Altered stimulus representation in rat auditory cortex is not causal for loss of consciousness under general anaesthesia.

BACKGROUND: Current concepts suggest that impaired representation of information in cortical networks contributes to loss of consciousness under anaesthesia. We tested this idea in rat auditory cortex using information theory analysis of multiunit responses recorded under three anaesthetic agents with different molecular targets: isoflurane, propofol, and dexmedetomidine. We reasoned that if changes in the representation of sensory stimuli are causal for loss of consciousness, they should occur regardless of the specific anaesthetic agent. METHODS: Spiking responses were recorded with chronically implanted microwire arrays in response to acoustic stimuli incorporating varied temporal and spectral dynamics. Experiments consisted of four drug conditions: awake (pre-drug), sedation (i.e. intact righting reflex), loss of consciousness (a dose just sufficient to cause loss of righting reflex), and recovery. Measures of firing rate, spike timing, and mutual information were analysed as a function of drug condition. RESULTS: All three drugs decreased spontaneous and evoked spiking activity and modulated spike timing. However, changes in mutual information were inconsistent with altered stimulus representation being causal for loss of consciousness. First, direction of change in mutual information was agent-specific, increasing under dexmedetomidine and decreasing under isoflurane and propofol. Second, mutual information did not decrease at the transition between sedation and LOC for any agent. Changes in mutual information under anaesthesia correlated strongly with changes in precision and reliability of spike timing, consistent with the importance of temporal stimulus features in driving auditory cortical activity. CONCLUSIONS: The primary sensory cortex is not the locus for changes in representation of information causal for loss of consciousness under anaesthesia.

Depression, marijuana use and early-onset marijuana use conferred unique effects on neural connectivity and cognition.

OBJECTIVE: Marijuana (MJ) use is common. Research shows risks for psychiatric illnesses, including major depressive disorder (MDD) and cognitive deficits with MJ use, particularly early-onset use. We investigated cognitive function, functional connectivity, and genetic risk with MDD alone and combined with MJ use, and differences between early-vs. late-onset/non-MJ use in youth. METHOD: A total of 74 youth in four groups were studied: healthy control, MDD, frequent MJ use and current/past MDD plus frequent MJ use. Psychiatric symptoms, cognitive performance and demographics were measured. Default mode network (DMN) brain connectivity was determined. Risk alleles in six genes of interest were evaluated. RESULTS: DMN differences among groups in reward-processing and motor control regions were found; the effects of MJ use and MDD were distinct. Early-onset MJ use was associated with lower IQ and hyperconnectivity within areas of the DMN. Early-onset MJ use was associated with the BDNF risk allele. CONCLUSIONS: Cognitive deficits linked with early-onset MJ use were present within several years after MJ use began and may result from, predispose to, or share a common cause with early-onset MJ use. The DMN was affected by MDD, MJ and their combination, as well as by early-onset MJ use. BDNF carrier state may predispose to early-onset MJ use.

Novel insights into maladaptive behaviours in Prader-Willi syndrome: serendipitous findings from an open trial of vagus nerve stimulation.

BACKGROUND: We report striking and unanticipated improvements in maladaptive behaviours in Prader-Willi syndrome (PWS) during a trial of vagus nerve stimulation (VNS) initially designed to investigate effects on the overeating behaviour. PWS is a genetically determined neurodevelopmental disorder associated with mild-moderate intellectual disability (ID) and social and behavioural difficulties, alongside a characteristic and severe hyperphagia. METHODS: Three individuals with PWS underwent surgery to implant the VNS device. VNS was switched on 3 months post-implantation, with an initial 0.25 mA output current incrementally increased to a maximum of 1.5 mA as tolerated by each individual. Participants were followed up monthly. RESULTS: Vagal nerve stimulation in these individuals with PWS, within the stimulation parameters used here, was safe and acceptable. However, changes in eating behaviour were equivocal. Intriguingly, unanticipated, although consistent, beneficial effects were reported by two participants and their carers in maladaptive behaviour, temperament and social functioning. These improvements and associated effects on food-seeking behaviour, but not weight, indicate that VNS may have potential as a novel treatment for such behaviours. CONCLUSIONS: We propose that these changes are mediated through afferent and efferent vagal projections and their effects on specific neural networks and functioning of the autonomic nervous system and provide new insights into the mechanisms that underpin what are serious and common problems affecting people with IDs more generally.

Cognitive control, reward-related decision making and outcomes of late-life depression treated with an antidepressant.

