Combination immunotherapy induces distinct T-cell repertoire responses when administered to patients with different malignancies.

BackgroundCTLA-4 blockade with ipilimumab is Food and Drug Administration-approved for melanoma as a monotherapy and has been shown to modulate the circulating T-cell repertoire. We have previously reported clinical trials combining CTLA-4 blockade with granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic melanoma patients and in metastatic castration resistant prostate cancer (mCRPC) patients. Here, we investigate the effect that cancer type has on circulating T cells in metastatic melanoma and mCRPC patients, treated with ipilimumab and GM-CSF.MethodsWe used next-generation sequencing of T-cell receptors (TCR) to compare the circulating T cells of melanoma and mCRPC patients receiving the same treatment with ipilimumab and GM-CSF by Wilcoxon rank sum test. Flow cytometry was utilized to investigate specific T-cell populations. TCR sequencing results were correlated with each T-cell subpopulation by Spearman's rank correlation coefficient. Of note, 14 metastatic melanoma patients had samples available for TCR sequencing and 21 had samples available for flow cytometry analysis; 37 mCRPC patients had samples available for sequencing of whom 22 have TCR data available at both timepoints; 20 of these patients had samples available for flow cytometry analysis and 16 had data available at both timepoints.ResultsWhile melanoma and mCRPC patients had similar pretreatment circulating T-cell counts, treatment induces greater expansion of circulating T cells in melanoma patients. Metastatic melanoma patients have a higher proportion of clones that increased more than fourfold after the treatment compared with mCRPC patients (18.9% vs 11.0%, p=0.017). Additionally, melanoma patients compared with mCRPC patients had a higher ratio of convergent frequency (1.22 vs 0.60, p=0.012). Decreases in clonality induced by treatment are associated with baseline CD8+ T-cell counts in both patient groups, but are more pronounced in the melanoma patients (r=-0.81, p<0.001 vs r=-0.59, p=0.02).Trial registration numbersNCT00064129; NCT01363206

Pengaruhmodel Pembelajaran Vak (Visual, Auditori, Kinestetik) Terhadap Kemampuan Menulis Puisi Oleh Siswa Kelas VIII SMP N. 2 Porsea Tahun Pembelajaran 2012/2013

This study aimed to clarify the effect of the learning model VAK (Visual, Auditory,Kinesthetic) the ability to write poetry by the students of class VIII SMP N.2 PorseaLearning Year 2012/2013. The population of this research is all eighth grade studentsas junior N.2 Porsea 266 people. Samples were taken at random as many as 30people.The method used in this study is an experimental method. The instrument usedis the argument essay writing test. The average value of post-test is 75.50, while forthe pre-test is is 67.1. Thus, it can be said that the average value of students\u27 ability towrite poetry after treatment (post-test) higher than before treatment (pre-test).Hypothesis testing is done by using the test "t". Test hypotheses derived from thecalculation of t = 2.95, then consulted with the table t at 5% significance level = 2.04.Since t = 2.95> t = 2.04 nil then the hypothesis (H) is rejected. It is proved that thelearning model VAK (Visual, Auditory, Kinesthetic) affects the ability to writepoetry class VIII SMP Porsea N.2

Hospital-Based Acute Care Use in Survivors of Septic Shock

OBJECTIVES: Septic shock is associated with increased long-term morbidity and mortality. However, little is known about the use of hospital-based acute care in survivors after hospital discharge. The objectives of the study were to examine the frequency, timing, causes, and risk factors associated with emergency department visits and hospital readmissions within 30 days of discharge. DESIGN: Retrospective cohort study. SETTING: Tertiary, academic hospital in the United States. PATIENTS: Patients admitted with septic shock (serum lactate ≥ 4 mmol/L or refractory hypotension) and discharged alive to a nonhospice setting between 2007 and 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The coprimary outcomes were all-cause hospital readmission and emergency department visits (treat-and-release encounters) within 30 days to any of the three health system hospitals. Of 269 at-risk survivors, 63 (23.4%; 95% CI, 18.2-28.5) were readmitted within 30 days of discharge and another 12 (4.5%; 95% CI, 2.3-7.7) returned to the emergency department for a treat-and-release visit. Readmissions occurred within 15 days of discharge in 75% of cases and were more likely in oncology patients (p=0.001) and patients with a longer hospital length of stay (p=0.04). Readmissions were frequently due to another life-threatening condition and resulted in death or discharge to hospice in 16% of cases. The reasons for readmission were deemed potentially related to the index septic shock hospitalization in 78% (49 of 63) of cases. The most common cause was infection related, accounting for 46% of all 30-day readmissions, followed by cardiovascular or thromboembolic events (18%). CONCLUSIONS: The use of hospital-based acute care appeared to be common in septic shock survivors. Encounters often led to readmission within 15 days of discharge, were frequently due to another acute condition, and appeared to result in substantial morbidity and mortality. Given the potential public health implications of these findings, validation studies are needed

Kata Ganti Orang Dalam Bahasa Inggris Dan Bahasa Selaru (Suatu Analisis Kontrastif)

This research attempts to identify and classify personal pronouns in English and Selaru language. The data are taken from interviewing some informants (native speakers) who was born in Selaru and understand the language and can interact effectively. The identified data are analyzed according to the concept of Bloomfield and then contrast them by using Lado\u27s concept. In analyzing the data, the writer uses descriptive method. The problems of this research ore focused on what are the personal pronouns in terms of form and function in English and Selaru language and what are the similarities and differences of personal pronouns in terms of form and function in English and Selaru language. The aims of the research are to identify and classify personal pronouns in English and Selaru language and to find out the similarities as well as dissimilarities of personal pronouns in both languages in terms of form and function. The results of this research shows that English and Selaru language has similarities and dissimilarities. Similarities in English and Selaru language which has the form of the first person, second, third, both singular and plural and dissimilarities in English and Selaru language namely: in English has object, possessive pronoun and third person singular neutral,whereas in selaru language not found

Declining Trends of Pneumococcal Meningitis in Gambian Children After the Introduction of Pneumococcal Conjugate Vaccines.

