position. Further, posterior ventilation defects secondary to acute lung injury could be re-inflated by applying positive end expiratory pressure, although at the expense of decreased gas transport efficiency in the anterior volumes. These findings suggest that our technique might prove highly valuable for evaluating lung transplants and lung resections, and could improve our understanding of optimal mechanical ventilator settings in acute lung injury.

Susceptibility to entomopathogens and modulation of basal immunity in two insect models at different temperatures.

In this work, we analysed the efficacy of different commercial bio-insecticides (Steinernema feltiae, Steinernema carpocapsae, Heterorhabditis bacteriophora and Bacillus thuringiensis) by valuating the mortality induced on two insect models, Galleria mellonella (Lepidoptera) and Sarcophaga africa (Diptera) after exposure to different temperatures (10, 20 and 30 °C). Moreover, we investigated the effects of temperature on the basal humoral immunity of the two target insects; particularly, phenoloxidase (PO) and lysozyme activity. Our results show that G. mellonella is susceptible to all bio-insecticides at all the examined temperatures, except when infected at 10 °C with S. carpocapsae and at 30 °C with S. feltiae and B. thuringiensis. S. africa is more susceptible at 30 °C to all bioinsecticides; whereas, when infected at 10 and 20 °C, H. bacteriophora is the most efficient. Temperature modulates PO activity of both G. mellonella and S. africa, otherwise variations in lysozyme activity is observed only in G. mellonella. Except for a possible correlation between the increased lysozyme activity and the delayed Bt efficacy recorded on G. mellonella at 30 °C, a different resistance to bio-insecticides at different temperatures does not seem to be associated to variations of the host basal immunity, probably due to immunoevasive and immunodepressive strategies of these entomopathogens.

Assessment of flip angle-TR equivalence for standardized dissolved-phase imaging of the lung with hyperpolarized 129Xe MRI.

PURPOSE: To investigate the feasibility of describing the impact of any flip angle-TR combination on the resulting distribution of the hyperpolarized xenon-129 (HXe) dissolved-phase magnetization in the chest using a single virtual parameter, TR90°,equiv . METHODS: HXe MRI scans with simultaneous gas- (GP) and dissolved-phase (DP) excitation were performed using 2D projection scans in mechanically ventilated rabbits. Measurements with DP flip angles ranging from 6-90° and TRs ranging from 8.3-500 ms were conducted. DP maps based on acquisitions of similar radio frequency pulse-induced relaxation rates were compared. RESULTS: The observed distribution of the DP magnetization was strongly affected by acquisition flip angle and TR. However, for flip angles up to 60°, measurements with the same radio frequency pulse-induced relaxation rates, resulted in very similar DP images despite the presence of significant macroscopic gas transport processes. For flip angles approaching 90°, the downstream signal component decreased noticeably relative to acquisitions with lower flip angles. Nevertheless, the total DP signal continued to follow an empirically verified conversion equation over the entire investigated parameter range, which yields the equivalent TR of a hypothetical 90° measurement for any experimental flip angle-TR combination. CONCLUSION: We have introduced a method for converting the flip angle and TR of a given HXe DP measurement to a standardized metric based on the virtual quantity, TR90°,equiv , using their equivalent RF relaxation rates. This conversion permits the comparison of measurements obtained with different pulse sequence types or by different research groups using various acquisition parameters.