The Impact of Hydrated Aluminosilicates Supplemented in Litter and Feed on Chicken Growth, Muscle Traits and Gene Expression in the Intestinal Mucosa

The aim of the study was to compare the production, muscle traits and gene expression in the intestinal mucosa of chickens supplemented with aluminosilicates in feed and litter simultaneously. A total of 300 Ross 308 were maintained for 42 days. Group 1 was the control group. In group 2, 0.650 kg/m2 of halloysite was added to the litter and 0.5–2% to the feed (halloysite and zeolite in a 1:1 ratio); in group 3, we added zeolite (0.650 kg/m2) to the litter and 0.5–2% to the feed. The production parameters, the slaughter yield and analyses of muscle quality were analyzed. There was a higher body weight, body weight gain and feed conversion ratio on day 18 and 33 in group 3, and a higher feed intake on day 19–33 in groups 2 and 3 than in 1. A lower water-holding capacity was found in the breasts of group 2 and in the legs of group 3 compared to group 1. The expression of genes related to the immune response, host defense and intestinal barrier and nutrient sensing in the intestinal tissue was analyzed. The results show a beneficial effect on the immune status of the host without an adverse effect on the expression of genes related to intestinal tightness or nutritional processes. Due to the growth, meat characteristics and the positive impact of immunostimulant and regulating properties, aluminosilicates can be suggested as a litter and feed additive in the rearing of chickens.

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QOL-49. THE IMPACT OF OTOTOXICITY AND VISUAL IMPAIRMENT ON EDUCATION IN CHILDREN TREATED FOR CNS TUMOURS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.704 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii440-iii440

Author(s):

Harriet Dulson ◽

Rachel McAndrew ◽

Mark Brougham

Keyword(s):

Visual Impairment ◽

Impaired Hearing ◽

Cranial Radiotherapy ◽

Radiotherapy Group ◽

Platinum Based Chemotherapy ◽

Cns Tumours ◽

Group 3 ◽

Group 2 ◽

The Impact ◽

Group 1

Abstract INTRODUCTION Children treated for CNS tumours experience a very high burden of adverse effects. Platinum-based chemotherapy and cranial radiotherapy can cause ototoxicity, which may be particularly problematic in patients who have impaired vision and cognition as a result of their tumour and associated treatment. This study assessed the prevalence of impaired hearing and vision and how this may impact upon education. METHODS 53 patients diagnosed with solid tumours in Edinburgh, UK between August 2013–2018 were included in the study. Patients were split into three groups according to treatment received: Group 1 – cisplatin-based chemotherapy and cranial radiotherapy; Group 2 - platinum-based chemotherapy, no cranial radiotherapy; Group 3 – benign brain tumours treated with surgery only. Data was collected retrospectively from patient notes. RESULTS Overall 69.5% of those treated with platinum-based chemotherapy experienced ototoxicity as assessed by Brock grading and 5.9% of patients had reduced visual acuity. Patients in Group 1 had the highest prevalence of both. 44.4% of patients in Group 1 needed increased educational support following treatment, either with extra support in the classroom or being unable to continue in mainstream school. 12.5% of Group 2 patients required such support and 31.3% in Group 3. CONCLUSIONS Children with CNS tumours frequently require support for future education but those treated with both platinum-based chemotherapy and cranial radiotherapy are at particular risk, which may be compounded by co-existent ototoxicity and visual impairment. It is essential to provide appropriate support for this patient cohort in order to maximise their educational potential.

