Guar gum and similar soluble fibers in the regulation of cholesterol metabolism: Current understandings and future research priorities

The hypocholesterolemic effects associated with soluble fiber consumption are clear from animal model and human clinical investigations. Moreover, the modulation of whole-body cholesterol metabolism in response to dietary fiber consumption, including intestinal cholesterol absorption and fecal sterol and bile acid loss, has been the subject of many published reports. However, our understanding of how dietary fibers regulate molecular events at the gene/protein level and alter cellular cholesterol metabolism is limited. The modern emphasis on molecular nutrition and rapid progress in ‘high-dimensional’ biological techniques will permit further explorations of the role of genetic polymorphisms in determining the variable interindividual responses to soluble fibers. Furthermore, with traditional molecular biology tools and the application of ‘omic’ technology, specific insight into how fibers modulate the expression of genes and proteins that regulate intestinal cholesterol absorption and alter hepatic sterol balance will be gained. Detailed knowledge of the molecular mechanisms by which soluble fibers reduce plasma cholesterol concentrations is paramount to developing novel fiber-based “cocktails” that target specific metabolic pathways to gain maximal cholesterol reductions

Resistant potato starch supplementation reduces serum histamine levels in healthy adults with links to attenuated intestinal permeability

Histamine from our diet or gut microbes can trigger gastrointestinal disturbances, and resistant potato starch (RPS) has previously been shown to alleviate these symptoms while increasing levels of health-associated bacteria such as Akkermansia through unknown mechanisms. Post hoc exploratory metabolomic analysis of serum amino acid, amine, and carnitine metabolites in participants consuming 3.5 g/day RPS or placebo (n = 48) was performed using liquid chromatography-mass spectrometry to determine whether RPS positively influences histamine metabolism and related parameters. Histamine levels were significantly reduced by RPS treatment, but histamine-degrading enzyme products were unaffected by RPS. RPS also reduced histamine-secreting Haemophilus and Lactobacillus. Further, metabolites associated with intestinal permeability, including 5-hydroxylysine, acetylspermidine, and short- and medium-chain carnitines ratios, were significantly reduced by RPS treatment, suggesting decreased serum histamine might be related to enhanced gut barrier function. These metabolomic findings expand the value of supplementing the diet with RPS

Development and immunogenicity of a prototype multivalent Group B Streptococcus bioconjugate vaccine

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Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

Multimodal imaging and spatial analysis of Ebola retinal lesions in 14 survivors of Ebola virus disease

Importance: Differentiation between Ebola retinal lesions and other retinal pathologies in West Africa is important, and the pathogenesis of Ebola retinal disease remains poorly understood. Objective: To describe the appearance of Ebola virus disease (EVD) retinal lesions using multimodal imaging to enable inferences on potential pathogenesis. Design, Setting, and Participants: This prospective case series study was carried out at 34 Military Hospital in Freetown, Sierra Leone. Ophthalmological images were analyzed from 14 consecutively identified survivors of EVD of Sierra Leonean origin who had identified Ebola retinal lesions. Main Outcomes and Measures: Multimodal imaging findings including ultra-widefield scanning laser ophthalmoscopy, fundus autofluorescence, swept-source optical coherence tomography (OCT), Humphrey visual field analysis, and spatial analysis. Results: The 14 study participants had a mean (SD) age of 37.1 (8.8) years; 6 (43%) were women. A total of 141 Ebola retinal lesions were observed in 22 of 27 eyes (81%) of these 14 survivors on ultra-widefield imaging. Of these, 41 lesions (29.1%) were accessible to OCT imaging. Retinal lesions were predominantly nonpigmented with a pale-gray appearance. Peripapillary lesions exhibited variable curvatures in keeping with the retinal nerve fiber layer projections. All lesions respected the horizontal raphe and spared the fovea. The OCT imaging demonstrated a V-shaped hyperreflectivity of the outer nuclear layer overlying discontinuities of the ellipsoid zone and interdigitation zone in the smaller lesions. Larger lesions caused a collapse of the retinal layers and loss of retinal thickness. Lesion shapes were variable, but sharp angulations were characteristic. Perilesional areas of dark without pressure (thinned ellipsoid zone hyporeflectivity) accompanied 125 of the 141 lesions (88.7%) to varying extents. Conclusions and Relevance: We demonstrate OCT evidence of localized pathological changes at the level of the photoreceptors in small lesions among survivors of EVD with retinal lesions. The relevance of associated areas of dark without pressure remains undetermined

The Global Task Force for Chronic Pain in People with HIV (PWH):Developing a research agenda in an emerging field

Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward

SPECIAL ISSUE HIV and CHRONIC PAIN (The Global Task Force for Chronic Pain in People with HIV (PWH): Developing a research agenda in an emerging field)

Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward