Preventable suicides involving medicines: A systematic case series of coroners' reports in England and Wales.

Background: In England and Wales coroners have a duty to write a report, called a Prevention of Future Deaths report or PFD, when they believe that actions should be taken to prevent future deaths. Coroners send PFDs to individuals and organisations who are required to respond within 56 days. Despite the increase in mental health concerns and growing use of medicines, deaths reported by coroners that have involved medicine-related suicides had not yet been explored. Therefore, this study aimed to systematically assess coroners' PFD reports involving suicides in which a medicine caused or contributed to the death to identify lessons for suicide prevention. Methods: Using the Preventable Deaths Tracker database (https://preventabledeathstracker.net/), 3037 coroners' PFD reports in England and Wales were screened for eligibility between July 2013 and December 2019. Reports were included if they involved suicide or intentional self-harm and prescribed or over-the-counter medication; illicit drugs were excluded. Following data extraction, descriptive statistics, document and content analysis were performed to assess coroners' concerns and the recipients of reports. Results: There were 734 suicide-related coroner reports, with 100 (14%) reporting a medicine. Opioids (40%) were the most common class involved, followed by antidepressants (30%). There was wide geographical variation in the writing of reports; coroners in Manchester wrote the most (18%). Coroners expressed 237 concerns; the most common were procedural inadequacies (14%, n = 32), inadequate documentation and communication (10%, n = 22), and inappropriate prescription access (9%, n = 21). 203 recipients received the PFDs, with most sent to NHS trusts (31%), clinical commissioning groups (10%), and general practices (10%), of which only 58% responded to the coroner. Conclusions: One in four coroner reports in England and Wales involved suicides, with one in seven suicide-related deaths involving a medicine. Concerns raised by coroners highlighted gaps in care that require action from the Government, health services, and prescribers to aid suicide prevention. Coroner reports should be routinely used and monitored to inform public health policy, disseminated nationally, and responses to coroners should be transparently enforced so that actions are taken to prevent future suicides.

Clinical features and outcomes of patients with myasthenia gravis admitted to an intensive care unit: A 20-year retrospective study.

Background: There are limited data on the clinical characteristics and outcomes of patients with myasthenia gravis (MG) admitted to the intensive care unit (ICU) at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). Objectives: The aim was to study the clinical characteristics and outcomes of patients with MG admitted to the CMJAH over two decades. Methods: A retrospective study was undertaken of patients with MG admitted to the multidisciplinary ICU of CMJAH over a 20-year period, from 1998 to 2017. Demographic data, clinical features, management and outcomes of patients were assessed and reviewed from the case records. Results: Thirty-four patients with MG were admitted to the ICU during this period: 24 female and 10 male. The mean age ± SD was 37.4 ± 13.0 years, with a range of 16 - 66 years. Four patients were human immunodeficiency virus (HIV)-positive. The mean length of stay (LOS) in ICU was 10.6 ± 20.1 days, ranging from 1 to 115 days. Two patients were diagnosed with MG in the ICU after failure to wean from the ventilator. Overall, 22 patients were intubated and ventilated on admission. Morbidities included self-extubation, aspiration pneumonia and iatrogenic pneumothorax. History of thymectomy was present in 12 patients. The treatments received for MG included pyridostigmine (73.5%), corticosteroids (55.9%), azathioprine (35.3%), plasmapheresis (26.5%) and intravenous immunoglobulin (8.8%). The overall mortality in the ICU was 5.9%. Conclusion: MG is a serious disorder with considerable morbidity and mortality. It is, however, a potentially manageable disease, provided that appropriate ICU resources are available. Contributions of the study: This study provides further insight into the characteristics and outcomes of myasthenia gravis patients in ICU, within a South African context.

Assessing housing exposures and interventions that impact healthy cities: a systematic overview of reviews.