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Association between serum oestradiol level on the hCG administration day and neonatal birthweight after IVF-ET among 3659 singleton live births

Scientific Reports ◽

10.1038/s41598-021-85692-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yu Liu ◽

Jing Li ◽

Wanyu Zhang ◽

Yihong Guo

Keyword(s):

Birth Weight ◽

Ovarian Stimulation ◽

Group 4 ◽

Group 6 ◽

Group 3 ◽

Group 5 ◽

Group 2 ◽

The Impact ◽

Ivf Et ◽

Group 1

AbstractOestradiol, an important hormone in follicular development and endometrial receptivity, is closely related to clinical outcomes of fresh in vitro fertilization-embryo transfer (IVF-ET) cycles. A supraphysiologic E2 level is inevitable during controlled ovarian hyper-stimulation (COH), and its effect on the outcome of IVF-ET is controversial. The aim of this retrospective study is to evaluate the association between elevated serum oestradiol (E2) levels on the day of human chorionic gonadotrophin (hCG) administration and neonatal birthweight after IVF-ET cycles. The data of 3659 infertile patients with fresh IVF-ET cycles were analysed retrospectively between August 2009 and February 2017 in First Hospital of Zhengzhou University. Patients were categorized by serum E2 levels on the day of hCG administration into six groups: group 1 (serum E2 levels ≤ 1000 pg/mL, n = 230), group 2 (serum E2 levels between 1001 and 2000 pg/mL, n = 524), group 3 (serum E2 levels between 2001 and 3000 pg/mL, n = 783), group 4 (serum E2 levels between 3001 and 4000 pg/mL, n = 721), group 5 (serum E2 levels between 4001 and 5000 pg/mL, n = 548 ), and group 6 (serum E2 levels > 5000 pg/mL, n = 852). Univariate linear regression was used to evaluate the independent correlation between each factor and outcome index. Multiple logistic regression was used to adjust for confounding factors. The LBW rates were as follows: 3.0% (group 1), 2.9% (group 2), 1.9% (group 3), 2.9% (group 4), 2.9% (group 5), and 2.0% (group 6) (P = 0.629), respectively. There were no statistically significant differences in the incidences of neonatal LBW among the six groups. We did not detect an association between peak serum E2 level during ovarian stimulation and neonatal birthweight after IVF-ET. The results of this retrospective cohort study showed that serum E2 peak levels during ovarian stimulation were not associated with birth weight during IVF cycles. In addition, no association was found between higher E2 levels and increased LBW risk. Our observations suggest that the hyper-oestrogenic milieu during COS does not seem to have adverse effects on the birthweight of offspring after IVF. Although this study provides some reference, the obstetric-related factors were not included due to historical reasons. The impact of the high estrogen environment during COS on the birth weight of IVF offspring still needs future research.

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THU0227 CAFFEINE INTAKE MODULATES DISEASE ACTIVITY AND CYTOKINES LEVELS IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2100 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 340.2-341

Author(s):

V. Orefice ◽

F. Ceccarelli ◽

C. Barbati ◽

R. Lucchetti ◽

G. Olivieri ◽

...

Keyword(s):

