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1.
Psychol Med ; 54(2): 385-398, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37458212

ABSTRACT

BACKGROUND: Anxiety disorders are highly prevalent and debilitating conditions that show high comorbidity rates in adolescence. The present article illustrates how Unified Protocol for Transdiagnostic Treatment of Emotional Disorders in Adolescents (UP-A) was adapted for Iranian adolescents with anxiety disorders. METHODS: A total of 54 adolescents with comorbid anxiety disorders participated in a randomized, waitlist-controlled trial of group weekly sessions of either UP-A or waitlist control (WLC). Primary and process of change outcomes were assessed at baseline, posttreatment, and 1-month follow-up. RESULTS: Significant changes were observed over time on major DSM-5 anxiety disorder symptoms (F(2, 51) = 117.09, p < 0.001), phobia type symptoms (F(2, 51) = 100.67, p < 0.001), and overall anxiety symptoms (F(2, 51) = 196.29, p < 0.001), as well as on emotion regulation strategies of reappraisal (F(2, 51) = 17.03, p < 0.001), and suppression (F(2, 51) = 21.13, p < 0.001), as well as on intolerance of uncertainty dimensions including prospective (F(2, 51) = 74.49, p < 0.001), inhibitory (F(2, 51) = 45.94, p < 0.001), and total intolerance of uncertainty (F(2, 51) = 84.42, p < 0.001), in favor of UP-A over WLC. CONCLUSION: Overall, results provide a cultural application of the UP-A and support the protocol as useful for improving anxiety disorders as well as modifying of emotion regulation strategies and intolerance of uncertainty dimensions in Iranian adolescents. Future directions and study limitations are discussed.


Subject(s)
Anxiety Disorders , Adolescent , Humans , Anxiety Disorders/therapy , Iran , Prospective Studies
2.
Bone Jt Open ; 4(7): 532-538, 2023 Jul 20.
Article in English | MEDLINE | ID: mdl-37470126

ABSTRACT

Aims: Classifying trochlear dysplasia (TD) is useful to determine the treatment options for patients suffering from patellofemoral instability (PFI). There is no consensus on which classification system is more reliable and reproducible for the purpose of guiding clinicians' management of PFI. There are also concerns about the validity of the Dejour Classification (DJC), which is the most widely used classification for TD, having only a fair reliability score. The Oswestry-Bristol Classification (OBC) is a recently proposed system of classification of TD, and the authors report a fair-to-good interobserver agreement and good-to-excellent intraobserver agreement in the assessment of TD. The aim of this study was to compare the reliability and reproducibility of these two classifications. Methods: In all, six assessors (four consultants and two registrars) independently evaluated 100 axial MRIs of the patellofemoral joint (PFJ) for TD and classified them according to OBC and DJC. These assessments were again repeated by all raters after four weeks. The inter- and intraobserver reliability scores were calculated using Cohen's kappa and Cronbach's α. Results: Both classifications showed good to excellent interobserver reliability with high α scores. The OBC classification showed a substantial intraobserver agreement (mean kappa 0.628; p < 0.005) whereas the DJC showed a moderate agreement (mean kappa 0.572; p < 0.005). There was no significant difference in the kappa values when comparing the assessments by consultants with those by registrars, in either classification system. Conclusion: This large study from a non-founding institute shows both classification systems to be reliable for classifying TD based on axial MRIs of the PFJ, with the simple-to-use OBC having a higher intraobserver reliability score than that of the DJC.

