Corrigendum: Dangers of Clostridium perfringens food poisoning in psychiatric patients.

[This corrects the article DOI: 10.4102/sajpsychiatry.v25i0.1339.].

Dangers of Clostridium perfringens food poisoning in psychiatric patients.

Clostridium perfringens food poisoning can be fatal in patients with chronic constipation. We report the investigation and management of a probable outbreak of C. perfringens food poisoning among psychiatric patients in Cape Town, South Africa, in 2013.

Piloting a mental health training programme for community health workers in South Africa: an exploration of changes in knowledge, confidence and attitudes.

BACKGROUND: There is a shortage of trained mental health workers in spite of the significant contribution of psychiatric disorders to the global disease burden. Task shifting, through the delegation of health care tasks to less specialised health workers such as community health workers (CHWs), is a promising approach to address the human resource shortage. CHWs in the Western Cape province of South Africa provide comprehensive chronic support which includes that for mental illness, but have thus far not received standardized mental health training. It is unknown whether a structured mental health training programme would be acceptable and feasible, and result improved knowledge, confidence and attitudes amongst CHWs. METHODS: We developed and piloted a mental health training programme for CHWs, in line with the UNESCO guidelines; the WHO Mental Health Gap Action Programme and the South African National framework for CHW training. In our quasi-experimental (before-after) cohort intervention study we measured outcomes at the start and end of training included: 1) Mental health knowledge, measured through the use of case vignettes and the Mental Health Knowledge Schedule; 2) confidence, measured with the Mental Health Nurse Clinical Confidence Scale; and 3) attitudes, measured with the Community Attitudes towards the Mentally Ill Scale. Knowledge measures were repeated 3 months later. Acceptability data were obtained from daily evaluation questionnaires and a training evaluation questionnaire, while feasibility was measured by participant attendance at training sessions. RESULTS: Fifty-eight CHWs received the training, with most (n = 56, 97.0%) attending at least 7 of the 8 sessions. Most participants (n = 29, 63.04%) demonstrated significant improvement in knowledge, which was sustained at 3-months. There was significant improvement in confidence, along with changes in attitude, indicating improved benevolence, reduced social restrictiveness, and increased tolerance to rehabilitation of the mentally ill in the community but there was no change in authoritarian attitudes. The training was acceptable and feasible. CONCLUSIONS: Mental health training was successful in improving knowledge, confidence and attitudes amongst trained CHWs. The training was acceptable and feasible. Further controlled studies are required to evaluate the impact of such training on patient health outcomes. TRIAL REGISTRATION: PACTR PACTR201610001834198 , Registered 26 October 2016.

Translating Pharmacometrics to a Pharmacoeconomic Model of COPD.

BACKGROUND: A model-based meta-analysis (MBMA) is a type of meta-regression that uses nonlinear mixed-effects models estimated on trial-level data to relate patient and trial characteristics, dosing, biomarkers, and outcomes of treatment. OBJECTIVES: To use a pharmacometric MBMA within a pharmacoeconomic model of chronic obstructive pulmonary disease (COPD). METHODS: A Markov microsimulation model was developed to estimate monthly changes in the key disease severity metrics of COPD (forced expiratory volume in 1 second [FEV1] and exacerbations) to compare a hypothetical drug that increases FEV1 to usual care. The MBMA was used to predict a baseline exacerbation rate in a group of actual trial patients, given their known baseline FEV1. The hypothetical drug increased FEV1, thereby decreasing individuals' predicted exacerbation rates. Individual patient simulations allowed stochastic changes in monthly FEV1 decline. RESULTS: In a sample of 1097 trial patients with a mean FEV1 of 50%, the MBMA predicted 0.93 exacerbations per year on average. The exacerbation rate ranged from 0.52 to 1.3 per year across moderate and severe patient subgroups. A hypothetical anti-inflammatory drug that increased FEV1 by 50 ml decreased exacerbations by 26%. Given a simplified estimation of costs and quality-adjusted life-years (QALYs) associated with COPD, a drug with a 50-ml increase priced at €35/mo had an incremental cost-effectiveness ratio ranging from €13,000/QALY to approximately €207,000/QALY across patient severity subgroups. CONCLUSIONS: The synergistic aspects of MBMA and pharmacoeconomic modeling are highlighted in this hypothetical example. Markov microsimulation modeling allows the finer predictions of MBMA to inform parameters. Such an approach has utility in both early-phase cost-effectiveness estimations and trial design.