Disease Activity ◽

Lupus Erythematosus ◽

Caffeine Intake ◽

Caffeine Consumption ◽

Group 4 ◽

Group 3 ◽

Group 2 ◽

The Impact ◽

Group 1

Background:Systemic lupus erythematosus (SLE) is an autoimmune disease mainly affecting women of childbearing age. The interplay between genetic and environmental factors may contribute to disease pathogenesis1. At today, no robust data are available about the possible contribute of diet in SLE. Caffeine, one of the most widely consumed products in the world, seems to interact with multiple components of the immune system by acting as a non-specific phosphodiesterase inhibitor2.In vitrodose-dependent treatment with caffeine seems to down-regulate mRNA levels of key inflammation-related genes and similarly reduce levels of different pro-inflammatory cytokines3.Objectives:We evaluated the impact of caffeine consumption on SLE-related disease phenotype and activity, in terms of clinimetric assessment and cytokines levels.Methods:We performed a cross-sectional study, enrolling consecutive patients and reporting their clinical and laboratory data. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2k)4. Caffeine intake was evaluated by a 7-day food frequency questionnaire, including all the main sources of caffeine. As previously reported, patients were divided in four groups according to the daily caffeine intake: <29.1 mg/day (group 1), 29.2-153.7 mg/day (group 2), 153.8-376.5 mg/day (group 3) and >376.6 mg/day (group 4)5. At the end of questionnaire filling, blood samples were collected from each patient to assess cytokines levels. These were assessed by using a panel by Bio-Plex assays to measure the levels of IL-6, IL-10, IL-17, IL-27, IFN-γ, IFN-α and Blys.Results:We enrolled 89 SLE patients (F/M 87/2, median age 46 years, IQR 14; median disease duration 144 months, IQR 150). The median intake of caffeine was 195 mg/day (IQR 160.5). At the time of the enrollment, 8 patients (8.9%) referred a caffeine intake < 29.1 mg/day (group 1), 27 patients (30.3%) between 29.2 and 153.7 mg/day (group 2), 45 patients (51%) between 153.8 and 376.5 mg/day (group 3) and 9 patients (10.1%) >376.6 mg/day (group 4). A negative correlation between the levels of caffeine and disease activity, evaluated with SLEDAI-2K, was observed (p=0.01, r=-0.26). By comparing the four groups, a significant higher prevalence of lupus nephritis, neuropsychiatric involvement, haematological manifestations, hypocomplementemia and anti-dsDNA positivity was observed in patients with less intake of caffeine (figure 1 A-E). Furthermore, patients with less intake of caffeine showed a significant more frequent use of glucocorticoids [group 4: 22.2%,versusgroup 1 (50.0%, p=0.0001), group 2 (55.5%, p=0.0001), group 3 (40.0%, p=0.009)]. Moving on cytokines analysis, a negative correlation between daily caffeine consumption and serum level of IFNγ was found (p=0.03, r=-0.2) (figure 2A); furthermore, patients with more caffeine intake showed significant lower levels of IFNα (p=0.02, figure 2B), IL-17 (p=0.01, figure 2C) and IL-6 (p=0.003, figure 2D).Conclusion:This is the first report demonstrating the impact of caffeine on SLE disease activity status, as demonstrated by the inverse correlation between its intake and both SLEDAI-2k values and cytokines levels. Moreover, in our cohort, patients with less caffeine consumption seems to have a more severe disease phenotype, especially in terms of renal and neuropsychiatric involvement. Our results seem to suggest a possible immunoregulatory dose-dependent effect of caffeine, through the modulation of serum cytokine levels, as already suggested byin vitroanalysis.References:[1]Kaul et alNat. Rev. Dis. Prim.2016; 2. Aronsen et alEurop Joul of Pharm2014; 3. Iris et alClin Immun.2018; 4. Gladman et al J Rheumatol. 2002; 5. Mikuls et alArth Rheum2002Disclosure of Interests:Valeria Orefice: None declared, Fulvia Ceccarelli: None declared, cristiana barbati: None declared, Ramona Lucchetti: None declared, Giulio Olivieri: None declared, enrica cipriano: None declared, Francesco Natalucci: None declared, Carlo Perricone: None declared, Francesca Romana Spinelli Grant/research support from: Pfizer, Consultant of: Novartis, Gilead, Lilly, Sanofi, Celgene, Speakers bureau: Lilly, cristiano alessandri Grant/research support from: Pfizer, Guido Valesini: None declared, Fabrizio Conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi

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Abstract 15948: Impact of Age on Safety of Radiofrequency Ablation in Patients With Atrial Fibrillation

Circulation ◽

10.1161/circ.130.suppl_2.15948 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Janet W Elcano ◽

Hui Nam Pak

Keyword(s):