AIM: There are direct links between housing and health. However, there is a lack of systematic reviews that bring together the evidence to outline the health impacts of exposures in housing and housing interventions. This article aims to address this gap by synthesising systematic reviews on the themes of housing exposures and interventions. METHODS: We searched four databases: Scopus (Elsevier), PsycINFO (OvidSP), Science Citation Index and Social Science Citation Index (Web of Science Core Collection), and the Sociology Collection (Proquest). We used keywords related to 'health' and 'city*' and included all types of reviews. We extracted data into a predesigned extraction form and synthesised information narratively. RESULTS: 745 articles were identified and screened, of which 256 reviews were included and 16 (6%) related to housing. All reviews related to housing exposures found that poor housing, including crowding, coldness, dampness, mould, and indoor air pollution had a negative impact on health. Most reviews found that housing interventions such as housing refurbishment, heating, and energy efficiency interventions positively impacted health outcomes. An online toolkit was developed to disseminate and communicate this research: https://www.healthycitiescommission.org/toolkit/. CONCLUSION: Governments have a pivotal role in addressing health issues related to housing interventions and exposures in housing. This includes interventions through building regulations following international guidance and financial assistance to encourage housing modifications that will improve health.

Assessing and comparing chest radiograph interpretation in the Department of Internal Medicine at the University of the Witwatersrand medical school, according to seniority.

Background: Chest radiographs are a common diagnostic tool in the internal medicine department, and correct interpretation is imperative for adequate patient management. Objectives: To determine the diagnostic accuracy of common pathologies in South Africa that are evident on chest radiographs, and to determine whether there are discrepancies according to different levels of qualification of doctors rotating through the internal medicine department, and which factors contribute to an accurate diagnosis. Methods: Fifteen chest radiographs with common pathologies were given to all doctors rotating through the Department of Internal Medicine at Chris Hani Baragwanath Academic Hospital, and they were asked to interpret them. Information pertaining to their experience, designation and confidence in chest radiograph interpretation was also obtained. Results: Diagnostic accuracy according to years of experience was as follows: 0 - 5 years 27.0%, 6 - 10 years 43.0%, and >10 years 47.9%. For different designations, accuracy was as follows: consultants 50.5%, registrars 40.9%, medical officers 36.4%, and interns 19.5%. Participants who were confident obtained a mean score of 39.4% and those who were not, a mean score of 31.6%. Conclusion: Chest radiographs are readily accessible and used daily in clinical practice in numerous facilities. An accurate diagnosis is important to provide quality healthcare. Improved training in interpretation for all, but especially for junior doctors, should be a priority in our training facilities. Study synopsis: What the study adds. This study tested the diagnostic accuracy with regard to common pathologies present on chest X ray by doctors rotating through, or stationed at the internal medicine department at an academic hospital. Implications of the findings. Interpretation of chest X-rays was generally poor but the study did find that this improves with experience and confidence in diagnostic ability. These findings are significant in that they indicate a need to implement improved teaching programs in radiological interpretation, especially at an undergraduate level.

Fear, anxiety, and production in laying hens with healed keel bone fractures.

For laying hens, the immediate aftermath and healing period of a keel fracture (KF) is characterized by reduced ability to perform species-specific behavior, access resources, and pain. However, the longer-term impacts, once the fracture is completely healed, are less clear. As well as acute pain and behavioral changes, a negative experience can shape future responses to putatively threatening stimuli, raising future fear, and anxiety levels during husbandry-related events. We aimed to determine whether hens that had previously sustained keel bone fractures, but were now outside of the peak age range for new fractures, showed higher fear and anxiety levels compared to intact hens. We also determined if healed keel bone fractures were associated with reduced production, changes in behavior and resource use. One hundred and fifty hens with a palpation score of 1 ( "KF") and 150 hens with a palpation score of 0 (keel fracture free, "KFF") were selected from a commercial farm at 63 wk of age and housed in 6 groups (3 × KF and 3 × KFF). We compared production (hen weight and feed consumption, egg quantity, quality and weight, floor eggs, shell thickness, and weight) and home pen behavior (behaviors and transitional movements) in both groups. Finally, we measured the responses of KF (n = 75) and KFF (n = 75) during tonic immobility, novel arena, and novel object tests. KF and KFF hens did not differ in their responses to the tonic immobility, novel arena, and novel object tests, nor were there differences between the 2 groups in home pen behavior and transitional movements. KFF birds were lighter and laid eggs with less eggshell membrane compared KF birds, but no differences were found between KF and KFF in any other production measures. We found no evidence that healed KFs were associated with detrimental welfare effects in laying hens, but further work is required to determine the mechanisms and implications of the lower body weight and egg shell membrane.

