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OBJECTIVES: Paediatric trauma elbow radiographs are difficult to interpret and there is a potential for harm if misdiagnosed. The primary goal of this study was to assess the ability of healthcare professionals internationally to interpret paediatric trauma elbow radiographs from the radiograph alone by formulating the correct diagnosis. METHODS: This prospective international study was conducted online via the Free Open Access Medical Education platform, Don't Forget the Bubbles (DFTB, ISSN 2754-5407). Participants were recruited via the DFTB social media accounts between 17 August and 14 September 2021. Submissions that were incomplete or from participants who do not interpret paediatric elbow radiographs in their clinical practice were excluded. Participants completed an online survey of demographic data followed by interpreting 10 trauma-indicated elbow radiographs, by selecting multiple-choice options. The primary outcome was correct diagnosis. RESULTS: Participant responses from 18 countries were analysed, with most responses from the UK, Australia and Ireland. Participants had backgrounds in emergency medicine (EM), paediatric emergency medicine (PEM), general practice (GP) and paediatrics, with over 70% having 6+ years of postgraduate experience. 3180 radiographs were interpreted by 318 healthcare professionals. Only nine (2.8%) participants correctly diagnosed all 10. The mean number of radiographs correctly interpreted was 5.44 (SD 2.3). The mean number for those with 6+ years of experience was 6.02 (SD 2.2). On reviewing the normal radiograph, 158 (49.7%) overcalled injuries. Participants with EM or PEM background were equally likely to have more correct answers than those from paediatric or GP backgrounds. CONCLUSION: Globally, healthcare professional's success in correctly diagnosing paediatric elbow injuries from radiographs was suboptimal in this non-clinical exercise, despite capturing quite an experienced cohort of clinicians. This study has provided us with detailed baseline data to accurately assess the impact of interventions aimed at improving clinicians' interpretation of paediatric elbow radiographs in future studies.
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Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of Leishmania donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (>60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme may be a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway.
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Resistencia a Medicamentos , Leishmania donovani , Leishmaniasis Visceral , Esterol 14-Desmetilasa , Leishmania donovani/enzimología , Esterol 14-Desmetilasa/metabolismo , Esterol 14-Desmetilasa/genética , Leishmaniasis Visceral/parasitología , Leishmaniasis Visceral/tratamiento farmacológico , Anfotericina B/farmacología , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/genética , NADPH-Ferrihemoproteína Reductasa/metabolismo , NADPH-Ferrihemoproteína Reductasa/genética , Antiprotozoarios/farmacología , Humanos , Ergosterol/metabolismoRESUMEN
A welcome resurgence in African animal trypanosomosis (AAT) research has resulted in advances in capabilities, foundational datasets, and understanding. Additionally, there is the prospect of the first new trypanocide in >60 years. However, it is vital to ensure that advances translate to improved and sustainable control in the field. A recent meeting, the Symposium on African Livestock Trypanosomes - Tanzania, convened stakeholders from across the spectrum of AAT research and control to ask how this can be achieved. Current constraints on progress were defined, as were critical gaps and opportunities that need addressing. There is a requirement and opportunity for the AAT research community to communicate, collaborate, and coordinate to maintain momentum and achieve the ultimate goal of sustainable AAT control.
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Tripanosomiasis Africana , Animales , Tripanosomiasis Africana/prevención & control , Ganado/parasitología , TrypanosomaRESUMEN
The lack of effective vaccines and the development of resistance to the current treatments highlight the urgent need for new anti-leishmanials. Sphingolipid metabolism has been proposed as a promising source of Leishmania-specific targets as these lipids are key structural components of the eukaryotic plasma membrane and are involved in distinct cellular events. Inositol phosphorylceramide (IPC) is the primary sphingolipid in the Leishmania species and is the product of a reaction mediated by IPC synthase (IPCS). The antihistamine clemastine fumarate has been identified as an inhibitor of IPCS in L. major and a potent anti-leishmanial in vivo. Here we sought to further examine the target of this compound in the more tractable species L. mexicana, using an approach combining genomic, proteomic, metabolomic and lipidomic technologies, with molecular and biochemical studies. While the data demonstrated that the response to clemastine fumarate was largely conserved, unexpected disturbances beyond sphingolipid metabolism were identified. Furthermore, while deletion of the gene encoding LmxIPCS had little impact in vitro, it did influence clemastine fumarate efficacy and, importantly, in vivo pathogenicity. Together, these data demonstrate that clemastine does inhibit LmxIPCS and cause associated metabolic disturbances, but its primary target may lie elsewhere.
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Antiprotozoarios , Antiprotozoarios/farmacología , Antiprotozoarios/química , Esfingolípidos/metabolismo , Hexosiltransferasas/genética , Hexosiltransferasas/metabolismo , Hexosiltransferasas/antagonistas & inhibidores , Leishmania/efectos de los fármacos , Leishmania/genética , Leishmania/enzimología , Animales , Leishmania mexicana/efectos de los fármacos , Leishmania mexicana/genética , Leishmania mexicana/enzimología , Glicoesfingolípidos/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismoRESUMEN
Although colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States, the overall incidence and mortality from the disease have declined in recent decades. In contrast, there has been a steady increase in the incidence of CRC in individuals under 50 years of age. Hereditary syndromes contribute disproportionately to early onset CRC (EOCRC). These include microsatellite instability high (MSI+) tumors arising in patients with Lynch Syndrome. However, most EOCRCs are not associated with familial syndromes or MSI+ genotypes. Comprehensive genomic profiling has provided the basis of improved more personalized treatments for older CRC patients. However, less is known about the basis of sporadic EOCRC. To define the genomic landscape of EOCRC we used DNA content flow sorting to isolate diploid and aneuploid tumor fractions from 21 non-hereditary cases. We then generated whole exome mutational profiles for each case and whole genome copy number, telomere length, and EGFR immunohistochemistry (IHC) analyses on subsets of samples. These results discriminate the molecular features of diploid and aneuploid EOCRC and provide a basis for larger population-based studies and the development of effective strategies to monitor and treat this emerging disease.
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Aneuploidia , Neoplasias Colorrectales , Diploidia , Inestabilidad de Microsatélites , Humanos , Neoplasias Colorrectales/genética , Persona de Mediana Edad , Femenino , Masculino , Adulto , Mutación , Receptores ErbB/genética , Edad de Inicio , Genómica/métodosRESUMEN
BACKGROUND: A Toddler's Fracture (TF) is classically an isolated, nondisplaced, distal-third diaphyseal tibial spiral fracture in younger children. A TF is stable and has a low risk of complication. There is lack of uniformity as to the optimal treatment for TF. Immobilisation with full above knee casting, below knee casting, splinting, controlled ankle motion boots and no immobilisation are all strategies currently in use. There is limited data from European centres regarding those treated without immobilisation. METHODS: A retrospective review of electronic medical and radiology records was performed to identify all children presenting to a multisite department of paediatric emergency medicine in Ireland from January to December 2022. Those with radiologically confirmed TF or a presumptive diagnosis of TF were included. Data retrieved for each child included initial treatment and the number of and reason for ED reattendances relating to the injury in the 6-month period following the injury. RESULTS: 166 children were identified, 96 with radiologically confirmed TF and 70 with presumptive diagnosis TF. Girls accounted for 47 % of presentations. Fall from a standing height (33 %) was the most common mechanism. 13 % (22/166) children were managed without immobilisation. Those with radiologically confirmed fracture (91/96) were significantly more likely to be immobilised than those with a presumptive diagnosis (53/70) (p = 0.001). In total 28 patients (17 % of total) represented to the ED within 6 months. The representation rate in those immobilised was 17 %, while in those not immobilised was 13 % (p = 0.66). CONCLUSION: In this cohort, those with no radiological evidence of fracture are more likely to be managed without immobilisation. There was no significant difference in PED representations between those immobilised and not immobilised.