Atrial Fibrillation ◽

Phrenic Nerve Palsy ◽

Adjusted Risk ◽

Ablation Time ◽

Group 4 ◽

Major Complications ◽

Group 3 ◽

Group 2 ◽

The Impact ◽

Group 1

Background: The incidence of atrial fibrillation (AF) is increasing in the elderly population, however, there is paucity of data on the safety outcomes of this patient subgroup thus we sought to investigate on the impact of age on the safety of catheter ablation for AF. Methods and Results: We included 1,293 (male 75%) patients enrolled in Yonsei AF Ablation Cohort database in Seoul, South Korea, from March 2009 to November 2013. We divided the patients into 4 groups according to age (Group 1, aged 17-49, N=295 ; Group 2 50-59, N=421; Group 3 60-69 N=408; and Group 4 ≥ 70, N=169) and evaluated the incidence of procedure related complications. No procedure-related death occurred in this study. There was a trend of increasing incidence of procedure related complications with age noted as follows: Group 1= 3.7%; Group 2= 4.0%; Group 3=6.6%; and Group 4 7.1%, (p= 0.15). There were 28 cases (2.2%) of major complications (Group 1=1.7%, Group 2=1.9%, Group 3=2%, Group 4 4.1%), tamponade being the most common. Major complications in group 4 include: tamponade 4 cases, phrenic nerve palsy 1 case, atrioesophaeal fistula 1 and 3rd degree AV block in 1 patient. Multivariate regression analysis shows ablation time (odds ratio (OR) 1.2 confidence interval (CI)1.0-1.017, p=0.017), procedure time (OR 1.008, CI 1.0-1.15, p=0.04), decreasing eGFR (OR 1.013, CI 1.002-1.026 p=0.018), coronary artery disease (CAD) (OR 1.847, CI 1.003-3.524, p0.04) and age (OR 1.028, CI 1.003-1.055, p=0.03) were associated with increased adjusted risk of total complications. Predictors of major complications include age (OR 1.044, CI 1.003-1.086, p0.02) and ablation time (OR 1.009, CI 0.999-1.000, p=0.033). Conclusion: Our data suggest that incidence of procedural complications in RFA of AF increase with age. Ablation time and age are independent predictors of a major complication.

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The impact of exogenous constitutional obesity on the systemic circulation in COVID-19 patients

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2021.04.54-61 ◽

2021 ◽

pp. 54-61

Author(s):

Д.С. Шилин ◽

К.Г. Шаповалов

Keyword(s):

