The Composition of Human Milk and Infant Faecal Microbiota Over the First Three Months of Life: A Pilot Study

peer-reviewedHuman milk contains a diverse array of bioactives and is also a source of bacteria for the developing infant gut. The aim of this study was to characterize the bacterial communities in human milk and infant faeces over the first 3 months of life, in 10 mother-infant pairs. The presence of viable Bifidobacterium and Lactobacillus in human milk was also evaluated. MiSeq sequencing revealed a large diversity of the human milk microbiota, identifying over 207 bacterial genera in milk samples. The phyla Proteobacteria and Firmicutes and the genera Pseudomonas, Staphylococcus and Streptococcus were the predominant bacterial groups. A core of 12 genera represented 81% of the microbiota relative abundance in milk samples at week 1, 3 and 6, decreasing to 73% at week 12. Genera shared between infant faeces and human milk samples accounted for 70–88% of the total relative abundance in infant faecal samples, supporting the hypothesis of vertical transfer of bacteria from milk to the infant gut. In addition, identical strains of Bifidobacterium breve and Lactobacillus plantarum were isolated from the milk and faeces of one mother-infant pair. Vertical transfer of bacteria via breastfeeding may contribute to the initial establishment of the microbiota in the developing infant intestine

Early prediction of clinical response to checkpoint inhibitor therapy in human solid tumors through mathematical modeling

Background:: Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies. Methods:: Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor-immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials. Results:: The derived parameters Λ and µ were both significantly different between responding versus nonresponding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within 2 months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology. Conclusions:: These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis. Funding:: We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies

The Composition of Human Milk and Infant Faecal Microbiota Over the First Three Months of Life: A Pilot Study

Human milk contains a diverse array of bioactives and is also a source of bacteria for the developing infant gut. The aim of this study was to characterize the bacterial communities in human milk and infant faeces over the first 3 months of life, in 10 mother-infant pairs. The presence of viable Bifidobacterium and Lactobacillus in human milk was also evaluated. MiSeq sequencing revealed a large diversity of the human milk microbiota, identifying over 207 bacterial genera in milk samples. The phyla Proteobacteria and Firmicutes and the genera Pseudomonas, Staphylococcus and Streptococcus were the predominant bacterial groups. A core of 12 genera represented 81% of the microbiota relative abundance in milk samples at week 1, 3 and 6, decreasing to 73% at week 12. Genera shared between infant faeces and human milk samples accounted for 70–88% of the total relative abundance in infant faecal samples, supporting the hypothesis of vertical transfer of bacteria from milk to the infant gut. In addition, identical strains of Bifidobacterium breve and Lactobacillus plantarum were isolated from the milk and faeces of one mother-infant pair. Vertical transfer of bacteria via breastfeeding may contribute to the initial establishment of the microbiota in the developing infant intestine

Long-term follow-up of post-cardiac surgery Mycobacterium chimaera infections: A 5-center case series

OBJECTIVES: In multiple countries, endovascular/disseminated Mycobacterium chimaera infections have occurred in post-cardiac surgery patients in association with contaminated, widely-distributed cardiac bypass heater-cooler devices. To contribute to long-term characterization of this recently recognized infection, we describe the clinical course of 28 patients with 3-7 years of follow-up for survivors. METHODS: Identified at five hospitals in the United States 2010-2016, post-cardiac surgery patients in the cohort had growth of Mycobacterium avium complex (MAC)/M. chimaera from a sterile site or surgical wound, or a clinically compatible febrile illness with granulomatous inflammation on biopsy. Case follow-up was conducted in May 2019. RESULTS: Of 28 patients, infection appeared to be localized to the sternum in four patients. Among 18 with endovascular/disseminated infection who received combination anti-mycobacterial treatment and had sufficient follow-up, 39% appeared to have controlled infection (>12 months), 56% died, and one patient is alive with relapsed bacteremia. While the number of patients is small and interpretation is limited, four (67%) of six patients who had cardiac prosthesis removal/replacement appeared to have controlled infection compared to three (25%) of 12 with retained cardiac prosthesis (p >0.14; Fisher's exact test). CONCLUSIONS: Given poor response to treatment and potential for delayed relapses, post-cardiac surgery M. chimaera infection warrants aggressive treatment and long-term monitoring

Irish Heart Attack Audit National Report 2017-2020

The Heartbeat audit of ST elevation myocardial infarction (STEMI) care was first developed in 2012 in order to assess the effectiveness and quality of the newly formed National Clinical Programme for Acute Coronary Syndrome (NCP-ACS) STEMI optimal reperfusion service under the auspices of Professor Kieran Daly, Health Service Executive (HSE) Clinical Lead, and Dr Siobhan Jennings, Consultant in Public Health Medicine, HSE. In 2019, this audit and attendant database came under the governance of the National Office of Clinical Audit (NOCA) by agreement with the HSE and evolved into the Irish Heart Attack Audit (IHAA). Although this is the first national IHAA report, it continues on from the two previously published NCP-ACS reports on the state of STEMI services across the country based on data collected in 2014 (HSE, 2015) and 2016 (HSE, 2018a). With a maturing database and systematic analytic capabilities through the NOCA structure, this report provides a detailed evaluation of STEMI care in Ireland for the years 2017 to 2020.<br

Irish Heart Attack Audit national report 2021

The Irish Heart Attack Audit National Report 2021 includes data from 1,491 patients with an ST elevation myocardial infarction (STEMI) who received treatment in a percutaneous coronary intervention (PCI) centre during 2021. STEMI was more common in males (n=1154, 77%), with females presenting at an older median age (67 years versus 61 years in males) and with a higher burden of comorbidities. The data provide detailed information about the care, processes and outcomes received by patients with a STEMI, and enable each participating hospital to benchmark itself against comparable hospitals in Ireland. The quality of care delivered is measured against national and international key quality indicators (KQIs), and opportunities for quality improvement (QI) are identified. </p