Objective monitoring tools for improved management of childhood asthma.

Asthma is a common chronic disease amongst children. Epidemiological studies showed that the mortality rate of asthma in children is still high worldwide. Asthma control is therefore essential to minimize asthma exacerbations, which can be fatal if the condition is poorly controlled. Frequent monitoring could help to detect asthma progression and ensure treatment effectiveness. Although subjective asthma monitoring tools are available, the results vary as they rely on patients' self-perception. Emerging evidence suggests several objective tools could have the potential for monitoring purposes. However, there is no consensus to standardise the use of objective monitoring tools. In this review, we start with the prevalence and severity of childhood asthma worldwide. Then, we detail the latest available objective monitoring tools, focusing on their effectiveness in paediatric asthma management. Publications of spirometry, fractional exhaled nitric oxide (FeNO), hyperresponsiveness tests and electronic monitoring devices (EMDs) between 2016 and 2023 were included. The potential advantages and limitations of each tool were also discussed. Overall, this review provides a summary for researchers dedicated to further improving objective paediatric asthma monitoring and provides insights for clinicians to incorporate different objective monitoring tools in clinical practices.

Oral Delivery of Photopolymerizable Nanogels Loaded with Gemcitabine for Pancreatic Cancer Therapy: Formulation Design, and in vitro and in vivo Evaluations.

Background: Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients. Methods: We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug. Results: Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91±7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07±19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM's AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙µg/mL) compared to oral free-GEM (19.04 hr∙µg/mL) after oral administration (p<0.01), highlighting NGs' efficacy in impeding rapid drug metabolism and enhancing retention. Conclusion: In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.

Synergistic combination of antimicrobial peptide and isoniazid as inhalable dry powder formulation against multi-drug resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) has posed a serious threat to global public health, and antimicrobial peptides (AMPs) have emerged to be promising candidates to tackle this deadly infectious disease. Previous study has suggested that two AMPs, namely D-LAK120-A and D-LAK120-HP13, can potentiate the effect of isoniazid (INH) against mycobacteria. In this study, the strategy of combining INH and D-LAK peptide as a dry powder formulation for inhalation was explored. The antibacterial effect of INH and D-LAK combination was first evaluated on three MDR clinical isolates of Mycobacteria tuberculosis (Mtb). The minimum inhibitory concentrations (MICs) and fractional inhibitory concentration indexes (FICIs) were determined. The combination was synergistic against Mtb with FICIs ranged from 0.25 to 0.38. The INH and D-LAK peptide at 2:1 mole ratio (equivalent to 1: 10 mass ratio) was identified to be optimal. This ratio was adopted for the preparation of dry powder formulation for pulmonary delivery, with mannitol used as bulking excipient. Spherical particles with mass median aerodynamic diameter (MMAD) of around 5 µm were produced by spray drying. The aerosol performance of the spray dried powder was moderate, as evaluated by the Next Generation Impactor (NGI), with emitted fraction and fine particle fraction of above 70 % and 45 %, respectively. The circular dichroism spectra revealed that both D-LAK peptides retained their secondary structure after spray drying, and the antibacterial effect of the combination against the MDR Mtb clinical isolates was successfully preserved. The combination was found to be effective against MDR Mtb isolates with KatG or InhA mutations. Overall, the synergistic combination of INH with D-LAK peptide formulated as inhaled dry powder offers a new therapeutic approach against MDR-TB.

Co-delivery of PD-L1- and EGFR-targeting siRNAs by synthetic PEG12-KL4 peptide to the lungs as potential strategy against non-small cell lung cancer.