Body Weight ◽

Vascular Wall ◽

Systemic Circulation ◽

Hemodynamic Changes ◽

Normal Body ◽

Bacterial Origin ◽

Normal Body Weight ◽

Group 2 ◽

The Impact ◽

Group 1

Актуальность: ожирение является одной из самых распространенных в мире причин развития сопутствующих заболеваний. у человека. В настоящий момент проблема СOVID-19 приводит к развитию и обострению сердечно-сосудистой патологии, сопровождающейся изменениями гемодинамики. Цель исследования - оценка зависимости изменений гемодинамики у пациентов с COVID-19 от алиментарно-конституционального ожирения. Методика. Исследование выполнено у 73 пациентов обоего пола с внебольничной полисегментарной вирусно-бактериальной пневмонией на фоне СOVID-19. Пациенты были разделены на 3 группы по индексу массы тела. В 1-ю группу вошли пациенты без избытка массы тела, 2-ю составили пациенты с избыточной массой тела, 3-ю - с ожирением 1 степени. Использован комплекс аппаратно-программного неинвазивного исследования центральной гемодинамики методом объемной компрессионной осциллометрии «КАП ЦГ осм- «Глобус» (Россия). Результаты. У пациентов с СOVID-19, страдающих ожирением I степени (30,0 - 34,9 кг/м2). выявлено статистически значимое снижение сердечного индекса относительно лиц с нормальной массой тела (на 10,8%, p=0,010). Пациенты с избытком массы тела имели более высокое диастолическое давление (на 10,5%, p=0,011) Показатель периферического сосудистого сопротивления у пациентов с СOVID-19 без избыточной массы тела был на 16.5% ниже, чем у пациентов с ожирением 1 степени. Удельное периферическое сопротивление сосудов у пациентов 1-й группы было на 10.3% меньше, чем у пациентов с избыточной массой тела. Податливость сосудистой стенки у пациентов 1-й группы была ниже на 22.5%, чем у пациентов с СOVID-19 и ожирением 1 степени. Заключение. У пациентов с внебольничной полисегментарной вирусно-бактериальной пневмонией на фоне СOVID-19 при ожирении 1 степени и избыточной массе тела выявляются значимые изменения гемодинамики относительно больных с нормальной массой тела. Background: Obesity is one of the most common causes of comorbidities worldwide. During the COVID-19 pandemic, development and increasing severity of cardiovascular disorders associated with hemodynamic changes has become increasingly relevant. Aims: The study aimed to evaluate the hemodynamic changes in COVID-19 patients depending on the severity of their exogenous constitutional obesity. Methods. 73 male and female patients with community-acquired polysegmental pneumonia of viral and bacterial origin associated with COVID-19 were enrolled in the study. The patients were allocated to three groups depending on the value of their body mass index (BMI). Group 1 included patients with normal body weight; Group 2 included overweight patients, and Group 3 included patients with grade 1 obesity (BMI 30.0-34.9 kg/m2). The measurements were performed using a technique of volumetric compression oscillometry on a non-invasive hemodynamic monitoring system KAP CG osm (Globus, Russia). Results. COVID-19 patients with grade 1 obesity (BMI 30.0-34.9 kg/m2) demonstrated a statistically significant 10.8% decrease in the cardiac index compared to patients with normal body weight (p=0.010). Overweight patients had 10.5% higher diastolic blood pressure (p=0.011). Peripheral vascular resistance (PVR) in COVID-19 patients with normal body weight was 16.5% lower than in patients with grade 1 obesity. PVR adjusted for body surface area in patients with normal body weight was 10.3% lower than in overweight patients. The compliance of the vascular wall in Group 1 patients was 22.5% lower than in COVID-19 patients with grade 1 obesity. Conclusion. COVID-19 patients with community-acquired, polysegmental pneumonia of viral and bacterial origin demonstrate significant hemodynamic changes compared to patients with normal body weights.

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Investigation of TAp63 gene Expression and Follicle Count Using Melatonin in Cisplatin-induced Ovarian Toxicity

10.21203/rs.3.rs-52313/v1 ◽

2020 ◽

Author(s):

Hacı Öztürk Şahin ◽

Mehmet Nuri Duran ◽

Fatma Sılan ◽

Ece Sılan ◽

Duygu Sıddıkoglu ◽

...

Keyword(s):

Gene Expression ◽

Female Rats ◽

Histological Evaluation ◽

Saline Control ◽

Control Group ◽

Ovarian Toxicity ◽

Significant Difference ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Background: Premature ovarian failure is among the most important side effects of chemotherapy during reproductive period. Preserving ovarian function is gradually gaining importance during oncologic treatment. The present study aims to investigate the potential of melatonin to protect from cisplatin-induced ovarian toxicity in rats. Twenty nine female rats were divided to three groups: Saline control group (Group 1), cisplatin group (Group 2), and cisplatin+melatonin group (Group 3). While the rats in Groups 2 and 3 were administered 5 mg/kg single dose of cisplatin via intra-peritoneal (IP) route, the rats in Group 3 were started on melatonin (20 mg/kg IP) before cisplatin administration and continued during 3 consecutive days. Ovaries were removed one week after cisplatin administration in all groups. Blood samples were obtained before the rats were decapited. Histological evaluation, follicle count, and classification were performed. TAp63 mRNA expression was evaluated using mRNA extraction and real-time polymerase chain reaction (PCR) method. Serum estradiol (E2) and anti-mullerian hormone (AMH) values were measured with enzyme immune-assay technology. Results: While primordial follicles were seen to decrease in Group 2 as compared to Group 1 (p:0.023), primordial follicle count was observed to be preserved significantly in melatonin group as compared to Group 2 (p:0.047). Moreover, cisplatin-induced histo-pathological morphology was preserved in favor of normal histology in melatonin group. A significant difference was not observed between groups with regard to mean serum AMH and E2 values (p:0.102 and p:0.411, respectively). While TAp63 gene expression significantly increased in Group 2 as compared to control group (p:0.001), we did not detect a statistically significant difference in cisplatin+melatonin group, although gene expression decreased (p:0.34). Conclusion: We conclude that concurrent administration of melatonin and cisplatin may protect from ovarian damage.

