A Double-Blind, Placebo-Controlled Trial to Assess Safety and Tolerability of (Thetanix) Bacteroides thetaiotaomicron in Adolescent Crohn's Disease.

INTRODUCTION: Thetanix (gastroresistant capsules containing lyophilized Bacteroides thetaiotaomicron) is a live biotherapeutic, under development for Crohn's disease, that antagonizes transcription factor nuclear factor kappa B, reducing proinflammatory cytokines, particularly tumor necrosis factor alpha. We aimed to assess safety and tolerability in adolescents with Crohn's disease in remission. METHODS: Subjects who were 16-18 years with Crohn's in remission (weighted pediatric Crohn's disease activity index <12.5) were recruited. Each active dose comprised ∼108.2±1.4 colony forming units of B. thetaiotaomicron (randomized 4:1 active:placebo). Part A was single dose. Part B involved 7.5 days twice daily dosing. Serial stools were analyzed for calprotectin, 16S rRNA sequencing, and B. thetaiotaomicron real-time polymerase chain reaction. Bloods were taken serially. Subjects reported adverse events and recorded temperature twice daily. RESULTS: Fifteen subjects were treated-8 in part A (75% men, median 17.1 years) and 10 in part B, including 3 from part A (80% men, median 17.1 years); all 18 completed. Seventy percent took concurrent immunosuppression. Reported compliance was >99% in part B. Two subjects reported adverse events deemed related-one in part A with eructation, flatulence, and reflux; one in part B with dizziness, abdominal pain, and headache. No serious adverse events were reported. There was no significant change in median calprotectin across part B (87.8 [4.4-447] to 50.5 [5.3-572], P = 0.44 by the Fisher exact test in the active group). No significant differences were found in microbiota profiles, but diversity seemed to increase in treated subjects. DISCUSSION: Thetanix, after single and multiple doses, was well tolerated. Although the numbers in this study were small, the safety profile seems good. Future studies should explore efficacy.

Differences in Fecal Microbiomes and Metabolomes of People With vs Without Irritable Bowel Syndrome and Bile Acid Malabsorption.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a heterogeneous disorder, but diagnoses and determination of subtypes are made based on symptoms. We profiled the fecal microbiomes of patients with and without IBS to identify biomarkers of this disorder. METHODS: We collected fecal and urine samples from 80 patients with IBS (Rome IV criteria; 16-70 years old) and 65 matched individuals without IBS (control individuals), along with anthropometric, medical, and dietary information. Shotgun and 16S ribosomal RNA amplicon sequencing were performed on feces, whereas urine and fecal metabolites were analyzed by gas chromatography and liquid chromatography-mass spectrometry. Co-occurrence networks were generated based on significant Spearman correlations between data. Bile acid malabsorption (BAM) was identified in patients with diarrhea by retention of radiolabeled selenium-75 homocholic acid taurine. RESULTS: Patients with IBS had significant differences in network connections between diet and fecal microbiomes compared with control individuals; these were accompanied by differences in fecal metabolomes. We did not find significant differences in fecal microbiota composition among patients with different IBS symptom subtypes. Fecal metabolome profiles could discriminate patients with IBS from control individuals. Urine metabolomes also differed significantly between patients with IBS and control individuals, but most discriminatory metabolites were related to diet or medications. Fecal metabolomes, but not microbiomes, could distinguish patients with IBS with vs those without BAM. CONCLUSIONS: Despite the heterogeneity of IBS, patients have significant differences in urine and fecal metabolomes and fecal microbiome vs control individuals, independent of symptom-based subtypes of IBS. Fecal metabolome analysis can be used to distinguish patients with IBS with vs those without BAM. These findings might be used for developing microbe-based treatments for these disorders.

Reducing inappropriate prescribing for older adults with advanced frailty: A review based on a survey of practice in four countries.

