Using machine learning to improve the diagnostic accuracy of the modified Duke/ESC 2015 criteria in patients with suspected prosthetic valve endocarditis - a proof of concept study.

INTRODUCTION: Prosthetic valve endocarditis (PVE) is a serious complication of prosthetic valve implantation, with an estimated yearly incidence of at least 0.4-1.0%. The Duke criteria and subsequent modifications have been developed as a diagnostic framework for infective endocarditis (IE) in clinical studies. However, their sensitivity and specificity are limited, especially for PVE. Furthermore, their most recent versions (ESC2015 and ESC2023) include advanced imaging modalities, e.g., cardiac CTA and [18F]FDG PET/CT as major criteria. However, despite these significant changes, the weighing system using major and minor criteria has remained unchanged. This may have introduced bias to the diagnostic set of criteria. Here, we aimed to evaluate and improve the predictive value of the modified Duke/ESC 2015 (MDE2015) criteria by using machine learning algorithms. METHODS: In this proof-of-concept study, we used data of a well-defined retrospective multicentre cohort of 160 patients evaluated for suspected PVE. Four machine learning algorithms were compared to the prediction of the diagnosis according to the MDE2015 criteria: Lasso logistic regression, decision tree with gradient boosting (XGBoost), decision tree without gradient boosting, and a model combining predictions of these (ensemble learning). All models used the same features that also constitute the MDE2015 criteria. The final diagnosis of PVE, based on endocarditis team consensus using all available clinical information, including surgical findings whenever performed, and with at least 1 year follow up, was used as the composite gold standard. RESULTS: The diagnostic performance of the MDE2015 criteria varied depending on how the category of 'possible' PVE cases were handled. Considering these cases as positive for PVE, sensitivity and specificity were 0.96 and 0.60, respectively. Whereas treating these cases as negative, sensitivity and specificity were 0.74 and 0.98, respectively. Combining the approaches of considering possible endocarditis as positive and as negative for ROC-analysis resulted in an excellent AUC of 0.917. For the machine learning models, the sensitivity and specificity were as follows: logistic regression, 0.92 and 0.85; XGBoost, 0.90 and 0.85; decision trees, 0.88 and 0.86; and ensemble learning, 0.91 and 0.85, respectively. The resulting AUCs were, in the same order: 0.938, 0.937, 0.930, and 0.941, respectively. DISCUSSION: In this proof-of-concept study, machine learning algorithms achieved improved diagnostic performance compared to the major/minor weighing system as used in the MDE2015 criteria. Moreover, these models provide quantifiable certainty levels of the diagnosis, potentially enhancing interpretability for clinicians. Additionally, they allow for easy incorporation of new and/or refined criteria, such as the individual weight of advanced imaging modalities such as CTA or [18F]FDG PET/CT. These promising preliminary findings warrant further studies for validation, ideally in a prospective cohort encompassing the full spectrum of patients with suspected IE.

The impact of the multidisciplinary Endocarditis Team on the management of infective endocarditis.

BACKGROUND: In their latest guidelines for infective endocarditis (IE) (2015), the European Society of Cardiology (ESC) introduced the implementation of the Endocarditis Team (ET) to facilitate the management of IE. This study presents our experiences and the diagnostic and therapeutic impact of the ET on the management of IE. METHODS: From 2016-2020, data of all patients with suspected IE referred to the ET were prospectively collected. The final diagnosis was defined by the ET as either rejected, possible or definite IE. Diagnostic impact was scored as any change in initial diagnosis, the frequency of additional diagnostic tests advised by the ET and any change in diagnosis after these tests. Therapeutic impact was scored as any change in antibiotic therapy or change from conservative to invasive therapy or vice versa. RESULTS: A total of 321 patients (median age 67 [55-77] years, 71% male) were enrolled. The final diagnosis was rejected IE in 47 (15%), possible IE in 34 (11%) and definite IE in 240 (75%) patients. A change of initial diagnosis was seen in 53/321(17%) patients. Additional microbiological tests were advised in 69/321 (21%) patients, and additional imaging tests in 136/321 (42%) patients, which resulted in subsequent change in diagnosis in 23/321 (7%) patients. Any change in antibiotic treatment was advised in 135/321 (42%) patients, and change from initial conservative to additional surgical treatment in 15/321 (5%) patients. CONCLUSION: The ET had a clear impact on the therapeutic policy for patients with suspected IE and is useful in the management of this life-threatening disease. Broad implementation is warranted.