BACKGROUND: Small interfering RNA (siRNA) holds great promise for treating various lung diseases, but the lack of safe and efficient pulmonary siRNA delivery systems has hindered its advance into the clinics. The epidermal growth factor receptor (EGFR) which promotes cell proliferation, and the programmed cell death ligand 1 (PD-L1) which plays a crucial role in suppressing cytotoxic T cells activity, are two important targets for treating non-small cell lung cancer (NSCLC). Here, we explored the potential of PEG12-KL4, a synthetic peptide, to deliver siRNA to various NSCLC cells and to lung tissues in mice. METHODS: PEG12-KL4 was used to transfect siRNAs targeted at both EGFR and PD-L1 into NSCLC cells. Immunoblotting was used to evaluate the siRNA silencing effects in HCC827 and NCI-H1975 NSCLC cells. CD8+ T cell-mediated NSCLC cell killing was employed to demonstrate the functional effects of PD-L1 siRNA knock-down. Fluorescent siRNAs were used to visualise siRNA uptake in cells as well as to enable biodistribution studies in BALB/c mice. RESULTS: Our results showed that PEG12-KL4 was efficient in mediating siRNA knock-down of EGFR and PD-L1 in various NSCLC cells. Importantly, the PEG12-KL4 peptide enabled significantly better siRNA delivery than the commercial Lipofectamine 2000 reagent. We hypothesised that PEG12-KL4 peptide enabled siRNA to either escape from or bypass endosomal degradation as indicated by confocal fluorescence imaging. Notably, combined knock-down of EGFR and PD-L1 in NCI-H1975 cells resulted in better effector T cell-mediated cancer cell killing than knock-down of PD-L1 alone. Moreover, biodistribution of PEG12-KL4/siRNA complexes following intravenous administration revealed poor lung delivery with the fluorescent siRNA accumulating in the liver. In contrast, intratracheal delivery of PEG12-KL4/siRNA complexes resulted in the fluorescent siRNA to be detected in the lung with retarded renal excretion. CONCLUSION: In conclusion, we demonstrated that the co-delivery of siRNAs targeting EGFR and PD-L1 using PEG12-KL4 is feasible and represents a promising future strategy to treat NSCLC, whereby pulmonary siRNA delivery is favourable to intravenous administration.

Storage stability of lysostaphin solution and its pulmonary delivery.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a leading causative pathogen of nosocomial pneumonia with an alarming in-hospital mortality rate of 30%. Last resort antibiotic, vancomycin, has been increasingly used to treat MRSA infections, but the rapid emergence of vancomycin-resistant strains urges the development of alternative treatment strategies against MRSA-associated pneumonia. The bacteriolytic enzyme, lysostaphin, targeting the cell wall peptidoglycan of S. aureus, has been considered as a promising alternative for MRSA infections. Its proteinaceous nature is likely benefit from direct delivery to the lungs, but the challenges for successful pulmonary delivery of lysostaphin lying on a suitable inhalation device and a formulation with sufficient storage stability. In this study, the applicability of a vibrating mesh nebulizer (Aerogen Solo®) and a soft mist inhaler (Respimat®) was investigated. Both devices were capable of aerosolizing lysostaphin solution into inhalable droplets and caused minimum antibacterial activity loss. In addition, lysostaphin stabilized with phosphate-buffered saline and 0.1% Tween 80 was proved to have acceptable stability for at least 12 months when stored at 4 °C. These promising data encourage further clinical development of lysostaphin for management of MRSA-associated lung infections.

Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile.

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.

Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-l-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery.

The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) exhibits remarkable anticancer efficacy; however, its therapeutic potential is hindered by its toxicity to gastrointestinal (GI) tissues. We recently reported the discovery of DRP-104, a tumor-targeted DON prodrug with excellent efficacy and tolerability, which is currently in clinical trials. However, DRP-104 exhibits limited aqueous solubility, and the instability of its isopropyl ester promoiety leads to the formation of an inactive M1-metabolite, reducing overall systemic prodrug exposure. Herein, we aimed to synthesize DON prodrugs with various ester and amide promoieties with improved solubility, GI stability, and DON tumor delivery. Twenty-one prodrugs were synthesized and characterized in stability and pharmacokinetics studies. Of these, P11, tert-butyl-(S)-6-diazo-2-((S)-2-(2-(dimethylamino)acetamido)-3-phenylpropanamido)-5-oxo-hexanoate, showed excellent metabolic stability in plasma and intestinal homogenate, high aqueous solubility, and high tumor DON exposures and preserved the ideal tumor-targeting profile of DRP-104. In conclusion, we report a new generation of glutamine antagonist prodrugs with improved physicochemical and pharmacokinetic attributes.