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Moldes Quirúrgicos , Inmovilización , Fracturas de la Tibia , Humanos , Estudios Retrospectivos , Femenino , Masculino , Preescolar , Lactante , Fracturas de la Tibia/diagnóstico por imagen , Fracturas de la Tibia/fisiopatología , Radiografía , Irlanda , Férulas (Fijadores) , Fijación de Fractura/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Vasculature plays a crucial role in the progression of prostate cancer (PC). Changes to the prostatic native vessels have not been studied since 2000 when Garcia et al. demonstrated marked media hypercellularity and increased artery thickness in prostatic native arteries within PC. We aim to further evaluate and characterize prostatic native vessels with a more accurate method with the use of virtual slides and digital analysis. DESIGN: Pathologist-annotated whole-mount digital slides from 96 entirely submitted prostatectomies were annotated for PC (color-coded by Gleason) using Omero platform. A subset of 44 cases met criteria for further analysis of media thickness, cellularity, and wall thickness to lumen ratio. Cases were included based on containing ≥5 native arteries (≥100⯵m diameter) encased on at least 3 sides by PC, with vessels (≥100⯵m diameter) designated as controls if they were ≥ 1000⯵m away from PC. Annotated vessels were segmented and processed using Matlab 2023b. Mean media thickness (corrected for oblique sections), media: lumen ratio (based on numbers of pixels), and media cellularity (nuclei count) were studied by analysis with SPSS by linear mixed model with nested random effects for subject and slide to account for repeated measures. RESULTS: Vessels encased by PC showed greater media thickness (p=0.02), cellularity (p=0.02) and wall thickness/lumen ratio (p= <0.001) compared to vessels away from PC. These values showed an increasing trend according to stage in cellularity (p=0.14), media thickness (p=0.12) and wall thickness/ lumen ratio (p= 0.33) with higher stage (pT3). A Gleason group comparison showed a borderline-significant gradewise trend when analyzing wall thickness/lumen ratio (p=0.06). Grade 5 emerged as significantly different (p=0.02) from grades 3 or 4 non-cribriform. CONCLUSIONS: Similar to the 2000 study, increased media thickness and hypercellularity of vessels encased by PC were evident compared to controls. Borderline grade-dependent increased vessel cellularity changes were seen, suggesting a possible role in PC progression; the predictive value of these changes for outcome is uncertain. Whether the etiology of changes reflects locally increased intravascular pressure of vessels within tumor should be investigated.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/patología , Próstata/patología , Procesamiento de Imagen Asistido por Computador , Prostatectomía , Núcleo Celular/patologíaRESUMEN
Objectives: To determine the percentage of patients across Ireland who are discharged from the Emergency Department (ED) with an antimicrobial prescription, the indication, classification of infections, and guideline compliance. To identify potential areas for antimicrobial stewardship (AMS) interventions in the ED. Patients and methods: A multicentre, prospective cohort analysis study in EDs across eight hospitals in Ireland. At each site, patients aged 1â month and older who presented to the ED and were discharged directly from the ED were included. A random selection of records of patients discharged from the ED were reviewed until a minimum of 30 records with an infection diagnosis resulting in an antibiotic prescription were obtained per hospital. The number of patient discharges with no antibiotic prescriptions were included to calculate the denominator. The indication, infection classification and guideline compliance data were collected on the 30 prescriptions in the participating hospitals. Results: A total of 2619 patient records were reviewed. Of these, 249 (9.5%) patients were discharged with antimicrobial prescriptions from the ED. Most (158; 63%) were classified as probable bacterial infection, 21 (8%) as probable viral, and 18 (7%) had no documented evidence of infection. Three indications accounted for 73% of antimicrobial prescriptions: skin/soft tissue infection; ear, nose and throat infection; and urinary tract infection. Overall guideline compliance was 64%. Conclusions: Several areas for AMS interventions to optimize antimicrobial prescribing in the ED were identified, including targeted local and national guideline reviews, delayed prescribing, improved point-of-care testing and prescriber and patient education.
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Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer patient derived-tumor xenograft (PDTX) models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using whole-exome sequencing. PDTX 3D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular-targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6i. This combination was evaluated in PDTX three-dimensional (3D) spheroids and in vivo experiments with responses measured by tumor volumes, PSA, and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single-agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, whereas tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single-agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in patients with mCRPC whose tumor expresses wild-type retinoblastoma 1.