The effect of knee extensor open kinetic chain resistance training in the ACL-injured knee.

PURPOSE: To investigate the effect of different loads of knee extensor open kinetic chain resistance training on anterior knee laxity and function in the ACL-injured (ACLI) knee. METHODS: Fifty-eight ACLI subjects were randomised to one of three (12-week duration) training groups. The STAND group trained according to a standardised rehabilitation protocol. Subjects in the LOW and HIGH group trained as did the STAND group but with the addition of seated knee extensor open kinetic chain resistance training at loads of 2 sets of 20 repetition maximum (RM) and 20 sets of 2RM, respectively. Anterior knee laxity and measurements of physical and subjective function were performed at baseline, 6 and 12 weeks. Thirty-six subjects were tested at both baseline and 12 weeks (STAND n = 13, LOW n = 11, HIGH n = 12). RESULTS: The LOW group demonstrated a reduction in 133 N anterior knee laxity between baseline and 12 weeks testing when compared to the HIGH and the STAND groups (p = 0.009). Specifically, the trained-untrained knee laxity decreased an average of approximately 5 mm in the LOW group while remaining the same in the other two groups. CONCLUSION: Twelve weeks of knee extensor open kinetic chain resistance training at loads of 2 sets of 20RM led to a reduction in anterior knee laxity in the ACLI knee. This reduction in laxity does not appear to offer any significant short-term functional advantages when compared to a standard rehabilitation protocol. These results indicate that knee laxity can be decreased with resistance training of the thigh muscles. LEVEL OF EVIDENCE: Randomised controlled trial, Level II.

A Survey of the Practice of Electroconvulsive Therapy in South Africa.

OBJECTIVES: The aim of this study was to describe the contemporary practice of electroconvulsive therapy (ECT) in South Africa. METHODS: A 36-item questionnaire was sent to all hospitals that practiced ECT in a 12-month period between 2011 and 2012. RESULTS: Forty-two institutions had an ECT machine on site, but 13 institutions reported nonuse. Electroconvulsive therapy services were available in only 6 of the 9 provinces. Questionnaires were sent to the 29 active sites. Twenty-four units (82.8%) responded, and of these, 20 institutions (68.9%) responded to question on the number of patients treated with ECT. Pre-ECT procedures commonly involved informed consent, a physical examination, and basic blood investigations. Bilateral, unilateral, and bifrontal electrode placements were used, whereas dose titration methods and seizure monitoring were used by most respondents. The number of persons treated with ECT per 10,000 persons per year was 0.22, whereas the number of ECT procedures performed per 10,000 persons per year was 1.19. The most common indication for ECT was depression, with most patients being between the ages of 18 and 59 years. CONCLUSIONS: The characteristics and rate of ECT utilization in South Africa have been determined and generally emulated international guidelines and trends. However, accessibility to services and aspects such as training and accreditation could be improved.

Influence of weaning timing advice and associated weaning behaviours in a survey of black and minority ethnic groups in the UK.

OBJECTIVE: To assess understanding of the Department of Health weaning guidelines and weaning influences in a self-selected sample of black and minority ethnic (BME) parents, residing in London. DESIGN: A face-to-face, questionnaire-facilitated survey among Black African, Black Caribbean and South Asian parents. SETTING: An opportunistic sample of parents was recruited from Sure Start centres, churches and play groups across key London boroughs. SUBJECTS: Three hundred and forty-nine interviews were included; 107 Black African, fifty-four Black Caribbean, 120 South Asian and sixty-four of Black mixed-race ethnicity. RESULTS: Fifty-two per cent of Black and 66 % of South Asian parents had accurate understanding of the guidelines. Inaccurate knowledge of the guidelines was associated with weaning before 17 weeks (P < 0·001); 36 % of Black Africans and 31 % of Black Caribbeans were weaned before 4 months compared with 16 % of South Asians. All BME groups were most influenced by weaning information from the previous generations of mothers in their families, which was associated with earlier weaning (21·5 (SD 6·5) v. 24·1 (SD 4·2) weeks; F(2,328) = 5·79, P = 0·003), and less so by professional infant feeding advice, which was associated with a later weaning age (23·7 (SD 5·1) v. 20·7 (SD 5·7) weeks; F(1,344) = 34·7, P < 0·001). CONCLUSIONS: Lack of awareness of the Department of Health weaning guidelines is common among these BME populations, whose weaning behaviour is strongly influenced by informal advice. Further research is necessary to elucidate the influences on weaning in these populations and to facilitate the development of infant feeding support which is salient for BME groups in the UK.