Obesity management for the hepatologist-What to do, how to do it and why?

Obesity is highly prevalent in hepatology clinics and has a significant impact on chronic liver disease and patient management. Hepatologists and gastroenterologists need to be actively engaged in the management of obesity. This review provides a detailed approach to this challenging comorbidity.

Turner syndrome: skin, liver, eyes, dental and ENT evaluation should be improved.

Introduction: Turner syndrome association with multi-organ system comorbidities highlights the need for effective implementation of follow-up guidelines. We aimed to assess the adequacy of care with international guidelines published in 2007 and 2017 and to describe the phenotype of patients. Methods: In this multicenter retrospective descriptive cohort study, we collected growth and pubertal parameters, associated comorbidities, treatment, and karyotype in patients diagnosed at age <18 years between 1993 and 2022. We assessed age-appropriate recommendation follow-up (children, adolescents and adults) according to the 2007 guidelines if the last visit was before 2017 (18 recommendations) and the 2017 guidelines if the last visit was after 2017 (19 recommendations). Results: We included 68 patients followed at Lausanne University Hospital (n=64) and at Neuchatel Regional Hospital (RHNe) (n=4). 2.9% of patients underwent all recommended investigations.Overall, 68.9 ± 22.5% and 78.5 ± 20.6% of the recommendations were followed, before and after 2017 respectively. High implementation rates were found for height, weight and BMI (100%), cardiac (80 to 100%) and renal (90 to 100%) imaging. Low implementation rates were found for Ear, Nose and Throat (ENT) (56.5%), skin (38.5%), dental (23.1%), ophthalmological (10%) and cholestasis (0 to 29%) assessments, depending on age and time of visit. In adults (n=33), the mean proportion of followed recommendations was lower before than after 2017: 63.5 ± 25.8% vs. 78.7 ± 23.4%, p=0.039. Conclusion: Growth parameters, cardiac and renal imaging are well followed. However, efforts should be made for dental, ENT, ophthalmological, skin and cholestasis assessments. Adequacy of follow-up improved with the quality of transition to adult care.

Delivery technology of inhaled therapy for asthma and COPD.

Inhaled therapy is the cornerstone of the management of asthma and chronic obstructive pulmonary disease (COPD). Drugs such as bronchodilators and corticosteroids are administered directly to the airways for local effect and rapid onset of action while systemic exposure and side effects are minimized. There are four major types of inhaler devices used clinically to generate aerosols for inhalation, namely, pressurized metered-dose inhalers (pMDIs), nebulizers, Soft Mist™ inhalers (SMIs) and dry powder inhalers (DPIs). Each of them has its own unique characteristics that can target different patient groups. For instance, patients' inhaler technique is critical for pMDIs and SMIs to achieve proper drug deposition in the lung, which could be challenging for some patients. Nebulizers are designed to deliver aerosols to patients during tidal breathing, but they require electricity to operate and are less portable than other devices. DPIs are the only device that delivers aerosols in dry powder form with better stability, but they rely on patients' inspiration effort for powder dispersion, rendering them unsuitable for patients with compromised lung function. Choosing a device that can cater for the need of individual patient is paramount for effective inhaled therapy. This chapter provides an overview of inhaled therapy for the management of asthma and COPD. The operation principles, merits and limitations of different delivery technologies are examined. Looking ahead, the challenges of delivering novel therapeutics such as biologics through the pulmonary route are also discussed.

Enhanced powder dispersion of dual-excipient spray-dried powder formulations of a monoclonal antibody and its fragment for local treatment of severe asthma.