The management of medications in persons with frailty presents challenges. There is evidence of inappropriate prescribing and a lack of consensus among healthcare professionals on the judicious use of medications, particularly for patients with more severe frailty. This study reviews the evidence on the use of commonly prescribed pharmacological treatments in advanced frailty based on a questionnaire of prescribing practices and attitudes of healthcare professionals at different stages in their careers, in different countries. A convenience sample of those attending hospital grand rounds in Ireland, Canada and Australia/New Zealand (ANZ) were surveyed on the management of 18 medications in advanced frailty using a clinical vignette (man with severe dementia, Clinical Frailty Scale 7/9). Choices were to continue or discontinue (stop now or later) medications. In total, 298 respondents from Ireland (n = 124), Canada (n = 110), and ANZ (n = 64) completed the questionnaire, response rate 97%, including 81 consultants, 40 non-consultant hospital doctors, 134 general practitioners and 43 others (nurses, pharmacists, and medical students). Most felt that statins (88%), bisphosphonates (77%) and cholinesterase inhibitors (76%) should be discontinued. Thyroid replacement (88%), laxatives (83%) and paracetamol (81%) were most often continued. Respondents with experience in geriatric, palliative and dementia care were significantly more likely to discontinue medications. Age, gender and experience working in nursing homes did not contribute to the decision. Reflecting the current literature, there was no clear consensus on inappropriate prescribing, although respondents preferentially discontinued medications for secondary prevention. Experience significantly predicted the number and type discontinued, suggesting that education is important in reducing inappropriate prescribing for people in advanced states of frailty.

Prebiotic supplementation in frail older people affects specific gut microbiota taxa but not global diversity.

BACKGROUND: There are complex interactions between aging, frailty, diet, and the gut microbiota; modulation of the gut microbiota by diet could lead to healthier aging. The purpose of this study was to test the effect of diets differing in sugar, fat, and fiber content upon the gut microbiota of mice humanized with microbiota from healthy or frail older people. We also performed a 6-month dietary fiber supplementation in three human cohorts representing three distinct life-stages. METHODS: Mice were colonized with human microbiota and then underwent an 8-week dietary intervention with either a high-fiber/low-fat diet typical of elderly community dwellers or a low-fiber/high-fat diet typical of long-stay residential care subjects. A cross-over design was used where the diets were switched after 4 weeks to the other diet type to identify responsive taxa and innate immunity changes. In the human intervention, the subjects supplemented their normal diet with a mix of five prebiotics (wheat dextrin, resistant starch, polydextrose, soluble corn fiber, and galactooligo-saccharide) at 10 g/day combined total, for healthy subjects and 20 g/day for frail subjects, or placebo (10 g/day maltodextrin) for 26 weeks. The gut microbiota was profiled and immune responses were assayed by T cell markers in mice, and serum cytokines in humans. RESULTS: Humanized mice maintained gut microbiota types reflecting the respective healthy or frail human donor. Changes in abundance of specific taxa occurred with the diet switch. In mice with the community type microbiota, the observed differences reflected compositions previously associated with higher frailty. The dominance of Prevotella present initially in community inoculated mice was replaced by Bacteroides, Alistipes, and Oscillibacter. Frail type microbiota showed a differential effect on innate immune markers in both conventional and germ-free mice, but a moderate number of taxonomic changes occurring upon diet switch with an increase in abundance of Parabacteroides, Blautia, Clostridium cluster IV, and Phascolarctobacterium. In the human intervention, prebiotic supplementation did not drive any global changes in alpha- or beta-diversity, but the abundance of certain bacterial taxa, particularly Ruminococcaceae (Clostridium cluster IV), Parabacteroides, Phascolarctobacterium, increased, and levels of the chemokine CXCL11 were significantly lower in the frail elderly group, but increased during the wash-out period. CONCLUSIONS: Switching to a nutritionally poorer diet has a profound effect on the microbiota in mouse models, with changes in the gut microbiota from healthy donors reflecting previously observed differences between elderly frail and non-frail individuals. However, the frailty-associated gut microbiota did not reciprocally switch to a younger healthy-subject like state, and supplementation with prebiotics was associated with fewer detected effects in humans than diet adjustment in animal models.