3.
JAMA Psychiatry ; 80(10): 991-999, 2023 10 01.
Article in English | MEDLINE | ID: mdl-37466983

ABSTRACT

Importance: A transdiagnostic treatment, the Unified Protocol, is as effective as single diagnostic protocols in comorbid emotional disorders in clinical populations. However, its effects on posttraumatic stress disorder and other emotional disorders in individuals living in war and armed conflict contexts have not been studied. Objective: To evaluate the efficacy of a cultural and contextual adaptation of the Unified Protocol (CXA-UP) on posttraumatic stress disorder, anxiety, and depression compared to waitlist control in individuals exposed to armed conflict in Colombia. Design, Setting, and Participants: From April 2017 to March 2020, 200 participants 18 years and older were randomly assigned to the CXA-UP or to a waitlist condition. CXA-UP consisted of 12 to 14 twice-a-week or weekly individual 90-minute face-to-face sessions. Outcomes were assessed at baseline, posttreatment, and 3 months following treatment. Analyses were performed and compared for all randomly allocated participants (intent-to-treat [ITT]) and for participants who completed all sessions and posttreatment measures (per protocol [PP]). The study took place at an outpatient university center and included individuals who were registered in the Colombian Victims Unit meeting DSM-5 diagnostic criteria for posttraumatic stress disorder, anxiety, or depression or were severely impaired by anxiety or depression. Individuals who were receiving psychological therapy, were dependent on alcohol or drugs, were actively suicidal or had attempted suicide in the previous 2 months, had psychosis or bipolar disorder, or were cognitively impaired were excluded. Intervention: CXA-UP or waitlist. Main Outcomes and Measures: Primary outcomes were changes in anxiety, depression, and somatic scores on the Patient Health Questionnaire and Posttraumatic Stress Disorder Checklist for DSM-5. Results: Among the 200 participants (160 women [80.0%]; 40 men [20.0%]; mean [SD] age, 43.1 [11.9] years), 120 were randomized to treatment and 80 to waitlist. Results for primary outcomes in the ITT analysis showed a significant pretreatment-to-posttreatment reduction when comparing treatment and waitlist on the posttraumatic stress disorder checklist for DSM-5 scores (slope [SE], -31.12 [3.00]; P < .001; Cohen d, 0.90; 90% CI, 0.63-1.19), 9-item Patient Health Questionnaire (PHQ-9) (slope [SE],-11.94 [1.30]; P < .001; Cohen d, 0.77; 90% CI, 0.52-1.06), PHQ-anxiety (slope [SE], -6.52 [0.67]; P < .001; Cohen d, 0.82; 90% CI, 0.49-1.15), and PHQ-somatic (slope [SE], -8.31 [0.92]; P < .001; Cohen d, 0.75; 90% CI, 0.47-1.04). Conclusions and Relevance: In this study, significant reductions and large effect sizes in all measures of different emotional disorders showed efficacy of a single transdiagnostic intervention in individuals exposed to armed conflicts. Trial Registration: ClinicalTrials.gov Identifier: NCT03127982.


Subject(s)
Anxiety Disorders , Stress Disorders, Post-Traumatic , Male , Humans , Female , Adult , Colombia , Anxiety Disorders/therapy , Stress Disorders, Post-Traumatic/diagnosis , Stress Disorders, Post-Traumatic/therapy , Stress Disorders, Post-Traumatic/psychology , Anxiety/diagnosis , Anxiety/therapy , Armed Conflicts , Treatment Outcome
4.
J Nerv Ment Dis ; 211(9): 711-720, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37432031

ABSTRACT

ABSTRACT: Although evidence-based psychological treatments such as cognitive behavioral therapy (CBT) have strong empirical support for reducing anxiety and depression symptoms, CBT outcome research often does not report race and ethnicity variables, or assess how well CBT works for people from historically excluded racial and ethnic groups. This study presents post hoc analyses comparing treatment retention and symptom outcomes for participants of color ( n = 43) and White participants ( n = 136) from a randomized controlled efficacy trial of CBT. χ 2 tests and one-way ANCOVA showed no observable differences between the two samples on attrition or on clinician-rated measures of anxiety and depression at posttreatment and follow-up. Moderate to large within-group effect sizes on anxiety and depression were found for Black, Latinx, and Asian American participants at almost all time points. These preliminary findings suggest that CBT for anxiety and comorbid depression may be efficacious for Black, Asian American, and Latinx individuals.


Subject(s)
Cognitive Behavioral Therapy , Depression , Humans , Depression/therapy , Skin Pigmentation , Anxiety/therapy , Cognition , Treatment Outcome
5.
Biomater Sci ; 11(9): 3335-3353, 2023 May 02.
Article in English | MEDLINE | ID: mdl-36960608