BACKGROUND: Acute bacterial meningitis remains a major cause of childhood mortality in sub-Saharan Africa. We document findings from hospital-based sentinel surveillance of bacterial meningitis among children <5 years of age in The Gambia, from 2010 to 2016. METHODS: Cerebrospinal fluid (CSF) was collected from children admitted to the Edward Francis Small Teaching Hospital with suspected meningitis. Identification of Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis (meningococcus), and Haemophilus influenzae was performed by microbiological culture and/or polymerase chain reaction where possible. Whole genome sequencing was performed on pneumococcal isolates. RESULTS: A total of 438 children were admitted with suspected meningitis during the surveillance period. The median age of the patients was 13 (interquartile range, 3-30) months. Bacterial meningitis was confirmed in 21.4% (69/323) of all CSF samples analyzed. Pneumococcus, meningococcus, and H. influenzae accounted for 52.2%, 31.9%, and 16.0% of confirmed cases, respectively. There was a significant reduction of pneumococcal conjugate vaccine (PCV) serotypes, from 44.4% in 2011 to 0.0% in 2014, 5 years after PCV implementation. The majority of serotyped meningococcus and H. influenzae belonged to meningococcus serogroup W (45.5%) and H. influenzae type b (54.5%), respectively. Meningitis pathogens were more frequently isolated during the dry dusty season of the year. Reduced susceptibility to tetracycline, trimethoprim-sulfamethoxazole, and chloramphenicol was observed. No resistance to penicillin was found. CONCLUSIONS: The proportion of meningitis cases due to pneumococcus declined in the post-PCV era. However, the persistence of vaccine-preventable meningitis in children aged <5 years is a major concern and demonstrates the need for sustained high-quality surveillance

Serologic responses to the PfEMP1 DBL-CIDR head structure may be a better indicator of malaria exposure than those to the DBL-α tag

BackgroundPlasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) antigens play a critical role in host immune evasion. Serologic responses to these antigens have been associated with protection from clinical malaria, suggesting that antibodies to PfEMP1 antigens may contribute to natural immunity. The first N-terminal constitutive domain in a PfEMP1 is the Duffy binding-like alpha (DBL-α) domain, which contains a 300 to 400 base pair region unique to each particular protein (the DBL-α "tag"). This DBL-α tag has been used as a marker of PfEMP1 diversity and serologic responses in malaria-exposed populations. In this study, using sera from a malaria-endemic region, responses to DBL-α tags were compared to responses to the corresponding entire DBL-α domain (or "parent" domain) coupled with the succeeding cysteine-rich interdomain region (CIDR).MethodsA protein microarray populated with DBL-α tags, the parent DBL-CIDR head structures, and downstream PfEMP1 protein fragments was probed with sera from Malian children (aged 1 to 6&nbsp;years) and adults from the control arms of apical membrane antigen 1 (AMA1) vaccine clinical trials before and during a malaria transmission season. Serological responses to the DBL-α tag and the DBL-CIDR head structure were measured and compared in children and adults, and throughout the season.ResultsMalian serologic responses to a PfEMP1's DBL-α tag region did not correlate with seasonal malaria exposure, or with responses to the parent DBL-CIDR head structure in either children or adults. Parent DBL-CIDR head structures were better indicators of malaria exposure.ConclusionsLarger PfEMP1 domains may be better indicators of malaria exposure than short, variable PfEMP1 fragments such as DBL-α tags. PfEMP1 head structures that include conserved sequences appear particularly well suited for study as serologic predictors of malaria exposure

Combination immunotherapy induces distinct T-cell repertoire responses when administered to patients with different malignancies

Background CTLA-4 blockade with ipilimumab is Food and Drug Administration-approved for melanoma as a monotherapy and has been shown to modulate the circulating T-cell repertoire. We have previously reported clinical trials combining CTLA-4 blockade with granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic melanoma patients and in metastatic castration resistant prostate cancer (mCRPC) patients. Here, we investigate the effect that cancer type has on circulating T cells in metastatic melanoma and mCRPC patients, treated with ipilimumab and GM-CSF.Methods We used next-generation sequencing of T-cell receptors (TCR) to compare the circulating T cells of melanoma and mCRPC patients receiving the same treatment with ipilimumab and GM-CSF by Wilcoxon rank sum test. Flow cytometry was utilized to investigate specific T-cell populations. TCR sequencing results were correlated with each T-cell subpopulation by Spearman’s rank correlation coefficient. Of note, 14 metastatic melanoma patients had samples available for TCR sequencing and 21 had samples available for flow cytometry analysis; 37 mCRPC patients had samples available for sequencing of whom 22 have TCR data available at both timepoints; 20 of these patients had samples available for flow cytometry analysis and 16 had data available at both timepoints.Results While melanoma and mCRPC patients had similar pretreatment circulating T-cell counts, treatment induces greater expansion of circulating T cells in melanoma patients. Metastatic melanoma patients have a higher proportion of clones that increased more than fourfold after the treatment compared with mCRPC patients (18.9% vs 11.0%, p=0.017). Additionally, melanoma patients compared with mCRPC patients had a higher ratio of convergent frequency (1.22 vs 0.60, p=0.012). Decreases in clonality induced by treatment are associated with baseline CD8+ T-cell counts in both patient groups, but are more pronounced in the melanoma patients (r=−0.81, p&lt;0.001 vs r=−0.59, p=0.02).Trial registration numbers NCT00064129; NCT01363206