Survey of Pharmaceutical Industry's Best Practices around In Vitro Transporter Assessment and Implications for Drug Development: Considerations from the International Consortium for Innovation and Quality for Pharmaceutical Development Transporter Working Group.

The International Consortium for Innovation and Quality in Pharmaceutical Development Transporter Working Group had a rare opportunity to analyze a crosspharma collation of in vitro data and assay methods for the evaluation of drug transporter substrate and inhibitor potential. Experiments were generally performed in accordance with regulatory guidelines. Discrepancies, such as not considering the impact of preincubation for inhibition and free or measured in vitro drug concentrations, may be due to the retrospective nature of the dataset and analysis. Lipophilicity was a frequent indicator of crosstransport inhibition (P-gp, BCRP, OATP1B, and OCT1), with high molecular weight (MW ≥500 Da) also common for OATP1B and BCRP inhibitors. A high level of overlap in in vitro inhibition across transporters was identified for BCRP, OATP1B1, and MATE1, suggesting that prediction of DDIs for these transporters will be common. In contrast, inhibition of OAT1 did not coincide with inhibition of any other transporter. Neutrals, bases, and compounds with intermediate-high lipophilicity tended to be P-gp and/or BCRP substrates, whereas compounds with MW <500 Da tended to be OAT3 substrates. Interestingly, the majority of in vitro inhibitors were not reported to be followed up with a clinical study by the submitting company, whereas those compounds identified as substrates generally were. Approaches to metabolite testing were generally found to be similar to parent testing, with metabolites generally being equally or less potent than parent compounds. However, examples where metabolites inhibited transporters in vitro were identified, supporting the regulatory requirement for in vitro testing of metabolites to enable integrated clinical DDI risk assessment. SIGNIFICANCE STATEMENT: A diverse dataset showed that transporter inhibition often correlated with lipophilicity and molecular weight (>500 Da). Overlapping transporter inhibition was identified, particularly that inhibition of BCRP, OATP1B1, and MATE1 was frequent if the compound inhibited other transporters. In contrast, inhibition of OAT1 did not correlate with the other drug transporters tested.

Relationship between trauma, psychological distress and help-seeking among corrective service workers.

BACKGROUND: Corrective service workers (CSWs) are at high risk of post-traumatic stress disorder (PTSD) and other mental health problems. Prevalence rates and help-seeking behaviours are under-researched within this population. AIMS: To assess rates of PTSD and distress, and identify predictors of intention to seek help, among workers at an Australian corrective service agency. METHODS: A cross-sectional online survey was used to collect data on staff demographics, employment, PTSD symptoms and current distress. Participants received a tailored feedback report including referral to relevant mental health services (where applicable) and were asked to indicate their likelihood of seeking help. Prevalence data are reported. Binary logistic regression was used to examine relationships between participant characteristics and help-seeking for those with probable PTSD and/or high psychological distress. RESULTS: Participants (n=1001) were predominantly men (56.8%) with a mean age of 46.72 (SD=11.00). Over half (58.0%) were classified as probable PTSD cases, and one-third (33.0%) were experiencing high psychological distress. Around a third (34.3%) of participants with probable PTSD and/or elevated distress indicated they were likely to seek help. Older age and fewer years of service were associated with increased help-seeking intentions. CONCLUSIONS: CSWs were found to be experiencing probable PTSD at higher rates than reported in previous studies. Relatively few intended to seek help from mental health services, despite being provided with personalised screening and feedback along with access to specialised care. Future research should investigate the potential role of organisational support as a facilitator of help-seeking within this population.

Selective Prevention of Depression in Workers Using a Smartphone App: Randomized Controlled Trial.

