How effective are digital interventions in increasing flu vaccination among pregnant women? A systematic review and meta-analysis.

BACKGROUND: Flu can have serious consequences for pregnant woman and unborn babies. Vaccination provides safe and effective protection, yet uptake among pregnant women is below national targets. Digital interventions are effective at increasing adherence to health interventions. AIMS: This review aimed to establish whether digital interventions are effective at increasing rates of flu vaccination among pregnant women, and to determine the overall effect size. METHOD: Systematic searches identified digital intervention trials, aiming to increase rate of flu vaccination among pregnant women. Random-effects meta-analysis provided a combined effect size and examined which mode of digital interventions had the largest effects on flu vaccination. RESULTS: Ten studies were included in the review. The majority of digital interventions were more effective at increasing rates of flu vaccination (7-81.3% uptake) than usual care or non-digital interventions (7.3-47.1% uptake). When meta-analysed, digital interventions had a small, non-significant effect (odds ratio [OR] = 1.29, 95% confidence interval [CI]: 0.71, 2.31), P = 0.40. Text messages (OR = 1.25, 95% CI: 0.58, 2.67), P = 0.57 appeared less effective than other digital interventions (OR = 1.58, 95% CI: 1.02, 2.46), P = 0.04. CONCLUSIONS: Overall, there is a lack of high-quality studies reporting the effectiveness of digital interventions at increasing flu vaccination during pregnancy. Future interventions may benefit from using video or social media to communicate messages for maximum success in targeting an increase in rates of flu vaccination in pregnancy.

Liquid crystal nanoparticle platform for increased efficacy of cationic antimicrobials against biofilm infections.

Bacterial biofilm infections tolerate high concentrations of antibiotics and are insidiously challenging to treat. Liquid crystal nanoparticles (LCNPs) advance the efficacy of tobramycin in biofilm-related infections by increasing the penetration of antibiotics across the biofilm matrix. Herewith, we develop the LCNPs as a platform technology, demonstrating that the LCNPs can increase the efficacy of two antibiotic classes (i.e. aminoglycosides and colistin) in P. aeruginosa biofilm infections. In C. elegans, the LCNPs potentiated the antimicrobial effect and significantly improved the survival of the nematodes. In mice with a full-thickness excisional wound, LCNPs were non-toxic and did not impair wound repair. Compared to the unformulated antibiotic treatment, tobramycin-LCNPs reduced the chronic bacterial load by 100-fold in the wound. This was also emulated in an ex vivo P. aeruginosa porcine wound infection model. The LCNPs represent a versatile platform technology that improves the efficacy of cationic antibiotics against biofilm infections utilizing multiple administration routes.

Tobramycin Liquid Crystal Nanoparticles Eradicate Cystic Fibrosis-Related Pseudomonas aeruginosa Biofilms.

Pseudomonas aeruginosa biofilms cause persistent and chronic infections, most known clinically in cystic fibrosis (CF). Tobramycin (TOB) is a standard anti-pseudomonal antibiotic; however, in biofilm infections, its efficacy severely decreases due to limited permeability across the biofilm matrix. Herewith, a biomimetic, nanostructured, lipid liquid crystal nanoparticle-(LCNP)-formulation is discovered to significantly enhance the efficacy of TOB and eradicate P. aeruginosa biofilm infections. Using an advanced, biologically-relevant co-culture model of human CF bronchial epithelial cells infected with P. aeruginosa biofilms at an air-liquid interface, nebulized TOB-LCNPs completely eradicated 1 × 109 CFU mL-1 of P. aeruginosa after two doses, a 100-fold improvement over the unformulated antibiotic. The enhanced activity of TOB is not observed with a liposomal formulation of TOB or with ciprofloxacin, an antibiotic that readily penetrates biofilms. It is demonstrated that the unique nanostructure of the LCNPs drives the enhanced penetration of TOB across the biofilm barrier, but not through the healthy lung epithelium barrier, significantly increasing the available antibiotic concentration at the site of infection. The LCNPs are an innovative strategy to improve the performance of TOB as a directed pulmonary therapy, enabling the administration of lower doses, reducing the toxicity, and amplifying the anti-biofilm activity of the anti-pseudomonal antibiotic.