ABSTRACT

Lipopolyplexes (LPDs) are of considerable interest for use as gene delivery vehicles. Here LPDs have been prepared from cationic vesicles (composed of a 1 : 1 molar ratio of DOTMA with the neutral helper lipid, DOPE), singly branched cationic peptides and plasmid DNA. All peptides contained a linker sequence (cleaved by endosomal furin) attached to a targeting sequence selected to bind human airway epithelial cells and mediate gene delivery. The current study investigates the effects of novel Arg-containing cationic peptide sequences on the biophysical and transfection properties of LPDs. Mixed His/Arg cationic peptides were of particular interest, as these sequences have not been previously used in LPD formulations. Lengthening the number of cationic residues in a homopolymer from 6 to 12 in each branch reduced transfection using LPDs, most likely due to increased DNA compaction hindering the release of pDNA within the target cell. Furthermore, LPDs containing mixed Arg-containing peptides, particularly an alternating Arg/His sequence exhibited an increase in transfection, probably because of their optimal ability to complex and subsequently release pDNA. To confer stability in serum, LPDs were prepared in 0.12 M sodium chloride solution (as opposed to the more commonly used water) yielding multilamellar LPDs with very high levels of size reproducibility and DNA protection, especially when compared to the (unilamellar) LPDs formed in water. Significantly for the clinical applications of the LPDs, those prepared in the presence of sodium chloride retained high levels of transfection in the presence of media supplemented with fetal bovine serum. This work therefore represents a significant advance for the optimisation of LPD formulation for gene delivery, under physiologically relevant conditions, in vivo.


Subject(s)
Peptides , Sodium Chloride , Humans , Reproducibility of Results , Transfection , Peptides/chemistry , DNA/chemistry , Plasmids/genetics , Liposomes/chemistry
6.
Menopause ; 30(3): 235-236, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36749902
8.
Psychother Res ; : 1-13, 2022 Sep 28.
Article in English | MEDLINE | ID: mdl-36169615

ABSTRACT

Objective The therapeutic alliance is related to treatment outcome but less is known about the agreement on alliance between patients and therapists and its relationship to outcomes. We examined the association of patient-therapist congruence of alliance perceptions, early and late in cognitive behavioral therapy for panic disorder in relation to symptom reduction and dropout. Method: Patients (n = 181) and their therapists provided alliance ratings early and late during 11-session treatment. Independent evaluators rated patients' symptomatic levels post-treatment. Polynomial regression and response surface analysis were used to examine congruence as a predictor of outcome. Results: Early in therapy, stronger combined patient-therapist alliances, regardless of agreement, predicted lower symptom severity at the end of therapy and a lower likelihood of dropout. Late in treatment, the outcome was worse when therapist ratings of the alliance were higher than those of the patient. Conclusions: Therapist-patient agreement on the strength of the alliance is important for symptom improvement and dropout. The study highlights the importance of understanding the dyadic nature of the alliance and its impact on therapeutic change.

9.
Trials ; 23(1): 721, 2022 Aug 31.
Article in English | MEDLINE | ID: mdl-36045387

ABSTRACT

BACKGROUND: Research has shown that internet-based cognitive behavioural therapy (iCBT) can be a very promising solution to increase access to and the dissemination of evidence-based treatments to all of the population in need. However, iCBT is still underutilized in clinical contexts, such as primary care. In order to achieve the effective implementation of these protocols, more studies in ecological settings are needed. The Unified Protocol (UP) is a transdiagnostic CBT protocol for the treatment of emotional disorders, which includes depression, anxiety and related disorders, that has shown its efficacy across different contexts and populations. An internet-based UP (iUP) programme has recently been developed as an emerging internet-based treatment for emotional disorders. However, the internet-delivered version of the UP (iUP) has not yet been examined empirically. The current project seeks to analyse the effectiveness of the iUP as a treatment for depression, anxiety and related emotional disorders in a primary care public health setting. METHODS: The current study will employ a parallel-group, randomized controlled trial design. Participants will be randomly assigned to (a) the internet-based Unified Protocol (iUP), or (b) enhanced waiting list control (eWLC). Randomization will follow a 2:1 allocation ratio, with sample size calculations suggesting a required sample of 120 (iUP=80; eWLC=40). The Mini-International Neuropsychiatric Interview (M.I.N.I.) will be used for assessing potential participants. The Overall Anxiety Severity and Impairment Scale (OASIS) and the Overall Depression Severity and Impairment Scale (ODSIS) as well as other standardized questionnaires will be used for assessments at baseline, 4 weeks, 8 weeks and 12 weeks from baseline and for the iUP condition during the follow-up. DISCUSSION: Combining the advantages of a transdiagnostic treatment with an online delivery format may have the potential to significantly lower the burden of emotional disorders in public health primary care setting. Anxiety and depression, often comorbid, are the most prevalent psychological disorders in primary care. Because the iUP allows for the treatment of different disorders and comorbidity, this treatment could represent an adequate choice for patients that demand mental health care in a primary care setting. TRIAL REGISTRATION: ISRCTN18056450 https://doi.org/10.1186/ISRCTN18056450 .


