Polysaccharide utilization loci and nutritional specialization in a dominant group of butyrate-producing human colonic Firmicutes

Acknowledgements The Rowett Institute of Nutrition and Health (University of Aberdeen) receives financial support from the Scottish Government Rural and Environmental Sciences and Analytical Services (RESAS). POS is a PhD student supported by the Scottish Government (RESAS) and the Science Foundation Ireland, through a centre award to the APC Microbiome Institute, Cork, Ireland. Data Summary The high-quality draft genomes generated in this work were deposited at the European Nucleotide Archive under the following accession numbers: 1. Eubacterium rectale T1-815; CVRQ01000001–CVRQ0100 0090: http://www.ebi.ac.uk/ena/data/view/PRJEB9320 2. Roseburia faecis M72/1; CVRR01000001–CVRR010001 01: http://www.ebi.ac.uk/ena/data/view/PRJEB9321 3. Roseburia inulinivorans L1-83; CVRS01000001–CVRS0 100 0151: http://www.ebi.ac.uk/ena/data/view/PRJEB9322Peer reviewedPublisher PD

Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases.

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro. GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer

Fetal growth trajectories and measures of insulin resistance in young adults

Context: Events during gestation greatly influence the risk of cardiometabolic diseases including diabetes in offspring during later life. Objective: This study aimed to investigate relationships between serial ultrasound-derived fetal growth trajectories and markers of insulin resistance in young adults in the Raine Study, an Australian pregnancy cohort. Methods: Linear mixed modeling examined the relationship between fetal growth trajectory groups, constructed using serial ultrasound-based abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs, and offspring Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as a marker of diabetes risk, at 20 (n = 414), 22 (n = 385), and 27 (n = 431) years. Analyses were adjusted for age, sex, ethnicity, socioeconomic status, adult lifestyle factors, and maternal factors during pregnancy. Results: The study identified 7 AC, 5 FL, and 5 HC growth trajectory groups. Compared to the average-stable (reference) group, a low-falling AC growth trajectory (26%; P = .005) and 2 low HC growth trajectories (20%; P = .006% and 8%; P = .021) were associated with higher adult HOMA-IR. Trajectories representing a high-stable FL and a rising HC were associated with 12% (P = .002) and 9% (P = .021) lower adult HOMA-IR, respectively, compared to the reference group. Conclusion: Restricted fetal HC and AC from early pregnancy are associated with higher relative insulin resistance in the offspring during adulthood. These data strengthen our understanding of the importance of the intrauterine environment and its effect on the risk of predisposition to adult diabetes and related metabolic disorders

Patterns of Lumbar Disc Degeneration: Magnetic Resonance Imaging Analysis in Symptomatic Subjects

Study Design: Cross-sectional study. Purpose: To evaluate lumbar disc degeneration (LDD) on magnetic resonance imaging (MRI) in symptomatic subjects to accumulate baseline data on the pattern of degeneration. Overview of Literature: LDD plays an important role in the diagnosis and treatment of low-back pain in patients. Few studies have focused on the pattern of LDD to understand how the lumbar spine ages. Methods: This study included 1,095 patients (mean age, 44.29 years; range, 16–85 years) who underwent upright lumbar MRI. LDD was graded into five categories (I–V). Positive LDD was defined as grade III or greater. The prevalence and pattern of LDD were ana-lyzed, and the correlations between age and total grade of LDD were evaluated. Results: The average number of LDD levels and the total grade of LDD increased with age. LDD moved cephalad with age. The rate of LDD increased rapidly during the decade before the prevalence of LDD and became \u3e 50%. In the single-level LDD group, the levels L5–S1 were the most common levels (60.3%). In the two-level group, L4–L5 and L5–S1 were the most common levels (53.5%). In the three-level group, L3–L4, L4–L5, and L5–S1 were the most common levels (55.7%). In the multilevel LDD group, contiguous multilevel disc degeneration (CMDD) was more common than the skipped level disc degeneration (SLDD). The levels L4–L5 were the most com-mon levels in the CMDD group, and L5–S1 were the most common levels among SLDD. Conclusions: LDD was found to correlate with age, and the specific patterns and rates of LDD depended on lumbar disc level and age. These LDD pattern data can be used before spinal procedures to predict the probability of natural LDD progression with age