PSP toxin levels and plankton community composition and abundance in size-fractionated vertical profiles during spring/summer blooms of the toxic dinoflagellate Alexandrium fundyense in the Gulf of Maine and on Georges Bank, 2007, 2008, and 2010: 2. Plankton community composition and abundance.

As part of the Gulf of Maine Toxicity (GOMTOX) project, we determined Alexandrium fundyense abundance, paralytic shellfish poisoning (PSP) toxin levels in various plankton size fractions, and the community composition of potential grazers of A. fundyense in plankton size fractions during blooms of this toxic dinoflagellate in the coastal Gulf of Maine and on Georges Bank in spring and summer of 2007, 2008, and 2010. PSP toxins and A. fundyense cells were found throughout the sampled water column (down to 50 m) in the 20-64 µm size fractions. While PSP toxins were widespread throughout all size classes of the zooplankton grazing community, the majority of the toxin was measured in the 20-64 µm size fraction. A. fundyense cellular toxin content estimated from field samples was significantly higher in the coastal Gulf of Maine than on Georges Bank. Most samples containing PSP toxins in the present study had diverse assemblages of grazers. However, some samples clearly suggested PSP toxin accumulation in several different grazer taxa including tintinnids, heterotrophic dinoflagellates of the genus Protoperidinium, barnacle nauplii, the harpacticoid copepod Microsetella norvegica, the calanoid copepods Calanus finmarchicus and Pseudocalanus spp., the marine cladoceran Evadne nordmanni, and hydroids of the genus Clytia. Thus, a diverse assemblage of zooplankton grazers accumulated PSP toxins through food-web interactions. This raises the question of whether PSP toxins pose a potential human health risk not only from nearshore bivalve shellfish, but also potentially from fish and other upper-level consumers in zooplankton-based pelagic food webs.

PSP toxin levels and plankton community composition and abundance in size-fractionated vertical profiles during spring/summer blooms of the toxic dinoflagellate Alexandrium fundyense in the Gulf of Maine and on Georges Bank, 2007, 2008, and 2010: 1. Toxin levels.

As part of the NOAA ECOHAB funded Gulf of Maine Toxicity (GOMTOX) project, we determined Alexandrium fundyense abundance, paralytic shellfish poisoning (PSP) toxin composition, and concentration in quantitatively-sampled size-fractionated (20-64, 64-100, 100-200, 200-500, and > 500 µm) particulate water samples, and the community composition of potential grazers of A. fundyense in these size fractions, at multiple depths (typically 1, 10, 20 m, and near-bottom) during 10 large-scale sampling cruises during the A. fundyense bloom season (May-August) in the coastal Gulf of Maine and on Georges Bank in 2007, 2008, and 2010. Our findings were as follows: (1) when all sampling stations and all depths were summed by year, the majority (94% ± 4%) of total PSP toxicity was contained in the 20-64 µm size fraction; (2) when further analyzed by depth, the 20-64 µm size fraction was the primary source of toxin for 97% of the stations and depths samples over three years; (3) overall PSP toxin profiles were fairly consistent during the three seasons of sampling with gonyautoxins (1, 2, 3, and 4) dominating (90.7% ± 5.5%), followed by the carbamate toxins saxitoxin (STX) and neosaxitoxin (NEO) (7.7% ± 4.5%), followed by n-sulfocarbamoyl toxins (C1 and 2, GTX5) (1.3% ± 0.6%), followed by all decarbamoyl toxins (dcSTX, dcNEO, dcGTX2&3) (< 1%), although differences were noted between PSP toxin compositions for nearshore coastal Gulf of Maine sampling stations compared to offshore Georges Bank sampling stations for 2 out of 3 years; (4) surface cell counts of A. fundyense were a fairly reliable predictor of the presence of toxins throughout the water column; and (5) nearshore surface cell counts of A. fundyense in the coastal Gulf of Maine were not a reliable predictor of A. fundyense populations offshore on Georges Bank for 2 out of the 3 years sampled.