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Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Neoplasias de la Próstata Resistentes a la Castración , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Humanos , Masculino , Ratones , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Metástasis de la Neoplasia , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease with current treatments marred by severe side effects or delivery issues. To identify novel classes of compounds for the treatment of HAT, high throughput screening (HTS) had previously been conducted on bloodstream forms of T. b. brucei, a model organism closely related to the human pathogens T. b. gambiense and T. b. rhodesiense. This HTS had identified a number of structural classes with potent bioactivity against T. b. brucei (IC50 ≤ 10 µM) with selectivity over mammalian cell-lines (selectivity index of ≥10). One of the confirmed hits was an aroyl guanidine derivative. Deemed to be chemically tractable with attractive physicochemical properties, here we explore this class further to develop the SAR landscape. We also report the influence of the elucidated SAR on parasite metabolism, to gain insight into possible modes of action of this class. Of note, two sub-classes of analogues were identified that generated opposing metabolic responses involving disrupted energy metabolism. This knowledge may guide the future design of more potent inhibitors, while retaining the desirable physicochemical properties and an excellent selectivity profile of the current compound class.
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Parásitos , Tripanocidas , Trypanosoma brucei brucei , Trypanosoma , Tripanosomiasis Africana , Animales , Humanos , Tripanocidas/química , Trypanosoma brucei rhodesiense , Guanidina/farmacología , Tripanosomiasis Africana/tratamiento farmacológico , Tripanosomiasis Africana/parasitología , Guanidinas/farmacología , Metabolismo Energético , MamíferosRESUMEN
Trypanosoma brucei is a causative agent of the Human and Animal African Trypanosomiases. The mammalian stage parasites infect various tissues and organs including the bloodstream, central nervous system, skin, adipose tissue and lungs. They rely on ATP produced in glycolysis, consuming large amounts of glucose, which is readily available in the mammalian host. In addition to glucose, glycerol can also be used as a source of carbon and ATP and as a substrate for gluconeogenesis. However, the physiological relevance of glycerol-fed gluconeogenesis for the mammalian-infective life cycle forms remains elusive. To demonstrate its (in)dispensability, first we must identify the enzyme(s) of the pathway. Loss of the canonical gluconeogenic enzyme, fructose-1,6-bisphosphatase, does not abolish the process hence at least one other enzyme must participate in gluconeogenesis in trypanosomes. Using a combination of CRISPR/Cas9 gene editing and RNA interference, we generated mutants for four enzymes potentially capable of contributing to gluconeogenesis: fructose-1,6-bisphoshatase, sedoheptulose-1,7-bisphosphatase, phosphofructokinase and transaldolase, alone or in various combinations. Metabolomic analyses revealed that flux through gluconeogenesis was maintained irrespective of which of these genes were lost. Our data render unlikely a previously hypothesised role of a reverse phosphofructokinase reaction in gluconeogenesis and preclude the participation of a novel biochemical pathway involving transaldolase in the process. The sustained metabolic flux in gluconeogenesis in our mutants, including a triple-null strain, indicates the presence of a unique enzyme participating in gluconeogenesis. Additionally, the data provide new insights into gluconeogenesis and the pentose phosphate pathway, and improve the current understanding of carbon metabolism of the mammalian-infective stages of T. brucei.
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Gluconeogénesis , Trypanosoma brucei brucei , Animales , Humanos , Gluconeogénesis/genética , Trypanosoma brucei brucei/genética , Trypanosoma brucei brucei/metabolismo , Transaldolasa/metabolismo , Glicerol/metabolismo , Glucosa/metabolismo , Fosfofructoquinasas/metabolismo , Carbono/metabolismo , Adenosina Trifosfato/metabolismo , MamíferosRESUMEN
BACKGROUND: Despite the vast majority of fevers representing benign self-limiting illnesses, caregiver anxiety regarding fever is high. Empowering caregivers with knowledge to safely and appropriately manage fever at home has the potential to reduce demands upon healthcare services. AIM: To improve caregiver knowledge about fever and its management in children via an educational intervention. METHODS: Caregivers of children over 6 months presenting with fever to a Paediatric Emergency Department were recruited. A pre-intervention survey was completed to ascertain caregiver knowledge about fever and its management. The intervention of (i) an infographic about fever, with (ii) a short video on fever was viewed. A post-intervention survey re-assessed knowledge. The primary outcome was the correct definition of fever as a temperature ≥38 °C. RESULTS: Caregivers (n = 51) who correctly defined fever increased from 41% (n = 21) pre-intervention to 94% (n = 48) post-intervention. There was a reduction in common misconceptions about fever, including a higher fever representing a more serious infection (76% vs. 8%). Caregivers reported they were less likely to seek emergency healthcare due to the height and nature of the fever alone. CONCLUSIONS: A simple brief educational intervention can rapidly increase caregiver knowledge about fever in children. There is a continuing need for clear, easily-accessible information for caregivers on this topic. IMPACT: Parental knowledge about fever and how to manage it in their children is low. A simple brief educational intervention can significantly increase caregiver knowledge about fever. A combined written and audiovisual approach is effective and well-received by parents. Educating caregivers has the potential to improve the management of childhood fever at home and to reduce the burden on healthcare services, as well as reduce unpleasant hospital visits for children and their caregivers.