BACKGROUND: There is increasing evidence that depression can be prevented; however, universal approaches have had limited success. Appropriate targeting of interventions to at-risk populations has been shown to have potential, but how to selectively determine at-risk individuals remains unclear. Workplace stress is a risk factor for depression and a target for intervention, but few interventions exist to prevent depression among workers at risk due to heightened stress. OBJECTIVE: This trial aimed to evaluate the efficacy of a smartphone-based intervention in reducing the onset of depression and improving related outcomes in workers experiencing at least moderate levels of stress. METHODS: A randomized controlled trial was conducted with participants who were currently employed and reported no clinically significant depression and at least moderate stress. The intervention group (n=1053) were assigned Anchored, a 30-day self-directed smartphone app-based cognitive behavioral- and mindfulness-based intervention. The attention-control group (n=1031) were assigned a psychoeducation website. Assessment was performed via web-based self-report questionnaires at baseline and at 1-, 3-, and 6-month postbaseline time points. The primary outcome was new depression caseness aggregated over the follow-up period. The secondary outcomes included depressive and anxiety symptoms, stress, well-being, resilience, work performance, work-related burnout, and quality of life. Analyses were conducted within an intention-to-treat framework using mixed modeling. RESULTS: There was no significant between-group difference in new depression caseness (z score=0.69; P=.49); however, those in the Anchored arm had significantly greater depressive symptom reduction at 1 month (Cohen d=0.02; P=.049) and 6 months (Cohen d=0.08; P=.03). Anchored participants also showed significantly greater reduction in anxiety symptoms at 1 month (Cohen d=0.07; P=.04) and increased work performance at 1 month (Cohen d=0.07; P=.008) and 6 months (Cohen d=0.13; P=.01), compared with controls. Notably, for Anchored participants completing at least two-thirds of the intervention, there was a significantly lower rate of depression onset (1.1%, 95% CI 0.0%-3.7%) compared with controls (9.0%, 95% CI 6.8%-12.3%) at 1 month (z score=4.50; P<.001). Significant small to medium effect sizes for most secondary outcomes were seen in the highly engaged Anchored users compared with controls, with effects maintained at the 6-month follow-up for depressive symptoms, well-being, stress, and quality of life. CONCLUSIONS: Anchored was associated with a small comparative reduction in depressive symptoms compared with controls, although selective prevention of case-level depression was not observed in the intention-to-treat analysis. When users adequately engaged with the app, significant findings pertaining to depression prevention, overall symptom reduction, and functional improvement were found, compared with controls. There is a need for a greater focus on engagement techniques in future research. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000178943; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378592.

Evolution of tetraspanin antigens in the zoonotic Asian blood fluke Schistosoma japonicum.

BACKGROUND: Despite successful control efforts in China over the past 60 years, zoonotic schistosomiasis caused by Schistosoma japonicum remains a threat with transmission ongoing and the risk of localised resurgences prompting calls for a novel integrated control strategy, with an anti-schistosome vaccine as a core element. Anti-schistosome vaccine development and immunisation attempts in non-human mammalian host species, intended to interrupt transmission, and utilising various antigen targets, have yielded mixed success, with some studies highlighting variation in schistosome antigen coding genes (ACGs) as possible confounders of vaccine efficacy. Thus, robust selection of target ACGs, including assessment of their genetic diversity and antigenic variability, is paramount. Tetraspanins (TSPs), a family of tegument-surface antigens in schistosomes, interact directly with the host's immune system and are promising vaccine candidates. Here, for the first time to our knowledge, diversity in S. japonicum TSPs (SjTSPs) and the impact of diversifying selection and sequence variation on immunogenicity in these protiens were evaluated. METHODS: SjTSP sequences, representing parasite populations from seven provinces across China, were gathered by baiting published short-read NGS data and were analysed using in silico methods to measure sequence variation and selection pressures and predict the impact of selection on variation in antigen protein structure, function and antigenic propensity. RESULTS: Here, 27 SjTSPs were identified across three subfamilies, highlighting the diversity of TSPs in S. japonicum. Considerable variation was demonstrated for several SjTSPs between geographical regions/provinces, revealing that episodic, diversifying positive selection pressures promote amino acid variation/variability in the large extracellular loop (LEL) domain of certain SjTSPs. Accumulating polymorphisms in the LEL domain of SjTSP-2, -8 and -23 led to altered structural, functional and antibody binding characteristics, which are predicted to impact antibody recognition and possibly blunt the host's ability to respond to infection. Such changes, therefore, appear to represent a mechanism utilised by S. japonicum to evade the host's immune system. CONCLUSION: Whilst the genetic and antigenic geographic variability observed amongst certain SjTSPs could present challenges to vaccine development, here we demonstrate conservation amongst SjTSP-1, -13 and -14, revealing their likely improved utility as efficacious vaccine candidates. Importantly, our data highlight that robust evaluation of vaccine target variability in natural parasite populations should be a prerequisite for anti-schistosome vaccine development.