Supersaturated-Silica Lipid Hybrids Improve in Vitro Solubilization of Abiraterone Acetate.

PURPOSE: Abiraterone acetate (AbA) is a poorly water-soluble drug with an oral bioavailability of <10% and a significant pharmaceutical food effect. We aimed to develop a more efficient oral solid-state lipid-based formulation for AbA using a supersaturated silica-lipid hybrid (super-SLH) approach to achieve high drug loading, improve in vitro solubilization and mitigate the food effect, while gaining a mechanistic insight into how super-SLH are digested and release drug. METHODS: The influence of super-SLH saturation level and lipid type on the physicochemical properties and in vitro solubilization during lipolysis of the formulations was investigated and compared to the commercial product, Zytiga. RESULTS: Super-SLH achieved significantly greater levels of AbA solubilization compared to Zytiga. Solubilization was influenced by the AbA saturation level, which determined the solid state of AbA and the relative amount of lipid, and the lipid utilized, which determined its degree of digestion and the affinity of the lipid and digestion products to the silica. A fine balance existed between achieving high drug loads using supersaturation and improving performance using the lipid-based formulation approach. The non-supersaturated SLH prepared with Capmul PG8 mitigated the 3-fold in vitro food effect. CONCLUSION: SLH and super-SLH improve in vitro solubilization of AbA, remove the food effect and demonstrate potential to improve oral bioavailability in vivo. Graphical Abstract Abiraterone acetate was formulated as silica-lipid hybrids and demonstrated enhanced in vitro solubilization in comparison to pure abiraterone acetate and commercial product, Zytiga.

Supersaturated Silica-Lipid Hybrid Oral Drug Delivery Systems: Balancing Drug Loading and In Vivo Performance.

Supersaturated silica-lipid hybrid (super-SLH) drug carriers are a recent strategy to improve the drug loading of oral solid lipid based formulations, however they are yet to be studied in vivo. This study investigated the in vivo pharmacokinetics (PK) of super-SLH containing ibuprofen (IBU), as a model Biopharmaceutics Classification Scheme (BCS) class II drug, analyzing the influence of supersaturated drug loading on oral bioavailability and assessing in vitro-in vivo correlation (IVIVC). In addition, super-SLH was directly compared with spray-dried SLH and Nurofen to explore its potential advantages over the well-established and commercial formulations. Fasted male Sprague-Dawley rats were administered formulation suspensions (10 mg/kg IBU) via oral gavage, and blood samples were acquired and plasma was analyzed for IBU concentrations over 24 hours. In vivo, super-SLH with drug loads of 9.5 (99.5% saturated) and 19.3% w/w (227% saturated) achieved bioavailabilities equal to spray-dried SLH and 2.2-fold greater than Nurofen. This effect diminished for super-SLH with a drug load of 29.1% w/w (389% saturated), which exhibited a bioavailability of less than Nurofen due to its greater extent of supersaturation and larger content of crystalline IBU. The super-SLH containing 19.3% w/w IBU provided the greatest PK performance, achieving the same degree of bioavailability enhancement as spray-dried SLH and requiring 63% less formulation. A significant positive IVIVC was observed between the performances of the formulations. These findings indicate the potential of super-SLH as an improved oral solid lipid based formulation strategy for enhancing oral bioavailability of other BCS class II drugs.

Montmorillonite and Laponite Clay Materials for the Solidification of Lipid-Based Formulations for the Basic Drug Blonanserin: In Vitro and in Vivo Investigations.