Core competencies in critical care for general medical practitioners in South Africa: A Delphi study.

Background: Despite a high burden of disease that requires critical care services, there are a limited number of intensivists in South Africa (SA). Medical practitioners at district and regional public sector hospitals frequently manage critically ill patients in the absence of intensivists, despite these medical practitioners having had minimal exposure to critical care during their undergraduate training. Objectives: To identify core competencies in critical care for medical practitioners who provide critical care services at public sector hospitals in SA where intensivists are not available to direct patient management. Methods: A preliminary list of core competencies in critical care was compiled. Thereafter, 13 national and international experts were requested to achieve consensus on a final list of core competencies that are required for critical care by medical practitioners, using a modified Delphi process. Results: A final list of 153 core competencies in critical care was identified. Conclusion: The core competencies identified by this study could assist in developing training programmes for medical practitioners to improve the quality of critical care services provided at district and regional hospitals in SA. Contribution of the study: The study provides consensus on a list of core competencies in critical care that non-intensivist medical practitioners managing critically ill patients in healthcare settings in South Africa, especially where intensivists are not readily available, should have. The list can form the core content of training programmes aimed at improving critical care competence of general medical practitioners, and in this way hopefully improve the overall outcomes of critically ill patients in South Africa.

Risk factors and outcomes of sepsis-associated acute kidney injury in intensive care units in Johannesburg, South Africa.

BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) has been shown to be a significant contributor to morbidity and mortality in both children and adults with critical illness. In sub-Saharan Africa, there is a lack of information on factors associated with development of SA-AKI and outcomes after intensive care unit (ICU) admission. OBJECTIVES: To assess the rate of SA-AKI, factors associated with its development, and predictors of mortality at 90 days in critically ill patients admitted to the ICU with sepsis. METHODS: This was a prospective observational study conducted at two of the biggest teaching hospitals in Johannesburg, South Africa, from 15 February 2016 to 15 February 2020. The study included consecutive patients with confirmed sepsis who were admitted to the ICU within 24 hours of admission to hospital. The primary outcome of the study was development of SA-AKI (defined according to Kidney Disease Improving Global Outcome (KDIGO) criteria), and secondary outcomes were risk factors for SA-AKI and predictors of mortality at 90 days. Multivariate logistic regression analysis was employed to determine the factors associated with SA-AKI and 90-day mortality. RESULTS: In total, 327 critically ill patients with sepsis admitted to the ICUs were included in the study. The median (interquartile range) age was 39 (30 - 52) years, and 185 patients (56.6%) developed SA-AKI. Of these patients, blacks and whites comprised 91.0% and 6.1%, respectively, and the prevalent comorbidities were HIV/AIDS (19.3%), hypertension (14.2%) and diabetes mellitus (10.1%). Patients with SA-AKI were likely to be older and of male gender, and to have cardiovascular disease, malignancies, hypotension and a low serum albumin level. In multivariate analysis, the predictors of SA-AKI were age ≥55 years (odds ratio (OR) 2.43; 95% confidence interval (CI) 1.27 - 4.65), inotropic support (OR 3.61; 95% CI 2.18 - 5.96) and a low serum albumin level (OR 2.93; 95% CI 1.40 - 6.13). SA-AKI and need for inotropic support were respectively associated with 1.9-fold and 1.7-fold increased mortality at 90 days after ICU admission. CONCLUSION: SA-AKI was found to be frequent in this study in two tertiary hospital ICUs in Johannesburg, and the need for inotropic support predicted mortality after ICU admission.

The optimal management of the patient with COVID-19 pneumonia: HFNC, NIV/CPAP or mechanical ventilation?

