RESUMEN
BACKGROUND: In New Zealand, an estimated 10% of women and people presumed female at birth have endometriosis, a disease characterised by the presence of tissue similar to the lining of the uterus, outside of the uterus. AIMS: The purpose of this study was to characterise the research priorities of New Zealand endometriosis patients and their support networks in alignment with an Australian study. This will allow researchers to be able to ensure their research aligns with closing research gaps prioritised by those who directly experience the impacts of the disease. METHODS AND MATERIALS: There were 1262 responses to an online Qualtrics survey advertised through Endometriosis New Zealand's social media accounts and mailing list to reach endometriosis patients and their support networks. RESULTS: Overall, the highest research priorities for surgically or radiologically confirmed endometriosis patients, clinically suspected endometriosis patients, chronic pelvic pain patients, and their parents, partners, family members and friends were the management and treatment of endometriosis, followed by understanding endometriosis' cause, and improved capacity to diagnose endometriosis earlier. The key differences between the priorities of symptomatic participants and supporters were that symptomatic participants placed a significantly higher priority on understanding the cause of endometriosis, and supporters placed a significantly higher priority on improving the diagnosis of endometriosis. CONCLUSIONS: There is alignment between the ranking of general research priority areas for endometriosis in Australasia, allowing for clear priorities for future research teams to structure their work around patient-centredness.
RESUMEN
Endometriosis is a common condition with varying delays from symptom onset to diagnosis reported internationally. In New Zealand, the previously accepted average delay to diagnosis was 8.6-8.7 years. An online survey completed by the largest cohort of self-reported New Zealand-confirmed endometriosis patients (n = 1024) for the collection of delay to diagnosis was conducted in September and October of 2023. The results revealed an average delay of 9.7 ± 7.1 years overall, with a significantly longer delay in the North Island than in the South. This study identifies potential factors for future research that may influence diagnostic delays in New Zealand.
RESUMEN
Striations are present on ultrasonography of the intermediate (middle) patellar ligament in the transverse plane, which can be confused with tears. Comparison to the contralateral limb is often performed to help differentiate anatomic variation from pathologic change. The purposes of this prospective, observational study were to describe the striation patterns in Warmbloods and Quarter Horses, determine if these patterns are bilaterally symmetrical, and compare striation characteristics between Warmbloods and Quarter Horses. The intermediate patellar ligaments of six Warmblood horses and six Quarter horses, free from clinical signs of hindlimb lameness and in full work, were examined ultrasonographically. Striation pattern, striation number, and the transverse-sectional areas for intermediate patellar ligaments were compared between Warmbloods and Quarter horses. Striation patterns were also compared for the left and right limbs of each horse. A significant difference between breeds was identified at the mid-portion of the intermediate patellar ligament when both left and right ligaments were included (P = 0.02) and when comparing the right intermediate patellar ligament (P = 0.02). There were no other significant breed differences, and a parallel pattern was the most common pattern type. Two-thirds of the horses in this study had bilaterally symmetrical patterns within the distal aspect of their intermediate patellar ligaments, while one-third of the population were asymmetric. These results show that comparison of the contralateral limb during ultrasonography to determine if changes within the distal aspect of the intermediate patellar ligament are normal striations versus tears may lead to misdiagnosis in one-third of horses, regardless of breed. Other signs of pathology on ultrasonography should be used instead.
Asunto(s)
Enfermedades de los Caballos , Ligamento Rotuliano , Animales , Enfermedades de los Caballos/patología , Caballos , Cojera Animal/diagnóstico por imagen , Cojera Animal/patología , Ligamentos/diagnóstico por imagen , Ligamentos/patología , Ligamento Rotuliano/diagnóstico por imagen , Estudios Prospectivos , Ultrasonografía/veterinariaRESUMEN
Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore and are proposed to act by a novel but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine MIPS-0004373 across the mammalian life cycle stages of the parasite and profiled the kinetics of activity against blood and transmission stage parasites in vitro and in vivo. MIPS-0004373 demonstrated rapid and potent activity against P. falciparum, with excellent in vitro activity against all asexual blood stages. Prolonged in vitro drug exposure failed to generate stable resistance de novo, suggesting a low propensity for the emergence of resistance. Excellent activity was observed against sexually committed ring stage parasites, but activity against mature gametocytes was limited to inhibiting male gametogenesis. Assessment of liver stage activity demonstrated good activity in an in vitro P. berghei model but no activity against Plasmodium cynomolgi hypnozoites or liver schizonts. The bis-1,2,4-triazine MIPS-0004373 efficiently cleared an established P. berghei infection in vivo, with efficacy similar to that of artesunate and chloroquine and a recrudescence profile comparable to that of chloroquine. This study demonstrates the suitability of bis-1,2,4-triazines for further development toward a novel treatment for acute malaria.