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Hyaluronan affects extravascular water in lungs of unanesthetized rabbits

Journal of Applied Physiology ◽

10.1152/jappl.1989.66.6.2595 ◽

1989 ◽

Vol 66 (6) ◽

pp. 2595-2599 ◽

Cited By ~ 30

Author(s):

J. Bhattacharya ◽

T. Cruz ◽

S. Bhattacharya ◽

B. A. Bray

Keyword(s):

Body Weight ◽

Water Content ◽

Extravascular Lung Water ◽

Volume Expansion ◽

The Other ◽

Lung Water ◽

Intravenous Saline ◽

Group 3 ◽

Group 2 ◽

Group 1

We have determined whether changes in lung hyaluronan content affect extravascular water in lungs of unanesthetized rabbits. Three groups of experiments were performed. In group 1 (n = 12), no infusions were given; in group 2, nine pairs of rabbits received either intravenous hyaluronidase (750 U.kg-1.min-1) or an equivalent volume of saline; in group 3, nine pairs of rabbits received either hyaluronidase or saline, followed by intravenous saline infusion amounting to 24% of body weight. At the end of each experiment, one lung was analyzed for extravascular lung water by the wet-dry method. Except for group 3, in all animals the other lung was analyzed for hyaluronan content by a method that involved hydrolyzing lung hyaluronan with fungal hyaluronidase to release reducing N-acetyl glucosamine groups, which were quantified. In group 1, lung hyaluronan, which varied from 50 to 159 micrograms/g dry wt (mean 106 +/- 35 micrograms/g dry wt), significantly correlated with variation in extravascular lung water (mean 4.2 +/- 0.3 g/g dry wt). In group 2 rabbits given hyaluronidase, lung hyaluronan was 40% lower and extravascular lung water was 14.6% lower than in paired controls (P less than 0.01). In group 3, volume expansion did not affect lung water, except after hyaluronidase when lung water was 47% higher than paired controls. We conclude that in the lung the content of hyaluronan is one of the determinants of extravascular water content.

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P4766Edoxaban Treatment in routiNe clinical prActice for patients with atrial fibrillation (AF) in Europe (ETNA-AF-Europe): 1-year follow-up according to body mass index

European Heart Journal ◽

10.1093/eurheartj/ehz745.1142 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

T Weiss ◽

R De Caterina ◽

P Kelly ◽

P Monteiro ◽

J C Deharo ◽

...

Keyword(s):

