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.

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.

A national effectiveness trial of an eHealth program to prevent alcohol and cannabis misuse: responding to the replication crisis.

BACKGROUND: The burden of disease attributable to alcohol and other drug (AOD) use in young people is considerable. Prevention can be effective, yet few programs have demonstrated replicable effects. This study aimed to replicate research behind Climate Schools: Alcohol and Cannabis course among a large cohort of adolescents. METHODS: Seventy-one secondary schools across three States participated in a cluster-randomised controlled trial. Year 8 students received either the web-based Climate Schools: Alcohol and Cannabis course (Climate, n = 3236), or health education as usual (Control, n = 3150). Outcomes were measured via self-report and reported here for baseline, 6- and 12-months for alcohol and cannabis knowledge, alcohol, cannabis use and alcohol-related harms. RESULTS: Compared to Controls, students in the Climate group showed greater increases in alcohol- [standardised mean difference (SMD) 0.51, p < 0.001] and cannabis-related knowledge (SMD 0.49, p < 0.001), less increases in the odds of drinking a full standard drink[(odds ratio (OR) 0.62, p = 0.014], and heavy episodic drinking (OR 0.49, p = 0.022). There was no evidence for differences in change over time in the odds of cannabis use (OR 0.57, p = 0.22) or alcohol harms (OR 0.73, p = 0.17). CONCLUSIONS: The current study provides support for the effectiveness of the web-based Climate Schools: Alcohol and Cannabis course in increasing knowledge and reducing the uptake of alcohol. It represents one of the first trials of a web-based AOD prevention program to replicate alcohol effects in a large and diverse sample of students. Future research and/or adaptation of the program may be warranted with respect to prevention of cannabis use and alcohol harms.

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.

IVIVC for Extended Release Hydrophilic Matrix Tablets in Consideration of Biorelevant Mechanical Stress.

PURPOSE: When establishing IVIVC, a special problem arises by interpretation of averaged in vivo profiles insight of considerable individual variations in term of time and number of mechanical stress events in GI-tract. The objective of the study was to investigate and forecast the effect of mechanical stress on in vivo behavior in human of hydrophilic matrix tablets. METHODS: Dissolution profiles for the marketed products were obtained at different conditions (stirring speed, single- or repeatable mechanical stress applied) and convoluted into C-t profiles. Vice versa, published in vivo C-t profiles of the products were deconvoluted into absorption profiles and compared with dissolution profiles by similarity factor. RESULTS: Investigated hydrophilic matrix tablets varied in term of their resistance against hydrodynamic stress or single stress during the dissolution. Different scenarios, including repeatable mechanical stress, were investigated on mostly prone Seroquel® XR 50 mg. None of the particular scenarios fits to the published in vivo C-t profile of Seroquel® XR 50 mg representing, however, the average of individual profiles related to scenarios differing by number, frequency and time of contraction stress. When different scenarios were combined in different proportions, the profiles became closer to the original in vivo profile including a burst between 4 and 5 h, probably, due to stress-events in GI-tract. CONCLUSION: For establishing IVIVC of oral dosage forms susceptible mechanical stress, a comparison of the deconvoluted individual in vivo profiles with in vitro profiles of different dissolution scenarios can be recommended.

Reboot Online: A Randomized Controlled Trial Comparing an Online Multidisciplinary Pain Management Program with Usual Care for Chronic Pain.

OBJECTIVE: Chronic pain is a prevalent and burdensome condition. Reboot Online was developed to address treatment barriers traditionally associated with accessing face-to-face chronic pain management programs. It is a comprehensive multidisciplinary online treatment program, based on an existing and effective face-to-face multidisciplinary pain program (the Reboot program). DESIGN & PARTICIPANTS: A CONSORT-compliant randomized controlled trial was conducted, enrolling adults who had experienced pain for three months or longer. METHODS: Participants were randomly allocated to either an eight-lesson multidisciplinary pain management program, Reboot Online (N = 41), or to a usual care (UC) control group (N = 39). Clinical oversight was provided by a multidisciplinary team remotely, including physiotherapists and clinical psychologists. Participants were measured at baseline, post-treatment (week 16), and three-month follow-up (week 28). RESULTS: Intention-to-treat analyses revealed that Reboot Online was significantly more effective than UC at increasing pain self-efficacy (g = 0.69) at post-treatment, and these gains were maintained at follow-up. Similarly, Reboot Online was significantly more effective than UC on several secondary measures at post-treatment and follow-up, including movement-based fear avoidance and pain-related disability, but it did not significantly reduce pain interference or depression compared with UC. Clinician input was minimal, and adherence to Reboot Online was moderate, with 61% of participants (N = 25) completing all eight lessons. CONCLUSIONS: Reboot Online presents a novel approach to multidisciplinary pain management and offers an accessible, efficacious alternative and viable treatment option for chronic pain management.