The advent of biologics has brought renewed hope for patients with severe asthma, a condition notorious for being hampered by poor response to conventional therapies and adverse drug reactions owing to corticosteroid dependence. However, biologics are administered as injections, thereby precluding the benefits inhalation therapy could offer such as increased bioavailability at the site of action, minimal systemic side effects, non-invasiveness, and self-administration. Here, 2-hydroxypropyl-beta-cyclodextrin and ʟ-leucine were co-spray-dried, as protein stabiliser and dispersion enhancer, respectively, at various weight ratios to produce a series of formulation platforms. Powder aerosolisation characteristics and particle morphology were assessed for suitability for pulmonary delivery. The selected platform with the best aerosol performance, a 1:1 ratio of the excipients, was then incorporated with a monoclonal antibody directed against IL-4 receptor alpha or its antigen-binding fragment. The dual-excipient antibody formulations exhibited emitted fraction of at least 80% and fine particle fraction exceeding 60% in cascade impactor study, while the residual moisture content was within a desirable range between 1% and 3%. The in vitro antigen-binding ability and inhibitory potency of the spray-dried antibody were satisfactorily preserved. The results from this study corroborate the viability of inhaled solid-state biomacromolecules as a promising treatment approach for asthma.

Synthesis and Properties of Sucrose- and Lactose-Based Aromatic Ester Surfactants as Potential Drugs Permeability Enhancers.

The delivery of therapeutics across biological membranes (e.g., mucosal barriers) by avoiding invasive routes (e.g., injection) remains a challenge in the pharmaceutical field. As such, there is the need to discover new compounds that act as drug permeability enhancers with a favorable toxicological profile. A valid alternative is represented by the class of sugar-based ester surfactants. In this study, sucrose and lactose alkyl aromatic and aromatic ester derivatives have been synthesized with the aim to characterize them in terms of their physicochemical properties, structure-property relationship, and cytotoxicity, and to test their ability as permeability enhancer agents across Calu-3 cells. All of the tested surfactants showed no remarkable cytotoxic effect on Calu-3 cells when applied both below and above their critical micelle concentration. Among the explored molecules, lactose p-biphenyl benzoate (URB1420) and sucrose p-phenyl benzoate (URB1481) cause a reversible ~30% decrease in transepithelial electrical resistance (TEER) with the respect to the basal value. The obtained result matches with the increased in vitro permeability coefficients (Papp) calculated for FTIC-dextran across Calu-3 cells in the presence of 4 mM solutions of these surfactants. Overall, this study proposes sucrose- and lactose-based alkyl aromatic and aromatic ester surfactants as novel potential and safe permeation enhancers for pharmaceutical applications.

Factors Associated With the Quality of Life of Nursing Home Residents During the COVID-19 Pandemic: A Cross-Sectional Study.

OBJECTIVES: Quality of life (QoL) of nursing home (NH) residents is critical, yet understudied, particularly during the COVID-19 pandemic. Our objective was to examine whether COVID-19 outbreaks, lack of access to geriatric professionals, and care aide burnout were associated with NH residents' QoL. DESIGN: Cross-sectional study (July to December 2021). SETTING AND PARTICIPANTS: We purposefully selected 9 NHs in Alberta, Canada, based on their COVID-19 exposure (no or minor/short outbreaks vs repeated or extensive outbreaks). We included data for 689 residents from 18 care units. METHODS: We used the DEMQOL-CH to assess resident QoL through video-based care aide interviews. Independent variables included a COVID-19 outbreak in the NH in the past 2 weeks (health authority records), care unit-levels of care aide burnout (9-item short-form Maslach Burnout Inventory), and resident access to geriatric professionals (validated facility survey). We ran mixed-effects regression models, adjusted for facility and care unit (validated surveys), and resident covariates (Resident Assessment Instrument-Minimum Data Set 2.0). RESULTS: Recent COVID-19 outbreaks (ß = 0.189; 95% CI: 0.058-0.320), higher proportions of emotionally exhausted care aides on a care unit (ß = 0.681; 95% CI: 0.246-1.115), and lack of access to geriatric professionals (ß = 0.216; 95% CI: 0.003-0.428) were significantly associated with poorer resident QoL. CONCLUSIONS AND IMPLICATIONS: Policies aimed at reducing infection outbreaks, better supporting staff, and increasing access to specialist providers may help to mitigate how COVID-19 has negatively affected NH resident QoL.