Asunto(s)
Malaria , Parásitos , Animales , Malaria/tratamiento farmacológico , Masculino , Plasmodium berghei , Triazinas/farmacologíaRESUMEN
BACKGROUND: Gaze following difficulties are considered an early marker of autism, thought likely to cumulatively impact the development of social cognition, language and social skills. Subtle differences in gaze following abilities may contribute to the diverse range social and communicative autistic characteristics observed across people with genetic syndromes, such as Cornelia de Lange (CdLS) and fragile X (FXS) syndromes. AIMS: To compare profiles of 1) visual attention to the eye region at critical points of the attention direction process, 2) whether children follow the gaze cue to the object, and 3) participant looking time to the target object following the gaze cue between groups and conditions. MATERIALS AND METHODS: Children with CdLS (N = 11) and FXS (N = 8) and autistic (N = 22) and neurotypical (N = 15) children took part in a passive viewing paradigm adapted from Senju and Csibra (2008), in which videos of a central cue (ball/cartoon face/human face) directed attention towards one of two objects. Visual attention patterns were recorded via eye tracking technology. RESULTS: Neurotypical children were used as a reference group against which the autistic, CdLS and FXS groups were compared. Although autistic children looked at the eye region for significantly less time, they looked at the target object as frequently and for a similar duration as neurotypical children. Children with FXS looked at the target as frequently as neurotypical children but looked at it for comparatively less time. Both neurotypical children and children with CdLS frequently looked at the eye region, but children with CdLS were less likely to look at the target than neurotypical children. CONCLUSIONS: Findings provide preliminary evidence of unique patterns of visual attention and gaze following strategies in children with CdLS, children with FXS and autistic children. These unique gaze following patterns may underpin the distinct profiles of social and communication autistic traits observed between these groups.
Asunto(s)
Trastorno Autístico , Síndrome de Cornelia de Lange , Síndrome del Cromosoma X Frágil , Niño , Humanos , Comunicación , LenguajeRESUMEN
Mammalian DNA replication employs several RecQ DNA helicases to orchestrate the faithful duplication of genetic information. Helicase function is often coupled to the activity of specific nucleases, but how helicase and nuclease activities are co-directed is unclear. Here we identify the inactive ubiquitin-specific protease, USP50, as a ubiquitin-binding and chromatin-associated protein required for ongoing replication, fork restart, telomere maintenance and cellular survival during replicative stress. USP50 supports WRN:FEN1 at stalled replication forks, suppresses MUS81-dependent fork collapse and restricts double-strand DNA breaks at GC-rich sequences. Surprisingly we find that cells depleted for USP50 and recovering from a replication block exhibit increased DNA2 and RECQL4 foci and that the defects in ongoing replication, poor fork restart and increased fork collapse seen in these cells are mediated by DNA2, RECQL4 and RECQL5. These data define a novel ubiquitin-dependent pathway that promotes the balance of helicase: nuclease use at ongoing and stalled replication forks.
RESUMEN
The Susan D. Flynn Oncology Nursing Fellowship is an eight-week immersive experience that allows rising senior nursing students to gain clinical experience and promotes professional development in oncology nursing.