Internet-delivered psychological interventions for clinical anxiety and depression in perinatal women: a systematic review and meta-analysis.

Perinatal anxiety and depression are common and associated with negative outcomes if left untreated. Internet-delivered treatments can improve treatment accessibility and have demonstrated effectiveness in treating anxiety and depression in the general adult population. However, little is known about how effective and acceptable these interventions are for perinatal women. This paper describes a systematic review and preliminary meta-analysis of internet-delivered psychological interventions for the treatment of clinical anxiety and depression in perinatal women. A systematic search was carried out of seven electronic databases. Seven studies evaluating six distinct internet-delivered psychological interventions were identified. Of the seven studies included, two were open trials and five were randomized controlled trials with a total of 595 participants. Preliminary findings indicate large improvements in depression (Hedges g = 1.67; 95% CI 1.38-1.96) and anxiety (Hedges g = 1.08; 95% CI 0.80-1.36) from pre- to post-treatment. However, between-group differences between interventions and control conditions were only moderate for depression (Hedges g = 0.60; 95% CI 0.43-0.78) and anxiety (Hedges g = 0.54; 95% CI 0.24-0.85). While our preliminary findings are promising, this review identifies an area of research still in its early stages with significant gaps in the literature that need to be addressed. Further research is needed to establish the efficacy and acceptability of these interventions in this population, especially for antenatal depression and anxiety disorders.

Metformin Hydrochloride and Sitagliptin Phosphate Fixed-Dose Combination Product Prepared Using Melt Granulation Continuous Processing Technology.

The development of oral solid dosage forms, such as tablets that contain a high dose of drug(s), requires polymers and other additives to be incorporated at low levels as possible, to keep the final tablet weight low, and, correspondingly, the dosage form size small enough to be acceptable from a patient perspective. Additionally, a multi-step batch-based manufacturing process is usually required for production of solid dosage forms. This study presents the development and production, by twin-screw melt granulation technology, of a high-dose immediate-release fixed-dose combination (FDC) product of metformin hydrochloride (MET) and sitagliptin phosphate (SIT), with drug loads of 80% w/w and 6% w/w, respectively. For an 850/63 mg dose of MET/SIT, the final weight of the caplets was approximately 1063 mg compared with 1143 mg for the equivalent dose in Janumet®, the marketed product. Mixtures of the two drugs and polymers were melt-granulated at temperatures below the individual melting temperatures of MET and SIT (231.65 and 213.89°C, respectively) but above the glass transition temperature or melting temperature of the binder(s) used. By careful selection of binders, and processing conditions, direct compressed immediate-release caplets with desired product profiles were successfully produced. The melt granule formulations before compression showed good flow properties, were larger in particle size than individual starting API materials and were easily compressible. Melt granulation is a suitable platform for developing direct compressible high-dose immediate-release solid dosage forms of FDC products.

A New Method of Constructing a Drug-Polymer Temperature-Composition Phase Diagram Using Hot-Melt Extrusion.

Current experimental methodologies used to determine the thermodynamic solubility of an API within a polymer typically involves establishing the dissolution/melting end point of the crystalline API within a physical mixture or through the use of the glass transition temperature measurement of a demixed amorphous solid dispersion. The measurable "equilibrium" points for solubility are normally well above the glass transition temperature of the system, meaning extrapolation is required to predict the drug solubility at pharmaceutically relevant temperatures. In this manuscript, we argue that the presence of highly viscous polymers in these systems results in experimental data that exhibits an under or overestimated value relative to the true thermodynamic solubility. In previous work, we demonstrated the effects of experimental conditions and their impact on measured and predicted thermodynamic solubility points. In light of current understanding, we have developed a new method to limit error associated with viscosity effects for application in small-scale hot-melt extrusion (HME). In this study, HME was used to generate an intermediate (multiphase) system containing crystalline drug, amorphous drug/polymer-rich regions as well as drug that was molecularly dispersed in polymer. An extended annealing method was used together with high-speed differential scanning calorimetry to accurately determine the upper and lower boundaries of the thermodynamic solubility of a model drug-polymer system (felodipine and Soluplus). Compared to our previously published data, the current results confirmed our hypothesis that the prediction of the liquid-solid curve using dynamic determination of dissolution/melting end point of the crystalline API physical mixture presents an underestimation relative to the thermodynamic solubility point. With this proposed method, we were able to experimentally measure the upper and lower boundaries of the liquid-solid curve for the model system. The relationship between inverse temperature and drug-polymer solubility parameter (χ) remained linear at lower drug loadings. Significantly higher solubility and miscibility between the felodipine-Soluplus system were derived from the new χ values.

Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Enhancing Cocrystal Yield.

Pharmaceutical cocrystals have attracted increasing attention over the past decade as an alternative way to modify the physicochemical properties and hence improve the bioavailability of a drug, without sacrificing thermodynamic stability. Our previous work has demonstrated the viability of in situ formation of ibuprofen/isonicotinamide cocrystal suspensions within a matrix carrier via a single-step hot melt extrusion (HME) process. The key aim of the current work is to establish optimized processing conditions to improve cocrystal yield within extruded matrices. The solubility of each individual cocrystal component in the matrix carrier was estimated using two different methods, calculation of Hansen solubility parameters and Flory-Huggins solution theory using a melting point depression measurement method, respectively. The latter was found to be more relevant to extrusion cocrystallization because of the ability to predict miscibility across a range of temperatures. The predictions obtained from the F-H phase diagrams were verified using ternary extrusion processing. Temperatures that promote solubilization of the parent reagents during processing and precipitation of the newly formed cocrystal were found to be the most suitable in generating high cocrystal yields. The incorporation of intensive mixing/kneading elements to the screw configuration was also shown to significantly improve the cocrystal yield when utilizing a matrix platform. This work has shown that intensive mixing, in combination with appropriate temperature selection, can significantly improve the cocrystal yield within a stable and low viscosity carrier during HME processing. Most importantly, this work reports, for the very first time in the literature, the use of the F-H phase diagrams to guide the most appropriate HME processing window to drive higher cocrystal yield.

A systematic review of psychological treatments for clinical anxiety during the perinatal period.

Maternal anxiety is common during the perinatal period, and despite the negative outcomes of anxiety on the mother and infant, its treatment has received limited attention. This paper describes the first review of psychological interventions for clinical anxiety during the perinatal period. A systematic search was carried out of six electronic databases. Five studies which evaluated psychological interventions for clinical anxiety in perinatal women were identified. Of the five studies included, four were open trials and one was a randomised controlled trial. Three studies evaluated group-based interventions; one study evaluated an online-delivered intervention; and one study a combined pharmacologic-psychological intervention. All participants demonstrated significant reductions in anxiety symptom severity from pre- to post-treatment. However, this review was limited to published literature evaluating treatments for clinical anxiety in perinatal women, which may have excluded important intervention studies and prevention programs, and unpublished literature. This review identifies an area of research that needs urgent attention, as very few studies have evaluated psychological treatments for perinatal anxiety. The studies included in this review demonstrate that symptoms of anxiety during the perinatal period appear to improve during treatment. Future research is needed to establish the efficacy of perinatal anxiety interventions in randomised controlled trials, whether reductions persist long term and whether benefits extend to other outcomes for the mother, infant and family.

Nursing lives in the blogosphere: A thematic analysis of anonymous online nursing narratives.

AIM: The aim of this study was to explore the work-life narratives of nurses through a thematic analysis of the nursing accounts they post in their publicly accessible, anonymous blogs. BACKGROUND: Many nurses participate on social media. Blogs have been advocated as a self-reflective tool in nursing practice, yet as far as the authors are aware, no previous studies have explored nurses' individual blogs for their potential to reveal nurses' perceptions of nursing work. DESIGN: The research design was qualitative description. METHODS: Between May-August 2015, Internet search engines were used to discover lists of nursing blogs recommended by organizations representing nurses' interests. Recommended blogs were purposively sampled. Four anonymous blogs written by nurses from different nursing specialties met the sampling criteria. All 520 of their entries from 2014 were read and copied into NVivo 10, where an inductive coding process was followed. FINDINGS: Three major themes arose in these nurses' online discussions of their work lives: they truly care about and value their nursing work, but they are feeling stressed and burnt out and they are using their anonymous blogs to share factors that frustrate them in their nursing work. Three main areas of frustration were revealed: teamwork problems, challenging patients and families, and management issues. CONCLUSION: Anonymous nursing blogs offer valuable, longitudinal insights into nurses' perceptions of their work lives. Nursing blogs should be further explored for ongoing insights into nurses' experiences of nursing work, as well as nurses' recommendations for addressing issues causing them to feel frustrated in their work environments.