The recent pandemic has seen unprecedented demand for respiratory support of patients with COVID-19 pneumonia, stretching services and clinicians. Yet despite the global numbers of patients treated, guidance is not clear on the correct choice of modality or the timing of escalation of therapy for an individual patient. This narrative review assesses the available literature on the best use of different modalities of respiratory support for an individual patient, and discusses benefits and risks of each, coupled with practical advice to improve outcomes. On current data, in an ideal context, it appears that as disease severity worsens, conventional oxygen therapy is not sufficient alone. In more severe disease, i.e. PaO2/FiO2 ratios below approximately 200, helmet-CPAP (continuous positive airway pressure) (although not widely available) may be superior to high-flow nasal cannula (HFNC) therapy or facemask non-invasive ventilation (NIV)/CPAP, and that facemask NIV/CPAP may be superior to HFNC, but with noted important complications, including risk of pneumothoraces. In an ideal context, invasive mechanical ventilation should not be delayed where indicated and available. Vitally, the choice of respiratory support should not be prescriptive but contextualised to each setting, as supply and demand of resources vary markedly between institutions. Over time, institutions should develop clear policies to guide clinicians before demand exceeds supply, and should frequently review best practice as evidence matures.

Computed tomography-derived fractional flow reserve (FFRCT) has no additional clinical impact over the anatomical Coronary Artery Disease - Reporting and Data System (CAD-RADS) in real-world elective healthcare of coronary artery disease.

AIM: To evaluate the impact of computed tomography-derived fractional flow reserve (FFRCT) compared to the anatomical Coronary Artery Disease - Reporting and Data System (CAD-RADS) in the elective assessment of coronary artery disease in real-world cardiology practise. MATERIALS AND METHODS: A retrospective review was undertaken of 1,239 coronary CT examinations from August 2018 to December 2019 with a minimum follow-up period of 1 year. Coronary disease was classified according to the CAD-RADS system. A non-occlusive ≥30% maximum diameter stenosis was considered eligible for FFRCT. Lesion-specific FFRCT and FFR were considered positive if ≤ 0.80. The patients were followed up using the hospital radiology information system and the electronic patient record. A positive outcome was defined by a subsequent invasive angiogram (ICA) showing disease requiring revascularisation or FFR ≤0.80 or a positive stress test or medical therapy for angina in CAD-RADS 4. RESULTS: Of the 1,145 analysable studies (mean follow up 618 ± 153 days) the incidence of a positive result was 7% with a 5.4% elective revascularisation rate. Two hundred and forty-five patients (CAD-RADS 2-4) had FFRCT. FFRCT reduced the accuracy of the CAD-RADS grade from 91% to 78.4% (p<0.001). In CAD-RADS 2, the accuracy is reduced from 99% to 90.7% (p=0.005), and in CAD-RADS 3 from 93.9% to 67.7% (p<0.001). In CAD-RADS 4, FFRCT increases accuracy from 69.4% to 75.5% (p=0.025), but 89.8% of FFRCT are positive and specificity is low (26.7%). CONCLUSION: In the present "real-world" practise, FFRCT does not improve standard radiological assessment of coronary disease graded by the CAD-RADS alone.

Comminuted intraarticular calcaneal fractures: Multiplanar VA locked plating and interlocked nailing incorporate longitudinal strut and provide superior stability - a biomechanical cadaveric study.