BACKGROUND: Executive processes consist of at least two sets of functions: one concerned with cognitive control and the other with reward-related decision making. Abnormal performance in both sets occurs in late-life depression. This study tested the hypothesis that only abnormal performance in cognitive control tasks predicts poor outcomes of late-life depression treated with escitalopram. METHOD: We studied older subjects with major depression (N = 53) and non-depressed subjects (N = 30). Executive functions were tested with the Iowa Gambling Test (IGT), Stroop Color-Word Test, Tower of London (ToL), and Dementia Rating Scale - Initiation/Perseveration domain (DRS-IP). After a 2-week placebo washout, depressed subjects received escitalopram (target daily dose: 20 mg) for 12 weeks. RESULTS: There were no significant differences between depressed and non-depressed subjects on executive function tests. Hierarchical cluster analysis of depressed subjects identified a Cognitive Control cluster (abnormal Stroop, ToL, DRS-IP), a Reward-Related cluster (IGT), and an Executively Unimpaired cluster. Decline in depression was greater in the Executively Unimpaired (t = -2.09, df = 331, p = 0.0375) and the Reward-Related (t = -2.33, df = 331, p = 0.0202) clusters than the Cognitive Control cluster. The Executively Unimpaired cluster (t = 2.17, df = 331, p = 0.03) and the Reward-Related cluster (t = 2.03, df = 331, p = 0.0433) had a higher probability of remission than the Cognitive Control cluster. CONCLUSIONS: Dysfunction of cognitive control functions, but not reward-related decision making, may influence the decline of symptoms and the probability of remission of late-life depression treated with escitalopram. If replicated, simple to administer cognitive control tests may be used to select depressed older patients at risk for poor outcomes to selective serotonin reuptake inhibitors who may require structured psychotherapy.

Myofascial trigger point (MTrP) size and elasticity properties can be used to differentiate characteristics of MTrPs in lower back skeletal muscle.

Myofascial trigger points (MTrPs) are localized contraction knots that develop after muscle overuse or an acute trauma. Significant work has been done to understand, diagnose, and treat MTrPs in order to improve patients suffering from their effects. However, effective non-invasive diagnostic tools are still a missing gap in both understanding and treating MTrPs. Effective treatments for patients suffering from MTrP mediated pain require a means to measure MTrP properties quantitatively and diagnostically both prior to and during intervention. Further, quantitative measurements of MTrPs are often limited by the availability of equipment and training. Here we develop ultrasound (US) based diagnostic metrics that can be used to distinguish the biophysical properties of MTrPs, and show how those metrics can be used by clinicians during patient diagnosis and treatment. We highlight the advantages and limitations of previous US-based approaches that utilize elasticity theory. To overcome these previous limitations, we use a hierarchical approach to distinguish MTrP properties by patients' reported pain and clinician measured palpation. We show how US-based measurements can characterize MTrPs with this approach. We demonstrate that MTrPs tend to be smaller, stiffer, and deeper in the muscle tissue for patients with pain compared to patients without pain. We provide evidence that more than one MTrP within a single US-image field increases the stiffness of neighboring MTrPs. Finally, we highlight a combination of metrics (depth, thickness, and stiffness) that can be used by clinicians to evaluate individual MTrPs in combination with standard clinical assessments.

Clinical course, management and outcomes of COVID-19 in HIV-infected renal transplant recipients: A case series.