Subject(s)
Depression , Internet-Based Intervention , Anxiety/diagnosis , Anxiety/therapy , Anxiety Disorders/diagnosis , Anxiety Disorders/psychology , Anxiety Disorders/therapy , Depression/diagnosis , Depression/therapy , Humans , Internet , Primary Health Care , Treatment Outcome
10.
Article in English | MEDLINE | ID: mdl-35682179

ABSTRACT

The COVID-19 pandemic, and the social distancing practices that followed, have been associated with increased prevalence of emotional disorders. However, not all individuals affected by COVID-19-related social distancing experienced elevations in emotional disorder symptoms. Understanding this phenomenon is of crucial public health significance given the burden of emotional disorders on individuals and systems. In this narrative review, we consider the differential impact of COVID-19-related social distancing on mental health outcomes from a transdiagnostic perspective. We argue that individuals high in negative affect and aversive reactivity to emotion, that is, neuroticism, and who respond to such emotional experiences with emotion-motivated avoidant coping, are most likely to experience emotional disorders in the context of COVID-19 social distancing. We acknowledge the pro-social and adaptive function of some types of avoidance during the pandemic, which may have initially buffered against negative mental health outcomes. Implications of this conceptualization for treatment of emotional disorders in the present sociocultural context are discussed.


Subject(s)
COVID-19 , COVID-19/epidemiology , Emotions , Humans , Mental Health , Pandemics , Physical Distancing
11.
Nanoscale ; 14(14): 5392-5403, 2022 Apr 07.
Article in English | MEDLINE | ID: mdl-35319029

ABSTRACT

Surfactants are used in a wide range of chemical and biological applications, and for pharmaceutical purposes are frequently employed to enhance the solubility of poorly water soluble drugs. In this study, all-atom molecular dynamics (MD) simulations and small-angle neutron scattering (SANS) experiments have been used to investigate the drug solubilisation capabilities of the micelles that result from 10 wt% aqueous solutions of the non-ionic surfactant, Triton X-100 (TX-100). Specifically, we have investigated the solubilisation of saturation amounts of the sodium salts of two nonsteroidal anti-inflammatory drugs: ibuprofen and indomethacin. We find that the ibuprofen-loaded micelles are more non-spherical than the indomethacin-loaded micelles which are in turn even more non-spherical than the TX-100 micelles that form in the absence of any drug. Our simulations show that the TX-100 micelles are able to solubilise twice as many indomethacin molecules as ibuprofen molecules, and the indomethacin molecules form larger aggregates in the core of the micelle than ibuprofen. These large indomethacin aggregates result in the destabilisation of the TX-100 micelle, which leads to an increase in the amount of water inside of the core of the micelle. These combined effects cause the eventual division of the indomethacin-loaded micelle into two daughter micelles. These results provide a mechanistic description of how drug interactions can affect the stability of the resulting nanoparticles.


Subject(s)
Ibuprofen , Micelles , Ibuprofen/chemistry , Indomethacin , Octoxynol , Surface-Active Agents/chemistry , Water/chemistry
12.
Biochim Biophys Acta Biomembr ; 1864(6): 183886, 2022 06 01.
Article in English | MEDLINE | ID: mdl-35143742

ABSTRACT

The stratum corneum's lipid matrix is a critical for the skin's barrier function and is primarily composed of ceramides (CERs), cholesterol (CHOL) and free fatty acids (FFAs). The lipids form a long periodicity phase (LPP), a unique trilayer unit cell structure. An enzyme driven pathway is implemented to synthesize these key lipids. If these enzymes are down- or upregulated as in inflammatory diseases, the final lipid composition is affected often altering the barrier function. In this study, we mimicked down regulation of enzymes involved in the synthesis of the sphingosine and CER amide bond. In a LPP lipid model, we substituted CER N-(tetracosanoyl)-sphingosine (CER NS) with either i) FFA C24 and free sphingosine, to simulate the loss of the CER amide bond, or ii) with FFA C24 and C18 to simulate the loss of the sphingosine headgroup. Our study shows the lipids in the LPP would not phase separate until at least 25% of the CER NS is substituted keeping the lateral packing and conformational ordering unaltered. Neutron diffraction studies showed that free sphingosine chains localized at the outer layers of the unit cell, while the remaining CER NS head group was concentrated in the inner headgroup layers. However, when FFA C18 was inserted, CER NS was dispersed throughout the LPP, resulting in an even distribution between the inner and outer water layers. The presented results highlight the importance of the CER NS headgroup structure and its interaction in combination with the carbon chain invariability for optimal lipid arrangement.