Prevalence of malnutrition using harmonized definitions in older adults from different settings - A MaNuEL study.

BACKGROUND & AIMS: Malnutrition is widespread among older people and related to poor outcome. Reported prevalences vary widely, also because of different diagnostic criteria used. This study aimed to describe prevalences in several populations of older persons in different settings using harmonized definitions. METHODS: Available studies within the Joint Programming Initiative (JPI) Knowledge Hub 'Malnutrition in the Elderly' (MaNuEL) were used to calculate and compare prevalences of malnutrition indicators: low BMI (<20 kg/m2; age-specific BMI <20 if age 65-<70 and <22 kg/m2 if age ≥70 years), previous weight loss (WL), moderate and severe decrease in food intake, and combined BMI <20 kg/m2 and/or WL in participants aged ≥65 years. RESULTS: Fifteen samples with in total 5956 participants (59.3% women) were included: 7 consisting of community-dwelling persons, 2 studies in geriatric day hospitals, 3 studies in hospitalized patients and 3 in nursing homes. Mean age of participants ranged between 67 and 87 years. Up to 4.2% of community-dwelling persons had a BMI <20 kg/m2, 1.6 and 9% of geriatric day hospital patients, 4.5-9.4% of hospital patients and 3.8-18.2% of nursing home residents. Using age-specific cut-offs doubled these prevalences. WL was reported in 2.3-10.5% of community-dwelling persons, 6% and 12.6% of geriatric day hospital patients, 5-14% of hospitalized patients and 4.5-7.7% of nursing home residents. Severe decrease in food intake was recorded in up to 9.6% of community-dwelling persons, 1.5% and 12% of geriatric day hospital patients, 3.4-34.2% of hospitalized patients and 1.5-8.2% of nursing home residents. The criteria age-specific BMI and WL showed opposing prevalences across all settings. Compared to women, low BMI and moderate decrease in food intake showed low prevalences in men but similar prevalences were observed for weight loss and severe decrease in food intake. In half of the study samples, participants in a younger age group had a higher prevalence of WL compared to those of an older age group. Prevalence of BMI <20 kg/m2 and WL at the same time did not exceed 2.6% in all samples. The highest prevalences were observed based on combined definitions when only one of the three criteria had to be present. CONCLUSIONS: Prevalences for different criteria vary between and within the settings which might be explained by varying functional status. The criteria used strongly affect prevalence and it may be preferable to look at each criterion separately as each may indicate a nutritional problem.

Measuring staff perception of end-of-life experience of older adults in long-term care.

BACKGROUND: Quality of dying and death receive far less attention than quality of life. Measuring the quality of care at end-of-life (EOL) in long-term care (LTC) is essential, to ensure high standards. METHODS: A questionnaire measuring staff perception of their patient's end of life experience (SPELE) was developed. Content validity (CVI) was assessed by a panel of experts, and piloting was conducted with dyads of healthcare assistants (n=15) and nurses (n=15). RESULTS: The SPELE captures facets of the quality of the death and dying experience from healthcare staff's perspective. Good group inter-rater reliability was observed among subscales. One exception was the pain and symptom experience scale. Kappa values showed little agreement between nurses and healthcare assistants for certain symptoms, including pain. CONCLUSION: Further testing of the questionnaire is required. However it is described as a useful mechanism to enable researchers and clinicians to explore quality of care at EOL.

Which Part of a Short, Global Risk Assessment, the Risk Instrument for Screening in the Community, Predicts Adverse Healthcare Outcomes?

