Nodal-paranodal antibodies in HIV-immune mediated radiculo-neuropathies: Clinical phenotypes and relevance.

BACKGROUND: The frequency of nodal-paranodal antibodies in HIV-infected patients with chronic immune-mediated radiculo-neuropathies (IMRN) has not been previously described. METHODS: HIV-infected patients who met the inclusion criteria for chronic IMRN were screened for immunoglobulin G (IgG) antibodies directed against nodal (neurofascin (NF)186) and paranodal (NF155, contactin-1 (CNTN1) and contactin-associated protein(Caspr1)) cell adhesion molecules, using a live, cell-based assay. To explore potential pathogenicity, binding of human IgG to myelinated co-cultures was assessed by incubation with patients' sera positive for nodal or paranodal antibodies. Normal human serum was added as a source of complement to assess for complement activation as a mechanism for myelin injury. RESULTS: Twenty-four HIV-infected patients with IMRN were included in the study, 15 with chronic inflammatory demyelinating polyneuropathy (CIDP), 4 with ventral root radiculopathies (VRR), and 5 with dorsal root ganglionopathies (DRG). Five patients with CIDP had combined central and peripheral demyelination (CCPD). Three patients (12.7%) tested positive for neurofascin IgG1 antibodies in the following categories: 1 patient with VRR was NF186 positive, and 2 patients were NF155 positive with DRG and mixed sensory-motor demyelinating neuropathy with optic neuritis, respectively. CONCLUSION: The frequency of nodal-paranodal antibodies is similar among IMRN regardless of HIV status. Interpretation of the results in the context of HIV is challenging as there is uncertainty regarding pathogenicity of the antibodies, especially at low titres. Larger prospective immune studies are required to delineate pathogenicity in the context of HIV, and to establish a panel of antibodies to predict for a particular clinical phenotype.

Artificial intelligence (AI) or augmented intelligence? How big data and AI are transforming healthcare: Challenges and opportunities.

The sanctity of the doctor-patient relationship is deeply embedded in tradition - the Hippocratic oath, medical ethics, professional codes of conduct, and legislation - all of which are being disrupted by big data and 'artificial' intelligence (AI). The transition from paper-based records to electronic health records, wearables, mobile health applications and mobile phone data has created new opportunities to scale up data collection. Databases of unimaginable magnitude can be harnessed to develop algorithms for AI and to refine machine learning. Complex neural networks now lie at the core of ubiquitous AI systems in healthcare. A transformed healthcare environment enhanced by innovation, robotics, digital technology, and improved diagnostics and therapeutics is plagued by ethical, legal and social challenges. Global guidelines are emerging to ensure governance in AI, but many low- and middle-income countries have yet to develop context- specific frameworks. Legislation must be developed to frame liability and account for negligence due to robotics in the same way human healthcare providers are held accountable. The digital divide between high- and low-income settings is significant and has the potential to exacerbate health inequities globally.

Patterns of disease on admission to children's wards and changes during a COVID-19 outbreak in KwaZulu-Natal Province, South Africa.

BACKGROUND: Major causes of under-5 child deaths in South Africa (SA) are well recognised, and child mortality rates are falling. The focus of child health is therefore shifting from survival to disease prevention and thriving, but local data on the non-fatal disease burden are limited. Furthermore, COVID-19 has affected children's health and wellbeing, both directly and indirectly. OBJECTIVES: To describe the pattern of disease on admission of children at different levels of care, and assess whether this has been affected by COVID-19. METHODS: Retrospective reviews of children's admission and discharge registers were conducted for all general hospitals in iLembe and uMgungundlovu districts in KwaZulu-Natal Province, SA, from January 2018 to September 2020. The Global Burden of Disease framework was adapted to create a data capture sheet with four broad diagnostic categories and 37 specific cause categories. Monthly admission numbers were recorded per cause category, and basic descriptive analysis was completed in Microsoft Excel. RESULTS: Overall, 36 288 admissions were recorded across 18 hospital wards, 32.0% at district, 49.8% at regional and 18.2% at tertiary level. Communicable diseases, perinatal conditions and nutritional deficiencies (CPNs) accounted for 37.4% of admissions, non-communicable diseases (NCDs) for 43.5% and injuries for 17.1%. The distribution of broad diagnostic categories varied across levels of care, with CPNs being more common at district level and NCDs more common at regional and tertiary levels. Unintentional injuries represented the most common cause category (16.6%), ahead of lower respiratory tract infections (16.1%), neurological conditions (13.6%) and diarrhoeal disease (8.4%). The start of the local COVID-19 outbreak coincided with a 43.1% decline in the mean number of monthly admissions. Admissions due to neonatal conditions and intentional injuries remained constant during the COVID-19 outbreak, while those due to other disease groups (particularly respiratory infections) declined. CONCLUSIONS: Our study confirms previous concerns around a high burden of childhood injuries in our context. Continued efforts are needed to prevent and treat traditional neonatal and childhood illnesses. Concurrently, the management of NCDs should be prioritised, and evidence-based strategies are sorely needed to address the high injury burden in SA.