Psychometric Properties of the Worry Behaviors Inventory: Replication and Extension in a Large Clinical and Community Sample.

BACKGROUND: The use of maladaptive behaviors by individuals with generalized anxiety disorder (GAD) is theoretically important and clinically meaningful. However, little is known about the specificity of avoidant behaviors to GAD and how these behaviors can be reliably assessed. AIMS: This study replicated and extended the psychometric evaluation of the Worry Behaviors Inventory (WBI), a brief self-report measure of avoidant behaviors associated with GAD. METHOD: The WBI was administered to a hospital-based sample of adults seeking treatment for symptoms of anxiety and/or depression (n = 639) and to a community sample (n = 55). Participants completed measures of symptom severity (GAD, depression, panic disorder, health anxiety, and personality disorder), and measures of checking, reassurance-seeking and behavioral inhibition. Analyses evaluated the factor structure, convergent, divergent, incremental, and discriminant validity, as well the temporal stability and treatment sensitivity of the WBI. RESULTS: The two-factor structure found in the preliminary psychometric evaluation of the WBI was replicated. The WBI was sensitive to changes across treatment and correlated well with measures of GAD symptom severity and maladaptive behaviors. The WBI was more strongly related to GAD symptom severity than other disorders. The WBI discriminated between clinical and community samples. CONCLUSIONS: The WBI provides clinicians and researchers with a brief, clinically meaningful index of problematic behaviors that may guide treatment decisions and contribute to our understanding of maintaining factors in GAD.

Maladaptive Behaviours Associated with Generalized Anxiety Disorder: An Item Response Theory Analysis.

BACKGROUND: Cognitive models of generalized anxiety disorder (GAD) suggest that maladaptive behaviours may contribute to the maintenance of the disorder; however, little research has concentrated on identifying and measuring these behaviours. To address this gap, the Worry Behaviors Inventory (WBI) was developed and has been evaluated within a classical test theory (CTT) approach. AIMS: As CTT is limited in several important respects, this study examined the psychometric properties of the WBI using an Item Response Theory approach. METHOD: A large sample of adults commencing treatment for their symptoms of GAD (n = 537) completed the WBI in addition to measures of GAD and depression symptom severity. RESULTS: Patients with a probable diagnosis of GAD typically engaged in four or five maladaptive behaviours most or all of the time in an attempt to prevent, control or avoid worrying about everyday concerns. The two-factor structure of the WBI was confirmed, and the WBI scales demonstrated good reliability across a broad range of the respective scales. Together with previous findings, our results suggested that hypervigilance and checking behaviours, as well as avoidance of saying or doing things that are worrisome, were the most relevant maladaptive behaviours associated with GAD, and discriminated well between adults with low, moderate and high degrees of the respective WBI scales. CONCLUSIONS: Our results support the importance of maladaptive behaviours to GAD and the utility of the WBI to index these behaviours. Ramifications for the classification, theoretical conceptualization and treatment of GAD are discussed.

Age-related cognitive decline and associations with sex, education and apolipoprotein E genotype across ethnocultural groups and geographic regions: a collaborative cohort study.