Treatment of comminuted intraarticular calcaneal fractures remains controversial and challenging. The aim of this study was to investigate the biomechanical performance of three different methods for fixation of such fractures. Comminuted calcaneal fractures, including Sanders III AB fracture of the posterior facet and Kinner II B fracture of the calcaneocuboid joint (CCJ) articular calcaneal surface, were created in 18 human cadaveric lower legs by osteotomizing. The ankle joint, medial soft tissues and midtarsal bones along with their ligaments were preserved. The specimens were randomized to three groups for fixation with either (1) 2.7 mm variable-angle locking lateral calcaneal plate (Group 1), (2) 2.7 mm variable-angle locking anterolateral calcaneal plate in combination with one 4.5 mm and one 6.5 mm cannulated screws (Group 2), or (3) interlocking calcaneal nail with 3.5 mm screws in combination with three separate 4.0 mm cannulated screws (Group 3). All specimens were biomechanically tested to failure under axial loading in midstance foot position. Each test commenced with a quasi-static compression ramp from 50 to 200 N, followed by progressively increasing cyclic loading at 2 Hz. Starting from 200 N, the peak load of each cycle increased at a rate of 0.2 N/cycle. Interfragmentary movements were captured by motion tracking. In addition, mediolateral X-rays were taken every 250 cycles with a triggered C-arm. Böhler angle after 5000 cycles (1200 N peak load) increased significantly more in Group 1 compared to both other groups (P ≤ 0.020). Varus deformation of 10° between the calcaneal tuberosity and the lateral calcaneal fragments was reached at significantly lower number of cycles in Group 1 compared the other groups (P ≤ 0.017). Both cycles to 10° plantar gapping between the anterior process and the calcaneal tuberosity fragments, and 2 mm displacement at the CCJ articular calcaneal surface revealed no significant differences among the groups (P ≥ 0.773). From a biomechanical perspective, treatment of comminuted intraarticular calcaneal fractures using anterolateral variable-angle locking plate with additional longitudinal screws or interlocked nail in combination with separate transversal screws provides superior stability as opposed to lateral variable-angle locked plating only.

Cartilage decisively shapes the glenoid concavity and contributes significantly to shoulder stability.

PURPOSE: Glenohumeral joint injuries frequently result in shoulder instability. However, the biomechanical effect of cartilage loss on shoulder stability remains unknown. The aim of the current study was to investigate biomechanically the effect of two severity stages of cartilage loss in different dislocation directions on shoulder stability. METHODS: Joint dislocation was provoked in 11 human cadaveric glenoids for 7 different directions between 3 o'clock (anterior) and 9 o'clock (posterior). Shoulder stability ratio (SSR) and concavity gradient were assessed in three states: intact, 3 mm and 6 mm simulated cartilage loss. The influence of cartilage loss on SSR and concavity gradient was statistically evaluated. RESULTS: Both SSR and concavity gradient decreased significantly between intact state and 6 mm cartilage loss in every dislocation direction (p ≤ 0.038), except concavity gradient in 4 o'clock direction. Thereby, anterior-inferior dislocation directions were associated with the highest decrease in both SSR and concavity gradient of up to 59.0% and 49.4%, respectively, being significantly bigger for SSR compared with all other dislocation directions (p ≤ 0.040). Correlations between concavity gradient and SSR for pooled dislocation directions were significant in each separate specimen's state (p < 0.001). CONCLUSION: From a biomechanical perspective, articular cartilage of the glenoid contributes significantly to the concavity gradient, correlating strongly with the associated loss in glenohumeral joint stability. The biggest effect of cartilage loss is observed in the most frequently occurring anterior-inferior dislocation directions, suggesting that surgical interventions to restore cartilage's surface and concavity should be considered for recurrent shoulder dislocations in presence of cartilage loss.

The impact of routine pulse oximetry use on outcomes in COVID-19-infected patients at increased risk of severe disease: A retrospective cohort analysis.

BACKGROUND: The phenomenon of silent hypoxaemia has been described in patients with COVID-19 pneumonia, which is characterised by low oxygen saturation levels of <90% in those who appear clinically well and do not show signs of significant respiratory distress. OBJECTIVES: To assess the impact on clinical outcomes for high-risk COVID-19 patients using a pulse oximeter to monitor oxygen saturation levels in a home setting. METHODS: We performed a retrospective cohort analysis using data from a large South African insurance administrator. Patients were categorised as high risk, based on age and specific underlying clinical conditions, or from predictive models derived from medical scheme administrative claims data. The impact of pulse oximetry home monitoring on COVID-19 clinical outcomes was investigated by the use of Cox proportional hazard models. RESULTS: Between 2 March 2020 and 31 October 2020, of 38 660 patients analysed, 8 115 were in the intervention group. The 60-day mortality rate for the evaluated high-risk population was 1.35%. After adjusting for age and comorbidity differences, the intervention group was found to have an adjusted hazard ratio of 0.52 (p<0.0001). No statistical significance was found between the intervened and control groups for admission to hospital, admission to intensive care unit (ICU) and use of mechanical ventilation. The intervention group had a lower median C-reactive protein (CRP) level on admission (p=0.03). After adjustment for admission CRP levels, elevated CRP was associated with an increased mortality (p<0.0001), while the statistical significance in mortality between the intervention and the control group was lost. CONCLUSIONS: High-risk COVID-19 patients who used a pulse oximeter to monitor oxygen saturation levels had significantly lower mortality rates compared with other high-risk patients. The mortality benefit may be explained by earlier presentation to hospital, as suggested by lower initial CRP levels.