Solid-state lipid-based formulations offer great potential for the improved oral delivery of poorly water-soluble drugs. This study investigates the use of the high-surface-area clay materials, montmorillonite and laponite, as solid carriers for lipid-based formulations. The unique cation-exchange properties of clay platelets were exploited to preload the ionizable hydrophobic compound, blonanserin, prior to encapsulating a drug-loaded lipid solution. Thus, solid-state lipid-based formulations with dual-loading capabilities were developed and studied. These formulations were compared with simple clay-based lipid formulations, where blonanserin was loaded in the lipid phase only. The drug release behavior of all clay-based formulations was assessed during in vitro dissolution studies under simulated gastric conditions and in vitro fasting intestinal lipolysis studies. Montmorillonite- and laponite-based lipid formulations significantly reduced blonanserin solubilization relative to a control lipid solution and silica-lipid hybrid particles, owing to incomplete drug release from the clay cation-exchange sites. This phenomenon was replicated during in vivo pharmacokinetic studies, whereby the bioavailability of simple clay-based lipid formulations was decreased relative to controls. Importantly, the solid-state dual-loaded montmorillonite-based lipid formulation provided an optimal pharmacokinetic performance, achieving the same degree of bioavailability enhancement as the control lipid solution. These findings indicate the potential of solid-state dual-loaded clay-based lipid formulations for increasing drug loading levels and enhancing the oral absorption of poorly soluble weak base compounds.

Ramizol® encapsulation into extended release PLGA micro- and nanoparticle systems for subcutaneous and intramuscular administration: in vitro and in vivo evaluation.

OBJECTIVE: Novel antibiotic Ramizol® is advancing to clinical trials for the treatment of gastrointestinal Clostridium difficile associated disease. Despite this, previous studies have shown a rapid plasma clearance upon intravenous administration and low oral bioavailability indicating pure drug is unsuitable for systemic infection treatment following oral dosing. The current study aims to investigate the development of poly-lactic-(co-glycolic) acid (PLGA) particles to overcome this limitation and increase the systemic half-life following subcutaneous and intramuscular dosing. SIGNIFICANCE: The development of new antibiotic treatments will help in combatting the rising incidence of antimicrobial resistance. METHODS: Ramizol® was encapsulated into PLGA nano and microparticles using nanoprecipitation and emulsification solvent evaporation techniques. Formulations were analyzed for particle size, loading level and encapsulation efficiency as well as in vitro drug release profiles. Final formulation was advanced to in vivo pharmacokinetic studies in Sprague-Dawley rats. RESULTS: Formulation technique showed major influence on particle size and loading levels with optimal loading of 9.4% and encapsulation efficiency of 92.06%, observed using emulsification solvent evaporation. Differences in formulation technique were also linked with subsequent differences in release profiles. Pharmacokinetic studies in Sprague-Dawley rats confirmed extended absorption and enhanced bioavailability following subcutaneous and intramuscular dosing with up to an 8-fold increase in Tmax and T1/2 when compared to the oral and IV routes. CONCLUSIONS: Subcutaneous and intramuscular dosing of PLGA particles successfully increased systemic half-life and bioavailability of Ramizol®. This formulation will allow further development of Ramizol® for systemic infection eradication.

A Topical Hydrogel with Deferiprone and Gallium-Protoporphyrin Targets Bacterial Iron Metabolism and Has Antibiofilm Activity.

Many infectious diseases are associated with multidrug-resistant (MDR) bacteria residing in biofilms that require high antibiotic concentrations. While oral drug delivery is frequently ineffective, topical treatments have the potential to deliver higher drug concentrations to the infection site while reducing systemic side effects. This study determined the antibiofilm activity of a surgical wound gel loaded with the iron chelator deferiprone (Def) and the heme analogue gallium-protoporphyrin (GaPP), alone and in combination with ciprofloxacin. Activity against MDR Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Acinetobacter johnsonii biofilms was assessed in the colony biofilm and artificial wound model by enumeration of CFU and correlative light/electron microscopy. While Staphylococcus biofilms were equally susceptible to GaPP and Def-GaPP gels (log10 reduction of 3.8 and 3.7, respectively), the Def-GaPP combination was crucial for significant activity against P. aeruginosa biofilms (log10 reduction of 1.3 for GaPP and 3.3 for Def-GaPP). When Def-GaPP gel was combined with ciprofloxacin, the efficacy exceeded the activity of the individual compounds. Def-GaPP delivered in a surgical wound gel showed significant antibiofilm activity against different MDR strains and could enhance the gel's wound-healing properties. Moreover, Def-GaPP indicated a potentiation of ciprofloxacin. This antibiofilm strategy has potential for clinical utilization as a therapy for topical biofilm-related infections.

Lipid Nanocarriers-Enabled Delivery of Antibiotics and Antimicrobial Adjuvants to Overcome Bacterial Biofilms.

The opportunistic bacteria growing in biofilms play a decisive role in the pathogenesis of chronic infectious diseases. Biofilm-dwelling bacteria behave differently than planktonic bacteria and are likely to increase resistance and tolerance to antimicrobial therapeutics. Antimicrobial adjuvants have emerged as a promising strategy to combat antimicrobial resistance (AMR) and restore the efficacy of existing antibiotics. A combination of antibiotics and potential antimicrobial adjuvants, (e.g., extracellular polymeric substance (EPS)-degrading enzymes and quorum sensing inhibitors (QSI) can improve the effects of antibiotics and potentially reduce bacterial resistance). In addition, encapsulation of antimicrobials within nanoparticulate systems can improve their stability and their delivery into biofilms. Lipid nanocarriers (LNCs) have been established as having the potential to improve the efficacy of existing antibiotics in combination with antimicrobial adjuvants. Among them, liquid crystal nanoparticles (LCNPs), liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) are promising due to their superior properties compared to traditional formulations, including their greater biocompatibility, higher drug loading capacity, drug protection from chemical or enzymatic degradation, controlled drug release, targeted delivery, ease of preparation, and scale-up feasibility. This article reviews the recent advances in developing various LNCs to co-deliver some well-studied antimicrobial adjuvants combined with antibiotics from different classes. The efficacy of various combination treatments is compared against bacterial biofilms, and synergistic therapeutics that deserve further investigation are also highlighted. This review identifies promising LNCs for the delivery of combination therapies that are in recent development. It discusses how LNC-enabled co-delivery of antibiotics and adjuvants can advance current clinical antimicrobial treatments, leading to innovative products, enabling the reuse of antibiotics, and providing opportunities for saving millions of lives from bacterial infections.

Antibiotic resistance and tolerance: What can drug delivery do against this global threat?

Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding rise in related deaths. Several reasons for this situation can be cited, such as the misuse of traditional antibiotics, the massive use of sanitizing measures, and the overuse of antibiotics in agriculture, fisheries, and cattle. AMR&T management requires a multifaceted approach involving various strategies at different levels, such as increasing the patient's awareness of the situation and measures to reduce new resistances, reduction of current misuse or abuse, and improvement of selectivity of treatments. Also, the identification of new antibiotics, including small molecules and more complex approaches, is a key factor. Among these, novel DNA- or RNA-based approaches, the use of phages, or CRISPR technologies are some potent strategies under development. In this perspective article, emerging and experienced leaders in drug delivery discuss the most important biological barriers for drugs to reach infectious bacteria (bacterial bioavailability). They explore how overcoming these barriers is crucial for producing the desired effects and discuss the ways in which drug delivery systems can facilitate this process.

Lytic activity of phages against bacterial pathogens infecting diabetic foot ulcers.

Complications of diabetes, such as diabetic foot ulcers (DFUs), are common, multifactorial in origin, and costly to treat. DFUs are the cause of nearly 90% of limb amputations among persons with diabetes. In most chronic infections such as DFU, biofilms are involved. Bacteria in biofilms are 100-1000 times more resistant to antibiotics than their planktonic counterparts. Multidrug-resistant (MDR) Staphylococcus aureus and Pseudomonas aeruginosa infections in DFUs may require alternative therapeutic agents such as bacteriophages ("phages"). This study describes the lytic activity of phage cocktails AB-SA01 (3-phage cocktail) and AB-PA01 (4-phage cocktail), which target S. aureus and P. aeruginosa, respectively. The host range and lytic effect of AB-SA01 and AB-PA01 on a planktonic culture, single-species biofilm, and mixed-species biofilm were evaluated. In vitro testing showed that 88.7% of S. aureus and 92.7% of P. aeruginosa isolates were susceptible to AB-SA01 and AB-PA01, respectively, in the planktonic state. The component phages of AB-SA01 and AB-PA01 infected 66% to 94.3% of the bacterial isolates tested. Furthermore, AB-SA01 and AB-PA01 treatment significantly (p < 0.05) reduced the biofilm biomass of their hosts, regardless of the antibiotic-resistant characteristics of the isolates and the presence of a non-susceptible host. In conclusion, the strong lytic activity, broad host range, and significant biofilm biomass reduction of AB-SA01 and AB-PA01 suggest the considerable potential of phages in treating antibiotic-resistant S. aureus and P. aeruginosa infections alone or as coinfections in DFUs.

Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study.

ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

Inulin-lipid hybrid (ILH) microparticles promote pH-triggered release of rifampicin within infected macrophages.

Intracellular bacteria serve as a problematic source of infection due to their ability to evade biological immune responses and the inability for conventional antibiotics to efficiently penetrate cellular membranes. Subsequently, new treatment approaches are urgently required to effectively eradicate intracellular pathogens residing within immune cells (e.g. macrophages). In this study, the poorly soluble and poorly permeable antibiotic, rifampicin, was re-purposed via micro-encapsulation within inulin-lipid hybrid (ILH) particles for the treatment of macrophages infected with small colony variants of Staphylococcus aureus (SCV S. aureus). Rifampicin-encapsulated ILH (Rif-ILH) microparticles were synthesized by spray drying a lipid nano-emulsion, with inulin dissolved throughout the aqueous phase and rifampicin pre-loaded within the lipid phase. Rif-ILH were strategically designed and engineered with pH-responsive properties to promote lysosomal drug release upon cellular internalization, while preventing premature rifampicin release in plasma-simulating media. The pH-responsiveness of Rif-ILH was controlled by the acid-mediated hydrolysis of the inulin coating, where exposure to acidic media simulating the lysosomal environment of macrophages triggered hydrolysis of the oligofructose chain and the subsequent diffusion of rifampicin from Rif-ILH. This pH-provoked release mechanism, as well as the ability for ILH microparticles to be more readily internalized by macrophages, was found to be influential in triggering a 2.9-fold increase in intracellular rifampicin concentration within infected macrophages, compared to the pure drug. The subsequent increase in exposure of intracellular pathogens to rifampicin leads to a ~ 2-log improvement in antibacterial activity for Rif-ILH, at a rifampicin dose of 2.5 µg/mL. Thus, the reduction in viability of intracellular SCV S. aureus, in the absence of cellular toxicity, is indicative of ILH microparticles serving as a unique approach for the safe and efficacious delivery of antibiotics to phagocytic cells for the treatment of intracellular infections.

General practice experiences for parents of children with intellectual disability: a systematic review.

BACKGROUND: Parents of children diagnosed with intellectual disability are at increased risk of mental and physical health difficulties compared with other parents. They are likely to regularly seek medical treatment for their health concerns from general practice as well as on behalf of their child with intellectual disability, yet there is limited evaluation of the role general practice plays for this patient group. AIM: To explore parents' experiences of general practice support when caring for a child with intellectual disability. DESIGN & SETTING: Systematic review of studies reporting experiences of general practice as described by parents who care for children with intellectual disability. METHOD: Databases were searched using a pre-defined search strategy. Studies were included based on detailed inclusion criteria, title, abstract, and full-text screening. Quality assessment was conducted using the Mixed Methods Appraisal Tool (MMAT). A narrative synthesis was conducted. RESULTS: A total of nine studies were identified. There was a clear absence of data on parents' own health experience and consultation in general practice. Findings related to navigating general practice on behalf of their child's health including accessibility of general practice and positive and negative experiences of GPs. CONCLUSION: Findings from this review highlight priority areas for research, including further exploration of parents' perspectives on seeking support specifically for their own health concerns, while caring for a child with intellectual disability, to bring more awareness and understanding of the role general practice plays in supporting the health of this carer group. This review also considers implications for clinical services, including tailoring appointments for this patient group as a priority for continuity of care, which may result in improved experiences of general practice and encourage better communication.

Lipid Liquid Crystal Nanoparticles: Promising Photosensitizer Carriers for the Treatment of Infected Cutaneous Wounds.