Atrial Fibrillation ◽

Body Weight ◽

Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Normal Weight ◽

Routine Practice ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Background Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), and available routine care data have so far broadly confirmed the safety of different NOACs in routine practice. However, such data for edoxaban are scarce, especially in extremely low and high body weight (BW). These extreme BWs may affect the bioavailability, distribution, and half-life of NOACs and, consequently, outcomes of treatment. Methods We analysed outcomes in normal-weight (BMI 18.5–25) vs overweight (BMI 25–30) and obese (BMI >30) patients enrolled into the ETNA-AF-Europe observational study (NCT02944019) collecting information on patients treated with edoxaban in 825 sites in 10 European countries. This snapshot analysis set includes data of 7,672 patients (56.3% of all enrolled patients) which have completed their 1-year follow-up visit (mean follow-up: 343.5 days). Results Median patient age was 74 years for all patients, 76 years for patients with a BMI 18.5–25 (group 1), 75 years for patients with BMI 25–30 (group 2), and 72 for patients with a BMI >30 (group 3). CrCl was 64 mL/min for patients with a BMI 18.5–25, 68 mL/min for patients with BMI 25–30, and 72 mL/min for patients with a BMI >30. The CHA2DS2-VASc (mean 3.1±1.38) and HAS-BLED (mean 2.5±1.10) score did not differ significantly between groups. As expected, diabetes and hypertension were significantly less prevalent in leaner patients and - accordingly - inversely correlated to age. There was no correlation between body weight and life-threatening bleeding (group 1: 0.28%; group 2: 0.40%; group 3: 0.14%). Also, stroke rates (group 1: 0.74%; group 2: 0.81%; group 3: 0.76%) did not differ between groups. Conclusion BMI, within the range here assessed, does not affect 1-year outcomes in European AF patients treated with edoxaban. Acknowledgement/Funding Daiichi Sankyo Europe GmbH, Munich, Germany

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Multidose Priming and Delayed Boosting Improve PfSPZ Vaccine Efficacy against Heterologous P. falciparum Controlled Human Malaria Infection

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1294 ◽

2020 ◽

Cited By ~ 1

Author(s):

Kirsten E Lyke ◽

Alexandra Singer ◽

Andrea A Berry ◽

Sharina Reyes ◽

Sumana Chakravarty ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Vaccine Efficacy ◽

Malaria Infection ◽

Human Malaria ◽

Group 4 ◽

Controlled Human Malaria Infection ◽

Group 3 ◽

Group 2 ◽

The Impact ◽

Group 1

Abstract Background A live-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine (PfSPZ Vaccine) has shown up to 100% protection against controlled human malaria infection (CHMI) using homologous parasites (same Pf strain as in the vaccine). Using a more stringent CHMI, with heterologous parasites (different Pf strain), we assessed the impact of higher PfSPZ doses, a novel multi-dose prime regimen, and a delayed vaccine boost upon vaccine efficacy. Methods Four groups of 15 healthy, malaria-naïve adults were immunized. Group (Grp) 1 received five doses of 4.5x10 5 PfSPZ (days 1, 3, 5, 7; week 16). Grps 2, 3 and 4 received three doses (weeks 0, 8, 16) with Gp 2 receiving 9.0×10 5/dose, Grp 3 receiving 18.0×10 5/dose, and Grp 4 receiving 27.0×10 5 for dose 1 and 9.0×10 5 for doses 2 and 3. VE was assessed by heterologous CHMI after 12 or 24 weeks. Volunteers not protected at 12 weeks were boosted prior to repeat CHMI at 24 weeks. Results At 12-week CHMI, 6/15 (40%) Group 1 (P=0.04), 3/15 (20%) Group 2 vs. 0/8 controls remained aparasitemic. At 24-week CHMI, 3/13 (23%) Group 3, 3/14 (21%) Group 4 vs. 0/8 controls remained aparasitemic (Groups 2-4, VE not significant). Post-boost, 9/14 (64%) vs. 0/8 controls remained aparasitemic (3/6 Group 1, P=0.025; 6/8 Group 2, P=0.002). Conclusions Four stacked, priming injections (multi-dose priming) showed 40% VE against heterologous CHMI, while dose escalation of PfSPZ using single dose priming was not significantly protective. Boosting unprotected subjects improved VE at 24 weeks to 64%.

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NOD2/CARD15 Genotype and HLA-DPB1 Matching Status Can Be Used To Predict Disease Relapse in Recipients of an Unrelated Donor Haematopoietic Stem Cell Transplant for Acute Leukaemia.