Asunto(s)
Bachillerato en Enfermería , Estudiantes de Enfermería , Humanos , Enfermería Oncológica/educación , Estudiantes de Enfermería/psicología , BecasRESUMEN
Endometriosis is an invasive condition that affects 10% of women (and people assigned as female at birth) worldwide. The purpose of this study was to characterize the relative invasiveness of three available endometriotic cell lines (EEC12Z, iEc-ESCs, tHESCs) to cancer cell lines (MDA-MB-231, SW1353 and EM-E6/E7/TERT) and assess whether the relative invasiveness was consistent across different invasion assays. All cell lines were subjected to transwell, spheroid drop, and spheroid-gel invasion assays, and stained for vimentin, cytokeratin, E-Cadherin and N-Cadherin to assess changes in expression. In all assays, endometriotic cell lines showed comparable invasiveness to the cancer cell lines used in this study, with no significant differences in invasiveness identified. EEC12Z cells that had invaded within the assay periods showed declines in E-Cadherin expression compared to cells that had not invaded within the assay period, without significant changes in N-Cadherin expression, which may support the hypothesis that an epithelial-to-mesenchymal transition is an influence on the invasiveness shown by this peritoneal endometriosis cell line.
Asunto(s)
Neoplasias Endometriales , Endometriosis , Recién Nacido , Femenino , Humanos , Endometriosis/metabolismo , Línea Celular , Cadherinas/genética , Cadherinas/metabolismo , Mama/metabolismo , Neoplasias Endometriales/genética , Movimiento Celular , Invasividad NeoplásicaRESUMEN
Introduction: Endometriosis is a common condition with average delays to diagnosis in New Zealand of almost 9 years. Methods: In total, 50 endometriosis patients participated in anonymous, asynchronous, online group discussions about their priorities, and their experiences with the development of symptoms, seeking a diagnosis, and receiving appropriate treatment. Results: Higher subsidy of care was the top change endometriosis patients wanted, followed by more research funding. When asked to choose whether research should be focused on improving diagnosis or improving treatment methods, the results were evenly split. Within this cohort, patients highlighted that they did not know the difference between normal menstrual discomfort and pathological endometriotic pain. If, upon seeking help, medical practitioners classified their symptoms as "normal," these dismissals could instill doubt in patients, which made it more difficult for them to continue to seek a diagnosis and effective treatments. Patients who did not express dismissal had a significantly shorter delay from symptom onset to diagnosis of 4.6 ± 3.4 years vs. 9.0 ± 5.2 years. Conclusion: Doubt is a frequent experience for endometriosis patients in New Zealand, which was reinforced by some medical practitioners who were dismissive of their pain and thus prolonged the patient's delay to diagnosis.
RESUMEN
Endometriosis is a chronically painful, invasive, inflammatory disease, with limited treatment options and long delays to diagnosis, which impacts 10% of females in New Zealand. Introduction: As part of a larger group discussion study, this paper covers three themes associated with endometriosis patient experiences: intensity of pain, diagnostic tool shortcomings and perspectives of treatment options. Materials and methods: The goal of this research was the inclusion of patient voices to guide research priorities. In early 2022, 50 New Zealand endometriosis patients participated in anonymous, asynchronous, text-based group discussions on the VisionsLive platform. The patients ranged in age from 18-48. The patients answered 50 questions, 23 text-based and 27 quantitative, and then took part in online group discussions. Results and discussion: The average age of symptom onset was 15.3 years, while the average delay from symptom onset to a working or surgically confirmed diagnosis was 7.91 years. The top five reported symptoms within the cohort were pain-based, and the participants discussed the many impacts of this pain on their work and education. The four main diagnostic tools employed on this cohort were abdominal ultrasound (72%), transvaginal ultrasound (68%), laparoscopy (82%) and sharing their symptom history with a medical practitioner (88%). The most common emotions patients experienced following receiving a diagnosis of endometriosis were relief (86%), feeling overwhelmed (54%), and anger (32%). The main treatments offered to this cohort were pain relief (96%), laparoscopic surgery (84%) and the combined oral contraceptive pill (80%). Of these three treatments, only laparoscopic surgery was viewed positively by the majority of users, with 67% considering laparoscopy an effective treatment, compared to 46% of users for pain relief, and 25% of users for the combined oral contraceptive pill. Conclusions: Gathering the voice of patients revealed that long delays to diagnosis and dismissal by medical practitioners frequently manifests as a reaction of relief by patients once diagnosed. Results also showed treatment options such as pain relief and hormonal medications were often considered ineffective, but were routinely offered as the first, or only, options for patients. It is therefore important that both quicker routes to diagnosis and more effective treatment options be developed.
