Hot melt extruded High-Dose amorphous solid dispersions containing lumefantrine and Soluplus.

Over the last 15 years, a small number of paediatric artemisinin-based combination therapy products have been marketed. These included Riamet® and Coartem® dispersible tablets, a combination of artemether and lumefantrine, co-developed by the Medicines for Malaria Venture and Novartis. Disappointingly, patient compliance, requirement for high-fat meal, and sporadic drug dissolution behaviours following administration still result in considerable challenges for these products. The first and foremost barrier that needs addressed for successful delivery of the artemether/lumefantrine combination is the poor solubility of lumefantrine within the gastrointestinal fluids. In this work, amorphous solid dispersions of lumefantrine within Soluplus®-based matrices have been manufactured using hot melt extrusion as a potential formulation strategy to achieve enhanced dissolution and apparent solubility. The drug loading capacity of Soluplus® to accommodate amorphous lumefantrine, whilst ensuring improved in-vitro dissolution performance, was investigated. The extrusion process employed a variety of processing parameters, including various temperature profiles and different production scales. The influence of variation in extrusion conditions upon the physical stability of manufactured amorphous solid dispersions was also examined. This allowed for a greater understanding of the role of extrusion processing conditions on the performance of supersaturated amorphous solid dispersions during dissolution and storage. This may allow for the design and manufacture of drug enabled formulations with lower drug dosing and thus a lower risk of adverse effects.

Carbon Dots in Photodynamic/Photothermal Antimicrobial Therapy.

Antimicrobial resistance (AMR) presents an escalating global challenge as conventional antibiotic treatments become less effective. In response, photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as promising alternatives. While rooted in ancient practices, these methods have evolved with modern innovations, particularly through the integration of lasers, refining their efficacy. PDT harnesses photosensitizers to generate reactive oxygen species (ROS), which are detrimental to microbial cells, whereas PTT relies on heat to induce cellular damage. The key to their effectiveness lies in the utilization of photosensitizers, especially when integrated into nano- or micron-scale supports, which amplify ROS production and enhance antimicrobial activity. Over the last decade, carbon dots (CDs) have emerged as a highly promising nanomaterial, attracting increasing attention owing to their distinctive properties and versatile applications, including PDT and PTT. They can not only function as photosensitizers, but also synergistically combine with other photosensitizers to enhance overall efficacy. This review explores the recent advancements in CDs, underscoring their significance and potential in reshaping advanced antimicrobial therapeutics.

An 'all-world ageing' perspective and its wider ethics of care: An empirical illustration.

Recent commentaries have proposed 'all-world ageing' as a new perspective for social scientific ageing research. It is based on the theoretical observation that the ageing process involves all forms of entities co-ageing relationally with each other, and with their surrounds. Its disciplinary implications hence being that what we categorize as ageing in social scientific ageing research should not be limited to human bodies, and that ageing non-humans should be brought under its purview. To empirically illustrate these theoretical and disciplinary assertions, and explore their implications, the current paper reports a study of how people co-age with non-humans they interact with in their daily lives. Sixteen people aged 66-90 were interviewed, ten of them also being observed at those times. The findings show some intricate and diverse relations that involve their co-ageing with varied biological entities and nature surrounds (such as plants, domestic animals and green spaces) and varied non-biological entities and non-nature surrounds (such as materials, technologies, accommodations, organizations and infrastructures). Meanwhile, important crosscutting themes - including lifespan, function and aesthetics - emerge as objectives of care, valued and exercised in broad terms. This empirical reconnaissance shows the potential for an all-world ageing perspective to engage diverse societal challenges and inform diverse areas of practice as part of a wider ethics of care. From it, a number of important considerations and undertakings arise for future scholarship.

In Situ Eutectic Formation in a Polymeric Matrix via Hot-Melt Reactive Extrusion and the Use of Partial Least Squares Regression Modeling for Reaction Yield Determination.