BACKGROUND: HIV-infected kidney transplant recipients with COVID-19 are at increased risk of acute illness and death owing to their underlying comorbidities and chronic immunosuppression. OBJECTIVES: To describe the incidence, clinical presentation and course of COVID-19, vaccination status, and SARS-CoV-2 antibody positivity rate among HIV-infected-to-HIV-infected kidney transplant recipients in South Africa (SA). METHODS: This retrospective study reports on rates of SARS-CoV-2 infection, COVID-19 and mortality among SA HIV-infected kidney transplant recipients who received organs from HIV-infected donors (HIV positive to HIV positive), before and after vaccination. Patient demographics, clinical presentation, course, management and disease outcomes were analysed. Antibody serology tests were performed between May and September 2022. RESULTS: Among 39 HIV-positive-to-HIV-positive transplant recipients, 11 cases of COVID-19 were diagnosed from March 2020 to September 2022. Six patients (55%) required hospitalisation, of whom 3 were admitted to a high-care unit or intensive care unit. Two patients required mechanical ventilation, and 2 received acute dialysis. One patient was declined access to intensive care. Four patients (10%) died of COVID-19 pneumonia. All the COVID-19-positive patients had at least one comorbidity. Vaccination data were available for 24 patients, of whom 5 had refused SARS-CoV-2 vaccination. SARS-CoV-2 antibody data were available for 20 patients; 4 vaccinated patients had a negative nucleocapsid protein antibody test and a positive spike protein antibody test, suggesting vaccination-acquired immunity. The remaining 16 patients demonstrated immunity that was probably due to COVID infection, and of these, 14 were also vaccinated. Of the 11 COVID-19 cases, only 1 was observed after vaccination. CONCLUSION: In our case series, ~10% of the HIV-positive-to-HIV-positive transplant recipients died of COVID-19 pneumonia. This mortality rate appears higher than figures reported in other transplant cohorts. However, it is likely that the actual number of cases of SARS-CoV-2 infection was much higher, as the study only included polymerase chain reaction-confirmed cases. It remains unclear whether HIV infection, transplant or the combination of the two drives poorer outcomes, and larger studies adjusting for important demographic and biological factors may isolate these effects.

The state of paediatric deceased-organ donation at a South African tertiary public- sector hospital: A 14-year analysis.

BACKGROUND: Solid-organ transplantation (SOT) has been proven to be a highly effective and life-saving treatment modality for adults and children suffering from end-stage organ failure. However, high paediatric waiting-list mortality has been reported, and children may suffer irreversible physical and deleterious psychological effects if not transplanted timeously. OBJECTIVES: To identify in-hospital barriers to organ donation and gain a better understanding of the paediatric donor landscape. METHODS: A retrospective descriptive study of consecutive deceased-donor referrals at Red Cross War Memorial Children's Hospital over a 14-year period, from 1 January 2007 to 31 December 2020. RESULTS: During the study period, 156 in-hospital deaths were recorded in the trauma unit and 1 425 in the paediatric intensive care unit. Ninety-three of the 1 581 patients (5.9%) were referred to the on-call transplant co-ordinator as potential organ donors, of whom 69% had been involved in a traumatic accident, including 52% in road traffic collisions. The mean age of the potential donors was 7 years with 60.2% being boys. On initial assessment, 67 of the 93 potential donors (72%) were assessed as eligible for donation of at least one solid organ. The transplant co-ordinator attempted to approach all families for consent; however, five families/next of kin could not be located despite multiple attempts. Among the remaining 62 eligible donors, 44 families/next-of-kin declined consent for solid-organ donation, resulting in a consent rate of 29% (n=18). Several families refused consent for religious reasons. One of the consented donors did not proceed to procurement as there were no suitable recipients. Seventeen donors proceeded to theatre, the intention being solid-organ procurement, but in 2 donors the organs were assessed as being unsuitable for transplant. From the remaining 15 donors, a total of 46 organs were procured and successfully transplanted: 14 livers, 30 kidneys and 2 hearts. CONCLUSION: During the 14-year study period, only 15 deceased donors could be utilised for SOT, as a result of low in-hospital referral (5.9%) and consent rates (29%). The reasons for low referral and consent rates are complex and often multifactorial, which the current study was not designed to investigate in sufficient detail. Future studies should be designed to further interrogate our findings, while accommodating for nuances specific to the paediatric deceased-donor population and their families.

Kidney transplant utilising donors after circulatory death: The first report from the African continent.

BACKGROUND: At Groote Schuur Hospital in Cape Town, South Africa, the number of deceased organ donors has declined over the past 2 decades, necessitating a more liberal approach to donor selection. In 2007, measures to expand the deceased kidney donor pool were implemented, including an HIV positive-to-positive transplant programme and the utilisation of extended-criteria donors as well as donors after circulatory death (DCDs). OBJECTIVES: To report on our institutional experience with DCD kidney transplants and to encourage this approach among other African centres to improve access to transplantation. METHODS: An observational cohort study of consecutive DCD kidney transplants at Groote Schuur Hospital over a 17-year period was performed. Primary endpoints were 1-, 2- and 5-year graft and patient survival. Secondary endpoints included the incidence of delayed graft function (DGF), 30-day morbidity, length of stay, and donor and recipient clinical characteristics. RESULTS: Fifteen DCD procurements were performed, with no kidneys discarded. Thirty kidney transplants were performed, with a median (interquartile range) cold ischaemic time of 11.5 (8 - 14) hours. The incidence of DGF was 60.0%, and 30-day morbidity (other than DGF) was 20.0%. Graft survival at 1, 2 and 5 years was 100%, 96.0% and 73.7%, respectively. Patient survival at 1, 2 and 5 years was 93.3%, 93.3% and 88.4%, respectively. CONCLUSION: Long-term graft and patient survival was comparable with the international literature. DCD may present a unique opportunity to expand deceased donation throughout Africa, particularly in areas affected by a lack of brain death legislation and religious or cultural objections to donation after brain death.