BACKGROUND: The prevalence of dementia varies around the world, potentially contributed to by international differences in rates of age-related cognitive decline. Our primary goal was to investigate how rates of age-related decline in cognitive test performance varied among international cohort studies of cognitive aging. We also determined the extent to which sex, educational attainment, and apolipoprotein E ε4 allele (APOE*4) carrier status were associated with decline. METHODS AND FINDINGS: We harmonized longitudinal data for 14 cohorts from 12 countries (Australia, Brazil, France, Greece, Hong Kong, Italy, Japan, Singapore, Spain, South Korea, United Kingdom, United States), for a total of 42,170 individuals aged 54-105 y (42% male), including 3.3% with dementia at baseline. The studies began between 1989 and 2011, with all but three ongoing, and each had 2-16 assessment waves (median = 3) and a follow-up duration of 2-15 y. We analyzed standardized Mini-Mental State Examination (MMSE) and memory, processing speed, language, and executive functioning test scores using linear mixed models, adjusted for sex and education, and meta-analytic techniques. Performance on all cognitive measures declined with age, with the most rapid rate of change pooled across cohorts a moderate -0.26 standard deviations per decade (SD/decade) (95% confidence interval [CI] [-0.35, -0.16], p < 0.001) for processing speed. Rates of decline accelerated slightly with age, with executive functioning showing the largest additional rate of decline with every further decade of age (-0.07 SD/decade, 95% CI [-0.10, -0.03], p = 0.002). There was a considerable degree of heterogeneity in the associations across cohorts, including a slightly faster decline (p = 0.021) on the MMSE for Asians (-0.20 SD/decade, 95% CI [-0.28, -0.12], p < 0.001) than for whites (-0.09 SD/decade, 95% CI [-0.16, -0.02], p = 0.009). Males declined on the MMSE at a slightly slower rate than females (difference = 0.023 SD/decade, 95% CI [0.011, 0.035], p < 0.001), and every additional year of education was associated with a rate of decline slightly slower for the MMSE (0.004 SD/decade less, 95% CI [0.002, 0.006], p = 0.001), but slightly faster for language (-0.007 SD/decade more, 95% CI [-0.011, -0.003], p = 0.001). APOE*4 carriers declined slightly more rapidly than non-carriers on most cognitive measures, with processing speed showing the greatest difference (-0.08 SD/decade, 95% CI [-0.15, -0.01], p = 0.019). The same overall pattern of results was found when analyses were repeated with baseline dementia cases excluded. We used only one test to represent cognitive domains, and though a prototypical one, we nevertheless urge caution in generalizing the results to domains rather than viewing them as test-specific associations. This study lacked cohorts from Africa, India, and mainland China. CONCLUSIONS: Cognitive performance declined with age, and more rapidly with increasing age, across samples from diverse ethnocultural groups and geographical regions. Associations varied across cohorts, suggesting that different rates of cognitive decline might contribute to the global variation in dementia prevalence. However, the many similarities and consistent associations with education and APOE genotype indicate a need to explore how international differences in associations with other risk factors such as genetics, cardiovascular health, and lifestyle are involved. Future studies should attempt to use multiple tests for each cognitive domain and feature populations from ethnocultural groups and geographical regions for which we lacked data.

Web-Based Cognitive Behavior Therapy for Depression in People With Diabetes Mellitus: A Randomized Controlled Trial.

BACKGROUND: Depression is twice as common in diabetes mellitus (DM) as the general population and is associated with adverse health outcomes, but access to evidence-based therapies such as cognitive behavioral therapy (CBT) is limited in routine diabetes care. Past research has shown that generic Internet-based cognitive behavioral therapy (iCBT) is an effective treatment for depression in the general population, but it has never been evaluated in people with comorbid depression and DM. OBJECTIVE: The aim of our study was to examine the efficacy of a generic 6-lesson iCBT delivered over 10 weeks in people with major depressive disorder (MDD) and DM. METHODS: Participants with comorbid MDD and DM (type 1 or 2) were recruited online and randomized to an iCBT program with therapist support provided by phone and email (n=42) or a treatment as usual (TAU, n=49) control group. Outcomes were assessed through Web-based self-report questionnaires and the trial was Web-based with no face-to-face components. Primary outcomes were self-reported depression (patient health questionnaire-9, PHQ-9), diabetes-related distress (problem areas in diabetes, PAID), and self-reported glycemic control (hemoglobin A1c, HbA1c). Secondary outcomes were general distress (Kessler 10-item psychological distress scale, K-10) and disability (short form 12-item, SF-12), generalized anxiety (generalized anxiety disorder 7-item, GAD-7), and somatization (PHQ-15). The iCBT group was assessed at 3 months. RESULTS: A total of 27 participants (66%; 27/41) completed the iCBT program. Analyses indicated between-group superiority of iCBT over TAU at posttreatment on PHQ-9 (g=0.78), PAID (g=0.80), K-10 (g=1.06), GAD-7 (g=0.72), and SF-12 mental well-being scores (g=0.66), but no significant differences in self-reported HbA1c levels (g=0.14), SF-12 physical well-being, or PHQ-15 scores (g=0.03-0.21). Gains were maintained at 3-month follow-up in the iCBT group, and the 87% (27/31) of iCBT participants who were interviewed no longer met criteria for MDD. Clinically significant change following iCBT on PHQ-9 scores was 51% (21/41) versus 18% (9/49) in TAU. CONCLUSIONS: iCBT for depression is an efficacious, accessible treatment option for people with diabetes. Future studies should explore whether tailoring of iCBT programs improves acceptability and adherence, and evaluate the long-term outcomes following iCBT. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN): 12613001198718; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365208&isReview=true (Archived by WebCite at http://www.webcitation.org/6qCR8Fi9V).

