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.

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.

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

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

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.

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.

Patient preferences for the integration of mental health counseling and chronic disease care in South Africa.

PURPOSE: To describe patient perceptions of the acceptability of integrating mental health counseling within primary care facilities in the Western Cape province of South Africa and their preferences for the way in which this care is delivered. PATIENTS AND METHODS: Qualitative interviews with 30 purposively selected patients receiving treatment for HIV or diabetes within primary care facilities who screened positive for depression using the Center for Epidemiological Studies Depression Scale or hazardous alcohol use through the Alcohol Use Disorders Identification Test. RESULTS: Participants articulated high levels of unmet need for mental health services and strong associations between poor mental health and the challenges of living with a chronic disease. Consequently, they considered it acceptable to offer screening and mental health counseling within the context of chronic disease care. They thought counseling would be highly relevant if it helped patients develop adaptive strategies for coping with stress and negative emotions. Irrespective of chronic disease, patients indicated a preference for lay counselors rather than existing clinicians as potential delivery agents, supporting a task-shared approach to mental health counseling delivery in primary care settings. Some expressed concern about the feasibility of using lay counselors already present in facilities to deliver this service, suggesting that additional counselors might be needed. CONCLUSION: Findings demonstrate a need for mental health counseling within the context of chronic disease care in South Africa. Task-shared approaches, using lay counselors, seem acceptable to patients - provided counselors are selected to ensure they possess the qualities associated with effective counselors. Findings have informed the design of a task-shared mental health program that is responsive to the preferences of patients with chronic diseases.

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.

Comparing dedicated and designated models of integrating mental health into chronic disease care: study protocol for a cluster randomized controlled trial.

BACKGROUND: In low- and middle-income countries (LMIC), it is uncertain whether a "dedicated" approach to integrating mental health care (wherein a community health worker (CHW) has the sole responsibility of delivering mental health care) or a "designated" approach (wherein a CHW provides this service in addition to usual responsibilities) is most effective and cost-effective. This study aims to compare the effectiveness and cost-effectiveness of these two models of service integration relative to treatment as usual (TAU) for improving mental health and chronic disease outcomes among patients with HIV or diabetes. METHODS/DESIGN: This is a cluster randomised trial. We will randomise 24 primary health care facilities in the Western Cape Province of South Africa to one of three study arms. Within each cluster, we will recruit 25 patients from HIV and 25 from diabetes services for a total sample of 1200 participants. Eligible patients will be aged 18 years or older, take medication for HIV or diabetes, and screen positive on the Alcohol Use Disorder Identification Test for hazardous/harmful alcohol use or depression on the Centre for Epidemiology Scale on Depression. Participants recruited in clinics assigned to the designated or dedicated approach will receive three sessions of motivational interviewing and problem-solving therapy, while those recruited at TAU-assigned clinics will be referred for further assessment. Participants will complete an interviewer-administered questionnaire at baseline, and at 6 and 12 months post-enrolment to assess change in self-reported outcomes. At these end points, we will test HIV RNA viral load for participants with HIV and HbA1c levels for participants with diabetes. Primary outcomes are reductions in self-reported hazardous/harmful alcohol use and risk of depression. Secondary outcomes are improvements in adherence to chronic disease treatment, biomarkers of chronic disease outcomes, and health-related quality of life. Mixed-effect linear regression models will model the effect of the interventions on primary and secondary outcomes. The cost-effectiveness of each approach will be assessed using incremental cost-effectiveness ratios. DISCUSSION: Study findings will guide decision-making around how best to integrate mental health counselling into chronic disease care in a LMIC setting. TRIAL REGISTRATION: Pan African Clinical Trials Registry, Trial registration number: ACTR201610001825403 . Registered 17 October 2016.

Improving adherence in mental health service users with severe mental illness in South Africa: a pilot randomized controlled trial of a treatment partner and text message intervention vs. treatment as usual.

OBJECTIVES: Medication non-adherence is a significant problem in treatment of severe mental disorders and is associated with poor clinical outcomes and increased demand on services. Task-shifting interventions incorporating mobile health may improve adherence in mental health service users in low- and middle-income countries. Seventy-seven participants were recruited from a psychiatric hospital in Cape Town, with 42 randomized to receive the intervention and 35 to treatment as usual. Intervention pairs underwent treatment-partner contracting and psychoeducation, and received monthly text message reminders of clinic appointments. Primary outcomes were intervention acceptability and feasibility. Secondary outcome for efficacy were adherence to clinic visit; relapse; quality of life; symptomatic relief and medication adherence. RESULTS: Treatment partner and psychoeducation components were acceptable and feasible. The text message component was acceptable but not feasible in its current form. Efficacy outcomes favoured the intervention but did not reach statistical significance. A treatment-partner intervention is acceptable and feasible in a low- and middle-income setting. Work is needed to ensure that additional components of such interventions are tailored to the local context. Appropriately powered efficacy studies are needed. Trial Registration PACTR PACTR201610001830190, Registered 21 October 2016 (Retrospectively registered).