RESUMEN
Endometriosis is an inflammatory chronic pain condition caused by uterine tissue growing outside of the uterus that afflicts at least 11% of women (and people assigned female at birth) worldwide. This condition results in a substantial burden to these women, and society at large. Although endometriosis was first identified over 160 years ago, substantial knowledge gaps remain, including confirmation of the disease's etiology. Research funding for endometriosis is limited, with funding from bodies like the National Institutes of Health (NIH) constituting only 0.038% of the 2022 health budget-for a condition that affects 6.5 million women in the US alone and over 190 million worldwide. A major issue is that diagnosis of endometriosis is frequently delayed because surgery is required to histologically confirm the diagnosis. This delay increases symptom intensity, the risk of central and peripheral sensitization and the costs of the disease for the patient and their nation. Current conservative treatments of presumed endometriosis are pain management and birth control. Both of these methods are flawed and can be entirely ineffective for the reduction of patient suffering or improving ability to work, and neither addresses the severe infertility issues or higher risk of certain cancers. Endometriosis research deserves the funding and attention that befits a disease with its substantial prevalence, effects, and economic costs. This funding could improve patient outcomes by introducing less invasive and more timely methods for diagnosis and treatment, including options such as novel biomarkers, nanomedicine, and microbiome alterations.
RESUMEN
BACKGROUND: Individuals with genetic syndromes show unique profiles of repetitive behaviours and restricted interests (RRBs). The executive dysfunction account of RRBs suggests that in autistic (AUT) individuals executive function impairments underpin RRBs, but not communication and social interaction autistic characteristics. AIMS: To 1) describe profiles of behavioural manifestations of executive function (EF behaviours) and 2) explore the relationship between EF behaviours and autistic traits across individuals with Cornelia de Lange (CdLS), fragile X (FXS) and Rubinstein-Taybi syndromes (RTS), and AUT individuals. METHOD: Carers completed the Behavior Rating Inventory of Executive Function - Preschool Version and the Social Communication Questionnaire. Data reporting on 25 individuals with CdLS (Mage = 18.60, SD = 8.94), 25 with FXS (Mage = 18.48, SD = 8.80), 25 with RTS (Mage = 18.60, SD = 8.65) and 25 AUT individuals (Mage = 18.52, SD = 8.65) matched on chronological age and adaptive ability were included in analyses. RESULTS: All groups showed impairments across EF behaviours compared to two-to-three-year-old typically developing normative samples with no differences between groups. Different EF behaviours predicted RRBs in the syndrome groups with no associations found in the AUT group. CONCLUSIONS: Syndrome related differences should be considered when developing targeted interventions that focus on EF behaviours and/or RRBs in these groups.
Asunto(s)
Trastorno Autístico , Síndrome de Cornelia de Lange , Síndrome del Cromosoma X Frágil , Síndrome de Rubinstein-Taybi , Preescolar , Función Ejecutiva , HumanosRESUMEN
The clinical relationship between equine limb lameness and secondary back dysfunction is largely unknown. Proper function of the spine is critical to maintain the integrity of the kinetic chain and attenuate forces from the appendicular skeleton. The musculus multifidus (m. multifidus) is the primary muscle providing spinal intersegmental stabilization and a functional relationship between m. multifidus hypertrophy and equine postural stability has been established. The relationship between equine thoracolumbar m. multifidus cross-sectional area (CSA) and limb lameness is unknown. The objective was to evaluate ultrasonographic changes in thoracolumbar m. multifidus CSA in horses with chronic single limb lameness, compared with sound horses. We hypothesized that the CSA of m. multifidus, ipsilateral to the lame limb would be smaller than the contralateral side, and within the sound group there would be no difference between sides. Thirty-six horses were enrolled, with twelve horses per group: sound, forelimb lame, and hindlimb lame. M. multifidus CSA was measured ultrasonographically at multiple spinal levels and compared between groups, spinal levels, and sides. M. multifidus CSA at the spinal level T18 was significantly larger than at all other measured levels, regardless of group (P ≤ .05). CSA at all levels was significantly larger in sound horses than the forelimb lame group, regardless of side (P = .002). This is the first study to evaluate the impact of chronic lameness on the axial skeleton and showed a decrease in m. multifidus CSA with forelimb lameness. These results support that axial skeletal adaptation occurs in response to naturally occurring chronic lameness.