The effect of thigh muscle activity on anterior knee laxity in the uninjured and anterior cruciate ligament-injured knee.

PURPOSE: The main purpose of this study was to describe the nature of the relationship between hamstring muscle activity and anterior knee laxity. METHODS: This was a cross-sectional study. Anterior knee laxity was measured at 133N and manual maximal forces using the KT2000 knee arthrometer, in 8 ACL-injured and 13 uninjured individuals. Electromyographic activity of the lateral hamstrings was measured during laxity testing. Subjects contracted the hamstrings during anterior knee laxity testing at eight predetermined levels of maximal voluntary isometric contraction. RESULTS: Volitional contraction of the lateral hamstrings reduced anterior knee laxity logarithmically for both the 133N and manual maximal tests in both the ACL-injured and uninjured knees. A simple linear regression model, with the log of percentage of maximum lateral hamstrings activity as the sole predictor, explained approximately 70-80% of the variation in anterior knee laxity. Both ACL-injured and uninjured subjects reduced anterior knee laxity at the same rate with increases in muscle activity. However, initial lateral hamstrings muscle activity had a greater effect on percentage anterior knee laxity scores in the ACL-injured as compared to the uninjured knee. CONCLUSIONS: Lateral hamstrings activity reduces anterior knee laxity in a nonlinear manner, whereby the initial lower level of activation produces the greatest change in anterior knee laxity. Therefore, hamstrings muscle activity must be monitored during anterior knee laxity testing.

An online survey of knowledge of the weaning guidelines, advice from health visitors and other factors that influence weaning timing in UK mothers.

The UK weaning guidelines recommend the introduction of solid food at or around 6 months. The evidence suggests that knowledge of the guidelines is high, although only a small minority of parents wait until 6 months to wean. The aim of this study was to assess understanding of the UK weaning guidelines in a sample of UK parents and investigate the associations of this understanding with weaning timing, and in comparison to other influencing factors. This study conducted an online survey of UK parents. Eligible participants had weaned a child since the introduction of the current guidelines. Of 3607 participants, 86% accurately understood the guidelines. Eighty-seven per cent of health visitors were reported to have advised weaning at or around 6 months. Knowledge of the guidelines was associated with later weaning (independently of demographic factors) (P < 0.001) but did not ensure compliance: 80% of mothers who weaned before 24 weeks and 65% who weaned before 17 weeks were aware of the guidelines. Younger mothers (P < 0.001), those receiving benefits (P < 0.001), those educated only to 16 (P < 0.001) and minority ethnic groups (P < 0.001) had lower levels of awareness. Poor understanding of the guidelines was the most reliable predictor of early weaning (P = 0.021) together with young maternal age (P = 0.014). Following the baby-led weaning approach was the most reliable predictor of those weaning at 26 weeks, together with the Internet being the most influential source of advice. Understanding of the current weaning guidelines is high and is a key independent predictor of weaning age in this population.

A mindful approach to physician self-care.

There has been an increasing awareness of the importance of physician mental health. Several South African studies show a high prevalence of burnout among doctors. Burnout is characterised by three components: exhaustion, depersonalisation, and a sense of a lack of efficacy. Burnout is a result of both external and internal pressures. While lifestyle modification is essential, mindfulness-informed programmes promote self-regulation and resilience. Mindfulness programmes comprise three components: present moment awareness, perspective-taking and wisdom, and compassion. Physician wellness begins with individuals recognising the need of self-care and giving themselves permission to prioritise this. Ongoing identification of self-care needs and acting compassionately to address these needs is essential.

Model-informed drug development of autologous CAR-T cell therapy: Strategies to optimize CAR-T cell exposure leveraging cell kinetic/dynamic modeling.