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.

Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline.

PURPOSE: To assess the link between early tumor shrinkage (ETS) and progression-free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data. METHODS: Tumor size data from 921 patients with first-line mRCC who received interferon-alpha, sunitinib, sorafenib or axitinib in two Phase III studies were modeled. The relationship between model-based estimates of ETS at week 8 as well as the baseline prognostic factors and PFS was tested in multivariate log-logistic models. Model performance was evaluated using simulations of PFS distributions and hazard ratio (HR) across treatments for the two studies. In addition, an external validation was conducted using data from an independent Phase II RCC study. The relationship between expected HR of an investigational treatment vs. sunitinib and the differences in ETS was simulated. RESULTS: A model with a nonlinear ETS-PFS link was qualified to predict PFS distribution by ETS quartiles as well as to predict HRs of sunitinib vs. interferon-alpha and axitinib vs. sorafenib. The model also performed well in simulations of an independent study of axitinib (external validation). The simulations suggested that if a new investigational treatment could further reduce the week 8 ETS by 30 % compared with sunitinib, an expected HR [95 % predictive interval] of the new treatment vs. sunitinib would be 0.59 [0.46, 0.79]. CONCLUSION: A model has been developed that uses early changes in tumor size to predict the HR for PFS differences between treatment arms for first-line mRCC. Such a model may have utility in predicting the outcome of ongoing studies (e.g., as part of interim futility analyses), supporting early decision making and future study design for investigational agents in development for this indication.

Caregiving for mental health service users: A study exploring the perceptions of mental health service users and their caregivers in Cape Town, South Africa.

BACKGROUND: Our study explores perceptions of the caregiver support for mental health service users (MHSUs) in a low- to middle-income country setting. MATERIALS: We conducted in-depth individual interviews with 16 MHSUs and their treatment partners/caregivers from a treatment partner and text-message intervention study. DISCUSSION: Treatment partners/caregivers felt obligated to care for MHSUs, but had a limited understanding of mental illness. They found supporting adherence to treatment difficult due to a number of factors including violence, food insecurity and substance abuse. CONCLUSION: Socioeconomic and environmental factors affecting the lives of MHSUs have impact on caregiver relationships with MHSUs in their care.

Modeling and simulations relating overall survival to tumor growth inhibition in renal cell carcinoma patients.

PURPOSE: To assess the link between tumor growth inhibition (TGI) and overall survival (OS) based on historical renal cell carcinoma (RCC) data. To illustrate how simulations can help to identify TGI thresholds based on target OS benefit [i.e., hazard ratio (HR) compared with standard of care] to support new drug development in RCC. METHODS: Tumor size (TS) data were modeled from 2552 patients with first-line or refractory RCC who received temsirolimus, interferon, sunitinib, sorafenib or axitinib in 10 Phase II or Phase III studies. Three model-based TGI metrics estimates [early tumor shrinkage (ETS) at week 8, 10 or 12, time to tumor growth (TTG) and growth rate] as well as baseline prognostic factors were tested in multivariate lognormal models of OS. Model performance was evaluated by posterior predictive check of the OS distributions and hazard ratio across treatments. RESULTS: TTG was the best TGI metric to predict OS. However, week 8 ETS had a satisfactory performance and was employed in order to maximize clinical utilization. The week 8 ETS to OS model was then used to simulate clinically relevant ETS thresholds for future Phase II studies with investigational treatments. CONCLUSIONS: The published OS model and resultant simulations can be leveraged to support Phase II design and predict expected OS and HR (based on early observed TGI data obtained in Phase II or Phase III studies), thereby informing important mRCC development decisions, e.g., Go/No Go and dose regimen selection.

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.

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.

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.

A novel method for classifying starch digestion by modelling the amylolysis of plant foods using first-order enzyme kinetic principles.

Studying starch amylolysis kinetics in vitro is valuable for predicting the postprandial glycaemic response to starch intake. Prediction of starch amylolysis behaviour is challenging however, because of the many physico-chemical factors which influence amylolysis. The Logarithm of Slope (LOS) method for analysis of digestibility curves using first-order enzyme kinetics can identify and quantify nutritionally important starch fractions. The early stages of in vitro amylolysis of hydrothermally processed chickpea and durum wheat with variable degrees of structural integrity were studied. The end-point product concentration (C∞) and the pseudo first-order digestibility rate constant k, obtained from LOS analysis, were then used to compute predictive digestibility curves for evaluation of the model performance. LOS analysis enabled rapid identification of nutritionally important starch-fractions. It was clear that purified starches and flours were digested by a single-phase process, but starch amylolysis in macroparticles occurred by a two-phase system that reflected differences in substrate accessibility. The model gave an excellent fit to data obtained from a range of heterogeneous materials. It provides a rigorous means of studying the mechanisms of starch amylolysis in samples of varying complexity, and we strongly recommend its use for the rapid and accurate predictions of amylolysis. Such predictions have implications for prevention and management of type 2 diabetes mellitus and obesity.