The Impact of COVID-19 on the Utilization of Public Sector Radiological Services in the Western Cape Province of South Africa.

Background Coronavirus (COVID-19) was officially declared a pandemic in March 2020 and has had a major impact on global healthcare services, including radiology. However, little is known about the full impact of COVID-19 on the utilization of diagnostic imaging in Africa's public healthcare sector. Objectives The objective of this study was to compare public sector diagnostic imaging utilization by modality for the whole Western Cape Province (WCP) of South Africa (SA), as well as its metropolitan and rural areas, in 2019 and 2020 in terms of the absolute number of investigations and investigations per 1000 people. Method We performed a retrospective analysis of Western Cape Government Department of Health and Wellness and Stats SA District Council 2021 Mid-Year Population Estimates data. All diagnostic imaging investigations performed in 2019 and 2020 were collated and stratified by imaging modality, geographic region (metropolitan/rural), and calendar year. Data are presented as the total number of investigations and investigations per 1000 people. We calculated mammography utilization for women aged 40-70 years and compared data for 2019 and 2020. Results Between 2019 and 2020, the provincial population increased by 1.9%, while total imaging investigations and investigations per 1000 people decreased by 19% (1,384,941 vs. 1,123,508, -261,433) and 20% (262/103 vs. 208/103), respectively. Total numerical decline was highest in plain radiographs (1,005,545 vs. 800,641, -204,904), accounting for more than three-quarters (78%) of the total reduction. Percentage decline was most pronounced for mammography, as utilization was almost halved (15.7/103 vs. 8.9/103, -43%), whereas computed tomography was the least impacted (17.9/103 vs. 16.7/103, -12%) with the remaining modalities decreasing between approximately one-quarter and one-fifth (magnetic resonance imaging = 26%, fluoroscopy = 25%, general radiographs = 23%, ultrasound = 16%, chest radiographs = 18%). Proportional metropolitan (-18.7%) and rural decreases (-19.3%) were similar. Conclusion COVID-19 had a substantial impact on WCP imaging services, decreasing overall radiological investigations by almost one-fifth. The greatest impact was on elective investigations, particularly mammography. Although the proportional impact was similar for the metropolitan and rural areas, COVID-19 nonetheless exacerbated existing discrepancies in imaging utilization between the geographical regions. The medium- and long-term clinical impacts of decreased imaging are still to be defined.

A 6-year audit of public-sector MR utilisation in the Western Cape province of South Africa.

Background: Disparities in MR access between different countries and healthcare systems are well documented. Determinants of unequal access within the same healthcare system and geographical region are poorly understood. Objective: An analysis of public sector MR utilisation in South Africa's Western Cape province (WCP). Methods: A retrospective study of WCP MR and population data for 2013 and 2018. MR units/106 people, studies, and studies/103 people were calculated for each year, for the whole province and the 'western' and 'eastern' referral pathways, stratified by age (0-14 years, > 14 years). Results: Between 2013 and 2018, the WCP population increased 8% (4.63 vs 5.08 × 106 people) while MR resources were unchanged ('western' = 2 units; 'eastern' = 1), equating to decreasing access (units/106 people) for the province (0.65 vs 0.59; -9.2%), the 'western' (0.97 vs 0.9; -7.2%) and 'eastern' (0.39 vs 0.35; -10.3%) pathways. In 2013, 40% (4005/10 090) of studies were in the 'eastern' pathway serving 55% (2 066 079/4 629 051) of the population. Between 2013 and 2018 'eastern' population growth (n = 286 781) exceeded 'western' (n = 168 469) by 70% (n = 118 312). By 2018, 38% (7939/12 848) of studies were performed in the 'eastern' pathway, then serving 56% (2 849 753/5 084 301) of the population. Among 0-14-year-olds, 'western' utilisation (studies/103 people) exceeded 'eastern' by a factor of approximately 2.4 throughout. In patients > 14 years, the utilisation differential increased from 1.78 to 1.98 in the review period. Conclusion: Ensuring equitable services on the same healthcare platform requires ongoing surveillance of resource and population distribution. MR access can serve as a proxy for equity in highly specialised services.