Autologous Chimeric antigen receptor (CAR-T) cell therapy has been highly successful in the treatment of aggressive hematological malignancies and is also being evaluated for the treatment of solid tumors as well as other therapeutic areas. A challenge, however, is that up to 60% of patients do not sustain a long-term response. Low CAR-T cell exposure has been suggested as an underlying factor for a poor prognosis. CAR-T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Importantly, "clear" dose-exposure relationships do not seem to exist for any of the currently approved CAR-T cell products. In other words, dose increases have not led to a commensurate increase in the measurable in vivo frequency of transferred CAR-T cells. Therefore, alternative approaches beyond dose titration are needed to optimize CAR-T cell exposure. In this paper, we provide examples of actionable variables - design elements in CAR-T cell discovery, development, and clinical practice, which can be modified to optimize autologous CAR-T cell exposure. Most of these actionable variables can be assessed throughout the various stages of discovery and development as part of a well-informed research and development program. Model-informed drug development approaches can enable such study and program design choices from discovery through to clinical practice and can be an important contributor to cell therapy effectiveness and efficiency.

Sources of weaning advice, comparisons between formal and informal advice, and associations with weaning timing in a survey of UK first-time mothers.

OBJECTIVE: The aim of the present study was to explore knowledge of the UK weaning guidelines and the sources of weaning advice used by UK first-time mothers. DESIGN: An online survey of UK parents; analysed using mixed methods. SETTING: Participants were recruited from a selection of parenting websites that hosted a link to the survey. SUBJECTS: In total, 1348 UK first-time mothers were included in the analysis. RESULTS: Knowledge of the guidelines was high (86 %) and associated with later weaning (P < 0·001), although 43 % of this sample weaned before 24 weeks. The majority of parents used multiple sources of information, the most influential being the health visitor (26 %), the Internet (25 %) and books (18 %). Fifty-six per cent said they received conflicting advice. Younger mothers and those of lower educational attainment were more likely to be influenced by advice from family, which was likely to be to wean earlier. Furthermore, those most influenced by their mother/grandmother were less likely to have accurate knowledge of the guidelines. In this population the Internet was used for weaning advice across all sociodemographic groups and was associated with a later weaning age, independently of sociodemographic factors (P < 0·001). Data from responses to a free-text question are used in illustration. CONCLUSIONS: The study suggests that first-time mothers have a good understanding of the weaning guidelines but seek weaning information from multiple sources, much of which is conflicting. Informal sources of weaning advice appear most influential in younger mothers and those of lower educational attainment, and result in earlier weaning.

PATHOGEN SURVEY AND PREDICTORS OF LYMPHOPROLIFERATIVE DISEASE VIRUS INFECTION IN WILD TURKEYS (MELEAGRIS GALLOPAVO).

Growing populations of Wild Turkeys (Meleagris gallopavo) may result in increased disease transmission among wildlife and spillover to poultry. Lymphoproliferative disease virus (LPDV) is an avian retrovirus that is widespread in Wild Turkeys of eastern North America, and infections may influence mortality and parasite co-infections. We aimed to identify individual and spatial risk factors of LPDV in Maine's Wild Turkeys. We also surveyed for co-infections between LPDV and reticuloendotheliosis virus (REV), Mycoplasma gallisepticum, and Salmonella pullorum to estimate trends in prevalence and examine covariance with LPDV. From 2017 to 2020, we sampled tissues from hunter-harvested (n=72) and live-captured (n=627) Wild Turkeys, in spring and winter, respectively, for molecular detection of LPDV and REV. In a subset of captured individuals (n=235), we estimated seroprevalence of the bacteria M. gallisepticum and S. pullorum using a plate agglutination test. Infection rates for LPDV and REV were 59% and 16% respectively, with a co-infection rate of 10%. Seroprevalence for M. gallisepticum and S. pullorum were 74% and 3.4%, with LPDV co-infection rates of 51% and 2.6%, respectively. Infection with LPDV and seroprevalence of M. gallisepticum and S. pullorum decreased, whereas REV infection increased, between 2018 and 2020. Females (64%), adults (72%), and individuals sampled in spring (76%) had higher risks of LPDV infection than males (47%), juveniles (39%), and individuals sampled in winter (57%). Furthermore, LPDV infection increased with percent forested cover (ß=0.014±0.007) and decreased with percent agriculture cover for juveniles (ß=-0.061±0.018) sampled in winter. These data enhance our understanding of individual and spatial predictors of LPDV infection in Wild Turkeys and aid in assessing the associated risk to Wild Turkey populations and poultry operations.

Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children.

The pharmacokinetics of voriconazole in children receiving 4 mg/kg intravenously (i.v.) demonstrate substantially lower plasma exposures (as defined by area under the concentration-time curve [AUC]) than those in adults receiving the same therapeutic dosage. These differences in pharmacokinetics between children and adults limit accurate prediction of pediatric voriconazole exposure based on adult dosages. We therefore studied the pharmacokinetics and tolerability of higher dosages of an i.v.-to-oral regimen of voriconazole in immunocompromised children aged 2 to <12 years in two dosage cohorts for the prevention of invasive fungal infections. The first cohort received 4 mg/kg i.v. every 12 h (q12h), then 6 mg/kg i.v. q12h, and then 4 mg/kg orally (p.o.) q12h; the second received 6 mg/kg i.v. q12h, then 8 mg/kg i.v. q12h, and then 6 mg/kg p.o. q12h. The mean values for the AUC over the dosing interval (AUCτ) for 4 mg/kg and 6 mg/kg i.v. in cohort 1 were 11,827 and 22,914 ng.h/ml, respectively, whereas the mean AUCτ values for 6 mg/kg and 8 mg/kg i.v. in cohort 2 were 17,249 and 29,776 ng.h/ml, respectively. High interpatient variability was observed. The bioavailability of the oral formulation in children was approximately 65%. The safety profiles were similar in the two cohorts and age groups. The most common treatment-related adverse event was increased gamma glutamyl transpeptidase levels. There was no correlation between adverse events and voriconazole exposure. In summary, voriconazole was tolerated to a similar degree regardless of dosage and age; the mean plasma AUCτ for 8 mg/kg i.v. in children approached that for 4 mg/kg i.v. in adults, thus representing a rationally selected dosage for the pediatric population.

Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies.

Voriconazole is a potent triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present population pharmacokinetic analysis evaluated voriconazole plasma concentration-time data from three studies of pediatric patients of 2 to <12 years of age, incorporating a range of single or multiple intravenous (i.v.) and/or oral (p.o.) doses. An appropriate pharmacokinetic model for this patient population was created using the nonlinear mixed-effect modeling approach. The final model described voriconazole elimination by a Michaelis-Menten process and distribution by a two-compartment model. It also incorporated a statistically significant (P < 0.001) influence of the CYP2C19 genotype and of the alanine aminotransferase level on clearance. The model was used in a number of deterministic simulations (based on various fixed, mg/kg of body weight, and individually adjusted doses) aimed at finding suitable i.v. and p.o. voriconazole dosing regimens for pediatric patients. As a result, 7 mg/kg twice a day (BID) i.v. or 200 mg BID p.o., irrespective of body weight, was recommended for this patient population. At these doses, the pediatric area-under-the-curve (AUC) distribution exhibited the least overall difference from the adult AUC distribution (at dose levels used in clinical practice). Loading doses or individual dosage adjustments according to baseline covariates are not considered necessary in administering voriconazole to children.

Assessing the efficiency of mixed effects modelling in quantifying metabolism based drug-drug interactions: using in vitro data as an aid to assess study power.