There has been a significant volume of work investigating the design and synthesis of new crystalline multicomponent systems via examining complementary functional groups that can reliably interact through the formation of noncovalent bonds, such as hydrogen bonds (H-bonds). Crystalline multicomponent molecular adducts formed using this approach, such as cocrystals, salts, and eutectics, have emerged as drug product intermediates that can lead to effective drug property modifications. Recent advancement in the production for these multicomponent molecular adducts has moved from batch techniques that rely upon intensive solvent use to those that are solvent-free, continuous, and industry-ready, such as reactive extrusion. In this study, a novel eutectic system was found when processing albendazole and maleic acid at a 1:2 molar ratio and successfully prepared using mechanochemical methods including liquid-assisted grinding and hot-melt reactive extrusion. The produced eutectic was characterized to exhibit a 100 °C reduction in melting temperature and enhanced dissolution performance (>12-fold increase at 2 h point), when compared to the native drug compound. To remove handling of the eutectic as a formulation intermediate, an end-to-end continuous-manufacturing-ready process enables feeding of the raw parent reagents in their respective natural forms along with a chosen polymeric excipient, Eudragit EPO. The formation of the eutectic was confirmed to have taken place in situ in the presence of the polymer, with the reaction yield determined using a multivariate calibration model constructed by combining spectroscopic analysis with partial least-squares regression modeling. The ternary extrudates exhibited a dissolution profile similar to that of the 1:2 prepared eutectic, suggesting a physical distribution (or suspension) of the in situ synthesized eutectic contents within the polymeric matrix.

Unravelling the interactions between small molecules and liposomal bilayers via molecular dynamics and thermodynamic modelling.

Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients - ranging from small molecule drugs to proteins and nucleic acids - these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility. This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications.

Kinetic and Thermodynamic Interplay of Polymer-Mediated Liquid-Liquid Phase Separation for Poorly Water-Soluble Drugs.

Understanding the interplay between kinetics and thermodynamics of polymer-mediated liquid-liquid phase separation is crucial for designing and implementing an amorphous solid dispersion formulation strategy for poorly water-soluble drugs. This work investigates the phase behaviors of a poorly water-soluble model drug, celecoxib (CXB), in a supersaturated aqueous solution with and without polymeric additives (PVP, PVPVA, HPMCAS, and HPMCP). Drug-polymer-water ternary phase diagrams were also constructed to estimate the thermodynamic behaviors of the mixtures at room temperature. The liquid-liquid phase separation onset point for CXB was detected using an inline UV/vis spectrometer equipped with a fiber optic probe. Varying CXB concentrations were achieved using an accurate syringe pump throughout this study. The appearance of the transient nanodroplets was verified by cryo-EM and total internal reflection fluoresence microscopic techniques. The impacts of various factors, such as polymer composition, drug stock solution pumping rates, and the types of drug-polymer interactions, are tested against the onset points of the CXB liquid-liquid phase separation (LLPS). It was found that the types of drug-polymer interactions, i.e., hydrogen bonding and hydrophobic interactions, are vital to the position and shapes of LLPS in the supersaturation drug solution. A relation between the behaviors of LLPS and its location in the CXB-polymer-water ternary phase diagram was drawn from the findings.

Towards a greater understanding of the deep eutectic phenomenon through examination of the lidocaine-NSAID therapeutic deep eutectic systems.

Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the "deep eutectic" region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds' physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids. In the current work, we probed the "deep eutectic" phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent Tg variations with strong positive deviations from predicted Tg values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound's glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the "deep eutectic" region there was still an ideal, or thermodynamically preferrable "THEDES point", which would exhibit excellent stability upon exposure to stress storage conditions. The discoveries of this study bring the literature one step closer to fully understanding the "therapeutic deep eutectic" phenomenon. Through correlation between parent reagents' physicochemical properties and the synthesised products' characteristics, we establish a more educated process for the prediction and engineering of THEDES.