The state of kidney replacement therapy in Eastern Cape Province, South Africa: A call to action.

BACKGROUND: South Africa (SA) is one of the most financially unequal countries in the world. This situation is highlighted by disparate access to healthcare, particularly provision of kidney replacement therapy (KRT). Unlike the private sector, public sector access to KRT is highly rationed, and patient selection is based on suitability for transplantation and capacity. OBJECTIVES: To investigate the state of the KRT service in Eastern Cape Province, SA, by analysing access to and provision of KRT in the province for individuals with end-stage kidney disease, as well as disparities between the private and public healthcare systems. METHODS: This was a retrospective descriptive study to examine KRT provision and temporal trends in the Eastern Cape. Data were obtained from the South African Renal Registry and the National Transplant Waiting List. KRT provision was compared between the three main referral centres, in Gqeberha (formerly Port Elizabeth), East London and Mthatha, and between the private and public healthcare systems. RESULTS: There were 978 patients receiving KRT in the Eastern Cape, with an overall treatment rate of 146 per million population (pmp). The treatment rate for the private sector was 1 435 pmp, compared with 49 pmp in the public sector. Patients treated in the private sector were older at initiation of KRT (52 v. 34 years), and more likely to be male, to be HIV positive, and to receive haemodialysis as their KRT modality. Peritoneal dialysis was more commonly used in Gqeberha and East London as the first and subsequent KRT modality, compared with Mthatha. There were no patients from Mthatha on the transplant waiting list. There were no waitlisted HIV-positive patients in the public sector in East London, compared with 16% of the public sector patients in Gqeberha. The kidney transplant prevalence rate was 58 pmp in the private sector and 19 pmp in the public sector, with a combined prevalence of 22 pmp, constituting 14.9% of all patients on KRT. We estimated the shortfall of KRT provision in the public sector to be ~8 606 patients. CONCLUSION: Patients in the private sector were 29 times more likely to access KRT than their public sector counterparts, who were on average 18 years younger at initiation of KRT, probably reflecting selection bias in an overburdened public health system. Transplantation rates were low in both sectors, and lowest in Mthatha. A large public sector KRT provision gap exists in the Eastern Cape and needs to be addressed urgently.

Examining the barriers faced by female surgical trainees: a qualitative study.

INTRODUCTION: Today, women make up 56% of medical students, yet just 13% of surgical consultants - a number that has remained static since 2013. This qualitative study explored some of the barriers to female success in modern surgery. METHODS: Semistructured qualitative interviews were undertaken primarily with female surgical trainees to determine the barriers they face. Male trainees and training programme directors (TPDs) were also interviewed for triangulation. RESULTS: 20 interviews were performed (16 female trainees, 3 male trainees, and 1 TPD) between October 2019 and March 2020. Family pressures and becoming a mother were significant barriers for women training in surgery - a barrier that did not apply to male trainees who were fathers, often resulting in women choosing to train less than full time (LTFT). Unfortunately LTFT training presents further obstacles for female trainees. The set-up of the national training programme in surgery provides many non-gender-specific barriers, chiefly moving hospital every 6 months causing disrupted training and long commutes, disproportionately affecting females with child care responsibilities. Sexism and discrimination are still common, both from colleagues and patients. Many participants perceived inherent differences between genders in communication and methods for coping with stress. CONCLUSION: Greater gender equality in surgery may be achieved by changes in the structure and organisation of training to reduce the tension between the professional role and the predominantly female-led role of raising children. Better equality and diversity training and awareness at all levels in surgery may help to mitigate some of the conscious and unconscious bias that still exists.

Near valve flows and potential blood damage during closure of a bileaflet mechanical heart valve.