Neutralisation of SARS-CoV-2 by monoclonal antibody through dual targeting powder formulation.

Neutralising monoclonal antibody (mAb) is an important weapon in our arsenal for combating respiratory viral infections. However, the effectiveness of neutralising mAb has been impeded by the rapid emergence of mutant variants. Early administration of broad-spectrum mAb with improved delivery efficiency can potentially enhance efficacy and patient outcomes. WKS13 is a humanised mAb which was previously demonstrated to exhibit broad-spectrum activity against SARS-CoV-2 variants. In this study, a dual targeting formulation strategy was designed to deliver WKS13 to both the nasal cavity and lower airways, the two critical sites of infection caused by SARS-CoV-2. Dry powders of WKS13 were first prepared by spray drying, with cyclodextrin used as stabiliser excipient. Two-fluid nozzle (TFN) was used to produce particles below 5 µm for lung deposition (C-TFN formulation) and ultrasonic nozzle (USN) was used to produce particles above 10 µm for nasal deposition (C-USN formulation). Gel electrophoresis and size exclusion chromatography studies showed that the structural integrity of mAb was successfully preserved with no sign of aggregation after spray drying. To achieve dual targeting property, C-TFN and C-USN were mixed at various ratios. The aerosolisation property of the mixed formulations dispersed from a nasal powder device was examined using a Next Generation Impactor (NGI) coupled with a glass expansion chamber. When the ratio of C-TFN in the mixed formulation increased, the fraction of particles deposited in the lung increased proportionally while the fraction of particles deposited in the nasal cavity decreased correspondingly. A customisable aerosol deposition profile could therefore be achieved by manipulating the mixing ratio between C-TFN and C-USN. Dual administration of C-TFN and C-USN powders to the lung and nasal cavity of hamsters, respectively, was effective in offering prophylactic protection against SARS-CoV-2 Delta variant. Viral loads in both the lung tissues and nasal wash were significantly reduced, and the efficacy was comparable to systemic administration of unformulated WKS13. Overall, dual targeting powder formulation of neutralising mAb is a promising approach for prophylaxis of respiratory viral infections. The ease and non-invasive administration of dual targeting nasal powder may facilitate the widespread distribution of neutralising mAb during the early stage of unpredictable outbreaks.

Co-Delivery of D-LAK Antimicrobial Peptide and Capreomycin as Inhaled Powder Formulation to Combat Drug-Resistant Tuberculosis.

INTRODUCTION: The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) posed a severe challenge to tuberculosis (TB) management. The treatment of MDR-TB involves second-line anti-TB agents, most of which are injectable and highly toxic. Previous metabolomics study of the Mtb membrane revealed that two antimicrobial peptides, D-LAK120-A and D-LAK120-HP13, can potentiate the efficacy of capreomycin against mycobacteria. AIMS: As both capreomycin and peptides are not orally available, this study aimed to formulate combined formulations of capreomycin and D-LAK peptides as inhalable dry powder by spray drying. METHODS AND RESULTS: A total of 16 formulations were prepared with different levels of drug content and capreomycin to peptide ratios. A good production yield of over 60% (w/w) was achieved in most formulations. The co-spray dried particles exhibited spherical shape with a smooth surface and contained low residual moisture of below 2%. Both capreomycin and D-LAK peptides were enriched at the surface of the particles. The aerosol performance of the formulations was evaluated with Next Generation Impactor (NGI) coupled with Breezhaler®. While no significant difference was observed in terms of emitted fraction (EF) and fine particle fraction (FPF) among the different formulations, lowering the flow rate from 90 L/min to 60 L/min could reduce the impaction at the throat and improve the FPF to over 50%. CONCLUSIONS: Overall, this study showed the feasibility of producing co-spray dried formulation of capreomycin and antimicrobial peptides for pulmonary delivery. Future study on their antibacterial effect is warranted.

The Effects of the Dopamine Transporter Ligands JJC8-088 and JJC8-091 on Cocaine versus Food Choice in Rhesus Monkeys.