Over-prescription of short-acting ß2-agonists for asthma in South Africa: Results from the SABINA III study.

Background: Asthma medication prescription trends, including those of short-acting ß2 -agonists (SABAs), are not well documented for South Africa (SA). Objectives: To describe demographics, disease characteristics and asthma prescription patterns in the SA cohort of the SABA use IN Asthma (SABINA) III study. Methods: An observational, cross-sectional study conducted at 12 sites across SA. Patients with asthma (aged ≥12 years) were classified by investigator-defined asthma severity, guided by the Global Initiative for Asthma (GINA) 2017 recommendations, and practice type (primary/ specialist care). Data were collected using electronic case report forms. Results: Overall, 501 patients were analysed - mean (standard deviation) age, 48.4 (16.6) years; 68.3% female - of whom 70.6% and 29.4% were enrolled by primary care physicians and specialists, respectively. Most patients were classified with moderate-to-severe asthma (55.7%; GINA treatment steps 3 - 5), were overweight or obese (70.7%) and reported full healthcare reimbursement (55.5%). Asthma was partly controlled/uncontrolled in 60.3% of patients, with 46.1% experiencing ≥1 severe exacerbations in the 12 months before the study visit. Overall, 74.9% of patients were prescribed ≥3 SABA canisters in the previous 12 months (over-prescription); 56.5% were prescribed ≥10 SABA canisters. Additionally, 27.1% of patients reported purchasing SABA over-the-counter (OTC); among patients with both SABA purchase and prescriptions, 75.4% and 51.5% already received prescriptions for ≥3 and ≥10 SABA canisters, respectively, in the preceding 12 months. Conclusion: SABA over-prescription and OTC purchase were common in SA, demonstrating an urgent need to align clinical practices with the latest evidence-based recommendations and regulate SABA OTC purchase to improve asthma outcomes. Study synopsis: What the study adds. This study provides valuable insights into asthma medication prescription patterns, particularly SABAs, across SA. Collection of this real-world data in patients treated in primary and specialty care demonstrates that SABA over-prescription and SABA OTC purchase are common, even in patients with mild asthma. These findings will enable clinicians and policymakers to make targeted changes to optimise asthma outcomes across the country Implications of the findings. SABA over-prescription represents a major public health concern in SA. Healthcare providers and policymakers will need to work together to promote educational initiatives aimed at patients, pharmacists and physicians, align clinical practices with the latest evidence-based recommendations, improve access to affordable medications and regulate SABA purchase without prescription.

Hard choices: Ethical challenges in phase 1 of COVID-19 vaccine roll-out in South Africa.

Access to COVID-19 vaccines has raised concerns globally. Despite calls for solidarity and social justice during the pandemic, vaccine nationalism, stockpiling of limited vaccine supplies by high-income countries and profit-driven strategies of global pharmaceutical manufacturers have brought into sharp focus global health inequities and the plight of low- and middle-income countries (LMICs) as they wait in line for restricted tranches of vaccines. Even in high-income countries that received vaccine supplies first, vaccine roll-out globally has been fraught with logistic and ethical challenges. South Africa (SA) is no exception. Flawed global institutional strategies for vaccine distribution and delivery have undermined public procurement platforms, leaving LMICs facing disproportionate shortages necessitating strict criteria for vaccine prioritisation. In anticipation of our first consignment of vaccines, deliberations around phase 1 roll-out were intense and contentious. Although the first phase focuses on healthcare personnel (HCP), the devil is in the detail. Navigating the granularity of prioritising different categories of risk in healthcare sectors in SA is complicated by definitions of risk in personal and occupational contexts. The inequitable public-private divide that characterises the SA health system adds another layer of complexity. Unlike other therapeutic or preventive interventions that are procured independently by the private health sector, COVID-19 vaccine procurement is currently limited to the SA government only, leaving HCP in the private sector dependent on central government allocation. Fair distribution among tertiary, secondary and primary levels of care is another consideration. Taking all these complexities into account, procedural and substantive ethical principles supporting a prioritisation approach are outlined. Within the constraints of suboptimal global health governance, LMICs must optimise progressive distribution of scarce vaccines to HCP at highest risk.

