Bile salt hydrolase acyltransferase activity expands bile acid diversity.

Bile acids (BAs) are steroid detergents in bile that contribute to the absorption of fats and fat-soluble vitamins while shaping the gut microbiome because of their antimicrobial properties1-4. Here we identify the enzyme responsible for a mechanism of BA metabolism by the gut microbiota involving amino acid conjugation to the acyl-site of BAs, thus producing a diverse suite of microbially conjugated bile acids (MCBAs). We show that this transformation is mediated by acyltransferase activity of bile salt hydrolase (bile salt hydrolase/transferase, BSH/T). Clostridium perfringens BSH/T rapidly performed acyl transfer when provided various amino acids and taurocholate, glycocholate or cholate, with an optimum at pH 5.3. Amino acid conjugation by C. perfringens BSH/T was diverse, including all proteinaceous amino acids except proline and aspartate. MCBA production was widespread among gut bacteria, with strain-specific amino acid use. Species with similar BSH/T amino acid sequences had similar conjugation profiles and several bsh/t alleles correlated with increased conjugation diversity. Tertiary structure mapping of BSH/T followed by mutagenesis experiments showed that active site structure affects amino acid selectivity. These MCBA products had antimicrobial properties, where greater amino acid hydrophobicity showed greater antimicrobial activity. Inhibitory concentrations of MCBAs reached those measured natively in the mammalian gut. MCBAs fed to mice entered enterohepatic circulation, in which liver and gallbladder concentrations varied depending on the conjugated amino acid. Quantifying MCBAs in human faecal samples showed that they reach concentrations equal to or greater than secondary and primary BAs and were reduced after bariatric surgery, thus supporting MCBAs as a significant component of the BA pool that can be altered by changes in gastrointestinal physiology. In conclusion, the inherent acyltransferase activity of BSH/T greatly diversifies BA chemistry, creating a set of previously underappreciated metabolites with the potential to affect the microbiome and human health.

Global chemical effects of the microbiome include new bile-acid conjugations.

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease1-9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units10), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches11-13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry14. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.

Impact of Prior Abdominal Procedures on Peritoneal Dialysis Catheter Outcomes: Findings From the North American Peritoneal Dialysis Catheter Registry.

RATIONALE & OBJECTIVE: A history of prior abdominal procedures may influence the likelihood of referral for peritoneal dialysis (PD) catheter insertion. To guide clinical decision making in this population, this study examined the association between prior abdominal procedures and outcomes in patients undergoing PD catheter insertion. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults undergoing their first PD catheter insertion between November 1, 2011, and November 1, 2020, at 11 institutions in Canada and the United States participating in the International Society for Peritoneal Dialysis North American Catheter Registry. EXPOSURE: Prior abdominal procedure(s) defined as any procedure that enters the peritoneal cavity. OUTCOMES: The primary outcome was time to the first of (1) abandonment of the PD catheter or (2) interruption/termination of PD. Secondary outcomes were rates of emergency room visits, hospitalizations, and procedures. ANALYTICAL APPROACH: Cumulative incidence curves were used to describe the risk over time, and an adjusted Cox proportional hazards model was used to estimate the association between the exposure and primary outcome. Models for count data were used to estimate the associations between the exposure and secondary outcomes. RESULTS: Of 855 patients who met the inclusion criteria, 31% had a history of a prior abdominal procedure and 20% experienced at least 1 PD catheter-related complication that led to the primary outcome. Prior abdominal procedures were not associated with an increased risk of the primary outcome (adjusted HR, 1.12; 95% CI, 0.68-1.84). Upper-abdominal procedures were associated with a higher adjusted hazard of the primary outcome, but there was no dose-response relationship concerning the number of procedures. There was no association between prior abdominal procedures and other secondary outcomes. LIMITATIONS: Observational study and cohort limited to a sample of patients believed to be potential candidates for PD catheter insertion. CONCLUSION: A history of prior abdominal procedure(s) does not appear to influence catheter outcomes following PD catheter insertion. Such a history should not be a contraindication to PD. PLAIN-LANGUAGE SUMMARY: Peritoneal dialysis (PD) is a life-saving therapy for individuals with kidney failure that can be done at home. PD requires the placement of a tube, or catheter, into the abdomen to allow the exchange of dialysis fluid during treatment. There is concern that individuals who have undergone prior abdominal procedures and are referred for a catheter might have scarring that could affect catheter function. In some institutions, they might not even be offered PD therapy as an option. In this study, we found that a history of prior abdominal procedures did not increase the risk of PD catheter complications and should not dissuade patients from choosing PD or providers from recommending it.