Although there are no Food and Drug Administration-approved treatments for cocaine use disorder, several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine versus food schedule of reinforcement. First, binding to striatal DAT was examined in cocaine-naïve monkey tissue. Next, intravenous pharmacokinetics of both JJC compounds were evaluated in cocaine-experienced male monkeys (n = 3/drug). In behavioral studies, acute and chronic administration of both compounds were evaluated in these same monkeys responding under a concurrent food versus cocaine (0 and 0.003-0.1 mg/kg per injection) schedule of reinforcement. In nonhuman primate striatum, JJC8-088 had higher DAT affinity compared with JJC8-091 (14.4 ± 9 versus 2730 ± 1270 nM, respectively). Both JJC compounds had favorable plasma pharmacokinetics for behavioral assessments, with half-lives of 1.1 hours and 3.5 hours for JJC8-088 (0.7 mg/kg, i.v.) and JJC8-091 (1.9 mg/kg, i.v.), respectively. Acute treatment with both compounds shifted the cocaine dose-response curve to the left. Chronic treatment with JJC8-088 decreased cocaine choice in two of the three monkeys, whereas JJC8-091 only modestly reduced cocaine allocation in one monkey. Differences in affinities of JJC8-091 DAT binding in monkeys compared with rats may account for the poor rodent-to-monkey translation. Future studies should evaluate atypical DAT blockers in combination with behavioral interventions that may further decrease cocaine choice. SIGNIFICANCE STATEMENT: Cocaine use disorder (CUD) remains a significant public health problem with no Food and Drug Administration-approved treatments. The ability of drugs that act in the brain in a similar manner to cocaine, but with lower abuse liability, has clinical implications for a treatment of CUD.

Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens.

12-Bis-THA Cl2 [12,12'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used.

Inhalable neutralizing antibodies - promising approach to combating respiratory viral infections.

Monoclonal antibodies represent an exciting class of therapeutics against respiratory viral infections. Notwithstanding their specificity and affinity, the conventional parenteral administration is suboptimal in delivering antibodies for neutralizing activity in the airways due to the poor distribution of macromolecules to the respiratory tract. Inhaled therapy is a promising approach to overcome this hurdle in a noninvasive manner, while advances in antibody engineering have led to the development of unique antibody formats which exhibit properties desirable for inhalation. In this Opinion, we examine the major challenges surrounding the development of inhaled antibodies, identify knowledge gaps that need to be addressed and provide strategies from a drug delivery perspective to enhance the efficacy and safety of neutralizing antibodies against respiratory viral infections.

Factors influencing participation in home, school, and community settings by children and adolescents with neuromuscular disorders: A qualitative descriptive study.

AIM: This study explored how children and adolescents with a neuromuscular disorder (NMD) and their parents experienced barriers and enablers to the child's participation. METHOD: This was a qualitative descriptive design. Fourteen semi-structured interviews were conducted (n = 13 mothers, n = 4 fathers, n = 8 children and adolescents) including one to three family members for each interview according to their preference. Data were analysed by content analysis, using the family of Participation-Related Constructs (fPRC), to characterize the components of participation. RESULTS: Meaningful participation was illustrated in the personal categories of the fPRC including the child's sense of self, preferences, and competence to perform activities. Enablers and barriers related to adaptive equipment and activity modification, social relationships, inclusion, accessibility to venues, social attitudes, and policies. INTERPRETATION: Personal motivators are critical to understanding what participation is meaningful to children and adolescents with NMDs. Social and physical supports within the child's immediate environment as well as accessibility and advocacy more widely in the community enable participation. The fPRC is a useful tool for understanding participation in these children; it informs how to support participation and suggests domains for evaluation in future intervention studies. Advocacy for participation should consider targets in the immediate and broader environments. WHAT THIS PAPER ADDS: The family of Participation-Related Constructs classified the components of participation for children and adolescents with neuromuscular disorders. Meaningful participation involved a complex interaction between personal and environmental factors. Barriers to participation included poor accessibility, lack of equipment, and social exclusion.