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Introduction The Western Cape Provincial Health Data Centre (PHDC) consolidates person-level clinical data across government services, leveraging sustained investments in patient registration systems, a unique identifier, and maturation of administrative and clinical digital health systems. Objectives The PHDC supports clinical care directly through tools for clinicians which integrate patient data or identify patients in need of interventions, and indirectly through supporting operational and epidemiological analyses.  Methods The PHDC is housed entirely within government. Data are processed from a range of source systems, usually daily, through distinct harmonisation and curation, beneficiation, and reporting processes. Linkage is predominantly through the unique identifier which doubles as a pervasive folder number, augmented by other identifiers. Further data processing includes triangulation of multiple data sources for enumerating health conditions, with assignment of certainty levels for each enumeration. Outputs include patient-specific email alerts, a web-based consolidated patient clinical viewing platform, filterable line-listings of patients with specific conditions and associated characteristics and outcomes, management reports and dashboards, and data releases in response to operational and research data requests.  Strict architectural, administrative and governance processes ensure privacy-protection.  Results In the past decade 8 million unique people are recorded as having sought healthcare in the provincial public sector health services, with current utilisation at 15 million attendances or admissions a year.  Cross-sectional enumeration of health conditions includes over 430 000 people with HIV, 500 000 with hypertension, 235 000 with diabetes. 110 000 pregnancies and 54 000 patients with tuberculosis are enumerated annually. Each year over 50 data requests are processed for internal and external requesters in accordance with data request and release governance processes.  Conclusions The single consolidated environment for person-level health data in the Western Cape has created new opportunities for supporting patient care, while improving the governance around access to and release of sensitive patient data.

The association between preterm delivery (PTD) and exposure to air pollutants has recently become a major concern. We investigated this relationship in Incheon, Republic of Korea, using spatial and temporal modeling to better infer individual exposures. The birth cohort consisted of 52,113 singleton births in 2001–2002, and data included residential address, gestational age, sex, birth date and order, and parental age and education. We used a geographic information system and kriging methods to construct spatial and temporal exposure models. Associations between exposure and PTD were evaluated using univariate and multivariate log-binomial regressions. Given the gestational age, birth date, and the mother’s residential address, we estimated each mother’s potential exposure to air pollutants during critical periods of the pregnancy. The adjusted risk ratios for PTD in the highest quartiles of the first trimester exposure were 1.26 [95% confidence interval (CI), 1.11–1.44] for carbon monoxide, 1.27 (95% CI, 1.04–1.56) for particulate matter with aerodynamic diameter ≤ 10 μm, 1.24 (95% CI, 1.09–1.41) for nitrogen dioxide, and 1.21 (95% CI, 1.04–1.42) for sulfur dioxide. The relationships between PTD and exposures to CO, NO2, and SO2 were dose dependent (p < 0.001, p < 0.02, p < 0.02, respectively). In addition, the results of our study indicated a significant association between air pollution and PTD during the third trimester of pregnancy. In conclusion, our study showed that relatively low concentrations of air pollution under current air quality standards during pregnancy may contribute to an increased risk of PTD. A biologic mechanism through increased prostaglandin levels that are triggered by inflammatory mediators during exposure periods is discussed.

BackgroundAntiretroviral treatment (ART) has been massively scaled up to decrease human immunodeficiency virus (HIV)–related morbidity, mortality, and HIV transmission. However, despite documented increases in ART coverage, morbidity and mortality have remained substantial. This study describes trends in the numbers and characteristics of patients with very advanced HIV disease in the Western Cape, South Africa.MethodsAnnual cross-sectional snapshots of CD4 distributions were described over 10 years, derived from a province-wide cohort of all HIV patients receiving CD4 cell count testing in the public sector. Patients with a first CD4 count <50 cells/µL in each year were characterized with respect to prior CD4 and viral load testing, ART access, and retention in ART care.ResultsPatients attending HIV care for the first time initially constituted the largest group of those with CD4 count <50 cells/µL, dropping proportionally over the decade from 60.9% to 26.7%. By contrast, the proportion who were ART experienced increased from 14.3% to 56.7%. In patients with CD4 counts <50 cells/µL in 2016, 51.8% were ART experienced, of whom 76% could be confirmed to be off ART or had recent viremia. More than half who were ART experienced with a CD4 count <50 cells/µL in 2016 were men, compared to approximately one-third of all patients on ART in the same year.ConclusionsOngoing HIV-associated morbidity now results largely from treatment-experienced patients not being in continuous care or not being fully virologically suppressed. Innovative interventions to retain ART patients in effective care are an essential priority for the ongoing HIV response.

Objectives: We aimed to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection, and whether protection against severe disease conferred by prior infection and/or vaccination was maintained. Methods: In this cohort study, we included public sector patients aged ≥20 years with a laboratory confirmed COVID-19 diagnosis between 14 November-11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalization or death and any hospitalization or death (all ≤14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection. Results: We included 5,144 patients from wave four and 11,609 from prior waves. Risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted Hazard Ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR:0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58). Conclusions: In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for an approximately 25% reduced risk of severe hospitalization or death compared to Delta.