A robust post-insertion method for the preparation of targeted siRNA LNPs.

Targeted delivery of nucleic acids is gaining momentum due to improved efficacy, selectivity, increased circulation time and enhanced tissue retention in target cells. Using nucleic acid-based therapies previously undruggable targets have proven now to be amenable for treatment. Currently, several methods for preparing targeted or labelled delivery vehicles for nucleic acids are based on liposomal formulations. Lipid nanoparticles (LNPs) are structurally different from liposomes and these methods should therefore be evaluated before being translated to siRNA LNPs preparation protocols. Here, we describe a robust and facile method for the preparation of targeted or fluorescently labelled siRNA LNPs. Using a copper free strain-promoted azide-alkyne cycloaddition (SPAAC) we demonstrate that post-insertion of ligand-lipid conjugates into preformed LNPs is superior to direct-surface modification because it preserves the physicochemical parameters of the LNPs. We found that the time point of solvent removal by dialysis is critical and affects the hydrodynamic diameter of the LNPs; post-insertion after dialysis shows the smallest increase in hydrodynamic diameter and polydispersity index (PDI). The post-insertion of ligand-lipid conjugates also proceeded with rapid kinetics and high efficacy over a wide temperature range. Using this optimised protocol, we generated siRNA LNPs containing both targeting and fluorescent tracking ligands allowing us to monitor siRNA LNP uptake kinetics in dependence of the targeting ligand. In aggregate, we describe a robust approach for the generation of targeted and labelled siRNA LNPs that allows their controlled and facile decoration with ligand combinations.

The incidence and characteristics of homicides in elderly compared with non-elderly age groups in Johannesburg, South Africa.

BACKGROUND: Even though the rate of eldercide (homicide in the age group ≥60 years) in South Africa (SA) is higher than the global rate, it receives little attention compared with homicide in younger (<60 years) age groups. OBJECTIVES: To: (i) establish the proportion and rates of eldercide relative to homicide in young adult and middle-aged populations, and determine whether proportions of homicide across the age groups differ by race; and (ii) determine differences in homicide victim and incident characteristics across the three age categories and establish whether these differences vary by race. METHODS: This retrospective study analysed homicide data for adults (aged ≥15 years) drawn from the National Injury Mortality Surveillance System (NIMSS) for the City of Johannesburg, SA (2001 - 2010). Percentages and rates were used to describe the incidence of eldercide (age ≥60 years) relative to homicide in middle age (35 - 59 years) and youth (15 - 34 years). Eldercide and middle-age and youth homicides were compared by sex, race, weapon used, scene of injury, day of the week and time of death. RESULTS: For the 10-year period 2001 - 2010, NIMSS registered a total of 14 678 adult homicide deaths for Johannesburg. Of these, a very small proportion (3.8%) were eldercides, 46.9% were middle-age homicides, and the majority (58.4%) were young adult homicides. The average annual eldercide rate (23.1/100 000) was also lower than the rate for the middle-aged (46.9/100 000) and young adult (58.4/100 000) groups. However, the difference in rates between the age groups decreased considerably over the study period. Race-specific patterns were observed in the distribution of homicide across age groups. Compared with the circumstantial patterns for youth and middle-age homicides, eldercide involved higher proportions of females and white victims, and greater use of blunt force and strangulation. Whereas homicides in the other age groups tended to occur in public spaces and during weekends and nights, eldercides occurred mainly in a home, during the week and during daytime. CONCLUSIONS: The characteristics of eldercide differ from those of youth and middle-age homicides. The specificities of the circumstances suggest that interventions should take cognisance of the temporal and spatial dimensions of eldercide and go beyond the regular security and policing measures to ensure the safety of the elderly in Johannesburg.

Dual-time-point FDG PET/CT imaging in prosthetic heart valve endocarditis.

PURPOSE: FDG PET/CT has been of increasing interest in the diagnostic workup of prosthetic heart valve endocarditis (PVE). Some reports advocate later imaging time points to improve the diagnostic accuracy for PVE. In this study, we compared standard and late FDG PET/CT images in patients with a clinical suspicion of PVE. MATERIALS AND METHODS: Fourteen scans in 13 patients referred for FDG PET/CT for suspicion of PVE performed at standard (60 min post injection) and late (150 min post injection) time points were scored based on visual interpretation and semi-quantitatively with SUVmax and target-to-background ratio (TBR, defined as [SUVmax valve/SUVmean blood pool]). Final diagnosis was based on surgical findings in all cases of infection (n = 6) and unremarkable follow-up in all others (n = 8). RESULTS: Late images were more prone to false positive interpretation for both visual and semi-quantitative analyses. Visual analysis of the standard images yielded 1 false negative and 1 false positive result. On the late images, no scans were false negative but 5 scans were false positive. CONCLUSION: Late FDG PET/CT imaging for PVE seems prone to false positive results. Therefore, late imaging should be interpreted with caution.

Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization.

BACKGROUND: Pazopanib is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Post hoc analysis of a clinical trial demonstrated a relationship between pazopanib trough concentrations (Cmin) and treatment efficacy. The aim of this study was to explore the pharmacokinetics and exposure-survival relationships of pazopanib in a real-world patient cohort. PATIENTS AND METHODS: Renal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated Cmin values and a threshold of > 20 mg/L, univariate and multivariate exposure-survival analyses were performed. RESULTS: Sixty-one patients were included, of which 16.4% were underexposed (mean Cmin < 20 mg/L) using the 800 mg fixed-dosed schedule. In univariate analysis Cmin > 20 mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5 weeks, n = 35, p = 0.027) and the overall population (25.0 vs. 8.8 weeks, n = 61, p = 0.012), but not in the sarcoma subgroup (18.7 vs. 8.8 weeks, n = 26, p = 0.142). In multivariate analysis Cmin > 20 mg/L was associated with hazard ratios of 0.25 (p = 0.021) in renal cancer, 0.12 (p = 0.011) in sarcoma and 0.38 (p = 0.017) in a pooled analysis. CONCLUSION: This study confirms that pazopanib Cmin > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Cmin monitoring of pazopanib can help identify patients with low Cmin for whom individualized treatment at a higher dose may be appropriate.

Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome.

BACKGROUND: The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower-risk myelodysplastic syndrome (MDS) from 17 European countries from both university hospitals and smaller regional hospitals. OBJECTIVE: The aim of this study was to describe the usage and clinical impact of erythropoiesis-stimulating agents (ESAs) in 1696 patients enrolled between 2008 and 2014. METHODS: The effects of ESAs on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. RESULTS: ESA treatment (median duration of 27.5 months, range 0-77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit (HR 0.82, 95% CI: 0.65-1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions (P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post-ESA treatment transfusion was 6.1 months (IQR: 4.3-15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0-47.8 months) in patients without prior transfusions (HR 2.4, 95% CI: 1.7-3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death (HR 0.65, 95% CI: 0.45-0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia (HR 0.71, 95% CI: 0.39-1.29, P = 0.27). CONCLUSION: Appropriate use of ESAs can significantly delay the onset of a regular transfusion need in patients with lower-risk MDS.

Household and caregiver characteristics and behaviours as predictors of unsafe exposure of children to paraffin appliances.

This study examines adult safety knowledge and practices regarding the use of paraffin cooking appliances. The use of these is common in South Africa with injury risks that are poorly understood. This cross-sectional study was in an informal settlement in Johannesburg, South Africa, where children were reportedly at high risk for burns. This study sought to clarify relationships between key risks and developed individual and composite variables from theoretical constructs and operational definitions of risks for burns. Risks included Child Use of Paraffin Appliances, Child Proximity to Cooking, Risky Stove Use, Caregiver's Burn Treatment Knowledge, Children Locked in House, Children Alone in House. Number of children remains as in proof as this was not a composite scale. Child Proximity to Cooking was associated with more children in the home. Households where children were in greater proximity to cooking were 6 times more likely to be left alone at home, with caregivers with no education over 100 times more likely to lock their children at home. Children locked in were often from homes where caregivers used appliances unsafely. In settings with hazardous energy use, compressed household configurations, and families with multiple children, Risky Stove Use and the practice of locking children in the home may be catastrophic.

Fungal pathogens of Proteaceae.