Cutaneous chronic wounds impose a silent pandemic that affects the lives of millions worldwide. The delayed healing process is usually complicated by opportunistic bacteria that infect wounds. Staphylococcus aureus is one of the most prevalent bacteria in infected cutaneous wounds, with the ability to form antibiotic-resistant biofilms. Recently, we have demonstrated the potential of gallium protoporphyrin lipid liquid crystalline nanoparticles (GaPP-LCNP) as a photosensitizer against S. aureus biofilms in vitro. Herein, we investigate the potential of GaPP-LCNP using a pre-clinical model of infected cutaneous wounds. GaPP-LCNP showed superior antibacterial activity compared to unformulated GaPP, reducing biofilm bacterial viability by 5.5 log10 compared to 2.5 log10 in an ex vivo model, and reducing bacterial viability by 1 log10 in vivo, while unformulated GaPP failed to reduce bacterial burden. Furthermore, GaPP-LCNP significantly promoted wound healing through reduction in the bacterial burden and improved early collagen deposition. These findings pave the way for future pre-clinical investigation and treatment optimizations to translate GaPP-LCNP towards clinical application.

Nanomaterials enabling clinical translation of antimicrobial photodynamic therapy.

Antimicrobial photodynamic therapy (aPDT) has emerged as a promising approach to aid the fight against looming antibiotic resistance. aPDT harnesses the energy of light through photosenstizers to generate highly reactive oxygen species that can inactivate bacteria and fungi with no resistance. To date aPDT has shown great efficacy against microbes causing localized infections in the skin and the oral cavity. However, its wide application in clinical settings has been limited due to both physicochemical and biological challenges. Over the past decade nanomaterials have contributed to promoting photosensitizer performance and aPDT efficiency, yet further developments are required to establish accredited treatment options. In this review we discuss the challenges facing the clinical application of aPDT and the opportunities that nanotechnology may offer to promote the safety and efficiency of aPDT.

Liquid crystalline lipid nanoparticle promotes the photodynamic activity of gallium protoporphyrin against S. aureus biofilms.

Antimicrobial photodynamic therapy (aPDT) has emerged as an innovative strategy to combat antibiotic resistant microbes; yet aPDT efficacies against biofilms are sub-optimal due to inability of photosenstizers to reach microbes embedded in biofilm matrix. To overcome this challenge, liquid crystal lipid nanoparticles (LCNP) were employed in this study as a smart, biocompatible and triggerable delivery system for the new photosensitizer gallium protoporphyrin (GaPP), due to their capabilities in promoting efficient antimicrobial delivery to biofilms. The relationship between GaPP loading of LCNP, reactive oxygen species (ROS) production and the in vitro antibacterial activity against two antibiotic resistant Staphylococcus aureus strains was established. LCNP substantially improved the antibacterial activity of GaPP, completely eradicating S. aureus and MRSA planktonic cultures, using a GaPP concentration of 0.8 µM and light dose 1.9 J/cm2. At the same concentration and light dose, unformulated GaPP triggered only a 4 log10 and 2 log10 reduction in respective planktonic cultures. Most importantly, the activity of GaPP against biofilms was enhanced by 2-fold compared to unformulated GaPP, reducing the viability of S. aureus and MRSA biofilms by 8 log10 and 5 log10, respectively. The biosafety of photoactivated GaPP-LCNP was evaluated against human fibroblasts, which indicated a high safety profile of the treatment. Therefore, these findings encourage further investigations of GaPP-LCNP as a potential treatment for localized chronic infections.

Liquid Crystal Nanoparticles Enhance Tobramycin Efficacy in a Murine Model of Pseudomonas aeruginosa Biofilm Wound Infection.

Chronic Pseudomonas aeruginosa wound infections are highly prevalent and often untreatable due to biofilm formation, resulting in high antimicrobial tolerance. Standard antibiotic therapy for P. aeruginosa infections involves tobramycin, yet it is highly ineffective as monotherapy as tobramycin cannot penetrate the biofilm to elicit its antimicrobial effect. Lipid liquid crystal nanoparticles (LCNPs) have previously been shown to increase the antimicrobial efficacy and penetration of tobramycin against P. aeruginosa biofilms in vitro and ex vivo. Here, for the first time, we have developed a chronic P. aeruginosa biofilm infection in full-thickness wounds in mice to examine the potential of LCNPs to improve the effect of tobramycin, preclinically. After three doses, administered once a day, tobramycin-LCNPs significantly reduced the P. aeruginosa bacterial load in murine wounds 1000-fold more than unformulated tobramycin, which in turn showed no significant difference to the saline control treatment. Consistent with the improved P. aeruginosa eradication, the tobramycin-LCNPs promoted wound healing. In comparison to previous in vitro and ex vivo data, we show a strong in vitro-in vivo correlation between P. aeruginosa biofilm infection models. The enhanced activity of tobramycin-LCNPs in vivo in the preclinical murine model demonstrates the strong potential of LCNPs as a next-generation formulation approach to improve the efficacy of tobramycin against P. aeruginosa biofilm wound infections.