The Risk Instrument for Screening in the Community (RISC) is a short, global risk assessment to identify community-dwelling older adults' one-year risk of institutionalisation, hospitalisation, and death. We investigated the contribution that the three components of the RISC (concern, its severity, and the ability of the caregiver network to manage concern) make to the accuracy of the instrument, across its three domains (mental state, activities of daily living (ADL), and medical state), by comparing their accuracy to other assessment instruments in the prospective Community Assessment of Risk and Treatment Strategies study. RISC scores were available for 782 patients. Across all three domains each subtest more accurately predicted institutionalisation compared to hospitalisation or death. The caregiver network's ability to manage ADL more accurately predicted institutionalisation (AUC 0.68) compared to hospitalisation (AUC 0.57, P = 0.01) or death (AUC 0.59, P = 0.046), comparing favourably with the Barthel Index (AUC 0.67). The severity of ADL (AUC 0.63), medical state (AUC 0.62), Clinical Frailty Scale (AUC 0.67), and Charlson Comorbidity Index (AUC 0.66) scores had similar accuracy in predicting mortality. Risk of hospitalisation was difficult to predict. Thus, each component, and particularly the caregiver network, had reasonable accuracy in predicting institutionalisation. No subtest or assessment instrument accurately predicted risk of hospitalisation.

The Risk Instrument for Screening in the Community (RISC): a new instrument for predicting risk of adverse outcomes in community dwelling older adults.

BACKGROUND: Predicting risk of adverse healthcare outcomes, among community dwelling older adults, is difficult. The Risk Instrument for Screening in the Community (RISC) is a short (2-5 min), global subjective assessment of risk created to identify patients' 1-year risk of three outcomes:institutionalisation, hospitalisation and death. METHODS: We compared the accuracy and predictive ability of the RISC, scored by Public Health Nurses (PHN), to the Clinical Frailty Scale (CFS) in a prospective cohort study of community dwelling older adults (n = 803), in two Irish PHN sectors. The area under the curve (AUC), from receiver operating characteristic curves and binary logistic regression models, with odds ratios (OR), compared the discriminatory characteristics of the RISC and CFS. RESULTS: Follow-up data were available for 801 patients. The 1-year incidence of institutionalisation, hospitalisation and death were 10.2, 17.7 and 15.6 % respectively. Patients scored maximum-risk (RISC score 3,4 or 5/5) at baseline had a significantly greater rate of institutionalisation (31.3 and 7.1 %, p < 0.001), hospitalisation (25.4 and 13.2 %, p < 0.001) and death (33.5 and 10.8 %, p < 0.001), than those scored minimum-risk (score 1 or 2/5). The RISC had comparable accuracy for 1-year risk of institutionalisation (AUC of 0.70 versus 0.63), hospitalisation (AUC 0.61 versus 0.55), and death (AUC 0.70 versus 0.67), to the CFS. The RISC significantly added to the predictive accuracy of the regression model for institutionalisation (OR 1.43, p = 0.01), hospitalisation (OR 1.28, p = 0.01), and death (OR 1.58, p = 0.001). CONCLUSION: Follow-up outcomes matched well with baseline risk. The RISC, a short global subjective assessment, demonstrated satisfactory validity compared with the CFS.

Screening for markers of frailty and perceived risk of adverse outcomes using the Risk Instrument for Screening in the Community (RISC).

BACKGROUND: Functional decline and frailty are common in community dwelling older adults, increasing the risk of adverse outcomes. Given this, we investigated the prevalence of frailty-associated risk factors and their distribution according to the severity of perceived risk in a cohort of community dwelling older adults, using the Risk Instrument for Screening in the Community (RISC). METHODS: A cohort of 803 community dwelling older adults were scored for frailty by their public health nurse (PHN) using the Clinical Frailty Scale (CFS) and for risk of three adverse outcomes: i) institutionalisation, ii) hospitalisation and iii) death, within the next year, from one (lowest) to five (highest) using the RISC. Prior to scoring, PHNs stated whether they regarded patients as frail. RESULTS: The median age of patients was 80 years (interquartile range 10), of whom 64% were female and 47.4% were living alone. The median Abbreviated Mental Test Score (AMTS) was 10 (0) and Barthel Index was 18/20 (6). PHNs regarded 42% of patients as frail, while the CFS categorized 54% (scoring ≥5) as frail. Dividing patients into low-risk (score one or two), medium-risk (score three) and high-risk (score four or five) using the RISC showed that 4.3% were considered high risk of institutionalization, 14.5% for hospitalization, and 2.7% for death, within one year of the assessment. There were significant differences in median CFS (4/9 versus 6/9 versus 6/9, p < 0.001), Barthel Index (18/20 versus 11/20 versus 14/20, p < 0.001) and mean AMTS scores (9.51 versus 7.57 versus 7.00, p < 0.001) between those considered low, medium and high risk of institutionalisation respectively. Differences were also statistically significant for hospitalisation and death. Age, gender and living alone were inconsistently associated with perceived risk. Frailty most closely correlated with functional impairment, r = -0.80, p < 0.001. CONCLUSION: The majority of patients in this community sample were perceived to be low risk for adverse outcomes. Frailty, cognitive impairment and functional status were markers of perceived risk. Age, gender and social isolation were not and may not be useful indicators when triaging community dwellers. The RISC now requires validation against adverse outcomes.