P-glycoprotein (Pgp), the ATP-binding cassette (ABC) transporter, confers multidrug resistance to cancer cells by extruding cytotoxic natural product amphipathic drugs using the energy of ATP hydrolysis. Our studies are directed toward understanding the mechanism of action of Pgp and recent work deals with the assessment of interaction between substrate and ATP sites and elucidation of the catalytic cycle of ATP hydrolysis. The kinetic analyses of ATP hydrolysis by reconstituted purified Pgp suggest that ADP release is the rate-limiting step in the catalytic cycle and the substrates exert their effect by modulating ADP release. In addition, we provide evidence for two distinct roles for ATP hydrolysis in a single turnover of Pgp, one in the transport of drug and the other in effecting conformational changes so as to reset the transporter for the next catalytic cycle. Detailed kinetic measurements determined that both nucleotide-binding domains behave symmetrically and during individual hydrolysis events the ATP sites are recruited in a random manner. Furthermore, only one nucleotide site hydrolyzes ATP at any given time, causing (in this site) a conformational change that drastically decreases (>30-fold) the affinity of the second site for ATP-binding. Thus, the blocking of ATP-binding to the second site while the first one is in catalytic conformation appears to be the basis for the alternate catalytic cycle of ATP hydrolysis by Pgp, and this may be applicable as well to other ABC transporters linked with the development of multidrug resistance.

Cancer cells resistant to chemically diverse drugs with multiple mechanisms of action are defined as exhibiting the multiple drug resistance (MDR) 1 phenotype. The best defined form of MDR in human cells is due to the overexpression of Pglycoprotein (Pgp). This 170-kDa plasma membrane protein is a member of the ATP-binding cassette (ABC) superfamily of transport proteins, and can extrude a range of hydrophobic anticancer drugs from cells against a concentration gradient and thus render cells resistant to cytotoxic chemotherapeutic agents. Analysis of hydropathy plots suggests that Pgp consists of two homologous halves each containing six transmembrane helices and one nucleotide-binding or ATP site in each half (1, 2).The extrusion of cytotoxic agents is powered by ATP hydrolysis, and the ATPase activity of Pgp has been studied in considerable detail. [␣-32 P]8-azido-ATP, a radiolabeled, photoaffinity analogue of ATP, has proved to be a valuable reagent in understanding interactions between nucleotide and Pgp (3-7). The use of [␣-32 P]8-azido-ATP along with orthovanadate (Vi) has permitted experimental strategies to elucidate the catalytic cycle (3,5,(7)(8)(9)(10)(11)(12). Vi inhibits Pgp ATPase activity by trapping nucleotide in the catalytic site to generate the transition state conformation, Pgp⅐ADP⅐Vi. It has been established that it is always a nucleoside diphosphate that is the trapped species (3, 13). Thus if ATP (or 8-azido-ATP) is used to initiate the reaction, at least one turnover of ATP hydrolysis, converting ATP to ADP, is essential for trapping to occur. This has allowed Vi-trapping experiments to be used to construct a catalytic scheme for ATP hydrolysis by Pgp.Our recent work (10 -12) has considerably expanded the original model for the catalytic scheme of Pgp proposed by Senior and co-workers (14). Our data suggest that ATP hydrolysis at one of the two ATP sites results in a dramatic conformational change where the affinities of both the substrate and the nucleotide for Pgp are drastically reduced. The fact that ATP binding to the second site is arrested while the first one is in a catalytic conformation appears to be the basis for alternate catalysis in Pgp (12). Moreover, for Pgp to regain the conformation that binds substrate with high affinity, the hydrolysis of an additional molecule of nucleotide is obligatory. Finally, we showed that release of ADP from the Pgp⅐ADP⅐P i transition state is the rate-limiting step in the catalytic cycle of ATP hydrolysis (11).Much of the work described above has benefited from the

The cellular source(s) and the clinical significance of persistent low‐level viremia, below 50 HIV RNA copies per ml of plasma, achieved in many patients with high adherence to highly active antiretroviral therapy (HAART) remain unclear. Also, it is not clear if residual plasma HIVs during HAART can become predominant populations in the rebounding plasma viral loads after therapy interruption. Since, different HIV quasispecies tend to compartmentalize in various cell types and tissue locations in patients during chronic infection, the phylogenetic relationships between HIV sequences amplified from residual plasma viruses and CD4 T cells of five patients on long‐term suppressive therapy were examined. Three of these patients stopped therapy voluntarily for 3 weeks, but only one of them demonstrated viral load rebound in plasma. In phylogenetic analyses, the residual plasma viruses were found to be distinct genetically from the majority of CD4 T cell‐associated virus populations in four of five patients. The compartmental analyses revealed that in all patients, plasma‐ and CD4 T cell‐derived viral sequences were compartmentalized separately. Interestingly, the plasma sequences obtained before and after HAART‐off in two patients were produced apparently from the same compartment, which was different from the circulating CD4 T cell‐compartment. These results suggest the possibility that residual plasma viruses in patients on long‐term suppressive HAART may be produced persistently from a cellular source yet to be identified, and are capable of spreading quickly in vivo, accounting for the rapid rebound of viral loads in plasma after therapy interruption. J. Med. Virol. 81:9–15, 2009. © 2008 Wiley‐Liss, Inc.