Relationships between intrauterine fetal growth trajectories and markers of adiposity and inflammation in young adults

Background: There is now good evidence that events during gestation significantly influence the developmental well-being of an individual in later life. This study aimed to investigate the relationships between intrauterine growth trajectories determined by serial ultrasound and subsequent markers of adiposity and inflammation in the 27-year-old adult offspring from the Raine Study, an Australian longitudinal pregnancy cohort. Methods: Ultrasound fetal biometric measurements including abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs (Gen1–Gen2) in the Raine Study were used to develop fetal growth trajectories using group-based trajectory modeling. Linear mixed modeling investigated the relationship between adult body mass index (BMI), waist circumference (WC), and high-sensitivity C-reactive protein (hs-CRP) of Gen2 at 20 (n = 485), 22 (n = 421) and 27 (n = 437) years and the fetal growth trajectory groups, adjusting for age, sex, adult lifestyle factors, and maternal factors during pregnancy. Results: Seven AC, five FL and five HC growth trajectory groups were identified. Compared to the average-stable (reference) group, a lower adult BMI was observed in two falling AC trajectories: (β = −1.45 kg/m2, 95% CI: −2.43 to −0.46, P = 0.004) and (β = −1.01 kg/m2, 95% CI: −1.96 to −0.05, P = 0.038). Conversely, higher adult BMI (2.58 kg/m2, 95% CI: 0.98 to 4.18, P = 0.002) and hs-CRP (37%, 95% CI: 9–73%, P = 0.008) were observed in a rising FL trajectory compared to the reference group. A high-stable HC trajectory associated with 20% lower adult hs-CRP (95% CI: 5–33%, P = 0.011). Conclusion: This study highlights the importance of understanding causes of the unique patterns of intrauterine growth. Different fetal growth trajectories from early pregnancy associate with subsequent adult adiposity and inflammation, which predispose to the risk of diabetes and cardiometabolic disease

The organisational and human resource challenges facing primary care trusts : protocol of a multiple case study

BACKGROUND: The study is designed to assess the organisational and human resource challenges faced by Primary Care Trusts (PCTs). Its objectives are to: specify the organisational and human resources challenges faced by PCTs in fulfilling the roles envisaged in government and local policy; examine how PCTs are addressing these challenges, in particular, to describe the organisational forms they have adopted, and the OD/HR strategies and initiatives they have planned or in place; assess how effective these structures, strategies and initiatives have been in enabling the PCTs to meet the organisational and human resources challenges they face; identify the factors, both internal to the PCT and in the wider health community, which have contributed to the success or failure of different structures, strategies and initiatives. METHODS: The study will be undertaken in three stages. In Stage 1 the key literature on public sector and NHS organisational development and human resources management will be reviewed, and discussions will be held with key researchers and policy makers working in this area. Stage 2 will focus on detailed case studies in six PCTs designed to examine the organisational and human resources challenges they face. Data will be collected using semi-structured interviews, group discussion, site visits, observation of key meetings and examination of local documentation. The findings from the case study PCTs will be cross checked with a Reference Group of up to 20 other PCG/Ts, and key officers working in organisational development or primary care at local, regional and national level. In Stage 3 analysis of findings from the preparatory work, the case studies and the feedback from the Reference Group will be used to identify practical lessons for PCTs, key messages for policy makers, and contributions to further theoretical development

Precisely tracking childhood death

Little is known about the specific causes of neonatal and under-five childhood death in high-mortality geographic regions due to a lack of primary data and dependence on inaccurate tools, such as verbal autopsy. To meet the ambitious new Sustainable Development Goal 3.2 to eliminate preventable child mortality in every country, better approaches are needed to precisely determine specific causes of death so that prevention and treatment interventions can be strengthened and focused. Minimally invasive tissue sampling (MITS) is a technique that uses needle-based postmortem sampling, followed by advanced histopathology and microbiology to definitely determine cause of death. The Bill & Melinda Gates Foundation is supporting a new surveillance system called the Child Health and Mortality Prevention Surveillance network, which will determine cause of death using MITS in combination with other information, and yield cause-specific population-based mortality rates, eventually in up to 12-15 sites in sub-Saharan Africa and south Asia. However, the Gates Foundation funding alone is not enough. We call on governments, other funders, and international stakeholders to expand the use of pathology-based cause of death determination to provide the information needed to end preventable childhood mortality