Mucoadhesive Polymeric Polyologels Designed for the Treatment of Periodontal and Related Diseases of the Oral Cavity.

The study objective was to design and characterise herein unreported polyologels composed of a range of diol and triol solvents and polyvinyl methyl ether-co-maleic acid (PVM/MA) and, determine their potential suitability for the treatment of periodontal and related diseases in the oral cavity using suitable in vitro methodologies. Polyologel flow and viscoelastic properties were controlled by the choice of solvent and the concentration of polymer. At equivalent polymer concentrations, polyologels prepared with glycerol (a triol) exhibited the greatest elasticity and resistance to deformation. Within the diol solvents (PEG 400, pentane 1,5-diol, propane 1,2-diol, propane 1,3-diol, and ethylene glycol), PEG 400 polyologels possessed the greatest elasticity and resistance to deformation, suggesting the importance of distance of separation between the diol groups. Using Raman spectroscopy bond formation between the polymer carbonyl group and the diol hydroxyl groups was observed. Polyologel mucoadhesion was influenced by viscoelasticity; maximum mucoadhesion was shown by glycerol polyologels at the highest polymer concentration (20% w/w). Similarly, the choice of solvent and concentration of PVM/MA affected the release of tetracycline from the polyologels. The controlled release of tetracycline for at least 10 h was observed for several polyologels, which, in combination with their excellent mucoadhesion and flow properties, offer possibilities for the clinical use of these systems to treat diseases within the oral cavity.

Use of solid thermolytic salts to facilitate microwave-induced in situ amorphization.

Moisture was frequently used as dielectric heating source in classical microwave-able systems to facilitate microwave-induced in situ amorphization, however such systems may face the potential of drug hydrolysis. In this study, solid thermolytic salts were proposed to function as moisture substitutes and their feasibility and impacts on microwave-induced in situ amorphization were investigated. It was found that NH4HCO3 was a promising solid alkaline salt to facilitate both microwave-induced in situ amorphization and in situ salt formation of acidic indomethacin (IND). Moreover, it could improve the chemical stability of the drug and the dissolution performance of compacts relative to classical moisture-based compacts upon microwaving. Further mechanistic study suggested that the in situ amorphization occurred prior to the in situ salt formation, especially in formulations with low drug loadings and high solid salt mass ratios. For compacts with low polymer ratios, in situ salt formation took place subsequently, where the previously amorphized IND within compacts could interact with the NH3 gas produced in situ by the decomposition of NH4HCO3 and form the ammonium IND salt. Microwaving time showed great impacts on the decomposition of NH4HCO3 and the in situ generation of water and NH3, which indirectly affected the amorphization and salt formation of IND. In comparison to the moisture-based systems, the NH4HCO3-based system showed a number of advantages, including the reduced potential of IND hydrolysis due to the absence of absorbed moisture, a wider category of applicable polymeric carriers other than hygroscopic polymers, and an increase in drug loading up to 50% (w/w).

Friendly Visiting Programs for Older People Experiencing Social Isolation: A Realist Review of what Works, for whom, and under what Conditions.

Many social interventions have been developed with the hopes of reducing and preventing social isolation among older people (e.g., recreation, arts-based programs and social prescription). Friendly visiting programs, also known as befriending schemes, have been a mainstay in this area for decades and are largely thought to be effective at reconnecting older people (≥ 60 years of age) experiencing isolation. Research and evaluations have yet to determine, however, how and why these programs may be most successful, and under what conditions. This article presents the findings of a realist synthesis aimed at identifying the critical mechanisms and contextual factors that lead to successful outcomes in friendly visiting programs. Seven studies are synthesized to inform a friendly visiting program theory accounting for key mechanisms (e.g., provision of informal support) and underlying contexts (e.g., training of volunteers) that can be used to inform future programs. Recommendations for future research are also presented.

Therapeutic deep eutectic solvents: A comprehensive review of their thermodynamics, microstructure and drug delivery applications.