Dynamic modulation of inequality aversion in human interpersonal negotiations.

Negotiating with others about how finite resources should be distributed is an important aspect of human social life. However, little is known about mechanisms underlying human social-interactive decision-making in gradually evolving environments. Here, we report results from an iterative Ultimatum Game (UG), in which the proposer's facial emotions and offer amounts were sampled probabilistically based on the participant's decisions. Our model-free results confirm the prediction that both the proposer's facial emotions and the offer amount should influence acceptance rates. Model-based analyses extend these findings, indicating that participants' decisions in the UG are guided by aversion to inequality. We highlight that the proposer's facial affective reactions to participant decisions dynamically modulate how human decision-makers perceive self-other inequality, relaxing its otherwise negative influence on decision values. This cognitive model underlies how offers initially rejected can gradually become more acceptable under increasing affective load (predictive accuracy ~86%). Furthermore, modelling human choice behaviour isolated the role of the central arousal systems, assessed by measuring pupil size. We demonstrate that pupil-linked central arousal systems selectively encode a key component of subjective decision values: the magnitude of self-other inequality. Taken together, our results demonstrate that, under affective influence, aversion to inequality is a malleable cognitive process.

Quantitation of Plasma Membrane Drug Transporters in Kidney Tissue and Cell Lines Using a Novel Proteomic Approach Enabled a Prospective Prediction of Metformin Disposition.

The successful prospective incorporation of in vitro transporter kinetics in physiologically based pharmacokinetic (PBPK) models to describe drug disposition remains challenging. Although determination of scaling factors to extrapolate in vitro to in vivo transporter kinetics has been facilitated by quantitative proteomics, no robust assessment comparing membrane recoveries between different cells/tissues has been made. HEK293 cells overexpressing OCT2, MATE1, and MATE2K or human kidney cortex were homogenized and centrifuged to obtain the total membrane fractions, which were subsequently subjected to liquid-liquid extraction followed by centrifugation and precipitation to isolate plasma membrane fractions. Plasma membrane recoveries determined by quantitation of the marker Na+/K+-ATPase in lysate and plasma membrane fractions were ≤20% but within 3-fold across different cells and tissues. A separate study demonstrated that recoveries are comparable between basolateral and apical membranes of renal proximal tubules, as measured by Na+/K+-ATPase and γ-glutamyl transpeptidase 1, respectively. The plasma membrane expression of OCT2, MATE1, and MATE2K was quantified and relative expression factors (REFs) were determined as the ratio between the tissue and cell concentrations. Corrections using plasma membrane recovery had minimal impact on REF values (<2-fold). In vitro transporter kinetics of metformin were extrapolated to in vivo using the corresponding REFs in a PBPK model. The simulated metformin exposures were within 2-fold of clinical exposure. These results demonstrate that transporter REFs based on plasma membrane expression enable a prediction of transporter-mediated drug disposition. Such REFs may be estimated without the correction of plasma membrane recovery when the same procedure is applied between different matrices. SIGNIFICANCE STATEMENT: Transporter REFs based on plasma membrane expression enable in vitro-in vivo extrapolation of transporter kinetics. Plasma membrane recoveries as determined by the quantification of sodium-potassium adenosine triphosphatase were comparable between the in vitro and in vivo systems used in the present study, and therefore had minimal impact on the transporter REF values.