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Cuidadores , Servicio de Urgencia en Hospital , Fiebre , Educación en Salud , Conocimientos, Actitudes y Práctica en Salud , Humanos , Fiebre/terapia , Cuidadores/educación , Femenino , Masculino , Preescolar , Lactante , Niño , Adulto , Encuestas y Cuestionarios , Padres/educaciónRESUMEN
BACKGROUND: Nitrous oxide (N2O) has multiple benefits in paediatric procedural sedation (PPS), but use is restricted by its limited analgesic properties. Analgesic potency could be increased by combining N2O and intranasal fentanyl (INF). We assessed safety and efficacy data from 10 years (2011-2021) of our N2O PPS programme. METHODS: Prospectively collected data from a sedation registry at a paediatric emergency department (PED) were reviewed. Total procedures performed with N2O alone or with INF, success rate, sedation depth and adverse events were determined. Contributing factors for these outcomes were assessed via regression analysis and compared between different N2O concentrations, N2O in combination with INF, and for physician versus nurse administered sedation. A post hoc analysis on factors associated with vomiting was also performed. RESULTS: 831 N2O procedural sedations were performed, 358 (43.1%) involved a combination INF and N2O. Nurses managed sedation in 728 (87.6%) cases. Median sedation depth on the University of Michigan Sedation Scale was 1 (IQR 1-2). Sedation was successful in 809 (97.4%) cases. Combination INF/N2O demonstrated higher median sedation scores (2 vs 1, p<0.001) and increased vomiting (RR 1.8, 95% CI 1.3 to 2.5), with no difference in sedation success compared with N2O alone. No serious adverse events (SAEs) were reported (desaturation, apnoea, aspiration, bradycardia or hypotension) regardless of N2O concentration or use of INF. 137 (16.5%) minor adverse events occurred. Vomiting occurred in 113 (13.6%) cases and was associated with higher concentrations of N2O and INF use, but not associated with fasting status. There were no differences in adverse events (RR 0.98, 95% CI 0.97 to 1.04) or success rates (RR 0.93, 95% CI 0.56 to 1.7) between physician provided and nurse provided sedation. CONCLUSION: N2O can provide effective PED PPS. No SAEs were recorded. INF may be an effective PPS adjunct but remains limited by increased rates of vomiting.
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Analgésicos , Óxido Nitroso , Niño , Humanos , Óxido Nitroso/farmacología , Óxido Nitroso/uso terapéutico , Fentanilo , Vómitos/etiología , Servicio de Urgencia en Hospital , Sedación Consciente/métodosRESUMEN
Digital transformation in healthcare during the COVID-19 pandemic led to the development of new hybrid models integrating physical and virtual care. The ability to provide remote care by telemedicine technologies and the need to better manage and control hospitals' occupancy accelerated growth in hospital-at-home programs. The Sheba Medical Center restructured to create Sheba Beyond as the first virtual hospital in Israel. These transformations enabled them to deliver hybrid services in their internal medicine unit by managing inpatient hospital-care with remote home-care based on the patients' medical condition. The hybrid services evolved to integrate care pathways multiplied by the mode of delivery-physical (in person) or virtual (technology enabled)-and the location of care-at the hospital or the patient home. The study examines this home hospitalization program pilot for internal medicine at Sheba Medical Center (MC). The research is based on qualitative semi-structured interviews with Sheba Beyond management, medical staff from the hospital and the Health Maintenance Organization (HMO), Architects, Information Technology (IT), Telemedicine and Medtech organizations. We investigated the implications of the development of hybrid services for the future design of the physical built-environment and the virtual technological platform. Our findings highlight the importance of designing for flexibility in the development of hybrid care services, while leveraging synergies across the built environment and digital platforms to support future models of care. In addition to exploring the potential for scalability in accelerating the flexibility of the healthcare system, we also highlight current barriers in professional, management, logistic and economic healthcare models.