Deep eutectic solvents (DES) are multicomponent liquids that are usually formed by coupling a hydrogen bond donor and acceptor leading to strong non-covalent (NC) intermolecular networking and profound depression in the melting point of the system. Pharmaceutically, this phenomenon has been exploited to improve drugs' physicochemical properties, with an established DES therapeutic subcategory, therapeutic deep eutectic solvents (THEDES). THEDES preparation is usually via straightforward synthetic processes with little involvement of sophisticated techniques, which, in addition to its thermodynamic stability, make these multi-component molecular adducts a very attractive alternative for drug enabling purposes. Other NC bonded binary systems (e.g., co-crystals and ionic liquids) are utilized in the pharmaceutical field for enhancing drug's behaviours. However, a clear distinction between these systems and THEDES is scarcely discussed in the current literature. Accordingly, this review provides a structure-based categorization for DES formers, a discussion of its thermodynamic properties and phase behaviour, and it clarifies the physicochemical and microstructure boundaries between DES and other NC systems. Additionally, a summary of its preparation techniques and their experimental conditions preparation is supplied. Instrumental analysis techniques can be used to characterize and differentiate DES from other NC mixtures, hence this review draws a road map to for this purpose. Since this work mainly focuses on pharmaceutical applications of DES, all types of THEDES including the highly discussed types (conventional, drugs dissolved in DES and polymer based) in addition to the less discussed categories are covered. Finally, the regulatory status of THEDES was investigated despite the current unclear situation.

Photosensitiser-incorporated microparticles for photodynamic inactivation of bacteria.

Antimicrobial resistance is an ever-growing global concern, making the development of alternative antimicrobial agents and techniques an urgent priority to protect public health. Antimicrobial photodynamic therapy (aPDT) is one such promising alternative, which harnesses the cytotoxic action of reactive oxygen species (ROS) generated upon irradiation of photosensitisers (PSs) with visible light to destroy microorganisms. In this study we report a convenient and facile method to produce highly photoactive antimicrobial microparticles, exhibiting minimal PS leaching, and examine the effect of particle size on antimicrobial activity. A ball milling technique produced a range of sizes of anionic p(HEMA-co-MAA) microparticles, providing large surface areas available for electrostatic attachment of the cationic PS, Toluidine Blue O (TBO). The TBO-incorporated microparticles showed a size-dependent effect on antimicrobial activity, with a decrease in microparticle size resulting in an increase in the bacterial reductions achieved when irradiated with red light. The >6 log10Pseudomonas aeruginosa and Staphylococcus aureus reductions (>99.9999%) achieved within 30 and 60 min, respectively, by TBO-incorporated >90 µm microparticles were attributed to the cytotoxic action of the ROS generated by TBO molecules bound to the microparticles, with no PS leaching from these particles detected over this timeframe. TBO-incorporated microparticles capable of significantly reducing the bioburden of solutions with short durations of low intensity red light irradiation and minimal leaching present an attractive platform for various antimicrobial applications.

The effects of surfactants on the performance of polymer-based microwave-induced in situ amorphization.

Microwave-induced in situ amorphization is a novel technology for preparing amorphous solid dispersions (ASDs) to address the challenges of their long-term physical stability and downstream processing. To date, only few types of dielectric materials have been reported for microwave-induced in situ amorphization, which restricted the extensive research of this technology. This study aimed to investigate the feasibility and mechanisms of utilizing the non-ionic surfactants, i.e. Kollisolv P124, Kolliphor RH40, D-ɑ-tocopheryl polyethylene glycol succinate (TPGS), Tween (T) 60 (T60), T65, T80 and T85, as plasticizers to facilitate microwave-induced in situ amorphization. It was found that the successful application of surfactants could be related with their low Tm, low Mw and high HLB. Kolliphor RH40 was selected as a typical surfactant due to its excellent dielectric heating ability, plasticizing effect and solubilizing effect when facilitating amorphization. Then, the dissolution-mediated in situ amorphization mechanism was investigated and intuitively demonstrated. For the most promising formulation, i.e. microwaved systems with Korlliphor RH40 at 1.5 (w/w) plasticizer/polymer ratio, a complete and fast in vitro dissolution was observed relative to the untreated systems. In conclusion, non-ionic surfactants had the potential to facilitate microwave-induced in situ amorphization, which provided a new direction in the formulation designation for microwave-able systems.