A position statement and practical guide to the use of particulate filtering facepiece respirators (N95, FFP2, or equivalent) for South African health workers exposed to respiratory pathogens including Mycobacterium tuberculosis and SARS-CoV-2.

SUMMARY: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is transmitted mainly by aerosol in particles <10 µm that can remain suspended for hours before being inhaled. Because particulate filtering facepiece respirators ('respirators'; e.g. N95 masks) are more effective than surgical masks against bio-aerosols, many international organisations now recommend that health workers (HWs) wear a respirator when caring for individuals who may have COVID-19. In South Africa (SA), however, surgical masks are still recommended for the routine care of individuals with possible or confirmed COVID-19, with respirators reserved for so-called aerosol-generating procedures. In contrast, SA guidelines do recommend respirators for routine care of individuals with possible or confirmed tuberculosis (TB), which is also transmitted via aerosol. In health facilities in SA, distinguishing between TB and COVID-19 is challenging without examination and investigation, both of which may expose HWs to potentially infectious individuals. Symptom-based triage has limited utility in defining risk. Indeed, significant proportions of individuals with COVID-19 and/or pulmonary TB may not have symptoms and/or test negative. The prevalence of undiagnosed respiratory disease is therefore likely significant in many general clinical areas (e.g. waiting areas). Moreover, a proportion of HWs are HIV-positive and are at increased risk of severe COVID-19 and death. RECOMMENDATIONS: Sustained improvements in infection prevention and control (IPC) require reorganisation of systems to prioritise HW and patient safety. While this will take time, it is unacceptable to leave HWs exposed until such changes are made. We propose that the SA health system adopts a target of 'zero harm', aiming to eliminate transmission of respiratory pathogens to all individuals in every healthcare setting. Accordingly, we recommend: the use of respirators by all staff (clinical and non-clinical) during activities that involve contact or sharing air in indoor spaces with individuals who: (i) have not yet been clinically evaluated; or (ii) are thought or known to have TB and/or COVID-19 or other potentially harmful respiratory infections;the use of respirators that meet national and international manufacturing standards;evaluation of all respirators, at the least, by qualitative fit testing; andthe use of respirators as part of a 'package of care' in line with international IPC recommendations. We recognise that this will be challenging, not least due to global and national shortages of personal protective equipment (PPE). SA national policy around respiratory protective equipment enables a robust framework for manufacture and quality control and has been supported by local manufacturers and the Department of Trade, Industry and Competition. Respirator manufacturers should explore adaptations to improve comfort and reduce barriers to communication. Structural changes are needed urgently to improve the safety of health facilities: persistent advocacy and research around potential systems change remain essential.

Lymphopenia and IgG2 subclass deficiency in patients with severe COVID-19 pneumonia.

BACKGROUND: COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) manifests with a range of disease severities. A small proportion of COVID-19 patients are severely ill; however, a significant proportion of these patients are critically ill, and require admission and mechanical ventilation, which is associated with a high mortality. OBJECTIVE: To identify factors that may predispose patients with COVID-19 to severe disease that requires mechanical ventilation (MV). METHODS: We performed a retrospective audit of patients admitted with COVID-19 pneumonia to the intensive care unit (ICU) and medical wards to evaluate the potential associations between comorbid conditions, lymphopenia and IgG subclass deficiency with a need for MV. RESULTS: A total of 51 patients were included in the study. Almost half of the patients (47%; n=24) were documented to have IgG2 deficiency, 43% (n=22) had lymphopenia and 37% (n=19) had combined lymphopenia and IgG2 subclass deficiency. Of the 24 patients who required MV, 75% had IgG2 subclass deficiency, 73% had lymphopenia and 50% had both. The relative risk for requiring MV was 2.64, 3.38 and 2.81 for lymphopenia, IgG2 subclass deficiency and both, respectively. CONCLUSION: These findings suggest that lymphopenia, low IgG2 concentrations or the combination of both may be used to identify patients with severe COVID-19 that are at increased risk for MV. This may facilitate earlier identification of patients at high risk, who may benefit from more intensive therapy.