Trends in public sector radiological usage in the Western Cape Province, South Africa: 2009-2019.

BACKGROUND: Although global use of medical imaging has increased significantly, little is known about utilisation trends in low- and middle-income countries (LMICs). OBJECTIVES: To evaluate changes over a decade in public sector diagnostic imaging utilisation at provincial level in a middle-income country. METHOD: A retrospective analysis of medical imaging utilisation in the Western Cape Province of South Africa in 2009 and 2019. Use of conventional radiography, ultrasonography (US), fluoroscopy, CT, MRI, digital subtraction angiography (DSA) and whole-body digital radiography was assessed by total studies and studies/103 people, for the whole province, the rural and metropolitan areas. Mammography utilisation was calculated for every 103 females aged 40-70 years. RESULTS: The provincial population and total imaging investigations increased by 25% and 32%, respectively, whilst studies/103 people increased by 5.5% (256 vs 270/103), with marked variation by modality. Provincial US, CT and MRI utilisation/103 people increased by 111% (20 vs 43/103), 78% (10 vs 18/103) and 32% (1.9 vs 2.5/103) respectively, whilst use of fluoroscopy (3.6 vs 3.7/103) and mammography (14.2 vs 15.9/103 women aged 40-70 years) was steady and plain radiography decreased by 20% (216 vs 196/103). For CT, mammography and fluoroscopy, percentage utilisation increases/103 people were higher in the rural than metropolitan areas. CONCLUSION: Population growth is the main driver of overall imaging utilisation in our setting. The relatively constant imaging workload per 1000 people, albeit with increasing ultrasound, CT and MR utilisation, and decreasing use of plain radiography, reflects improved provincial imaging infrastructure, and appropriate use of available resources.

Drug combination screening as a translational approach toward an improved drug therapy for chordoma.

PURPOSE: Drug screening programmes have revealed epidermal growth factor receptor inhibitors (EGFRis) as promising therapeutics for chordoma, an orphan malignant bone tumour, in the absence of a known genetic driver. Concurrently, the irreversible EGFRi afatinib (Giotrif®) is being evaluated in a multicentric Phase II trial. As tyrosine kinase inhibitor (TKI) monotherapies are invariably followed by resistance, we aimed to evaluate potential therapeutic combinations with EGFRis. METHODS: We screened 133 clinically approved anticancer drugs as single agents and in combination with two EGFRis (afatinib and erlotinib) in the clival chordoma cell line UM-Chor1. Synergistic combinations were analysed in a 7 × 7 matrix format. The most promising combination was further explored in clival (UM-Chor1, MUG-CC1) and sacral (MUG-Chor1, U-CH1) chordoma cell lines. Secretomes were analysed for receptor tyrosine kinase ligands (EGF, TGF-α, FGF-2 and VEGF-A) upon drug treatment. RESULTS: Drugs that were active as single agents (n = 45) included TKIs, HDAC and proteasome inhibitors, and cytostatic drugs. Six combinations were analysed in a matrix format: n = 4 resulted in a significantly increased cell killing (crizotinib, dabrafenib, panobinostat and doxorubicin), and n = 2 exhibited no or negligible effects (regorafenib, venetoclax). Clival chordoma cell lines were more responsive to combined EGFR-MET inhibition. EGFR-MET cross-talk (e.g. via TGF-α secretion) likely accounts for the synergistic effects of EGFR-MET inhibition. CONCLUSION: Our screen revealed promising combinations with EGFRis, such as the ALK/MET-inhibitor crizotinib, the HDAC-inhibitor panobinostat or the topoisomerase-II-inhibitor doxorubicin, which are part of standard chemotherapy regimens for various bone and soft-tissue sarcomas.

Towards equity: a retrospective analysis of public sector radiological resources and utilization patterns in the metropolitan and rural areas of the Western Cape Province of South Africa in 2017.