A new mathematical model derived from transient (creep) analysis to estimate the vaginal retention of semi-solid dosage forms.

The performance of vaginal drug delivery systems is dependent on their retention. This study presents a novel mathematical method to estimate the vaginal retention of semi-solids. Using creep analysis, the elastic and residual compliances are determined from the discrete retardation spectrum and used to determine the retention times (RT), defined as the time required for the formulations to enter the terminal viscous zone of deformation and hence flow. RT of commercially available products (CAP) and selected prototype formulations were determined, the estimated RT of CAP broadly aligning with their prescribed clinical usage. Candidate formulations composed of hydroxyethylcellulose (HEC, 3%/5%w/w) and polyacrylic acid (PAA, 1%/3%w/w) were manufactured using, and further diluted with simulant vaginal fluid (SVF) or simulant seminal fluid (SSF) and their RT subsequently determined. Increasing polymer concentration and pH enhanced the estimated RT whereas dilution reduced RT. Notably, the formulation composed of 5%HEC/3% PAA (SSF) maintained its RT on dilution due to swelling of suspended PAA particles, thus representing a strategy to develop vaginal semi-solids that are resistant to dilution and hence removal. The mathematical model described is reproducible, straightforward to use and is recommended as a tool in formulation development to estimate the retention of vaginal semi-solids.

High drug loading nanosized amorphous solid dispersion (NASD) with enhanced in vitro solubility and permeability: Benchmarking conventional ASD.

Through liquid-liquid phase separation (LLPS), it is possible to generate drug-rich nanoparticles during the dissolution of conventional amorphous solid dispersions (ASDs). These self-generated nanoparticles may improve the oral absorption of poorly water-soluble drugs by enhancing the drug's apparent solubility and effective membrane permeability. However, due to the high concentration threshold required for LLPS, conventional ASDs that can consistently generate drug-rich nanoparticles during dissolution are rare. More importantly, the quality of these meta-stable drug-rich nanoparticles is hard to control during dissolution, leading to inconsistency in formulation performances. This work has described a continuous twin-screw extrusion process capable of producing nanosized ASD (NASD) formulations that can offer better solubility and permeability enhancements over conventional ASD formulations. Two polymeric carriers, polyvinylpyrrolidone-co-vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), with a model hydrophobic drug celecoxib (BCS II), were formulated into both ASD and NASD formulations. Compared to the conventional ASD formulation, the prefabricated NASD (sizes ranging between 40 and 200 nm) embedded within a polyol matrix can be rapidly dispersed into a nanoparticle suspension in the presence of aqueous media. The resulting NASDs achieved drug loadings up to 80 % w/w and a maximum of 98 % encapsulation efficiency. Because of the TSE platform's high drug-loading capacity and high scalability, the developed method may be useful for continuously producing personalized nanomedicines.

Evaluating the effectiveness of a universal eHealth school-based prevention programme for depression and anxiety, and the moderating role of friendship network characteristics.