Blood damage and thrombosis are major complications that are commonly seen in patients with implanted mechanical heart valves. For this in vitro study, we isolated the closing phase of a bileaflet mechanical heart valve to study near valve fluid velocities and stresses. By manipulating the valve housing, we gained optical access to a previously inaccessible region of the flow. Laser Doppler velocimetry and particle image velocimetry were used to characterize the flow regime and help to identify the key design characteristics responsible for high shear and rotational flow. Impact of the closing mechanical leaflet with its rigid housing produced the highest fluid stresses observed during the cardiac cycle. Mean velocities as high as 2.4 m/s were observed at the initial valve impact. The velocities measured at the leaflet tip resulted in sustained shear rates in the range of 1500-3500 s(-1), with peak values on the order of 11,000-23,000 s(-1). Using velocity maps, we identified regurgitation zones near the valve tip and through the central orifice of the valve. Entrained flow from the transvalvular jets and flow shed off the leaflet tip during closure combined to generate a dominant vortex posterior to both leaflets after each valve closing cycle. The strength of the peripheral vortex peaked within 2 ms of the initial impact of the leaflet with the housing and rapidly dissipated thereafter, whereas the vortex near the central orifice continued to grow during the rebound phase of the valve. Rebound of the leaflets played a secondary role in sustaining closure-induced vortices.

One-year mortality after hospital admission as an indicator of palliative care need: A retrospective cohort study.

BACKGROUND: Globally there is increasing awareness of the need for end-of-life care and palliative care in hospitalised patients who are in their final year of life. Limited data are available on palliative care requirements in low- and middle-income countries, hindering the design and implementation of effective policies and health services for these patients. OBJECTIVES: To determine the proportion of patients who die within 1 year of their date of admission to public hospitals in South Africa (SA), as a proxy for palliative care need in SA. METHODS: This was a retrospective cohort study using record linkage of admission and mortality data. The setting was 46 acute-care public hospitals in Western Cape Province, SA. RESULTS: Of 10 761 patients (median (interquartile range (IQR)) age 44 (31 - 60) years) admitted to the 46 hospitals over a 2-week period in March 2012, 1 570 (14.6%) died within 1 year, the majority within the first 3 months. Mortality rose steeply with age. The median (IQR) age of death was 57.5 (45 - 70) years. A greater proportion of patients admitted to medical beds died within 1 year (21.3%) compared with those admitted to surgical beds (7.7%). CONCLUSIONS: Despite a median age <60 years at admission, a substantial percentage of patients admitted to public sector hospitals in SA are in the final year of their lives. This finding should be seen in the context of SA's high communicable and non-communicable disease burden and resource-limited public health system, and highlights the need for policy development, planning and implementation of end-of-life and palliative care strategies for hospitals and patients.

Low mortality of people living with diabetes mellitus diagnosed with COVID-19 and managed at a field hospital in Western Cape Province, South Africa.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) was declared an international pandemic by the World Health Organization in March 2020. Throughout the pandemic, the association between diabetes mellitus (DM) and more severe COVID-19 has been well described internationally, with limited data, however, on South Africa (SA). The role of field hospitals in the management of patients with COVID-19 in SA has not yet been described. OBJECTIVES: To describe the mortality and morbidity of people living with DM (PLWD) and comorbid COVID-19, as well as to shed light on the role of intermediate facilities in managing DM and COVID-19 during the pandemic. METHODS: This is a single-centre cross-sectional descriptive study that included all patients with confirmed COVID-19 and pre-existing or newly diagnosed DM (of any type) admitted to the Cape Town International Convention Centre (CTICC) Intermediate Care Bed Facility from June 2020 to August 2020. This study presents the profile of patients admitted to the CTICC, and reports on the clinical outcome of PLWD diagnosed with COVID-19, and additionally determines some associations between risk factors and death or escalation of care in this setting. RESULTS: There were 1 447 admissions at the CTICC, with a total of 674 (46.6%) patients who had confirmed DM, of whom 125 (19%) were newly diagnosed diabetics and 550 (81%) had pre-existing DM. Included in this group were 57 referrals from the telemedicine platform - a platform that identified high-risk diabetic patients with COVID-19 in the community, and linked them directly to hospital inpatient care. Of the 674 PLWD admitted, 593 were discharged alive, 45 were escalated to tertiary hospital requiring advanced care and 36 died. PLWD who died were older, had more comorbidities (specifically chronic obstructive pulmonary disease, congestive cardiac failure and chronic kidney disease) and were more likely to be on insulin. CONCLUSIONS: In a resource-limited environment, interdisciplinary and interfacility collaboration ensured that complicated patients with DM and COVID-19 were successfully managed in a field hospital setting. Telemedicine offered a unique opportunity to identify high-risk patients in the community and link them to in-hospital monitoring and care. Future studies should explore ways to optimise this collaboration, as well as to explore possibilities for early identification and management of high-risk patients.