Combining science and social engagement againstCovid-19 in a Brazilian Slum

ObjectivesFor many underdeveloped countries, strategies implemented by social communities allied to scientific knowledge may be a rote to attenuate the rapid spread of Covid-19 cases and allow services to the population. This work presents a joint effort collaboration between scientists and underserved community groups from a Brazilian slum/Santa Marta in Rio de Janeiro City in the fight against Covid-19. Measurements of contamination in the air near the ground, georeferencing of data of infected people, were regressed with sanitization activities aiming at reducing the Covid-19 incidence. MethodsWe monitored aerosol containing SARS-Cov-2 virus in outdoor ambient air using various virus collection mediums (solid, liquid, and gelatinous substrates) at different aerodynamic sizes. We implemented a local statistics survey for the Covid-19 database correlated with varying sanitization levels between April 2020 and June 2021 developed in the Santa Marta slum. FindingsWe detected the SARS-CoV-2 virus in the air near the ground in diameters ranging from 0.25 to 0.5 {micro}m, demonstrating that there is a circulation of the virus in the slum atmosphere. We demonstrate that Covid-19 cases for the Santa Marta slum were significatively lowered with improved sanitization levels (r = -0.74). ConclusionsDespite previous publications that discarded the use of sanitization as a relevant tool in the fight against Covid-19, our results suggest that profits can be achieved in mitigating Covid-19 in underserved community sites. Furthermore, a permanent sanitization activity may induce positive social behavior for the sake of combating Covid-19.

Coproporphyrin I Can Serve as an Endogenous Biomarker for OATP1B1 Inhibition: Assessment Using a Glecaprevir/Pibrentasvir Clinical Study.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the disposition of a variety of commonly prescribed drugs. The evaluation of OATP1B1/1B3 inhibition potential by investigational drugs is of interest during clinical drug development due to various adverse events associated with increased exposures of their substrates. Regulatory guidance documents on the in vitro assessment of OATP1B1/1B3 inhibition potential are conservative with up to a third of predictions resulting in false positives. This work investigated the utility of OATP1B1/1B3 endogenous biomarkers, coproporphyrin (CP)-I and CP-III, to assess clinical inhibition of OATP1B1/1B3 and potentially eliminate the need for prospective clinical drug-drug interaction (DDI) studies. Correlations between CP-I exposures and various OATP1B1 static DDI predictions were also evaluated. Glecaprevir/pibrentasvir (GLE/PIB) 300/120 mg fixed-dose combination is known to cause clinical inhibition of OATP1B1/1B3. In a clinical study evaluating the relative bioavailability of various formulations of GLE/PIB regimen, CP-I peak plasma concentration (Cmax ) ratio and 0-16-hour area under the concentration-time curve (AUC0-16 ) ratio relative to baseline increased with increasing GLE exposures, whereas there was a modest correlation between GLE exposure and CP-III Cmax ratio but no correlation with CP-III AUC0-16 ratio. This suggests that CP-I is superior to CP-III as an endogenous biomarker for evaluation of OATP1B1 inhibition. There was a significant correlation between CP-I and GLE Cmax (R2  = 0.65; P < 0.001) across individual subjects. Correlation analysis between GLE OATP1B1 R values and CP-I exposures (Cmax ratio and AUC0-16 ratio) suggests that an R value of > 3 can predict a biologically meaningful inhibition of OATP1B1 when the inhibitor clinical pharmacokinetic parameters are available.

Prodrug Strategies to Improve the Solubility of the HCV NS5A Inhibitor Pibrentasvir (ABT-530).

A research program to discover solubilizing prodrugs of the HCV NS5A inhibitor pibrentasvir (PIB) identified phosphomethyl analog 2 and trimethyl-lock (TML) prodrug 9. The prodrug moiety is attached to a benzimidazole nitrogen atom via an oxymethyl linkage to allow for rapid and complete release of the drug for absorption following phosphate removal by intestinal alkaline phosphatase. These prodrugs have good hydrolytic stability properties and improved solubility compared to PIB, both in aqueous buffer (pH 7) and FESSIF (pH 5). TML prodrug 9 provided superior in vivo performance, delivering high plasma concentrations of PIB in PK studies conducted in mice, dogs, and monkeys. The improved dissolution properties of these phosphate prodrugs provide them the potential to simplify drug dosage forms for PIB-containing HCV therapy.

A Pilot Evaluation of a Smartphone Application for Workplace Depression.