Subject(s)
Ceramides , Sphingosine , Ceramides/chemistry , Fatty Acids, Nonesterified/analysis , Fatty Acids, Nonesterified/chemistry , Neutron Diffraction , Skin/chemistry
13.
Behav Modif ; 46(1): 36-62, 2022 01.
Article in English | MEDLINE | ID: mdl-32752883

ABSTRACT

Exposure therapy works through inhibitory learning, whereby patients are exposed to stimuli that elicit anxiety in order to establish safety associations. Mindful emotion awareness, or nonjudgmental and present-focused attention toward emotions, may facilitate engagement in exposures, which may in turn enhance therapeutic outcome. This study utilizes a single-case experimental design (n = 6) to investigate the effect of mindful emotion awareness training on the use of avoidant strategies during exposures, distress during exposures, overall mindfulness, experiential avoidance, and symptom reduction in a sample of participants with social anxiety disorder. Data were analyzed using a combination of visual inspection and quantitative effect size metrics commonly applied in single-case experimental designs. To further investigate the relationship between distress and avoidant strategy use, contemporaneous and cross-lagged correlations were run. Results highlight individual differences in responses to mindful emotion awareness training and exposure exercises. Given these individual differences, repeated assessment and monitoring over the course of treatment may help clinicians most effectively identify treatment skills that will be most helpful for individual patients.


Subject(s)
Implosive Therapy , Mindfulness , Anxiety Disorders/psychology , Awareness/physiology , Emotions/physiology , Humans , Mindfulness/methods , Research Design
14.
Behav Ther ; 52(6): 1325-1338, 2021 11.
Article in English | MEDLINE | ID: mdl-34656189

ABSTRACT

The Unified Protocol (UP) for Transdiagnostic Treatment of Emotional Disorders is an emotion-focused, cognitive-behavioral intervention developed to address the full range of anxiety, depressive, and related disorders. The UP consists of core therapeutic skills that, though unique in focus, are each designed to promote an approach-oriented stance toward emotional experiences. The goal of the present investigation was to characterize changes in these skills for patients that received a course of treatment with the UP, as well as to examine associations between skills and symptoms changes. Patients with principal anxiety disorders, assigned to receive treatment with the UP (N = 88) as part of a randomized controlled trial, were included in this study. They completed validated self-report measures of UP skills (Understanding Emotions, Mindful Emotion Awareness, Cognitive Flexibility, Countering Emotional Behaviors, and Interoceptive Awareness and Tolerance), as well as clinician-rated measures of psychological symptoms. Skill measures improved significantly over the course of 12 to 16 UP treatment sessions and changes in these skills measures were associated with improvements in anxiety symptoms. Determining whether improvement on all the skills learned during a course of treatment with UP is associated with symptom remission is critical to establishing the most streamlined and efficient interventions that may ultimately be best suited to widespread dissemination.


Subject(s)
Cognitive Behavioral Therapy , Mindfulness , Anxiety/therapy , Anxiety Disorders/therapy , Emotions , Humans , Randomized Controlled Trials as Topic , Treatment Outcome
15.
Behav Ther ; 52(6): 1364-1376, 2021 11.
Article in English | MEDLINE | ID: mdl-34656192

ABSTRACT

Dropout from psychotherapy is common and can have negative effects for patients, providers, and researchers. A better understanding of when and why patients stop treatment early, as well as actionable factors contributing to dropout, has the potential to prevent it. Here, we examined dropout from a large randomized controlled trial of transdiagnostic versus single-diagnosis cognitive-behavioral treatment (CBT) for patients with anxiety disorders (n = 179; Barlow et al., 2017). We aimed to characterize the timing of and reasons for dropout and test whether participants who dropped out had different symptom trajectories than those who completed treatment. Results indicated that overall, the greatest risk of dropout was prior to the first treatment session. In single-diagnosis CBT, dropout risk was particularly elevated before the first session and after other early sessions, whereas in transdiagnostic CBT, dropout risk was low and stable before and during treatment. Participants most often dropped out due to failure to comply with study procedures or dissatisfaction with or desiring alternative treatment. Results from multilevel models showed that trajectories of anxiety symptoms did not significantly differ between dropouts and completers. These findings suggest that there may be specific time windows for targeted and timely interventions to prevent dropout from CBT.