Delirium in HIV-infected patients admitted to acute medical wards post universal access to antiretrovirals in South Africa.

BACKGROUND: Delirium is associated with increased mortality and length of hospital stay. Limited data are available from HIV-infected acute hospital admissions in developing countries. We conducted a prospective study of delirium among acute medical admissions in South Africa (SA), a developing country with universal antiretroviral therapy (ART) access and high burdens of tuberculosis (TB) and non-communicable disease. OBJECTIVES: To identify the prevalence of, risk factors for and outcomes of delirium in HIV-infected individuals in acute general medical admissions. METHODS: Three cohorts of adult acute medical admissions to Groote Schuur and Victoria Wynberg hospitals, Cape Town, SA, were evaluated for prevalent delirium within 24 hours of admission. Reference delirium testing was performed by either consultant physicians or neuropsychologists, using the Confusion Assessment Method. RESULTS: The study included 1 182 acute medical admissions, with 318 (26.9%) HIV-infected. The median (interquartile range) age and CD4 count were 35 (30 - 43) years and 132 (61 - 256) cells/µL, respectively, with 140/318 (44.0%) using ART on admission. The prevalence of delirium was 17.6% (95% confidence interval (CI) 13.7 - 22.1) among HIV-infected patients, and delirium was associated with increased inpatient mortality. In multivariable logistic regression analysis, factors associated with delirium were age ≥55 years (adjusted odds ratio (aOR) 6.95 (95% CI 2.03 - 23.67); p=0.002), and urea ≥15 mmol/L (aOR 4.83 (95% CI 1.7 - 13.44); p=0.003), while ART use reduced risk (p=0.014). A low CD4 count, an unsuppressed viral load and active TB were not predictors of delirium; nor were other previously reported risk factors such as non-opportunistic acute infections or polypharmacy. CONCLUSIONS: Delirium is common and is associated with increased mortality in HIV-infected acute medical admissions in endemic settings, despite increased ART use. Older HIV-infected patients with renal dysfunction are at increased risk for inpatient delirium, while those using ART on admission have a reduced risk.

In Vitro Clot Trapping Efficiency of the FDA Generic Inferior Vena Cava Filter in an Anatomical Model: An Experimental Fluid-Structure Interaction Benchmark.

PURPOSE: Robust experimental data for performing validation of fluid-structure interaction (FSI) simulations of the transport of deformable solid bodies in internal flow are currently lacking. This in vitro experimental study characterizes the clot trapping efficiency of a new generic conical-type inferior vena cava (IVC) filter in a rigid anatomical model of the IVC with carefully characterized test conditions, fluid rheological properties, and clot mechanical properties. METHODS: Various sizes of spherical and cylindrical clots made of synthetic materials (nylon and polyacrylamide gel) and bovine blood are serially injected into the anatomical IVC model under worst-case exercise flow conditions. Clot trapping efficiencies and their uncertainties are then quantified for each combination of clot shape, size, and material. RESULTS: Experiments reveal the clot trapping efficiency increases with increasing clot diameter and length, with trapping efficiencies ranging from as low as approximately 42% for small 3.2 mm diameter spherical clots up to 100% for larger clot sizes. Because of the asymmetry of the anatomical IVC model, the data also reveal the iliac vein of clot origin influences the clot trapping efficiency, with the trapping efficiency for clots injected into the left iliac vein up to a factor of 7.5 times greater than that for clots injected into the right iliac (trapping efficiencies of approximately 10% versus 75%, respectively). CONCLUSION: Overall, this data set provides a benchmark for validating simulations predicting IVC filter clot trapping efficiency and, more generally, low-Reynolds number FSI modeling.

A 10-year analysis of organ donor referrals to a South African tertiary public sector hospital.