Interventions delivered via mobile apps show particular promise in tackling the burden of common mental disorders. Appropriately targeting these interventions to at-risk populations is critical to their success. This pilot study aimed to assess the usability, feasibility, acceptability, and preliminary effects of an app-based intervention designed to target depressive symptoms in a stressed working population. Anchored, a smartphone app including a 30-day program of mindfulness and cognitive and behavioural therapeutic components, was tested in a pre-post pilot study with participants recruited via social media advertisements. Eligible participants (N = 81) were Australian adults who were employed and reported elevated stress levels on a single-item screening measure. Follow-up assessment occurred 5 weeks after baseline. The primary outcome measure was change in depressive symptoms, with secondary outcomes measuring change in anxiety, wellbeing, stress, resilience, exercise, alcohol use, absenteeism, and work performance. User feedback and in-app data were analysed to assess engagement and intervention adherence. At follow-up, there were significant reductions in depressive symptoms (t61 = 6.35; p < 0.001) and anxiety symptoms (t60 = 7.35; p < 0.001), along with significantly reduced cases of likely new onset depression compared to baseline (24% vs. 6%, p = 0.012). Significant improvements were also seen in wellbeing (t60 = -5.64; p < 0.001), resilience (t60 = -3.89; p < 0.001), stress (t61 = 11.18; p < 0.001), and alcohol use (t60 = 3.40; p = 0.001). Participants reported no significant changes in work performance, absenteeism or exercise. There were satisfactory levels of app usability, feasibility, and acceptability. Most participants found the app easy to use (93.2%), understood the app content well (83.0%), and rated the app highly or very highly overall (72.9%). User feedback suggestions were predominantly focused on improving app navigation and user interface. This pilot study provides encouraging evidence that Anchored has potentially beneficial effects, and is usable, feasible, and acceptable as an app-based intervention for the working population experiencing elevated stress. Further testing of Anchored in a randomised controlled trial is required to investigate its efficacy as an intervention for workplace mental ill-health.

Discovery of 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs for delivering nucleoside HCV NS5B polymerase inhibitors.

Our HCV research program investigated novel 2'-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5'-phosphoramidate prodrug of 2'-deoxy-2'-α-bromo-ß-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5'-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose).

ParentWorks: Evaluation of an Online, Father-Inclusive, Universal Parenting Intervention to Reduce Child Conduct Problems.

Evidence-based parenting interventions are effective in reducing conduct problems, yet these interventions have limited reach, and few involve the participation of fathers. This paper describes the outcomes of an open trial of ParentWorks, a universal, online, father-inclusive parenting intervention aiming to decrease childhood behavioural problems and promote positive parenting in mothers and fathers. A total of 388 families (456 individual parents; 36.6% fathers) were included in the study. Mixed model analyses showed significant decreases in child emotional/behavioural problems, dysfunctional parenting, interparental conflict, and parental mental health problems. The baseline severity of child behavioural problems significantly moderated the effects on child outcomes so that children with higher levels of problems benefitted more from the program. Participation of both caregivers in two-parent families, as well as parent sex, did not significantly affect the program outcomes. Results provide initial empirical support for the universal, self-directed, online parenting intervention, in addressing both child behavioural problems and parenting outcomes. Trial registration: ACTRN12616001223426, registered 05/09/2016.

Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.

Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.

Translation of In Vitro Transport Inhibition Studies to Clinical Drug-Drug Interactions for Glecaprevir and Pibrentasvir.

Glecaprevir and pibrentasvir are oral direct-acting antiviral agents approved in combination for treatment of chronic hepatitis C viral infection. In vitro studies identified the combination as potentially clinically relevant inhibitors of the efflux transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Glecaprevir inhibited P-gp, BCRP, OATP1B1, and OATP1B3 with IC50 values of 0.33, 2.3, 0.017, and 0.064 µM, respectively. Pibrentasvir inhibited P-gp, BCRP, and OATP1B1 with IC50 values of 0.036, 14, and 1.3 µM, respectively. Neither agent inhibited organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K. Open-label phase 1 clinical drug-drug interaction studies were conducted in healthy subjects to evaluate interaction potential of glecaprevir/pibrentasvir and coadministered selective substrates for P-gp (digoxin, dabigatran etexilate, and sofosbuvir), BCRP (rosuvastatin and sofosbuvir), and OATP1B1/3 (pravastatin and rosuvastatin). The pharmacokinetic maximum plasma concentration (C max) and area under the concentration-time curve (AUC) parameters were evaluated for probe substrates alone and in combination with glecaprevir/pibrentasvir. The C max central values increased by 72%, 105%, 123%, 462%, and 66% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively, and the AUC central values increased by 48%, 138%, 130%, 115%, and 125% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively. Exposure of sofosbuvir metabolite GS-331007 (nucleoside analog) was similar with or without glecaprevir/pibrentasvir. The outcomes of the clinical drug-drug interaction studies confirmed clinically relevant inhibition of P-gp, BCRP, and OATP1B1/3, and were used to provide dosing guidance for the concomitant use of glecaprevir/pibrentasvir with relevant transporter substrates.