BACKGROUND: The reduction of inequality is a key United Nations 2030 Sustainable Development Goal (WHO, Human Resources for Health: foundation for Universal Health Coverage and the post-2015 development agenda, 2014; Transforming our world: the 2030 Agenda for Sustainable Development .:. Sustainable Development Knowledge Platform, 2020). Despite marked disparities in radiological services globally, particularly between metropolitan and rural populations in low- and middle-income countries, there has been little work on imaging resources and utilization patterns in any setting (Transforming our world: the 2030 Agenda for Sustainable Development .:. Sustainable Development Knowledge Platform, 2020; WHO, Local Production and Technology Transfer to Increase Access to Medical Devices, 2019; European Society of Radiology (ESR), Insights Imaging 6:573-7, 2015; Maboreke et al., An audit of licensed Zimbabwean radiology equipment resources as a measure of healthcare access and equity, 2020; Kabongo et al., Pan Afr Med J 22, 2015; Skedgel et al., Med Decis Making 35:94-105, 2015; Mollura et al., J Am Coll Radiol 913-9, 2014; Culp et al., J Am Coll Radiol 12:475-80, 2015; Mbewe et al., An audit of licenced Zambian diagnostic imaging equipment and personnel, 2020). To achieve equity, a better understanding of the integral components of the so called "imaging enterprise" is important. The aim was to analyse a provincial radiological service in a middle-income country. METHODS: An institutional review board-approved retrospective audit of radiological data for the public healthcare sector of the Western Cape Province of South Africa for 2017, utilizing provincial databases. We conducted population-based analyses of imaging equipment, personnel, and service utilization data for the whole province, the metropolitan and the rural areas. RESULTS: Metropolitan population density exceeds rural by a factor of ninety (1682 vs 19 people/km2). Rural imaging facilities by population are double the metropolitan (20 vs 11/106 people). Metropolitan imaging personnel by population (112 vs 53/106 people) and equipment unit (1.7 vs 0.7/unit) are more than double the rural. Overall population-based utilization of imaging services was 30% higher in the metropole (289 vs 214 studies/103 people), with mammography (24 vs 5 studies/103 woman > 40 years) and CT (21 vs 6/103 people) recording the highest, and plain radiography (203 vs 171/103 people) the lowest differences. CONCLUSION: Despite attempts to achieve imaging equity through the provision of increased facilities/million people in the rural areas, differential utilization patterns persist. The achievement of equity must be seen as a process involving incremental improvements and iterative analyses that define progress towards the goal.

Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action.

Arginase 2 (ARG2) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine. The dysregulated expression of ARG2 within specific tumor microenvironments generates an immunosuppressive niche that effectively renders the tumor 'invisible' to the host's immune system. Increased ARG2 expression leads to a concomitant depletion of local L-arginine levels, which in turn leads to suppression of anti-tumor T-cell-mediated immune responses. Here we describe the isolation and characterization of a high affinity antibody (C0021158) that inhibits ARG2 enzymatic function completely, effectively restoring T-cell proliferation in vitro. Enzyme kinetic studies confirmed that C0021158 exhibits a noncompetitive mechanism of action, inhibiting ARG2 independently of L-arginine concentrations. To elucidate C0021158's inhibitory mechanism at a structural level, the co-crystal structure of the Fab in complex with trimeric ARG2 was solved. C0021158's epitope was consequently mapped to an area some distance from the enzyme's substrate binding cleft, indicating an allosteric mechanism was being employed. Following C0021158 binding, distinct regions of ARG2 undergo major conformational changes. Notably, the backbone structure of a surface-exposed loop is completely rearranged, leading to the formation of a new short helix structure at the Fab-ARG2 interface. Moreover, this large-scale structural remodeling at ARG2's epitope translates into more subtle changes within the enzyme's active site. An arginine residue at position 39 is reoriented inwards, sterically impeding the binding of L-arginine. Arg39 is also predicted to alter the pKA of a key catalytic histidine residue at position 160, further attenuating ARG2's enzymatic function. In silico molecular docking simulations predict that L-arginine is unable to bind effectively when antibody is bound, a prediction supported by isothermal calorimetry experiments using an L-arginine mimetic. Specifically, targeting ARG2 in the tumor microenvironment through the application of C0021158, potentially in combination with standard chemotherapy regimens or alternate immunotherapies, represents a potential new strategy to target immune cold tumors.