BACKGROUND: South Africa (SA) has one of the lowest deceased organ donor rates in the world (1.4 donors per million population), with thousands of patients awaiting solid-organ transplantation. In order to improve access to transplantation we have to clearly define the reasons for the low deceased donation rate, specific to the population we serve. OBJECTIVES: Review of actual donor statistics highlights our successes, yet is not able to contextualise the factors responsible for the unsuccessful conversion of referred organ donors to actual organ donors. In an attempt to identify key factors preventing referred donors from becoming actual donors, we analysed the donor referral patterns at our institution over a 10-year period. METHODS: This was a retrospective descriptive study of consecutive deceased donor referrals at Groote Schuur Hospital, Cape Town, SA (from January 2007 to December 2016), utilising a regional donor referral registry. Qualitative and quantitative data were collected and presented as descriptive statistics and temporal trends. RESULTS: Over the 10-year study period, 861 possible organ donors were referred, with a steady increase in the number of referrals over time. Of the referrals, 514 (59.7%) were eligible for donation of at least one solid organ. Of the 508 families that were approached for consent to donation, 342 declined consent for a variety of reasons, resulting in a consent rate of 32.7%. Ultimately, at least one solid organ was obtained from 159 of the 166 consented donors. Despite the increasing number of possible and eligible donors, a statistically significant decline in consent rate was observed over time (ptrend=0.023). Furthermore, increasing trends in medical (as opposed to trauma) (ptrend<0.001) and extended criteria (as opposed to standard criteria) donor referrals (ptrend<0.001) were observed over the 10-year study period. CONCLUSIONS: Donor referral patterns have changed over time, with a notable increase in medical and extended criteria donors. Despite the increase in possible and eligible donors, the consent rate has declined. Further qualitative and quantitative research studies are required to understand and address this trend.

CYP3A5 polymorphisms and their effects on tacrolimus exposure in an ethnically diverse South African renal transplant population.

BACKGROUND: Tacrolimus forms the cornerstone for immunosuppression in solid-organ transplantation. It has a narrow therapeutic window with wide inter- and intra-patient variability (IPV). Cytochrome P-450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The rs776746A>G (i.e. CYP3A5*3) single-nucleotide polymorphism in CYP3A5 alters tacrolimus predose trough concentration (C0) and may also affect IPV, which may lead to immune- and/or drug-mediated allograft injury. CYP3A5*3 may result in absent (*3/*3), partial (*1/*3) or normal (*1/*1) CYP3A5 expression. The effect of CYP3A5*3 on tacrolimus exposure and variability has not been examined in South African (SA) transplant recipients. OBJECTIVES: To determine the frequencies and effect of CYP3A5 and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) polymorphisms on tacrolimus C0/dose ratios in different ethnic groups attending a tertiary renal transplant clinic in SA, and other factors that may explain inter- and IPV in tacrolimus C0. METHODS: All consenting stable renal transplant recipients on tacrolimus at the Livingstone Hospital Renal Unit in Port Elizabeth, SA, were included. Tacrolimus concentrations were obtained using a microparticle enzyme immunoassay method (ARCHITECT analyser, Abbott Laboratories). Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 and *6 allelic variants. RESULTS: There were 43 participants (35% black African, 44% mixed ancestry and 21% white), with a mean age of 44.5 years, median duration post-transplant of 47 months and median (interquartile range) creatinine and estimated glomerular filtration rate levels of 118 (92 - 140) µmol/L and 62 (49 - 76) mL/min at study inclusion. The mean tacrolimus C0 in the study was 6.7 ng/mL, with no difference across the different ethnic groups. However, the mean total daily dose of tacrolimus required was 9.1 mg (0.12 mg/kg), 7.2 mg (0.09 mg/kg) and 4.3 mg (0.06 mg/kg) in black, mixed-ancestry and white patients, respectively (p=0.017). The frequencies for CYP3A5 expressors (i.e. CYP3A5*1/*1 + CYP3A5*1/*3 genotypes) were 72%, 100%, 76% and 12% for all patients combined and black, mixed-ancestry and white patients, respectively. The frequencies for CYP3A5 non-expressors (i.e. CYP3A5*3/*3 genotypes) were 0%, 24% and 88% among the black, mixed-ancestry and white patients, respectively. None of the patients carried the CYP3A5*6 allele. CYP3A5*1/*1 and CYP3A5*1/*3 genotype carriers required a two-fold increase in dose compared with the non-expressor genotype carriers, CYP3A5*3/*3 (p<0.05). CYP3A5*3/*3 carriers also demonstrated higher IPV than CYP3A5*1/*1 and *1/*3 carriers (18.1% v. 14.2%; p=0.125). CONCLUSIONS: Compared with global transplant populations, SA renal transplant recipients demonstrated a very high rate of CYP3A5 expression, with a significant impact on tacrolimus pharmacokinetics. Genetic variation in CYP3A5 expression affects tacrolimus dosing requirements, and knowing the CYP3A5 genotype of transplant patients may allow better dose prediction compared with current standard dosing recommendations in a multi-ethnic population. Overall, black African patients required higher doses of tacrolimus than their white counterparts. While further prospective studies are needed to better evaluate dosing algorithms, it would appear that the starting dose of tacrolimus should be higher in black and mixed-race patients.