Could human challenge studies for COVID-19 vaccines be justified in South Africa?

Although human challenge studies (HCSs) have been widely employed in vaccine development for malaria, dengue, typhoid and cholera, the role of this research design in COVID-19 remains controversial. While the potential social value of HCSs in the context of a pandemic is clear, bioethicists are divided on the ethics, given that effective treatment for COVID-19 has eluded us to date. While compelling ethics arguments have been offered on both sides of the debate, scientific and regulatory complexities may not have been fully appreciated. Furthermore, accelerated development of efficacious vaccine candidates in traditional clinical trials has diluted some of the arguments in favour of HCSs. In low- and middle-income country settings, including South Africa, the need for robust patient care conditions for the conduct of HCSs, coupled with considerations such as perceptions of risk, consent processes, remuneration, vaccine hesitancy, fear of exploitation and access to vaccines, makes HCSs challenging to justify.

The Critical Care Society of Southern Africa guidelines on the allocation of scarce critical care resources during the COVID-19 public health emergency in South Africa.

Letter by Gopalan et al. on article by Singh and Moodley (Singh JA, Moodley K. Critical care triaging in the shadow of COVID-19: Ethics considerations. S Afr Med J 2020;110(5):355-359. https://doi.org/10.7196/SAMJ.2020.v110i5.14778); and response by Singh and Moodley.

Comorbidity in context: Part 2. Ethicolegal considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa.

The COVID-19 pandemic has brought discussions around the appropriate and fair rationing of scare resources to the forefront. This is of special importance in a country such as South Africa (SA), where scarce resources interface with high levels of need. A large proportion of the SA population has risk factors associated with worse COVID-19 outcomes. Many people are also potentially medically and socially vulnerable secondary to the high levels of infection with HIV and tuberculosis (TB) in the country. This is the second of two articles. The first examined the clinical evidence regarding the inclusion of HIV and TB as comorbidities relevant to intensive care unit (ICU) admission triage criteria. Given the fact that patients with HIV or TB may potentially be excluded from admission to an ICU on the basis of an assumption of lack of clinical suitability for critical care, in this article we explore the ethicolegal implications of limiting ICU access of persons living with HIV or TB. We argue that all allocation and rationing decisions must be in terms of SA law, which prohibits unfair discrimination. In addition, ethical decision-making demands accurate and evidence-based strategies for the fair distribution of limited resources. Rationing decisions and processes should be fair and based on visible and consistent criteria that can be subjected to objective scrutiny, with the ultimate aim of ensuring accountability, equity and fairness.

Comorbidity in context: Part 1. Medical considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa.

Infectious diseases pandemics have devastating health, social and economic consequences, especially in developing countries such as South Africa. Scarce medical resources must often be rationed effectively to contain the disease outbreak. In the case of COVID-19, even the best-resourced countries will have inadequate intensive care facilities for the large number of patients needing admission and ventilation. The scarcity of medical resources creates the need for national governments to establish admission criteria that are evidence-based and fair. Questions have been raised whether infection with HIV or tuberculosis (TB) may amplify the risk of adverse COVID-19 outcomes and therefore whether these conditions should be factored in when deciding on the rationing of intensive care facilities. In light of these questions, clinical evidence regarding inclusion of these infections as comorbidities relevant to intensive care unit admission triage criteria is investigated in the first of a two-part series of articles. There is currently no evidence to indicate that HIV or TB infection on their own predispose to an increased risk of infection with SARS-CoV-2 or worse outcomes for COVID-19. It is recommended that, as for other medical conditions, validated scoring systems for poor prognostic factors should be applied. A subsequent article examines the ethicolegal implications of limiting intensive care access of persons living with HIV or TB.

Consent for critical care research after death from COVID-19: Arguments for a waiver.