Species of Leucadendron, Leucospermum and Protea (Proteaceae) are in high demand for the international floriculture market due to their brightly coloured and textured flowers or bracts. Fungal pathogens, however, create a serious problem in cultivating flawless blooms. The aim of the present study was to characterise several of these pathogens using morphology, culture characteristics, and DNA sequence data of the rRNA-ITS and LSU genes. In some cases additional genes such as TEF 1-α and CHS were also sequenced. Based on the results of this study, several novel species and genera are described. Brunneosphaerella leaf blight is shown to be caused by three species, namely B. jonkershoekensis on Protea repens, B. nitidae sp. nov. on Protea nitida and B. protearum on a wide host range of Protea spp. (South Africa). Coniothyrium-like species associated with Coniothyrium leaf spot are allocated to other genera, namely Curreya grandicipis on Protea grandiceps, and Microsphaeropsis proteae on P. nitida (South Africa). Diaporthe leucospermi is described on Leucospermum sp. (Australia), and Diplodina microsperma newly reported on Protea sp. (New Zealand). Pyrenophora blight is caused by a novel species, Pyrenophora leucospermi, and not Drechslera biseptata or D. dematoidea as previously reported. Fusicladium proteae is described on Protea sp. (South Africa), Pestalotiopsis protearum on Leucospermum cuneiforme (Zimbabwe), Ramularia vizellae and R. stellenboschensis on Protea spp. (South Africa), and Teratosphaeria capensis on Protea spp. (Portugal, South Africa). Aureobasidium leaf spot is shown to be caused by two species, namely A. proteae comb. nov. on Protea spp. (South Africa), and A. leucospermi sp. nov. on Leucospermum spp. (Indonesia, Portugal, South Africa). Novel genera and species elucidated in this study include Gordonomyces mucovaginatus and Pseudopassalora gouriqua (hyphomycetes), and Xenoconiothyrium catenata (coelomycete), all on Protea spp. (South Africa).

Paraprofessional home visitation program to prevent childhood unintentional injuries in low-income communities: a cluster randomized controlled trial.

OBJECTIVE: To investigate the effectiveness of a paraprofessional home visitation program (HVP) to improve home safety and prevent injuries among children living in low-income settings. METHODS: The HVP was implemented in two low-income communities in South Africa. In each community, approximately 200 households were randomly selected for the trial. Eligible households were those with children aged < or = 10 years. Intervention households received four visits, one every two weeks, by trained paraprofessionals that focused on a specific injury topic and consisted of: information dissemination about specific injury prevention practices; home inspection accompanied by information about home hazards; and the supply of safety devices. The key outcomes to measure the presence of home hazards were scores for burns (safety practices, paraffin, and electrical), poisoning, and falls. RESULTS: Significant reductions were found for injury risks related to burn safety practices. For injury risks related to electrical burns, paraffin burns, and poisoning, a decline was also noted although this was not statistically significant. No decline was noted for fall-related risks. CONCLUSIONS: Subject to further replication and evaluation, home visits by paraprofessionals providing safety education, home inspection, and safety devices be considered for integration into a comprehensive child injury prevention strategy in low-income communities.

First Record of Botrytis Flower Blight Caused by Botrytis cinerea on Geraldton Waxflower in South Africa.

Geraldton waxflower (Chamelaucium uncinatum Schauer, family Myrtaceae), indigenous to western Australia, is cultivated commercially in South Africa as a cut-flower crop and exported to markets in the Northern Hemisphere. In September 2000, disease symptoms were observed on 4-year-old plants in a commercial orchard of C. uncinatum cv. Ofir in Philippe, in the Western Cape Province. The base of the petals and the calyxes of the waxflowers showed brown necrotic lesions. Eventually the calyx and all the petals turned brown, and the flowers shriveled and abscised. B. cinerea Pers.:Fr was consistently isolated from affected petal and calyx tissues. When placed in a moist chamber, conidia and mycelia formed on the surface of dead and infected tissue. Koch's postulates were confirmed by spraying flower stems of C. uncinatum cv. Ofir with a spore suspension (1 × 106 conidia per ml). Inoculated flower stems were placed in a bottle filled with water and enclosed in transparent plastic bags for 24 h at 21°C. Typical symptoms developed on the petals and calyx within 3 days after inoculation. B. cinerea was reisolated from affected tissues. Botrytis flower blight or gray mold, causing a flower petal disease, has been recorded on C. uncinatum in Australia (1), but this is the first record of Botrytis flower blight of C. uncinatum in South Africa. Because Geraldton waxflower is a major cut-flower crop grown for export, this disease can cause significant losses to the industry, especially under cool, wet growing conditions. Reference: (1) A. Tomas et al. Aust. Plant Pathol. 24:26, 1995.

Poisoning with Boophane disticha: a forensic case.