Geographical thinking in nursing inquiry, part two: performance, possibility, and non-representational theory.

Part one in this two paper series reviewed the nature of geographical thinking in nursing research thus far. The current paper builds on it by looking forwards and providing a particular vision for future research. It argues that it is time to once again look to the parent discipline of human geography for inspiration, specifically to its turn towards non-representational theory, involving an emphasis on life that onflows prior to meaning, significance, and full cognition; on life's 'taking-place'. The paper introduces this way of viewing and animating the world. Some potential connections to nursing research and practice are suggested, as are some specific avenues for future inquiry. Explained is how, through non-representational theory, nursing might be re-imagined as something that reveals space-time.

An Infection-Responsive Approach To Reduce Bacterial Adhesion in Urinary Biomaterials.

Infection is an inevitable consequence of chronic urinary catheterization with associated problems of recurrent catheter encrustation and blockage experienced by approximately 50% of all long-term catheterized patients. In this work, we have exploited, for the first time, the reported pathogen-induced elevation of urine pH as a trigger for "intelligent" antimicrobial release from novel hydrogel drug delivery systems of 2-hydroxyethyl methacrylate and vinyl-functionalized nalidixic acid derivatives, developed as candidate infection-resistant urinary catheter coatings. Demonstrating up to 20-fold faster rates of drug release at pH 10, representing infected urine pH, than at pH 7 and achieving reductions of up to 96.5% in in vitro bacterial adherence, our paradigm of pH-responsive drug delivery, which requires no external manipulation, therefore represents a promising development toward the prevention of catheter-associated urinary tract infections in vivo.

Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterization.

Engineered cocrystals offer an alternative solid drug form with tailored physicochemical properties. Interestingly, although cocrystals provide many new possibilities, they also present new challenges, particularly in regard to their design and large-scale manufacture. Current literature has primarily focused on the preparation and characterization of novel cocrystals typically containing only the drug and coformer, leaving the subsequent formulation less explored. In this paper we propose, for the first time, the use of hot melt extrusion for the mechanochemical synthesis of pharmaceutical cocrystals in the presence of a meltable binder. In this approach, we examine excipients that are amenable to hot melt extrusion, forming a suspension of cocrystal particulates embedded in a pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model cocrystal reagent pair, formulations extruded with a small molecular matrix carrier (xylitol) were examined to be intimate mixtures wherein the newly formed cocrystal particulates were physically suspended in a matrix. With respect to formulations extruded using polymeric carriers (Soluplus and Eudragit EPO, respectively), however, there was no evidence within PXRD patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was established in this study that an appropriate carrier for a cocrystal reagent pair during HME processing should satisfy certain criteria including limited interaction with parent reagents and cocrystal product, processing temperature sufficiently lower than the onset of cocrystal Tm, low melt viscosity, and rapid solidification upon cooling.

Optimising Drug Solubilisation in Amorphous Polymer Dispersions: Rational Selection of Hot-melt Extrusion Processing Parameters.

The aim of this article was to construct a T-ϕ phase diagram for a model drug (FD) and amorphous polymer (Eudragit® EPO) and to use this information to understand the impact of how temperature-composition coordinates influenced the final properties of the extrudate. Defining process boundaries and understanding drug solubility in polymeric carriers is of utmost importance and will help in the successful manufacture of new delivery platforms for BCS class II drugs. Physically mixed felodipine (FD)-Eudragit(®) EPO (EPO) binary mixtures with pre-determined weight fractions were analysed using DSC to measure the endset of melting and glass transition temperature. Extrudates of 10 wt% FD-EPO were processed using temperatures (110°C, 126°C, 140°C and 150°C) selected from the temperature-composition (T-ϕ) phase diagrams and processing screw speed of 20, 100 and 200rpm. Extrudates were characterised using powder X-ray diffraction (PXRD), optical, polarised light and Raman microscopy. To ensure formation of a binary amorphous drug dispersion (ADD) at a specific composition, HME processing temperatures should at least be equal to, or exceed, the corresponding temperature value on the liquid-solid curve in a F-H T-ϕ phase diagram. If extruded between the spinodal and liquid-solid curve, the lack of thermodynamic forces to attain complete drug amorphisation may be compensated for through the use of an increased screw speed. Constructing F-H T-ϕ phase diagrams are valuable not only in the understanding drug-polymer miscibility behaviour but also in rationalising the selection of important processing parameters for HME to ensure miscibility of drug and polymer.