Pandemics challenge clinicians and scientists in many ways, especially when the virus is novel and disease expression becomes variable or unpredictable. Under such circumstances, research becomes critical to inform clinical care and protect future patients. Given that severely ill patients admitted to intensive care units are at high risk of mortality, establishing the cause of death at a histopathological level could prove invaluable in contributing to the understanding of COVID-19. Postmortem examination including autopsies would be optimal. However, in the context of high contagion and limited personal protective equipment, full autopsies are not being conducted in South Africa (SA). A compromise would require tissue biopsies and samples to be taken immediately after death to obtain diagnostic information, which could potentially guide care of future patients, or generate hypotheses for finding needed solutions. In the absence of an advance written directive (including a will or medical record) providing consent for postmortem research, proxy consent is the next best option. However, obtaining consent from distraught family members, under circumstances of legally mandated lockdown when strict infection control measures limit visitors in hospitals, is challenging. Their extreme vulnerability and emotional distress make full understanding of the rationale and consent process difficult either before or upon death of a family member. While it is morally distressing to convey a message of death telephonically, it is inhumane to request consent for urgent research in the same conversation. Careful balancing of the principles of autonomy, non-maleficence and justice becomes an ethical imperative. Under such circumstances, a waiver of consent, preferably followed by deferred proxy consent, granted by a research ethics committee in keeping with national ethics guidance and legislation, would fulfil the basic premise of care and research: first do no harm. This article examines the SA research ethics framework, guidance and legislation to justify support for a waiver of consent followed by deferred proxy consent, when possible, in urgent research after death to inform current and future care to contain the pandemic in the public interest.

Isolation and quarantine in South Africa during COVID-19: Draconian measures or proportional response?

In the midst of an unprecedented public health crisis, extraordinary containment measures must be implemented. These include both isolation and quarantine, either on a voluntary basis or enforced. In the transition from voluntary to mandatory isolation, conflicts arise at the intersection of ethics, human rights and the law. The Siracusa Principles adopted by the United Nations Economic and Social Council in 1985 and enshrined in international human rights legislation and guidelines specify conditions under which civil liberties may be infringed. In order for isolation processes in South Africa to claim legitimacy, it is important that these principles as well as national laws and constitutional rights are embedded in state action.

Comparative strategic approaches to COVID-19 in Africa: Balancing public interest with civil liberties.

As COVID-19 spreads rapidly across Africa, causing havoc to economies and disruption to already fragile healthcare systems, it is becoming clear that despite standardised global health strategies, national and local government responses must be tailored to their individual settings. Some African countries have adopted stringent measures such as national lockdown, quarantine or isolation, in combination with good hand hygiene, mandatory wearing of masks and physical distancing, to prevent an impending healthcare crisis. The impact of stringent measures in low- to middle-income African countries has bought time for healthcare facilities to prepare for the onslaught of COVID-19 cases, but some measures have been challenging to implement. In some settings, public health measures have been associated with serious violations of individual rights owing to abuse of power and gaps in implementation of well-intentioned policy. Collateral damage with regard to non-COVID-19 diseases that were suboptimally managed in pre-pandemic times may mean that lives lost from other diseases could exceed those saved from COVID-19. While individuals complying with lockdown regulations have embraced an acceptance of the concept of the common good, at a broad community level many are finding the transition from individualism to collective thinking required during a pandemic difficult to navigate. In this article, we look at government responses to the pandemic in six African countries (Malawi, South Africa, Uganda, Zambia, Zimbabwe and Botswana), and highlight ethical concerns arising in these contexts.

Medical cannabis: What practitioners need to know.

The South African (SA) Constitutional Court recently decriminalised the private cultivation, possession and use of cannabis by adults. Cannabis contains varying amounts of the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), depending on various cultivation factors. No commercial plant-derived cannabis products are currently registered by the SA Health Products Regulatory Authority (SAHPRA) for medical use. Such products are therefore unregulated, but are freely available in SA, and may be of inadequate quality and unverified composition, and not guaranteed to be safe or effective. SAHPRA has to date approved only one synthetic medical cannabis product, dronabinol. Evidence supporting benefit from medical cannabis exists for two drug-resistant childhood forms of epilepsy, Dravet syndrome and Lennox-Gastaut syndrome. Adjuvant therapy with medical cannabis can reduce seizure frequency for Lennox-Gastaut syndrome and Dravet syndrome by 18.8% and 22.8%, respectively, and may be beneficial for other rare forms of epilepsy. There is moderate evidence for chemotherapy-induced nausea and vomiting with the synthetic cannabinoids. Multiple sclerosis-associated spasticity showed a small clinical improvement in self-reported spasticity when a purified form of THC/CBD was added to existing therapy. Currently, low-level or no convincing evidence exists for the use of medical cannabis for chronic pain, sleep and weight disorders, and neuropsychiatric disorders. Cannabis is associated with a greater risk of adverse effects than active and placebo controls, and may be involved in clinically significant drug-drug interactions. The evolving regulatory and legal landscape on the use of medical cannabis will guide prescription and recreational use in the coming years.