BACKGROUND: Lifetime trajectories of mental ill-health are often established during adolescence. Effective interventions to prevent the emergence of mental health problems are needed. In the current study we assessed the efficacy of the cognitive behavioural therapy (CBT)-informed Climate Schools universal eHealth preventive mental health programme, relative to a control. We also explored whether the intervention had differential effects on students with varying degrees of social connectedness. METHOD: We evaluated the efficacy of the Climate Schools mental health programme (19 participating schools; average age at baseline was 13.6) v. a control group (18 participating schools; average age at baseline was 13.5) which formed part of a large cluster randomised controlled trial in Australian schools. Measures of internalising problems, depression and anxiety were collected at baseline, immediately following the intervention and at 6-, 12- and 18-months post intervention. Immediately following the intervention, 2539 students provided data on at least one outcome of interest (2065 students at 18 months post intervention). RESULTS: Compared to controls, we found evidence that the standalone mental health intervention improved knowledge of mental health, however there was no evidence that the intervention improved other mental health outcomes, relative to a control. Student's social connectedness did not influence intervention outcomes. CONCLUSION: These results are consistent with recent findings that universal school-based, CBT-informed, preventive interventions for mental health have limited efficacy in improving symptoms of anxiety and depression when delivered alone. We highlight the potential for combined intervention approaches, and more targeted interventions, to better improve mental health outcomes.

Design and scale-up of amorphous drug nanoparticles production via a one-step anhydrous continuous process.

Polymeric nanoparticle drug delivery systems are increasingly viewed as crucial building blocks for efficacious treatments of disease conditions. However, production methods at commercially practical scales pose a significant challenge for successfully translating such technology. This paper describes a novel, anhydrous, twin-screw extrusion (TSE) platform-based technology to overcome the issues associated with developing and scale-up production of nanoparticulate drug delivery systems. With polyol as the process medium, the proposed TSE platform enables the encapsulation of the drug and reduction of particle size in a one-step process without the requirement for organic solvents or water. pH-responsive nanoparticle drug delivery of two nonsteroidal anti-inflammatory drugs, naproxen, and celecoxib, was successfully produced using the TSE process. Remarkably, these resulted in nanoparticles with sizes ranging from 80 to 240 nm, up to 98 % drug encapsulation efficiency, and maximum production throughput of 400 g/hour. pH-responsive drug release for both naproxen and celecoxib was also achieved: immediate drug release with enhanced solubility was obtained for naproxen-Eudragit®E nanoparticles (6 times higher) at pH 1.2 and celecoxib-HPMCAS nanoparticles (15 times higher) at pH 6.8, whilst sustained drug release was achieved for naproxen-Eudragit®E nanoparticles at pH 6.8 and celecoxib-HPMCAS nanoparticles at pH 1.2. We expect this platform technology to streamline the development and scale-up production of various polymeric nanoparticle drug delivery systems.

Internet-delivered cognitive behaviour therapy for post-traumatic stress disorder: a randomised controlled trial and outcomes in routine care.

BACKGROUND: Despite its potential scalability, little is known about the outcomes of internet-based cognitive behaviour therapy (iCBT) for post-traumatic stress disorder (PTSD) when it is provided with minimal guidance from a clinician. AIM: To evaluate the outcomes of minimally guided iCBT for PTSD in a randomised control trial (RCT, Study 1) and in an open trial in routine community care (Study 2). METHOD: A RCT compared the iCBT course (n=21) to a waitlist control (WLC, n=19) among participants diagnosed with PTSD. The iCBT group was followed up 3 months post-treatment. In Study 2, treatment outcomes were evaluated among 117 adults in routine community care. PTSD symptom severity was the primary outcome in both studies, with psychological distress and co-morbid anxiety and depressive symptoms providing secondary outcomes. RESULTS: iCBT participants in both studies experienced significant reductions in PTSD symptom severity from pre- to post-treatment treatment (within-group Hedges' g=.72-1.02), with RCT findings showing maintenance of gains at 3-month follow-up. The WLC group in the RCT also significantly improved, but Study 1 was under-powered and the medium between-group effect favouring iCBT did not reach significance (g=0.64; 95% CI, -0.10-1.38). CONCLUSIONS: This research provides preliminary support for the utility of iCBT for PTSD when provided with minimal clinician guidance. Future studies are needed to clarify the effect of differing levels of clinician support on PTSD iCBT outcomes, as well as exploring how best to integrate iCBT into large-scale, routine clinical care of PTSD.