Blood ◽

10.1182/blood.v110.11.830.830 ◽

2007 ◽

Vol 110 (11) ◽

pp. 830-830

Author(s):

J. Alejandro Madrigal ◽

Neema P. Mayor ◽

Hazael Maldonado-Torres ◽

Bronwen E. Shaw ◽

Steven G.E. Marsh

Keyword(s):

Stem Cell ◽

Risk Group ◽

Haematopoietic Stem Cell ◽

Disease Relapse ◽

Unrelated Donors ◽

Group 3 ◽

Group 2 ◽

The Impact ◽

Risk Of Relapse ◽

Group 1

Abstract Haematopoietic Stem Cell Transplantation (HSCT) using volunteer Unrelated Donors (UD) has become an important and viable option in the treatment of Acute Leukaemia (AL). While matching donors and recipients usually refers to five of the classical HLA genes (HLA-A, -B, -C, -DRB1 and -DQB1), the impact of a sixth gene, HLA-DPB1, on the outcome of UD-HSCT is increasingly emerging. We have previously shown an increased risk of relapse with HLA-DPB1 matching and independently, with NOD2/CARD15 genotype. In light of these data, we have analysed a larger UD-HSCT cohort in order to establish the impact on transplant outcome when both HLA-DPB1 matching status and NOD2/CARD15 genotype are considered. HLA typing and NOD2/CARD15 genotyping was performed on 304 AL patients and their Anthony Nolan Trust volunteer unrelated donors. Transplants occurred between 1996 and 2005 at UK transplant centres. Diagnoses were ALL (47%) and AML (53%). 67% of the cohort were a 10/10 HLA match with 16% also being matched for HLA-DPB1. Myeloablative conditioning regimens were used in 74% of transplants. T-cell depletion was included in 82% of conditioning protocols. Bone marrow was used in 72% of transplants with the remaining 28% using peripheral blood stem cells. Two forms of post-transplant immunosuppression predominated, Cyclosporine A and Methotrexate (47%) and Cyclosporine A alone (38%). Previous studies on a subgroup of this cohort showed that HLA-DPB1 matching and NOD2/CARD15 SNPs independently caused an increase in disease relapse. Consequently, the cohort was grouped into three categories to reflect this risk, group 1 (DPB1 matched; NOD2/CARD15 SNP, n=24), group 2 (HLA-DPB1 matched; NOD2/CARD15 Wild-Type (WT) or HLA-DPB1 mismatched; NOD2/CARD15 SNP, n=112) and group 3 (HLA-DPB1 mismatched; NOD2/CARD15 WT, n=168). There was a significant difference in disease relapse between the three groups (1 year: group 1; 68%, group 2; 48%, group 3; 30%, p=0.0038). This finding persisted in multivariate analysis where being in either group 2 or 3 was protective towards relapse as compared to group 1 (RR 0.321; 95% CI 0.167–0.616; p=0.001 and RR 0.478; 95% CI 0.244–0.934; p=0.031 respectively). In the group with the highest relapse risk (group 1), this resulted in a decrease in Overall Survival (OS) (33% vs 54% in group 3, RR 0.617; 95% CI 0.359–1.060; p=0.080). The best OS was seen in the group with the lowest risk of relapse (group 3). Here, in addition to low relapse, there was increased acute and chronic Graft-versus-Host Disease (GvHD) (p=0.0019 and p=0.0058 respectively). In this cohort, cGvHD (in its limited form) was associated with a significantly lower incidence of relapse (p=0.0066) and better OS (p<0.0001). In concordance with our previous theories, it appears that being HLA-DPB1 matched and having NOD2/CARD15 SNPs predicts for the worst outcome with a significant increase in relapse and reduced OS. Conversely, the ideal pairing would be HLA-DPB1 mismatched and NOD2/CARD15 WT. These data suggest that prospectively typing AL patients for HLA-DPB1 and NOD2/CARD15 SNPs will allow the prediction of disease relapse, aGvHD and cGvHD and in addition will allow the effects of being independently HLA-DPB1 matched or having a NOD2/CARD15 SNP to be offset by intelligently selecting a suitable, less precarious donor.

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