Extensive sequence and structural evolution of Arginase 2 inhibitory antibodies enabled by an unbiased approach to affinity maturation.

Affinity maturation is a powerful technique in antibody engineering for the in vitro evolution of antigen binding interactions. Key to the success of this process is the expansion of sequence and combinatorial diversity to increase the structural repertoire from which superior binding variants may be selected. However, conventional strategies are often restrictive and only focus on small regions of the antibody at a time. In this study, we used a method that combined antibody chain shuffling and a staggered-extension process to produce unbiased libraries, which recombined beneficial mutations from all six complementarity-determining regions (CDRs) in the affinity maturation of an inhibitory antibody to Arginase 2 (ARG2). We made use of the vast display capacity of ribosome display to accommodate the sequence space required for the diverse library builds. Further diversity was introduced through pool maturation to optimize seven leads of interest simultaneously. This resulted in antibodies with substantial improvements in binding properties and inhibition potency. The extensive sequence changes resulting from this approach were translated into striking structural changes for parent and affinity-matured antibodies bound to ARG2, with a large reorientation of the binding paratope facilitating increases in contact surface and shape complementarity to the antigen. The considerable gains in therapeutic properties seen from extensive sequence and structural evolution of the parent ARG2 inhibitory antibody clearly illustrate the advantages of the unbiased approach developed, which was key to the identification of high-affinity antibodies with the desired inhibitory potency and specificity.

Trypophobia: an investigation of clinical features

Objective: Trypophobia refers to the fear of, or aversion to, clusters of holes. We assessed clinical features of trypophobia and investigated whether it most resembled a specific phobia or obsessive-compulsive disorder. Methods: An online survey was conducted to gather information on sociodemographic variables, course and duration, severity, associated features, comorbid psychiatric diagnoses, and levels of psychological distress and impairment in individuals with trypophobia. The survey also explored whether such individuals experienced more fear or disgust, and whether symptoms showed more resemblance to a specific phobia or to obsessive-compulsive disorder. Associations of symptom severity and duration with degree of impairment were investigated. Results: One hundred and ninety-five individuals completed the questionnaire. Symptoms were chronic and persistent. The most common associated comorbidities were major depressive disorder and generalized anxiety disorder. Trypophobia was associated with significant psychological distress and impairment. The majority of individuals experienced disgust rather than fear when confronted with clusters of holes, but were more likely to meet DSM-5 criteria for specific phobia than for obsessive-compulsive disorder. Symptom severity and duration were associated with functional impairment. Conclusions: Given that individuals with trypophobia suffer clinically significant morbidity and comorbidity, this condition deserves further attention from clinicians and researchers.

Trypophobia: an investigation of clinical features.

OBJECTIVE: Trypophobia refers to the fear of, or aversion to, clusters of holes. We assessed clinical features of trypophobia and investigated whether it most resembled a specific phobia or obsessive-compulsive disorder. METHODS: An online survey was conducted to gather information on sociodemographic variables, course and duration, severity, associated features, comorbid psychiatric diagnoses, and levels of psychological distress and impairment in individuals with trypophobia. The survey also explored whether such individuals experienced more fear or disgust, and whether symptoms showed more resemblance to a specific phobia or to obsessive-compulsive disorder. Associations of symptom severity and duration with degree of impairment were investigated. RESULTS: One hundred and ninety-five individuals completed the questionnaire. Symptoms were chronic and persistent. The most common associated comorbidities were major depressive disorder and generalized anxiety disorder. Trypophobia was associated with significant psychological distress and impairment. The majority of individuals experienced disgust rather than fear when confronted with clusters of holes, but were more likely to meet DSM-5 criteria for specific phobia than for obsessive-compulsive disorder. Symptom severity and duration were associated with functional impairment. CONCLUSIONS: Given that individuals with trypophobia suffer clinically significant morbidity and comorbidity, this condition deserves further attention from clinicians and researchers.

EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen.

Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.