Scales from the bulb are traditionally used as wound dressing after circumcision and as general wound dressing. Concoctions of the bulb taken orally cause sedation, analgesia, visual hallucinations, irrational behaviour, coma or death. A man ingested 150 ml of a concoction to see who placed a spell on him. He started to hallucinate, thinking that somebody was attacking him. He pulled his gun and fired shots randomly, killing one person and injuring others. A gas chromatograph/mass spectrometer was used to analyze a sample of the concoction. The sample contained buphandrin, buphanine and crinamidine (alkaloids) and eugenol. Buphanine has a pharmacological action similar to that of hyoscine and, when ingested in toxic quantities, leads to excitement, agitation, hallucinations and coma. Eugenol is a volatile oil with analgesic properties. Although itcould not be proved that the concoction was only from Boophane disticha, the components were similar to those found in Amaryllidaceae to which Boophane belongs. The man's behaviour could be ascribed to the ingestion of compounds found in B. disticha.

First Report of Botrytis Blight, Caused by Botrytis cinerea, on Hibiscus in South Africa.

Roselle (Hibiscus sabdariffa L.) is an annual herb grown in China, Thailand, Mexico, and Africa. Different plant parts are used for cold and hot beverages, food ingredients, edible oil, and medicinal properties. In May 1999, a disease was observed in a commercial field of 6-month-old H. sabdariffa plants in Eshowe, KwaZulu-Natal, South Africa. Stems of diseased plants had brown, sunken lesions covered with green-gray spore masses. Infected stems collapsed. Lesions initiated on stems expanded rapidly under cool, humid conditions. In some cases, lesions developed on the flower stalk and expanded to the calyx, causing death of the calyx. Leaves had no lesions or sporulation, but as stem blight progressed, leaves wilted and fell off. Botrytis cinerea Pers.:Fr. (1) was consistently isolated from affected stem and flower stalk tissues. The pathogen produced profuse conidia and mycelia on the surface of dead and infected stems and calyxes, which resulted in a moldy gray appearance. The average size of conidia produced on naturally infected stems ranged from 5.5 to 8.0 × 6.0 to 13.0 µm (average 6.5 × 9.2 µm). On potato dextrose agar (1-month-old culture), conidia ranged from 5.0 to 9.5 × 6.5 to 12.5 µm (average 7.3 × 8.7 µm) based on 50 spore measurements. Microsclerotia were round or irregular and ranged from 1.2 to 3.0 × 1.0 to 2.5 mm (average 2.1 × 2.0 mm). Koch's postulates were confirmed by spraying potted, 6-month-old H. sabdariffa plants with a spore suspension (1 × 105 conidia per ml). Inoculated plants were enclosed in transparent plastic bags for 7 days at 15 and 20°C (night and day) in a glasshouse. Typical symptoms developed on stems and calyxes within 7 days after inoculation. B. cinerea was reisolated from affected tissues. Botrytis gray mold blight has been recorded on H. rosa-sinensis L. and Hibiscus sp. in Florida (2), but this is the first report of Botrytis blight on Hibiscus spp. in South Africa. Because the disease can result in plant death, Botrytis blight may have a significant impact on the establishment and yield of this crop in the field, especially under cool, wet growing conditions. References: (1) M. B. Ellis. 1971. Dematiaceous Hyphomycetes. CAB, Kew, Surrey, England. (2) D. F. Farr et al. 1989. Fungi on Plants and Plant Products in the United States. The American Phytopathological Society, St. Paul, MN.

An observer-blind randomised parallel group study comparing the efficacy and tolerability of tenoxicam and piroxicam in the treatment of post-operative pain after oral surgery.

Tenoxicam and piroxicam were compared for analgesic efficacy in 58 patients undergoing removal of bilateral impacted third molar teeth, under general anaesthesia. Pain intensity was assessed over a 7 day period by the patient using verbal and visual analogue scales. The patients received one hour pre-operatively dormicum 7.5 mg orally and either tenoxicam 40 mg or piroxicam 40 mg rectally. This was followed by tenoxicam 20 mg daily in effervescent form, or piroxicam 20 mg daily in despersible tablet form for 7 days. Surgical and anaesthetic techniques were standardized for all patients. Therapeutic gain was assessed by comparing hourly pain levels 4 hours post-operatively and then twice daily for 7 days. Trismus was evaluated pre-operatively, at one hour, 24 hours and 7 days post-operatively. Analysis of the results showed a statistical significant difference between the treatment groups only 4 hours post-operatively, patients in the tenoxicam group experiencing less pain than those in the piroxicam group (p = < 0.05).