Gallium Protoporphyrin Liquid Crystalline Lipid Nanoparticles: A Third-Generation Photosensitizer against Pseudomonas aeruginosa Biofilms.

The looming antimicrobial resistance pandemic has encouraged the investigation of antimicrobial photodynamic therapy (aPDT) as a promising technology to combat recalcitrant bacterial infections caused by antibiotic resistant strains. Here, we report on the optimization and effective application of gallium protoporphyrin liquid crystalline lipid nanoparticles (GaPP-LCNP) as a photosensitizer for aPDT against the Gram-negative bacteria P. aeruginosa in both planktonic and biofilm modes of growth. LCNP significantly enhanced the performance of GaPP as photosensitizer by two-fold, which was correlated with higher antibacterial activity, reducing the viability of planktonic P. aeruginosa by 7 log10 using 0.8 µM GaPP-LCNP and a light dose of 17 J.cm-2. Importantly, GaPP-LCNP also reduced the viability of biofilms by 6 log10 at relatively low light dose of 34.2 J.cm-2 using only 3 µM GaPP-LCNP. The high antibiofilm activity of GaPP-LCNP at low GaPP-LCNP dose indicated the high efficiency and safety profile of GaPP-LCNP as a promising platform for photodynamic inactivation of recalcitrant infections.

First-time Mothers' Understanding and Use of a Pregnancy and Parenting Mobile App (The Baby Buddy App): Qualitative Study Using Appreciative Inquiry.

BACKGROUND: Internationally, there is increasing emphasis on early support for pregnant women to optimize the health and development of mothers and newborns. To increase intervention reach, digital and app-based interventions have been advocated. There are growing numbers of pregnancy health care apps with great variation in style, function, and objectives, but evidence about impact on pregnancy well-being and behavior change following app interaction is lacking. This paper reports on the qualitative arm of the independent multicomponent study exploring the use and outcomes of first-time mothers using the Baby Buddy app, a pregnancy and parenting support app, available in the National Health Service App Library and developed by a UK child health and well-being charity, Best Beginnings. OBJECTIVE: This study aims to understand when, why, and how first-time mothers use the Baby Buddy app and the perceived benefits and challenges. METHODS: This paper reports on the qualitative arm of an independent, longitudinal, mixed methods study. An Appreciative Inquiry qualitative approach was used with semistructured interviews (17/60, 28%) conducted with new mothers, either by telephone or in a focus group setting. First-time mothers were recruited from 3 study sites from across the United Kingdom. Consistent with the Appreciative Inquiry approach, mothers were prompted to discuss what worked well and what could have been better regarding their interactions with the app during pregnancy. Thematic analysis was used, and findings are presented as themes with perceived benefits and challenges. RESULTS: The main benefit, or what worked well, for first-time mothers when using the app was being able to access new information, which they felt was reliable and easy to find. This led to a feeling of increased confidence in the information they accessed, thus supporting family and professional communication. The main challenge was the preference for face-to-face information with a health care professional, particularly around specific issues that they wished to discuss in depth. What could have been improved included that there were some topics that some mothers would have preferred in more detail, but in other areas, they felt well-informed and thus did not feel a need to seek additional information via an app. CONCLUSIONS: Although this study included a small sample, it elicited rich data and insights into first-time mothers' app interactions. The findings suggest that easily accessible pregnancy information, which is perceived as reliable, can support first-time mothers in communicating with health care professionals. Face-to-face contact with professionals was preferred, particularly to discuss specific and personalized needs. Further studies on maternal and professional digital support preferences after the COVID-19 global pandemic and how they facilitate antenatal education and informed decision-making are recommended, particularly because digital solutions remain as a key element in pregnancy and early parenting care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1017/S1463423618000294.