The clinical assessment of metabolic drug-drug interactions (mDDI) may involve population-based pharmacokinetic (POPPK) assessment as part of Phase 3 clinical trials. The elements of such POPPK study design have not been linked to prior information from in vitro experiments. Using in vitro-in vivo extrapolation techniques, implemented within Simcyp algorithms, the influence of POPPK study design (sample size, concentration-time data points, proportion of the population receiving a concomitant medication (COMED)) was studied in relation to the inhibitory potency of the each COMED. Steady-state concentrations of a candidate compound (compound X; mainly metabolized by cytochrome P450 enzymes, CYP3A4 and CYP2D6) in the presence and absence of COMEDs (including ketoconazole, fluconazole, quinidine and paroxetine as inhibitors) were analysed using non-linear mixed effect modelling (NONMEM). The NONMEM operator was blind to the nature of the COMEDs and the inhibitory effects on model parameters were classified as either statistically (p>0.01 for a change in objective function) or kinetically (COMED effect>2 fold) significant. Using a population study size of 2000, no false-positive cases were identified and, except in one case, no false-negative interaction was observed when >2.5% of patients had received an interacting COMED. The findings increase the confidence in the ability of the mixed effects modelling approach to identify 'true' interactions. However, they also emphasize the importance of study design and the potential value of using pre-clinical information from in vitro studies. Recent US Food and Drug Administration guidance on mDDI has put more emphasis on the use of in vitro systems for detecting and anticipating such effects. Combining these data with the framework of non-linear mixed effect modelling seems a natural progression in the field of assessing mDDI.

Community health worker-delivered counselling for common mental disorders among chronic disease patients in South Africa: a feasibility study.

OBJECTIVES: To examine the feasibility and acceptability of integrating a 'designated' approach to community health worker (CHW)-delivered mental health counselling (where existing CHWs deliver counselling in addition to usual duties) and a 'dedicated' approach (where additional CHWs have the sole responsibility of delivering mental health counselling) into chronic disease care. DESIGN: A feasibility test of a designated and dedicated approach to CHW-delivered counselling and qualitative interviews of CHWs delivering the counselling. SETTING: Four primary healthcare clinics in the Western Cape, South Africa allocated to either a designated or dedicated approach and stratified by urban/rural status. PARTICIPANTS: Forty chronic disease patients (20 with HIV, 20 with diabetes) reporting hazardous alcohol use or depression. Interviews with seven CHWs. INTERVENTION: Three sessions of structured mental health counselling. MAIN OUTCOME MEASURES: We assessed feasibility by examining the proportion of patients who were willing to be screened, met inclusion criteria, provided consent, completed counselling and were retained in the study. Acceptability of these delivery approaches was assessed through qualitative interviews of CHWs. RESULTS: Regardless of approach, a fair proportion (67%) of eligible patients were willing to receive mental health counselling. Patients who screened positive for depression were more likely to be interested in counselling than those with hazardous alcohol only. Retention in counselling (85%) and the study (90%) was good and did not differ by approach. Both dedicated and designated CHWs viewed the counselling package as highly acceptable but requested additional training and support to facilitate implementation. CONCLUSIONS: Dedicated and designated approaches to CHW-delivered mental health counselling were matched in terms of their feasibility and acceptability. A comparative efficacy trial of these approaches is justified, with some adjustments to the training and implementation protocols to provide further support to CHWs.

A non-parametric method to analyse time-course of effect in the absence of pharmacokinetic data: application to inhaled bronchodilators.

In spite of the extensive use of long-acting beta(2)-agonist (LABA) bronchodilators in asthma, the actual mechanism of their in vivo duration of action is not well understood, primarily due to limitations of standard pharmacokinetic-pharmacodynamic (PKPD) analysis methodologies. We have developed a novel method of analysing lung efficacy vs. time profiles for LABAs that can be used to provide comparative information on the lung PK. We hypothesised that for compounds that do not differ in their PK at the site of PD action, but differ in their in vivo potencies, the relationship between the area under the effect curve (AUEC) and the observed maximum effect (OME) at different doses is described by the same sigmoid curve. We have illustrated this property for standard PKPD models by obtaining analytical solution and through simulations. Anaesthetised dog in vivo effect vs. time profiles were gathered for six inhaled LABA candidates that differ in their in vitro potencies. Neither lung nor systemic PK was available for any compound. Analysis of the AUEC vs. OME data, derived from the efficacy profiles, using nonlinear mixed effects modelling indicated that for four compounds, the observed differences in in vivo duration of action was due to differences in their in vivo potencies and not because of lung PK differences. Therefore, it was concluded that for these compounds, characterisation of lung PK was unlikely to differentiate their PKPD characteristics. Thus, the proposed approach helped focus resources during translational research leading to lead candidate selection.