Gut microbiota in older subjects: variation, health consequences and dietary intervention prospects.

Alterations in intestinal microbiota composition and function have been linked to conditions including functional gastrointestinal disorders, obesity and diabetes. The gut microbiome encodes metabolic capability in excess of that encoded by the human genome, and bacterially produced enzymes are important for releasing nutrients from complex dietary ingredients. Previous culture-based studies had indicated that the gut microbiota of older people was different from that of younger adults, but the detailed findings were contradictory. Small-scale studies had also shown that the microbiota composition could be altered by dietary intervention or supplementation. We showed that the core microbiota and aggregate composition in 161 seniors was distinct from that of younger persons. To further investigate the reasons for this variation, we analysed the microbiota composition of 178 elderly subjects for whom the dietary intake data were available. The data revealed distinct microbiota composition groups, which overlapped with distinct dietary patterns that were governed by where people lived: at home, in rehabilitation or in long-term residential care. These diet-microbiota separations correlated with cluster analysis of NMR-derived faecal metabolites and shotgun metagenomic data. Major separations in the microbiota correlated with selected clinical measurements. It should thus be possible to programme the microbiota to enrich bacterial species and activities that promote healthier ageing. A number of other studies have investigated the effect of certain dietary components and their ability to modulate the microbiota composition to promote health. This review will discuss dietary interventions conducted thus far, especially those in elderly populations and highlight their impact on the intestinal microbiota.

Bioprospecting in potato fields in the Central Andean Highlands: screening of rhizobacteria for plant growth-promoting properties.

The Central Andean Highlands are the center of origin of the potato plant (Solanum tuberosum). Ages of mutualism between potato plants and soil bacteria in this region support the hypothesis that Andean soils harbor interesting plant growth-promoting (PGP) bacteria. Therefore, the aim of this study was to isolate rhizobacteria from Andean ecosystems, and to identify those with PGP properties. A total of 585 bacterial isolates were obtained from eight potato fields in the Andes and they were screened for suppression of Phytophthora infestans and Rhizoctonia solani. Antagonistic mechanisms were determined and antagonistic isolates were further tested for phosphate solubilization, 1-aminocyclopropane-1-carboxylate (ACC) deaminase activity, and production of NH3- and indole-3-acetic acid (IAA). PGP was studied in healthy and R. solani diseased plantlets under growth room conditions. Performance was compared to the commercial strain B. subtilis FZB24(®) WG. Isolates were dereplicated with matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS), and identified with 16S rRNA gene sequencing and multi locus sequence analysis (MLSA). A total of 10% of the isolates were effective antagonists, of which many were able to solubilize phosphate, and produce IAA, ACC deaminase, NH3 and hydrogen cyanide (HCN). During growth room experiments, 23 antagonistic isolates were associated with plant growth-promotion and/or disease suppression. Ten isolates had a statistically significant impact on test parameters compared to the uninoculated control. Three isolates significantly promoted plant growth in healthy plantlets compared to the commercial strain, and seven isolates outperformed the commercial strain in in vitro R. solani diseased plantlets.