Subject(s)
Cognitive Behavioral Therapy , Patient Dropouts , Anxiety Disorders/diagnosis , Anxiety Disorders/therapy , Humans , Psychotherapy , Treatment Outcome
16.
Contemp Clin Trials ; 108: 106512, 2021 09.
Article in English | MEDLINE | ID: mdl-34284152

ABSTRACT

Alcohol Use Disorder (AUD) and anxiety disorders (ANX) are each highly prevalent and frequently co-occur, resulting in a complex clinical presentation. The existing literature to date has not yet identified how to best treat comorbid AUD/ANX, partially due to limitations in understanding what factors and mechanisms are implicated in their co-occurrence. This manuscript describes the rationale and methods for an ongoing randomized-controlled trial designed to evaluate the efficacy of a cognitive behavioral intervention, the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP), compared to Take Control (TC), a psychosocial and motivational treatment serving as a control condition in this study, for comorbid AUD/ANX. Sixty individuals with comorbid AUD/ANX will be randomized to UP or TC, and complete assessments at pre- and post-treatment, as well as one- and six-month follow-up points. We hypothesize that the UP, compared to TC, will result in significantly greater reductions in drinking-related outcomes, as well as anxiety and depressive-related outcomes. Additionally, the current study is designed to evaluate exploratory aims to contribute to our theoretical understanding of why AUD and ANX frequently co-occur. Specifically, we will examine the relationship between changes in AUD and ANX symptoms in relation to changes in emotional disorder mechanisms, such as emotion regulation. Because the UP is a transdiagnostic treatment that specifically targets underlying components of emotional disorders generally, it may be well suited to effectively target comorbid AUD/ANX.


Subject(s)
Alcoholism , Anxiety Disorders , Cognitive Behavioral Therapy , Alcoholism/epidemiology , Alcoholism/therapy , Anxiety Disorders/epidemiology , Anxiety Disorders/therapy , Comorbidity , Humans , Randomized Controlled Trials as Topic
17.
Behav Ther ; 52(4): 1008-1018, 2021 07.
Article in English | MEDLINE | ID: mdl-34134818

ABSTRACT

Homework assignments are an integral part of cognitive behavioral therapy, providing patients with opportunities to practice skills between sessions. Generally, greater homework compliance is associated with better treatment outcomes. However, fewer studies have examined the effect of homework quality on treatment outcomes. This study examined homework compliance and quality as predictors of outcome and attrition across five CBT protocols. A sample of 179 individuals with principal diagnoses of generalized anxiety disorder, panic disorder, social anxiety disorder, or obsessive-compulsive disorder were randomized to receive a transdiagnostic CBT protocol (the Unified Protocol) or a single-diagnosis CBT protocol corresponding to their principal diagnosis. The Unified Protocol had a lower homework burden than the majority of the single-diagnosis protocols, which varied in degree of assigned homework. Despite this, there were no differences in average homework compliance or quality across principal diagnosis, treatment condition, or their interaction. Homework quality was significantly related to all symptom outcomes (self-reported and clinician-rated anxiety and depressive symptoms, clinician-rated clinical severity). Homework compliance was significantly related to clinician-rated anxiety symptom outcomes. Additionally, greater homework quality and compliance were both significantly associated with increased odds of completing treatment, suggesting homework variables can be useful and easily obtainable predictors of treatment retention.