Asunto(s)
Enfermedades de los Caballos , Cojera Animal , Animales , Marcha/fisiología , Enfermedades de los Caballos/diagnóstico por imagen , Caballos , Cojera Animal/diagnóstico por imagen , Músculos , Músculos Paraespinales/diagnóstico por imagenRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,Rp), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC.
Asunto(s)
Replicación del ADN , Nucleósidos , Neoplasias Pancreáticas , Proteínas de Ciclo Celular/metabolismo , Daño del ADN , Proteínas de Unión al ADN/metabolismo , Humanos , Metalocenos , Nucleósidos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Fase S , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias PancreáticasRESUMEN
In endemic settings it is known that natural malaria immunity is gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage malaria immunity would occur following repeated parasite exposure by controlled human malaria infection (CHMI). We report the findings of repeat homologous blood-stage Plasmodium falciparum (3D7 clone) CHMI studies VAC063C (ClinicalTrials.gov NCT03906474) and VAC063 (ClinicalTrials.gov NCT02927145). In total, 24 healthy, unvaccinated, malaria-naïve UK adult participants underwent primary CHMI followed by drug treatment. Ten of these then underwent secondary CHMI in the same manner, and then six of these underwent a final tertiary CHMI. As with primary CHMI, malaria symptoms were common following secondary and tertiary infection, however, most resolved within a few days of treatment and there were no long term sequelae or serious adverse events related to CHMI. Despite detectable induction and boosting of anti-merozoite serum IgG antibody responses following each round of CHMI, there was no clear evidence of anti-parasite immunity (manifest as reduced parasite growth in vivo) conferred by repeated challenge with the homologous parasite in the majority of volunteers. However, three volunteers showed some variation in parasite growth dynamics in vivo following repeat CHMI that were either modest or short-lived. We also observed no major differences in clinical symptoms or laboratory markers of infection across the primary, secondary and tertiary challenges. However, there was a trend to more severe pyrexia after primary CHMI and the absence of a detectable transaminitis post-treatment following secondary and tertiary infection. We hypothesize that this could represent the initial induction of clinical immunity. Repeat homologous blood-stage CHMI is thus safe and provides a model with the potential to further the understanding of naturally acquired immunity to blood-stage infection in a highly controlled setting. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03906474, NCT02927145.
Asunto(s)
Malaria Falciparum , Malaria , Parásitos , Adulto , Animales , Humanos , Plasmodium falciparum , Reino UnidoRESUMEN
Local injection of corticosteroids is commonly performed in horses with sacroiliac (SI) region pain and/or dysfunction, ,and ultrasound findings of normal horses and those with SI pain have also been well described. However, no studies have been performed that have evaluated if ultrasound findings, injection technique, or medications injected affect prognosis for return to function. The objectives of the current study are to determine if findings on ultrasound, injection technique, or medications injected are predictive of return to function in horses with SI region pain and/or dysfunction. Medical records were evaluated for horses that had ultrasound exam of the SI region as well as local injection with corticosteroids. A client survey was sent to determine the horse's return to performance. Logistic regression was performed to determine which variables were predictive of horses with SI pain and/or dysfunction returning to performance. A return to the same or higher level of work was found in 26 of 42 (62%) of horses after SI injections, 4 of 42 (10%) of horses returned to a lower level of work, and 12 of 42 (28%) did not return to work at any level. Horses that were injected with methylprednisolone were 4.2 times more likely to return to performance than horses injected with triamcinolone. Factors evaluated on ultrasound of the SI region did not predict whether a horse would return to performance following SI region injection.