Immunosuppressive therapy for IgA nephropathy in children.

BACKGROUND: IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis. It is a heterogeneous disease with different presentations and high morbidity. Thirty per cent of adults and 20% of children (followed into adulthood) will have a 50% decline in kidney function or develop kidney failure after 10 years. OBJECTIVES: To determine the benefits and harms of immunosuppressive therapy for the treatment of IgAN in children. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 03 October 2023 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) investigating the treatment of IgAN in children with immunosuppressive therapies compared to placebo, no treatment, supportive care, standard therapy (Japanese protocol), other immunosuppressive therapies or non-immunosuppressive therapies. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias. Random effects meta-analyses were used to summarise estimates of treatment effects. Treatment effects were expressed as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and the mean difference (MD) and 95% CI for continuous outcomes. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs and the ROBIN-I tool for NRSIs. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). MAIN RESULTS: This review included 13 studies with 686 participants. Ten RCTs included 334 children and 191 adults, and three NRSIs included 151 participants, all children. Most participants had mild kidney disease. The risk of bias was unclear for most of the domains relating to allocation concealment, blinding of participants, personnel, and outcome assessment. In children with IgAN, it is uncertain if corticosteroid (steroid) therapy, compared to placebo reduces proteinuria (1 study, 64 children and young adults: RR 0.47, 95% CI 0.13 to 1.72; low certainty evidence) or the decline in estimated glomerular filtration rate (eGFR) (1 study, 64 children and young adults: RR 0.47, 95% CI 0.09 to 2.39; low certainty evidence). It is uncertain if steroids reduce proteinuria compared to supportive care (2 studies, 61 children: RR 0.04, 95% CI -0.83 to 0.72; low certainty evidence). Adverse events associated with steroid therapy were not assessed due to heterogeneity in steroid protocols, including dose and duration, and lack of systematic assessment for adverse events in the included studies. Azathioprine, mycophenolate mofetil, mizoribine, or cyclophosphamide alone or in combination with steroid therapy had uncertain effects on improving proteinuria or preventing eGFR decline in children with IgAN. Fish oil, vitamin E and tonsillectomy had uncertain effects on improving proteinuria or preventing eGFR decline. Effects of other immunosuppressive therapies, secondary outcomes and adverse events were not assessed due to insufficient data. AUTHORS' CONCLUSIONS: There is a lack of high-quality evidence to guide the management of IgAN in children. There is no evidence to indicate that steroids, other immunosuppressive therapies, or tonsillectomy, when added to optimal supportive care, prevent a decline in eGFR or proteinuria in children with IgAN. Available studies were few, with small numbers, low-quality evidence, high or uncertain risk of bias, did not systematically assess harms associated with treatment, or report net benefits or harms. Severe cases and atypical presentations of IgAN were not included in the reviewed studies, and our findings cannot be generalised to these situations.

Global variations in funding and use of hemodialysis accesses: an international report using the ISN Global Kidney Health Atlas.

BACKGROUND: There is a lack of contemporary data describing global variations in vascular access for hemodialysis (HD). We used the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to highlight differences in funding and availability of hemodialysis accesses used for initiating HD across world regions. METHODS: Survey questions were directed at understanding the funding modules for obtaining vascular access and types of accesses used to initiate dialysis. An electronic survey was sent to national and regional key stakeholders affiliated with the ISN between June and September 2022. Countries that participated in the survey were categorized based on World Bank Income Classification (low-, lower-middle, upper-middle, and high-income) and by their regional affiliation with the ISN. RESULTS: Data on types of vascular access were available from 160 countries. Respondents from 35 countries (22% of surveyed countries) reported that > 50% of patients started HD with an arteriovenous fistula or graft (AVF or AVG). These rates were higher in Western Europe (n = 14; 64%), North & East Asia (n = 4; 67%), and among high-income countries (n = 24; 38%). The rates of > 50% of patients starting HD with a tunneled dialysis catheter were highest in North America & Caribbean region (n = 7; 58%) and lowest in South Asia and Newly Independent States and Russia (n = 0 in both regions). Respondents from 50% (n = 9) of low-income countries reported that > 75% of patients started HD using a temporary catheter, with the highest rates in Africa (n = 30; 75%) and Latin America (n = 14; 67%). Funding for the creation of vascular access was often through public funding and free at the point of delivery in high-income countries (n = 42; 67% for AVF/AVG, n = 44; 70% for central venous catheters). In low-income countries, private and out of pocket funding was reported as being more common (n = 8; 40% for AVF/AVG, n = 5; 25% for central venous catheters). CONCLUSIONS: High income countries exhibit variation in the use of AVF/AVG and tunneled catheters. In low-income countries, there is a higher use of temporary dialysis catheters and private funding models for access creation.

Adjunctive fixation of the humeral epicondyle in a lateral condylar fracture model: Ex vivo comparison of pins and plates with a novel composite (AdhFix).

OBJECTIVE: To compare the biomechanical properties of using a novel composite construct (AdhFix) to an interfragmentary Kirschner wire or a reconstruction plate as adjunctive epicondylar stabilization in simulated lateral unicondylar humeral fractures. STUDY DESIGN: Cadaveric biomechanical assessment. SAMPLE POPULATION: Paired humeri harvested from skeletally mature dogs (14-41 kg), nine cadavers per group. METHODS: Simulated lateral unicondylar humeral fractures were stabilized with a transcondylar 4.5 mm cortical screw placed in lag fashion. Adjunct fixations consisting of a novel composite incorporating 2.7 mm cortical screws on one side, and either a 2.7 mm reconstruction plate or a 1.6 mm Kirschner wire on the contralateral side, were tested within paired humeri. Repaired humeri were axially loaded to failure and construct stiffness, yield load, and ultimate load were obtained from the load-deformation curves. RESULTS: In pairwise comparison, yield load was significantly higher for AdhFix group compared to the pin group, p = .016. No statistical significance was seen in the comparison between AdhFix group and the plate group, p = .25. CONCLUSION: Adhfix was mechanically superior to K-wires, and comparable to plate fixation, for adjunctive fixation in a lateral humeral condylar model. Our results support further investigation of the novel composite for adjunct fracture fixation in lateral humeral condylar fractures. CLINICAL SIGNIFICANCE: The novel composite tested may be a viable alternative for adjunct fixation of humeral condylar fractures, a technique that circumvents plate contouring.

Wilderness Medical Society Clinical Practice Guidelines for Spinal Cord Protection: 2024 Update.

The Wilderness Medical Society reconvened an expert panel to update best practice guidelines for spinal cord protection during trauma management. This panel, with membership updated in 2023, was charged with the development of evidence-based guidelines for management of the injured or potentially injured spine in wilderness environments. Recommendations are made regarding several parameters related to spinal cord protection. These recommendations are graded based on the quality of supporting evidence and balance the benefits and risks/burdens for each parameter according to American College of Chest Physicians methodology. Key recommendations include the concept that interventions should be goal-oriented (spinal cord/column protection in the context of overall patient and provider safety) rather than technique-oriented (immobilization). An evidence-based, goal-oriented approach excludes the immobilization of suspected spinal injuries via rigid collars or backboards.

ReDU: a framework to find and reanalyze public mass spectrometry data.

We present ReDU ( https://redu.ucsd.edu/ ), a system for metadata capture of public mass spectrometry-based metabolomics data, with validated controlled vocabularies. Systematic capture of knowledge enables the reanalysis of public data and/or co-analysis of one's own data. ReDU enables multiple types of analyses, including finding chemicals and associated metadata, comparing the shared and different chemicals between groups of samples, and metadata-filtered, repository-scale molecular networking.

Feature-based molecular networking in the GNPS analysis environment.

Molecular networking has become a key method to visualize and annotate the chemical space in non-targeted mass spectrometry data. We present feature-based molecular networking (FBMN) as an analysis method in the Global Natural Products Social Molecular Networking (GNPS) infrastructure that builds on chromatographic feature detection and alignment tools. FBMN enables quantitative analysis and resolution of isomers, including from ion mobility spectrometry.

Patient and Clinician Perspectives on Shared Decision Making in Vascular Access Selection: A Qualitative Study.

RATIONALE & OBJECTIVE: Collaborative approaches to vascular access selection are being increasingly encouraged to elicit patients' preferences and priorities where no unequivocally superior choice exists. We explored how patients, their caregivers, and clinicians integrate principles of shared decision making when engaging in vascular access discussions. STUDY DESIGN: Qualitative description. SETTING & PARTICIPANTS: Semistructured interviews with a purposive sample of patients, their caregivers, and clinicians from outpatient hemodialysis programs in Alberta, Canada. ANALYTICAL APPROACH: We used a thematic analysis approach to inductively code transcripts and generate themes to capture key concepts related to vascular access shared decision making across participant roles. RESULTS: 42 individuals (19 patients, 2 caregivers, 21 clinicians) participated in this study. Participants identified how access-related decisions follow a series of major decisions about kidney replacement therapy and care goals that influence vascular access preferences and choice. Vascular access shared decision making was strengthened through integration of vascular access selection with dialysis-related decisions and timely, tailored, and balanced exchange of information between patients and their care team. Participants described how opportunities to revisit the vascular access decision before and after dialysis initiation helped prepare patients for their access and encouraged ongoing alignment between patients' care priorities and treatment plans. Where shared decision making was undermined, hemodialysis via a catheter ensued as the most readily available vascular access option. LIMITATIONS: Our study was limited to patients and clinicians from hemodialysis care settings and included few caregiver participants. CONCLUSIONS: Findings suggest that earlier, or upstream, decisions about kidney replacement therapies influence how and when vascular access decisions are made. Repeated vascular access discussions that are integrated with other higher-level decisions are needed to promote vascular access shared decision making and preparedness.

Longitudinal microbial and molecular dynamics in the cystic fibrosis lung after Elexacaftor-Tezacaftor-Ivacaftor therapy.

BACKGROUND: Cystic fibrosis (CF) is a genetic disorder causing poor mucociliary clearance in the airways and subsequent respiratory infection. The recently approved triple therapy Elexacaftor-Tezacaftor-Ivacaftor (ETI) has significantly improved lung function and decreased airway infection in persons with CF (pwCF). This improvement has been shown to occur rapidly, within the first few weeks of treatment. The effects of longer term ETI therapy on lung infection dynamics, however, remain mostly unknown. RESULTS: Here, we applied 16S rRNA gene amplicon sequencing, untargeted metabolomics, and neutral models to high-resolution, longitudinally collected sputum samples from pwCF on ETI therapy (162 samples, 7 patients) and compared to similarly collected data set from pwCF not taking ETI (630 samples, 9 patients). Because ETI reduces sputum production, samples were collected in freezers provided in the subject's homes at least 3 months after first taking ETI, with those on ETI collecting a sample approximately weekly. The lung function (%ppFEV1) of those in our longitudinal cohort significantly improved after ETI (6.91, SD = 7.74), indicating our study cohort was responsive to ETI. The daily variation of alpha- and beta-diversity of both the microbiome and metabolome was higher for those on ETI, reflecting a more dynamic microbial community and chemical environment during treatment. Four of the seven subjects on ETI were persistently infected with Pseudomonas or Burkholderia in their sputum throughout the sampling period while the total bacterial load significantly decreased with time (R = - 0.42, p = 0.01) in only one subject. The microbiome and metabolome dynamics on ETI were personalized, where some subjects had a progressive change with time on therapy, whereas others had no association with time on treatment. To further classify the augmented variance of the CF microbiome under therapy, we fit the microbiome data to a Hubbell neutral dynamics model in a patient-stratified manner and found that the subjects on ETI had better fit to a neutral model. CONCLUSION: This study shows that the longitudinal microbiology and chemistry in airway secretions from subjects on ETI has become more dynamic and neutral and that after the initial improvement in lung function, many are still persistently infected with CF pathogens.