Prevalence and outcome of delirium among acute general medical inpatients in Cape Town, South Africa.

BACKGROUND: Delirium is a common, serious, underdiagnosed condition in medical and surgical inpatients with acute conditions. It is associated with increased risk of mortality and morbidity. Data of geriatric cohorts are largely limited to developed countries. OBJECTIVES: To describe prevalence, risk factors and outcomes of delirium among general medical patients admitted to two hospitals in Cape Town, South Africa. METHODS: This was a prospective cohort study of patients with acute conditions admitted to a general medical inpatient service in secondary- and tertiary-level public hospitals in the Metro West area of Cape Town. Patients ≥18 years of age were recruited daily from all acute medical admissions. Patients were excluded if they were aphasic or their Glasgow coma scale was <8/15. Delirium was diagnosed using the validated confusion assessment method (CAM) tool and performed by trained neuropsychologists. Demographic data were collected by a clinical team and short- and long-term mortality data were obtained using linkage analysis of hospitalised patients and routinely collected provincial death certification records. RESULTS: The median age of inpatients was 51 (interquartile range 36 - 65) years, 29% were HIV-infected and the overall prevalence of delirium was 12.3%. Multivariate predictors of delirium included the presence of an indwelling urinary catheter (odds ratio (OR) 4.47; confidence interval (CI) 2.43 - 8.23), admission with a central nervous system disease (OR 4.34; CI 2.79 - 7.90), pre-existing cognitive impairment (OR 3.02; CI 1.22 - 7.43) and immobility (OR 1.88; CI 1.01 - 3.51). HIV infection was not associated with increased risk of delirium. Delirium was associated with an increased risk of inhospital (delirium v. no delirium: 29% v. 12%; p<0.01) and 12-month (30% v. 20%; p<0.01) mortality, as well as increased length of hospital stay (7 days v. 5 days; p<0.01). CONCLUSIONS: In this cohort of medical inpatients (relatively young and with a high HIV prevalence) 1 of 8 (12.3%) patients was delirious. Delirium was associated with adverse outcomes. Delirium risk factors in this young cohort were similar to those in geriatric cohorts in developed countries, and neither HIV nor opportunistic infections increased risk.

A cell culture model of the blood-brain barrier.

Endothelial cells that make up brain capillaries and constitute the blood-brain barrier become different from peripheral endothelial cells in response to inductive factors found in the nervous system. We have established a cell culture model of the blood-brain barrier by treating brain endothelial cells with a combination of astrocyte-conditioned medium and agents that elevate intracellular cAMP. These cells form high resistance tight junctions and exhibit low rates of paracellular leakage and fluid-phase endocytosis. They also undergo a dramatic structural reorganization as they form tight junctions. Results from these studies suggest modes of manipulating the permeability of the blood-brain barrier, potentially providing the basis for increasing the penetration of drugs into the central nervous system.

Flavoured cigarettes, sensation seeking and adolescents' perceptions of cigarette brands.

OBJECTIVES: This study examined the interactive effects of cigarette package flavour descriptors and sensation seeking on adolescents' brand perceptions. METHODS: High school students (n = 253) were randomly assigned to one of two experimental conditions and sequentially exposed to cigarette package illustrations for three different brands. In the flavour descriptor condition, the packages included a description of the cigarettes as "cherry", while in the traditional descriptor condition the cigarette brands were described with common phrases found on tobacco packages such as "domestic blend." Following exposure to each package participants' hedonic beliefs, brand attitudes and trial intentions were assessed. Sensation seeking was also measured, and participants were categorised as lower or higher sensation seekers. RESULTS: Across hedonic belief, brand attitude and trial intention measures, there were interactions between package descriptor condition and sensation seeking. These interactions revealed that among high (but not low) sensation seekers, exposure to cigarette packages including sweet flavour descriptors led to more favourable brand impressions than did exposure to packages with traditional descriptors. CONCLUSIONS: Among high sensation seeking youths, the appeal of cigarette brands is enhanced through the use of flavours and associated descriptions on product packaging.