No Inhibition of MATE1/2K-Mediated Renal Creatinine Secretion Predicted With Ritonavir or Cobicistat.

Cobicistat has been reported to increase serum creatinine clinically without affecting glomerular filtration. This was ascribed to transient inhibition of MATE1-mediated renal creatinine secretion. Interestingly, a structurally similar drug, ritonavir, has not been associated with serum creatinine increases at the pharmacoenhancer dose. The present study was aimed to investigate the translation of in vitro MATE1/2K inhibition to clinical creatinine increase (cobicistat) and lack of it (ritonavir) considering their intracellular concentrations in renal proximal tubules. Uptake studies showed ritonavir and cobicistat are unlikely substrates for OCT2. The steady-state unbound concentration in the cytosol of human renal proximal tubule epithelial cells was comparable with the extracellular unbound concentration, suggesting that the entry of these compounds is predominantly mediated by passive diffusion. Ritonavir and cobicistat are MATE1 and MATE2K inhibitors with IC50 values of 3.1 and 90 µM (ritonavir), and 4.4 and 3.2 µM (cobicistat), respectively. However, the unbound cytosolic concentrations (Cu,cytosol) of ritonavir and cobicistat in human renal proximal tubule epithelial cells, 0.065 and 0.10 µM, respectively, after incubation with the clinical maximum total plasma concentrations at pharmacoenhancer doses does not support inhibition in vivo; Cu,cytosol >30 fold lower than IC50s. These results demonstrate that MATE1/2K inhibition is unlikely the mechanism of the clinical creatinine elevations with cobicistat.

Enhanced ultrasonographic imaging of the equine distal limb using saline injection of the digital flexor tendon sheath: A cadaver study.

Injuries to the structures within the digital flexor tendon sheath (DFTS) can lead to lameness with a variable degree of effusion in horses. In some cases, effusion is absent or minimal, and this may be related to the chronicity and type of injury, or veterinary interventions. The purpose of this study was to determine if saline injection into the DFTS would improve ultrasonographic and magnetic resonance imaging of the distal limb without introducing artifact. Nine normal equine cadaver forelimbs were collected. Non-weight-bearing ultrasonographic and magnetic resonance imaging (MRI) examination of each limb was performed pre- and immediately post-injection of the DFTS. The presence of fluid in the DFTS significantly improved the delineation of the deep digital flexor tendon, manica flexoria, and straight distal sesamoidean ligament visualised using both ultrasonography and MRI (P<0.05). Significant improvement in visualisation of the margins of the superficial digital flexor tendon was noted only with MRI (P<0.05). Saline distension did not alter the size/shape of the intra- and extrathecal structures. The findings of this study support further evaluation of this imaging technique in clinical cases with minimal DFTS effusion.

Perspectives on ParentWorks: Learnings from the development and national roll-out of a self-directed online parenting intervention.

Online parenting interventions are an increasingly viable alternative to face-to-face programs, as they can potentially overcome barriers to participation and increase program reach. The current paper describes learnings from the design, development and dissemination of ParentWorks, a self-directed online parenting intervention designed to be inclusive of both mothers and fathers. ParentWorks was promoted via a national media campaign and was accessible to all Australian parents through a dedicated website. Participants created a user account, engaged in a series of video modules, and completed assessment measures at pre-, post-program and 3-month follow-up. For two-caregiver families, parents were encouraged to participate together using a shared account. There was no direct practitioner support, although a range of innovative automated features were included to enhance participant motivation and encourage program completion. Several key lessons emerged from program development and implementation. These relate primarily to design and content of the program website, user account functionality, program structure and features, and data collection. Further research is needed particularly with regard to methods for increasing participant retention in self-directed online programs. The learnings described here will be relevant to those researching and developing online parenting interventions as well as other online mental health interventions aiming to reach a large population sample.

Keeping Parents Involved: Predicting Attrition in a Self-Directed, Online Program for Childhood Conduct Problems.