Subject(s)
Cognitive Behavioral Therapy , Obsessive-Compulsive Disorder , Panic Disorder , Phobia, Social , Anxiety Disorders/therapy , Humans , Obsessive-Compulsive Disorder/therapy , Treatment Outcome
18.
Int J Pharm ; 604: 120715, 2021 Jul 15.
Article in English | MEDLINE | ID: mdl-34048927

ABSTRACT

Lactose is present as an excipient in nearly half of all solid medicines. Despite the assumption of chemical stability, in aqueous solution, the chiral composition of lactose is prone to change. It is not known whether such epimerisation could also occur as solid crystalline α-lactose undergoes thermal desorption of its hydrated water. Thus, the aim of this study was to investigate the anomeric composition of lactose powders after heating in a differential scanning calorimeter. During thermal analysis, the heating cycles were interrupted to allow anomer-composition analysis by NMR. The onset for monohydrate desorption occurred at 143.8 ± 0.3 °C. Post water-loss, at 160 °C for example, α-lactose suffered partial conversion (11.6 ± 0.9%) to the ß-anomer. When held at 160 °C for 60 min this increased to 29.7 ± 0.8% ß-anomer (p < 0.05). This process of epimerisation was found to be close to zero-order with a rate constant of 0.28% per min-1. Optical microscopy indicated that the solid-state was maintained throughout thermal desorption and up to the onset of melting at 214.2 ± 0.9 °C. Only epimerisation was observed, with no additional chemical degradation detected by NMR. Similar results were observed when heating α-lactose to 190 °C, which resulted in a conversion of 29.1 ± 0.7% to ß-lactose. Thus, the exothermic peak observed after monohydrate loss, which has often been attributed to re-crystallisation, comprises a contribution from epimerisation. No epimerisation or hydrate loss was observed for ß-lactose powders when heated. In summary, it has been shown unequivocally for the first time that hydrate desorption (dehydration) leads to solid-state epimerisation in α-lactose powders.


Subject(s)
Dehydration , Lactose , Calorimetry, Differential Scanning , Crystallization , Excipients , Humans , Powders
19.
J Colloid Interface Sci ; 597: 278-288, 2021 Sep.
Article in English | MEDLINE | ID: mdl-33872884

ABSTRACT

Liquid lipid nanoparticles (LLN) are oil-in-water nanoemulsions of great interest in the delivery of hydrophobic drug molecules. They consist of a surfactant shell and a liquid lipid core. The small size of LLNs makes them difficult to study, yet a detailed understanding of their internal structure is vital in developing stable drug delivery vehicles (DDVs). Here, we implement machine learning techniques alongside small angle neutron scattering experiments and molecular dynamics simulations to provide critical insight into the conformations and distributions of the lipid and surfactant throughout the LLN. We simulate the assembly of a single LLN composed of the lipid, triolein (GTO), and the surfactant, Brij O10. Our work shows that the addition of surfactant is pivotal in the formation of a disordered lipid core; the even coverage of Brij O10 across the LLN shields the GTO from water and so the lipids adopt conformations that reduce crystallisation. We demonstrate the superior ability of unsupervised artificial neural networks in characterising the internal structure of DDVs, when compared to more conventional geometric methods. We have identified, clustered, classified and averaged the dominant conformations of lipid and surfactant molecules within the LLN, providing a multi-scale picture of the internal structure of LLNs.

20.
Small ; 17(6): e2004761, 2021 02.
Article in English | MEDLINE | ID: mdl-33470509

ABSTRACT

Self-assembled, lipid-based micelles, such as those formed by the short-chain phosphocholine, dihexanoylphosphatidylcholine (2C6PC), are degraded by the pancreatic enzyme, phospholipase A2 (PLA2). Degradation yields 1-hexanoyl-lysophosphocholine (C6LYSO) and hexanoic acid (C6FA) products. However, little is known about the behavior of these products during and after the degradation of 2C6PC. In this work, a combination of static and time-resolved small angle neutron scattering, as well as all-atom molecular dynamics simulations, is used to characterize the structure of 2C6PC micelles. In doing so a detailed understanding of the substrate and product aggregation behavior before, during and after degradation is gained. Consequently, the formation of mixed micelles containing 2C6PC, C6LYSO and C6FA is shown at every stage of the degradation process, as well as the formation of mixed C6LYSO/C6FA micelles after degradation is complete. The use of atomistic molecular dynamics has allowed us to characterize the structure of 2C6PC, 2C6PC/C6LYSO/C6FA, and C6LYSO/C6FA micelles throughout the degradation process, showing the localization of the different molecular species within the aggregates. In addition, the hydration of the 2C6PC, C6LYSO, and C6FA species both during micellization and as monomers in aqueous solution is documented to reveal the processes driving their micellization.


Subject(s)
Micelles , Molecular Dynamics Simulation , Digestion , Scattering, Small Angle
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