Critical care triaging in the shadow of COVID-19: Ethics considerations.

Since the World Health Organization declared coronavirus disease 2019 (COVID-19) a Public Health Emergency of International Concern, COVID-19 infection and the associated mortality have increased exponentially, globally. South Africa (SA) is no exception. Concerns abound over whether SA's healthcare system can withstand a demand for care that is disproportionate to current resources, both in the state and private health sectors. While healthcare professionals in SA have become resilient and adept at making difficult decisions in the face of resource limitations, a surge in COVID-19 cases could place a severe strain on the country's critical care services and necessitate unprecedented rationing decisions. This could occur at two critical points: access to ventilation, and withdrawal of intensive care in non- responsive or deteriorating cases. The ethical dimensions of decision-making at both junctures merit urgent consideration.

Impact of implementing an online interactive educational tool for future HIV "cure" research in an HIV clinic waiting room in Cape Town, South Africa.

Access to antiretroviral treatment (ART) in South Africa is suboptimal and erratic. For those on treatment, compliance remains a significant challenge. Interruptions to ART have negative implications for the individual and the epidemic. ART is therefore not a sustainable solution and there is an urgent need for a cure. As HIV cure research expands globally, the need to engage community members about cure is becoming a priority. It is vital that potential trial participants understand basic HIV cure research concepts. An online interactive educational tool was co-created with HIV stakeholders to engage and inform HIV research trial participants. The study was conducted with patients at the FAMCRU HIV clinic at Tygerberg Hospital in Cape Town, South Africa. The educational tool comprises two modules that provide information on HIV prevention, treatment and cure research. Participants completed a questionnaire before and after interacting with the programme. There was a significant increase in knowledge scores of participants demonstrated after using the tool. The interactive tool was successful in increasing participants' knowledge of HIV prevention, treatment and cure research.

Comorbidity in context: Part 1. Medical considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa

Infectious diseases pandemics have devastating health, social and economic consequences, especially in developing countries such as South Africa. Scarce medical resources must often be rationed effectively to contain the disease outbreak. In the case of COVID-19, even the best-resourced countries will have inadequate intensive care facilities for the large number of patients needing admission and ventilation. The scarcity of medical resources creates the need for national governments to establish admission criteria that are evidence-based and fair. Questions have been raised whether infection with HIV or tuberculosis (TB) may amplify the risk of adverse COVID-19 outcomes and therefore whether these conditions should be factored in when deciding on the rationing of intensive care facilities. In light of these questions, clinical evidence regarding inclusion of these infections as comorbidities relevant to intensive care unit admission triage criteria is investigated in the first of a two-part series of articles. There is currently no evidence to indicate that HIV or TB infection on their own predispose to an increased risk of infection with SARS-CoV-2 or worse outcomes for COVID-19. It is recommended that, as for other medical conditions, validated scoring systems for poor prognostic factors should be applied. A subsequent article examines the ethicolegal implications of limiting intensive care access of persons living with HIV or TB

Comorbidity in context: Part 2. Ethicolegal considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa

The COVID-19 pandemic has brought discussions around the appropriate and fair rationing of scare resources to the forefront. This is of special importance in a country such as South Africa (SA), where scarce resources interface with high levels of need. A large proportion of the SA population has risk factors associated with worse COVID-19 outcomes. Many people are also potentially medically and socially vulnerable secondary to the high levels of infection with HIV and tuberculosis (TB) in the country. This is the second of two articles. The first examined the clinical evidence regarding the inclusion of HIV and TB as comorbidities relevant to intensive care unit (ICU) admission triage criteria. Given the fact that patients with HIV or TB may potentially be excluded from admission to an ICU on the basis of an assumption of lack of clinical suitability for critical care, in this article we explore the ethicolegal implications of limiting ICU access of persons living with HIV or TB. We argue that all allocation and rationing decisions must be in terms of SA law, which prohibits unfair discrimination. In addition, ethical decision-making demands accurate and evidence-based strategies for the fair distribution of limited resources. Rationing decisions and processes should be fair and based on visible and consistent criteria that can be subjected to objective scrutiny, with the ultimate aim of ensuring accountability, equity and fairness