Positive parenting programs have a strong evidence base for improving parent-child relationships, strengthening families, and reducing childhood behavior disturbances. Their reach is less than optimal however, with only a minority of families in need of help participating. Father involvement is particularly low. Online, self-directed programs have the potential to improve participation rates. This article examines risk factors for dropout/attrition from a free, evidence-based, self-directed, father-inclusive parenting program, Parentworks, which was made available across Australia. Parents (N = 2,967) enrolled in the program and completed preintervention questionnaires. There was a steady and consistent loss of participants through the sequence of core program modules, until a final sample of 218 completed the postintervention questionnaire. A range of demographic and parent and child variables were tested as predictors of 3 subgroups: nonstarters, partial completers, and full completers. Nonstarters (n = 1,625) tended to have older children with fewer behavioral problems and report higher psychopathology and dysfunctional parenting than those who partially (n = 1,124) or fully completed. Contrary to findings from face-to-face research, single parents had the highest completion rates. Coparticipation of partners and interparental conflict had no impact on completion rates. Fathers participated at relatively high levels. Results show that parents with the greatest need tend to engage with online programs, and online programs may be particularly useful for fathers, single parents, and those in conflicted relationships. Directions for future program design and research are discussed.

Evaluation of 'The Father Effect' Media Campaign to Increase Awareness of, and Participation in, an Online Father-Inclusive Parenting Program.

There is substantial evidence that parenting programs are effective in improving parenting and child mental health outcomes. While there is increasing focus on delivering parenting interventions online to increase their reach and dissemination, fathers are underrepresented in all formats of parenting programs. However, research suggests that father participation is important for intervention effectiveness. This study evaluated the effectiveness of a media campaign for increasing awareness of, and participation in, an online father-inclusive parenting program called 'ParentWorks'. An 8-week campaign was conducted in Australia via social media channels, digital display advertising, digital television, and radio. To assess the impact of the campaign, data were obtained from caregivers registering for ParentWorks during the campaign period (n = 848) and an 8-week comparison period that occurred 3 months later (n = 254). Additionally, a nationally representative sample of 2021 caregivers of children aged 2-16 years completed an online survey. Survey questions asked about exposure to the campaign, registration for participation in ParentWorks, and knowledge of the importance of father participation in parenting programs. Three times as many caregivers registered during the 8-week media campaign compared to the comparison period, and a significantly greater proportion of male caregivers registered in the campaign versus the comparison period. The online survey found that 11% of caregivers reported exposure to the campaign, and significantly more fathers than mothers reported exposure. Results showed that those who were exposed to the campaign were significantly more likely to endorse the importance of father participation in parenting programs, than those not exposed to the campaign. The findings indicate that media campaigns appear to be an effective method of increasing awareness of online parenting programs and enhancing rates of father involvement.

Development and Psychometric Evaluation of the Father Engagement Questionnaire.

While there has been increasing interest in promoting father engagement in parenting interventions for child wellbeing, both research and practice endeavors have been hindered by a lack of a measure of father engagement practices. This paper reports the development and evaluation of a comprehensive, practitioner-report measure of father engagement practices--the Father Engagement Questionnaire (FEQ). Practitioners (N = 589; 84.5% females; mean age = 38.56) involved in delivering parenting interventions in Australia completed the FEQ, along with background demographics and questions regarding their own and organization's practice. A separate sample of 28 practitioners completed the FEQ twice, with a two-week interim, to assess test-retest stability of the measure. Exploratory factor analysis revealed five factors corresponding to the measure's five intended content areas: Confidence in Working with Fathers, Competence in Using Engagement Strategies, Perceived Effectiveness of Engagement Strategies, Frequency of Strategy Use, and Organizational Practices for Father Engagement. Each of these scales demonstrated adequate internal consistency reliability and test-retest stability. As the five scales appear to be related but distinct, it is recommended that the FEQ is used as a multidimensional measure of father engagement. In terms of predictive validity, higher scores on the Confidence in Working with Fathers, Frequency of Strategy Use, and Organizational Practices for Father Engagement scales were associated with a higher likelihood of practitioner-reported father attendance. The results provide support for adequate psychometric properties of the FEQ as a research and clinical tool for assessing and monitoring father engagement practices.