Maternal steroid levels and the autistic traits of the mother and infant.

BACKGROUND: Prenatal sex steroids have been associated with autism in several clinical and epidemiological studies. It is unclear how this relates to the autistic traits of the mother and how early this can be detected during pregnancy and postnatal development. METHODS: Maternal serum was collected from pregnant women (n = 122) before or during their first ultrasound appointment [mean = 12.7 (SD = 0.7) weeks]. Concentrations of the following were measured via immunoassays: testosterone, estradiol, dehydroepiandrosterone sulphate, progesterone; and sex hormone-binding globulin which was used to compute the free fractions of estradiol (FEI) and testosterone (FTI). Standardised human choriogonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) values were obtained from clinical records corresponding to the same serum samples. Mothers completed the Autism Spectrum Quotient (AQ) and for their infants, the Quantitative Checklist for Autism in Toddlers (Q-CHAT) when the infants were between 18 and 20 months old. RESULTS: FEI was positively associated with maternal autistic traits in univariate (n = 108, Pearson's r = 0.22, p = 0.019) and multiple regression models (semipartial r = 0.19, p = 0.048) controlling for maternal age and a diagnosis of PCOS. Maternal estradiol levels significantly interacted with fetal sex in predicting infant Q-CHAT scores, with a positive relationship in males but not females (n = 100, interaction term: semipartial r = 0.23, p = 0.036) after controlling for maternal AQ and other covariates. The opposite was found for standardised hCG values and Q-CHAT scores, with a positive association in females but not in males (n = 151, interaction term: r = -0.25, p = 0.005). LIMITATIONS: Sample size of this cohort was small, with potential ascertainment bias given elective recruitment. Clinical covariates were controlled in multiple regression models, but additional research is needed to confirm the statistically significant findings in larger cohorts. CONCLUSION: Maternal steroid factors during pregnancy are associated with autistic traits in mothers and their infants.

Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1.

ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation of the highly polymorphic ERAP1 has been implicated in autoimmune disease and cancer. To test this hypothesis and establish the role of ERAP1 in these disease areas, high affinity, cell permeable and selective chemical probes are essential. DG013A 1, is a phosphinic acid tripeptide mimetic inhibitor with reported low nanomolar affinity for ERAP1. However, this chemotype is a privileged structure for binding to various metal-dependent peptidases and contains a highly charged phosphinic acid moiety, so it was unclear whether it would display the high selectivity and passive permeability required for a chemical probe. Therefore, we designed a new stereoselective route to synthesize a library of DG013A 1 analogues to determine the suitability of this compound as a cellular chemical probe to validate ERAP1 as a drug discovery target.

Predictors of in-hospital mortality among HIV-positive patients presenting with an acute illness to the emergency department.

OBJECTIVES: Despite better access to antiretroviral therapy (ART) over recent years, HIV remains a major global cause of mortality. The present study aimed to identify predictors of in-hospital mortality among HIV-positive patients presenting to an emergency department (ED). METHODS: In this cross-sectional study, HIV-positive patients presenting to the Charlotte Maxeke Johannesburg Academic Hospital adult ED between 07 July 2017 and 18 October 2018 were prospectively enrolled. Data were compared between participants who survived to hospital discharge and those who died. The data were further subjected to univariate and multivariate logistic regression analyses to determine variables that were associated with in-hospital mortality. RESULTS: Of a total of 1224 participants, the in-hospital mortality was 13.6% (n = 166). On multivariate analysis, respiratory rate > 20 breaths/min [odds ratio (OR) = 1.90, P = 0.012], creatinine > 120 µmol/L (OR = 1.97, P = 0.006), oxygen saturation < 90% (OR = 2.09, P = 0.011), white cell count < 4.0 × 109 /L (OR = 2.09, P = 0.008), ART non-adherence or not yet on ART (OR = 2.39, P = 0.012), Glasgow Coma Scale < 15 (OR = 2.53, P = 0.000), albumin < 35 g/L (OR = 2.61, P = 0.002), lactate > 2 mmol/L (OR = 4.83, P = 0.000) and cryptococcal meningitis (OR = 6.78, P = 0.000) were significantly associated with in-hospital mortality. CONCLUSIONS: Routine clinical and laboratory parameters are useful predictors of in-hospital mortality in HIV-positive patients presenting to the ED with an acute illness. These parameters may be of value in guiding clinical decision-making, directing the appropriate use of resources and influencing patient disposition, and may also be useful in developing an outcome prediction tool.

Antiretroviral therapy non-adherence among HIV-positive patients presenting to an emergency department in Johannesburg, South Africa: Associations and reasons.

BACKGROUND: Suboptimal antiretroviral therapy (ART) adherence is associated with viral resistance, opportunistic infections and increased mortality. OBJECTIVES: To determine the rates of ART non-adherence and its associations, and also the reasons for ART non-adherence, among HIV-positive patients presenting to a major central hospital emergency department (ED). METHODS: Consecutive HIV-positive patients presenting to the Charlotte Maxeke Johannesburg Academic Hospital adult ED between 7 July 2017 and 18 October 2018 were prospectively enrolled. Self-reported adherence was assessed using the AIDS Clinical Trials Group Adherence Questionnaire (ACTG-AQ). RESULTS: Of the 1 224 consecutive HIV-positive participants enrolled, 761 (75.2%) were on ART at the time of ED presentation. Of these, 245 (32.2%) were non-adherent as per the ACTG-AQ. Participants not yet on ART prior to ED presentation had significantly higher in-hospital mortality than participants on ART (odds ratio 1.69; 95% confidence interval 1.21 - 2.34; p=0.002). Younger age, male sex, CD4 count <100 cells/µL, lack of viral suppression, a high National Early Warning Score 2 (≥7 points) and length of hospital stay ≥7 days were significantly associated with ART non-adherence (p<0.05). Forgetfulness (13.9%) and lack of social support, depression/stress/mental illness, and lack of money for transport to collect medications (9.9% each) were the most common reasons given for ART non-adherence. CONCLUSIONS: Of HIV-positive patients presenting to the ED, a high proportion were either not yet initiated on ART or ART non-adherent. HIV programmes should focus on HIV-positive ED attendees with the aim of identifying high-risk patients and providing adequate ART adherence support.

South African guidelines on the determination of death.

Death is a medical occurrence that has social, legal, religious and cultural consequences requiring common clinical standards for its diagnosis and legal regulation. This document compiled by the Critical Care Society of Southern Africa outlines the core standards for determination of death in the hospital context. It aligns with the latest evidence-based research and international guidelines and is applicable to the South African context and legal system. The aim is to provide clear medical standards for healthcare providers to follow in the determination of death, thereby promoting safe practices and high-quality care through the use of uniform standards. Adherence to such guidelines will provide assurance to medical staff, patients, their families and the South African public that the determination of death is always undertaken with diligence, integrity, respect and compassion, and is in accordance with accepted medical standards and latest scientific evidence. The consensus guidelines were compiled using the AGREE II checklist with an 18-member expert panel participating in a three-round modified Delphi process. Checklists and advice sheets were created to assist with application of these guidelines in the clinical environment (https://criticalcare.org.za/resource/death-determination-checklists/). Key points • Brain death and circulatory death are the accepted terms for defining death in the hospital context. • Death determination is a clinical diagnosis which can be made with complete certainty provided that all preconditions are met. • The determination of death in children is held to the same standard as in adults but cannot be diagnosed in children <36 weeks' corrected gestation. • Brain-death testing while on extra-corporeal membrane oxygenation is outlined. • Recommendations are given on handling family requests for accommodation and on consideration of the potential for organ donation. • The use of a checklist combined with a rigorous testing process, comprehensive documentation and adequate counselling of the family are core tenets of death determination. This is a standard of practice to which all clinicians should adhere in end-of-life care.