Asunto(s)
Enfermedades de los Caballos , Articulación Sacroiliaca , Corticoesteroides , Animales , Enfermedades de los Caballos/diagnóstico por imagen , Caballos , Inyecciones/veterinaria , Estudios Retrospectivos , Articulación Sacroiliaca/diagnóstico por imagenRESUMEN
BACKGROUND: Cornelia de Lange (CdLS), Fragile X (FXS) and Rubinstein-Taybi syndromes (RTS) evidence unique profiles of autistic characteristics. To delineate these profiles further, the development of early social cognitive abilities in children with CdLS, FXS and RTS was compared to that observed in typically developing (TD) and autistic (AUT) children. METHODS: Children with CdLS (N = 22), FXS (N = 19) and RTS (N = 18), completed the Early Social Cognition Scale (ESCogS). Extant data from AUT (N = 19) and TD (N = 86) children were used for comparison. RESULTS: Similar to AUT children, children with CdLS, FXS and RTS showed an overall delay in passing ESCogS tasks. Children with CdLS showed a similar degree of delay to AUT children and greater delay than children with FXS and RTS. The CdLS, FXS and RTS groups did not pass tasks in the same sequence observed in TD and AUT children. Children with CdLS (p = 0.04), FXS (p = 0.02) and RTS (p = 0.04) performed better on tasks requiring understanding simple intentions in others significantly more than tasks requiring joint attention skills. CONCLUSIONS: An underlying mechanism other than general cognitive delay may be disrupting early social cognitive development in children with CdLS, FXS and RTS. Factors that may disrupt early social cognitive development within these syndromes are discussed.
Asunto(s)
Trastorno Autístico , Síndrome de Cornelia de Lange , Síndrome del Cromosoma X Frágil , Síndrome de Rubinstein-Taybi , Niño , Cognición , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/psicología , Humanos , Síndrome de Rubinstein-Taybi/genéticaRESUMEN
This chapter describes the step-by-step methods employed by the Structural Genomics Consortium (SGC) for screening and producing proteins in the BacMam system. This eukaryotic expression system was selected and a screening process established in 2016 to enable production of highly challenging human integral membrane proteins (IMPs), which are a significant component of our target list. Here, we discuss our recently developed platform for identifying expression and monodispersity of IMPs from 3 mL of HEK293 cells.
Asunto(s)
Expresión Génica , Vectores Genéticos/genética , Proteínas de la Membrana , Células HEK293 , Humanos , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genéticaRESUMEN
Controlled human malaria infection (CHMI) provides a highly informative means to investigate host-pathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs and vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe and suitable for use in modern CHMI models are limited. Here, 2 healthy malaria-naive United Kingdom adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI. Parasitemia developed in both volunteers, and prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected RBCs. Following stringent safety screening, the parasite stabilate from one of these donors (PvW1) was thawed and used to inoculate 6 healthy malaria-naive United Kingdom adults by blood-stage CHMI, at 3 different dilutions. Parasitemia developed in all volunteers, who were then successfully drug treated. PvW1 parasite DNA was isolated and sequenced to produce a high-quality genome assembly by using a hybrid assembly method. We analyzed leading vaccine candidate antigens and multigene families, including the vivax interspersed repeat (VIR) genes, of which we identified 1145 in the PvW1 genome. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies.
Asunto(s)
Genoma/genética , Malaria Falciparum/genética , Animales , Voluntarios Sanos , Humanos , Masculino , Plasmodium vivaxRESUMEN
BACKGROUND: Development of an effective vaccine against the pathogenic blood-stage infection of human malaria has proved challenging, and no candidate vaccine has affected blood-stage parasitemia following controlled human malaria infection (CHMI) with blood-stage Plasmodium falciparum. METHODS: We undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the P. falciparum reticulocyte-binding protein homolog 5 (RH5), formulated in AS01B adjuvant. We assessed safety, immunogenicity, and efficacy against blood-stage CHMI. Trial registered at ClinicalTrials.gov, NCT02927145. FINDINGS: The RH5.1/AS01B formulation was administered using a range of RH5.1 protein vaccine doses (2, 10, and 50 µg) and was found to be safe and well tolerated. A regimen using a delayed and fractional third dose, in contrast to three doses given at monthly intervals, led to significantly improved antibody response longevity over â¼2 years of follow-up. Following primary and secondary CHMI of vaccinees with blood-stage P. falciparum, a significant reduction in parasite growth rate was observed, defining a milestone for the blood-stage malaria vaccine field. We show that growth inhibition activity measured in vitro using purified immunoglobulin G (IgG) antibody strongly correlates with in vivo reduction of the parasite growth rate and also identify other antibody feature sets by systems serology, including the plasma anti-RH5 IgA1 response, that are associated with challenge outcome. CONCLUSIONS: Our data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease. FUNDING: This study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC.