Effects of an Amino Acid-Based Formula Supplemented with Two Human Milk Oligosaccharides on Growth,Tolerability, Safety,and Gut Microbiome in Infants with Cow’s Milk Protein Allergy

This open-label, non-randomized, multicenter trial (Registration: {"type":"clinical-trial","attrs":{"text":"NCT 03661736","term_id":"NCT03661736"}}NCT 03661736) aimed to assess if an amino acid-based formula (AAF) supplemented with two human milk oligosaccharides (HMO) supports normal growth and is well tolerated in infants with a cow’s milk protein allergy (CMPA). Term infants aged 1–8 months with moderate-to-severe CMPA were enrolled. The study formula was an AAF supplemented with 2′-fucosyllactose (2′-FL) and lacto-N-neotetraose (LNnT). Infants were fed the study formula for 4 months and were offered to remain on the formula until 12 months of age. Tolerance and safety were assessed throughout the trial. Out of 32 infants (mean age 18.6 weeks; 20 (62.5%) male), 29 completed the trial. During the 4-month principal study period, the mean weight-for-age Z score (WAZ) increased from –0.31 at the baseline to +0.28 at the 4-months’ follow-up. Linear and head growth also progressed along the WHO child growth reference, with a similar small upward trend. The formula was well tolerated and had an excellent safety profile. When comparing the microbiome at the baseline to the subsequent visits, there was a significant on-treatment enrichment in HMO-utilizing bifidobacteria, which was associated with a significant increase in fecal short-chain fatty acids. In addition, we observed a significant reduction in the abundance of fecal Proteobacteria, suggesting that the HMO-supplemented study formula partially corrected the gut microbial dysbiosis in infants with CMPA.     

PorA variable regions of Neisseria meningitidis

Subtypes, defined by variation in the outer membrane protein PorA, are an integral part of the characterization scheme for Neisseria meningitidis. Identification of these variants remains important as the PorA protein is a major immunogenic component of several meningococcal vaccines under development, and characteristics of PorA are used to provide detailed epidemiologic information. Historically, serosubtypes have been defined by reactivity with a set of monoclonal antibodies. However, nucleotide sequence analyses of porA genes have established that the panel of serosubtyping monoclonal antibodies is not exhaustive, and many porA variants cannot be detected. In addition, the nomenclature system used to define subtypes is inadequate. We examined all available nucleotide sequences of the porA VR1 and VR2 regions to identify and define subtype families. A revised nomenclature scheme, compatible with the previous serologic nomenclature scheme, was devised. A Web-accessible database describing this nomenclature and its relationship to previous schemes was established (available from: http://neisseria.org/nm/typing/pora).     

Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer

Background To understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer.Methods Immunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression.Results Two patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete ‘punctate’ areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high ‘punctate’ IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus.Conclusions These results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.Subject terms: Prognostic markers, Colorectal cancer     

Brief Report: Dynamic calcium signals mediate the feeding response of the carnivorous sundew plant

Some of the most spectacular examples of botanical carnivory—in which predator plants catch and digest animals presumably to supplement the nutrient-poor soils in which they grow—occur within the Droseraceae family. For example, sundews of the genus Drosera have evolved leaf movements and enzyme secretion to facilitate prey digestion. The molecular underpinnings of this behavior remain largely unknown; however, evidence suggests that prey-induced electrical impulses are correlated with movement and production of the defense hormone jasmonic acid (JA), which may alter gene expression. In noncarnivorous plants, JA is linked to electrical activity via changes in cytoplasmic Ca²⁺. Here, we find that dynamic Ca²⁺ changes also occur in sundew (Drosera spatulata) leaves responding to prey-associated mechanical and chemical stimuli. Furthermore, inhibition of these Ca²⁺ changes reduced expression of JA target genes and leaf movements following chemical feeding. Our results are consistent with the presence of a conserved Ca²⁺-dependent JA signaling pathway in the sundew feeding response and provide further credence to the defensive origin of plant carnivory.     

Intensity of care in cancer patients in the last year of life: a retrospective data linkage study

Background Delivering high-quality palliative and end-of-life care for cancer patients poses major challenges for health services. We examine the intensity of cancer care in England in the last year of life.Methods We included cancer decedents aged 65+ who died between January 1, 2010 and December 31, 2017. We analysed healthcare utilisation and costs in the last 12 months of life including hospital-based activities and primary care.Results Healthcare utilisation and costs increased sharply in the last month of life. Hospital costs were the largest cost elements and decreased with age (0.78, 95% CI: 0.73–0.72, p < 0.005 for age group 90+ compared to age 65–69 and increased substantially with comorbidity burden (2.2, 95% CI: 2.09–2.26, p < 0.005 for those with 7+ comorbidities compared to those with 1–3 comorbidities). The costs were highest for haematological cancers (1.45, 95% CI: 1.38–1.52, p < 0.005) and those living in the London region (1.10, 95% CI: 1.02–1.19, p < 0.005).Conclusions Healthcare in the last year of life for advanced cancer patients is costly and offers unclear value to patients and the healthcare system. Further research is needed to understand distinct cancer populations’ pathways and experiences before recommendations can be made about the most appropriate models of care.Subject terms: Cancer, Cancer     

The consequences of risk reducing salpingo-oophorectomy: the case for a coordinated approach to long-term follow up post surgical menopause

Women with germline mutations in BRCA1 and BRCA2 genes have significantly increased lifetime risks of breast and ovarian cancer. To manage both the ovarian and breast cancer risks the current recommendation is undergo a risk reducing salpingo-oophorectomy (RRSO) prior to natural menopause. To date, studies have focussed on quality of life and sexual dysfunction in women who undergo RRSO, but few have reported on the wider physical consequences. We performed a questionnaire study in women with BRCA 1 or 2 gene mutations known to the Peter MacCallum Familial Cancer Centre. We gathered information about ovarian surgery, ongoing follow-up, management of risk factors including osteoporosis, and current severity of menopausal symptoms. Two hundred and nineteen women were surveyed. One hundred and forty-three of 157 responding participants (91?%) reported having RRSO. Sixty one were pre-menopausal at RRSO. Post surgical follow-up rates were generally low, and a minority of women reported recent bone density imaging or pharmaceutical prevention or treatment of osteoporosis. Menopausal symptoms appeared generally mild. No significant differences in symptom severity were observed in women who underwent a pre-menopausal RRSO compared to RRSO after natural menopause. These data indicate that a formalised follow-up protocol is necessary to optimally manage the consequences of a RRSO.     

Microfluidic analysis of cellular deformability of normal and oxidatively damaged red blood cells

Microfluidic analysis of blood has potential clinical value for determining normal and abnormal erythrocyte deformability. To determine if a microfluidic device could reliably measure intra‐ and inter‐personal variations of normal and oxidized human red blood cell (RBC), venous blood samples were collected from repeat donors over time. RBC deformability was defined by the cortical tension (pN/µm), as determined from the threshold pressure required to deform RBC through 2–2.5 μm funnel‐shaped constrictions. Oxidized RBC were prepared by treatment with phenazine methosulphate (PMS; 50 µM). Analysis of the control and oxidized RBC demonstrated that the microfluidic device could clearly differentiate between normal and mildly oxidized (20.13 ± 1.47 versus 27.51 ± 3.64 pN/µm) RBC. In vivo murine studies further established that the PMS‐mediated loss of deformability correlated with premature clearance. Deformability variation within an individual over three independent samplings (over 21 days) demonstrated minimal changes in the mean pN/µm. Moreover, inter‐individual variation in mean control RBC deformability was similarly small (range: 19.37–21.40 pN/µm). In contrast, PMS‐oxidized cells demonstrated a greater inter‐individual range (range: 25.97–29.90 pN/µm) reflecting the differential oxidant sensitivity of an individual's RBC. Importantly, similar deformability profiles (mean and distribution width; 20.49 ± 1.67 pN/µm) were obtained from whole blood via finger prick sampling. These studies demonstrated that a low cost microfluidic device could be used to reproducibly discriminate between normal and oxidized RBC. Advanced microfluidic devices could be of clinical value in analyzing populations for hemoglobinopathies or in evaluating donor RBC products post‐storage to assess transfusion suitability. Am. J. Hematol. 88:682–689, 2013. © 2013 Wiley Periodicals, Inc.