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INTRODUCTION: Machine learning as a clinical decision support system tool has the potential to assist clinicians who must make complex and accurate medical decisions in fast paced environments such as the emergency department. This paper presents a protocol for a scoping review, with the objective of summarising the existing research on machine learning clinical decision support system tools in the emergency department, focusing on models that can be used for paediatric patients, where a knowledge gap exists. MATERIALS AND METHODS: The methodology used will follow the scoping study framework of Arksey and O'Malley, along with other guidelines. Machine learning clinical decision support system tools for any outcome and population (paediatric/adult/mixed) for use in the emergency department will be included. Articles such as grey literature, letters, pre-prints, editorials, scoping/literature/narrative reviews, non-English full text papers, protocols, surveys, abstract or full text not available and models based on synthesised data will be excluded. Articles from the last five years will be included. Four databases will be searched: Medline (EBSCO), CINAHL (EBSCO), EMBASE and Cochrane Central. Independent reviewers will perform the screening in two sequential stages (stage 1: clinician expertise and stage 2: computer science expertise), disagreements will be resolved by discussion. Data relevant to the research question will be collected. Quantitative analysis will be performed to generate the results. DISCUSSION: The study results will summarise the existing research on machine learning clinical decision support tools in the emergency department, focusing on models that can be used for paediatric patients. This holds the promise to identify opportunities to both incorporate models in clinical practice and to develop future models by utilising reviewers from diverse backgrounds and relevant expertise.
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Sistemas de Apoyo a Decisiones Clínicas , Proyectos de Investigación , Adulto , Humanos , Niño , Toma de Decisiones Clínicas , Aprendizaje Automático , Servicio de Urgencia en Hospital , Literatura de Revisión como AsuntoRESUMEN
IMPORTANCE: In malaria drug discovery, understanding the mode of action of lead compounds is important as it helps in predicting the potential emergence of drug resistance in the field when these drugs are eventually deployed. In this study, we have employed metabolomics technologies to characterize the potential targets of anti-malarial drug candidates in the developmental pipeline at NITD. We show that NITD fast-acting leads belonging to spiroindolone and imidazothiadiazole class induce a common biochemical theme in drug-exposed malaria parasites which is similar to another fast-acting, clinically available drug, DHA. These biochemical features which are absent in a slower acting NITD lead (GNF17) point to hemoglobin digestion and inhibition of the pyrimidine pathway as potential action points for these drugs. These biochemical themes can be used to identify and inform on the mode of action of fast drug candidates of similar profiles in future drug discovery programs.
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Antimaláricos , Malaria Falciparum , Malaria , Humanos , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Plasmodium falciparum , Descubrimiento de Drogas , Malaria Falciparum/tratamiento farmacológico , Resistencia a MedicamentosRESUMEN
East Coast Fever (ECF) is a disease affecting cattle in sub-Saharan Africa, caused by the tick-borne Apicomplexan pathogen Theileria parva. The disease is a major problem for cattle farmers in affected regions and there are few methods of control, including a complex infection and treatment vaccine, expensive chemotherapy, and the more widespread tick control through acaricides. New intervention strategies are, therefore, sorely needed. Benzoxaboroles are a versatile class of boron-heterocyclic compounds with demonstrable pharmacological activity against a diverse group of pathogens, including those related to T. parva. In this study, the in vitro efficacy of three benzoxaboroles against the intracellular schizont stage of T. parva was investigated using a flow cytometry approach. Of the benzoxaboroles tested, only one showed any potency, albeit only at high concentrations, even though there is high protein sequence similarity in the CPSF3 protein target compared to other protozoan pathogen species. This finding suggests that benzoxaboroles currently of interest for the treatment of African animal trypanosomiasis, toxoplasmosis, cryptosporidiosis and malaria may not be suitable for the treatment of ECF. We conclude that testing of further benzoxaborole compounds is needed to fully determine whether any lead compounds can be identified to target T. parva.