Do locking plugs improve implant strength? Biomechanical comparison of polyaxial locking constructs with and without locking plugs in a fracture gap model.

BACKGROUND: The objective of this study was to investigate the effects of locking plugs and the biomechanical properties of a 3.5 mm 8-hole polyaxial locking plate in a fracture gap model. Our hypothesis was that locking plugs would increase the strength and stiffness of the construct. Twelve 3.5 mm 8-hole plates were used to evaluate two different construct designs (with locking plugs vs. without locking plugs) with validated bone substitutes in a 25 mm bridging osteosynthesis gap model. Each construct was subjected to a single cycle four-point bending load to failure using a servo-hydraulic testing machine. Bending stiffness, bending strength, and bending structural stiffness were calculated and compared using an unpaired Student´s t-test. RESULTS: The plating construct with locking plugs did not show any significant increase in terms of bending stiffness, bending strength, and bending structural stiffness compared to plating construct without locking plugs in a 25 mm gap fracture model during a single cycle four-point bending. CONCLUSIONS: Under the conditions tested, filling empty plate holes with locking plugs in bridging osteosynthesis does not increase stiffness or strength of the plate-bone construct.

A multiomic analysis of in situ coral-turf algal interactions.

Viruses, microbes, and host macroorganisms form ecological units called holobionts. Here, a combination of metagenomic sequencing, metabolomic profiling, and epifluorescence microscopy was used to investigate how the different components of the holobiont including bacteria, viruses, and their associated metabolites mediate ecological interactions between corals and turf algae. The data demonstrate that there was a microbial assemblage unique to the coral-turf algae interface displaying higher microbial abundances and larger microbial cells. This was consistent with previous studies showing that turf algae exudates feed interface and coral-associated microbial communities, often at the detriment of the coral. Further supporting this hypothesis, when the metabolites were assigned a nominal oxidation state of carbon (NOSC), we found that the turf algal metabolites were significantly more reduced (i.e., have higher potential energy) compared to the corals and interfaces. The algae feeding hypothesis was further supported when the ecological outcomes of interactions (e.g., whether coral was winning or losing) were considered. For example, coral holobionts losing the competition with turf algae had higher Bacteroidetes-to-Firmicutes ratios and an elevated abundance of genes involved in bacterial growth and division. These changes were similar to trends observed in the obese human gut microbiome, where overfeeding of the microbiome creates a dysbiosis detrimental to the long-term health of the metazoan host. Together these results show that there are specific biogeochemical changes at coral-turf algal interfaces that predict the competitive outcomes between holobionts and are consistent with algal exudates feeding coral-associated microbes.

Baat Gene Knockout Alters Post-Natal Development, the Gut Microbiome, and Reveals Unusual Bile Acids in Mice.

Bile acids (BAs) are steroid detergents in bile that contribute to fat absorption, cell signaling, and microbiome interactions. The final step in their synthesis is amino acid conjugation with either glycine or taurine in the liver by the enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT). Here, we describe the microbial, chemical, and physiological consequences of Baat gene knockout. Baat-/- mice were underweight after weaning but quickly exhibited catch-up growth. At three weeks of age, KO animals had increased phospholipid excretion and decreased subcutaneous fat pad mass, liver mass, glycogen staining in hepatocytes, and hepatic vitamin A stores, but these were less marked in adulthood. Additionally, KO mice had an altered microbiome in early life. Their BA pool was highly enriched in cholic acid but not completely devoid of conjugated BAs. KO animals had 27-fold lower taurine-conjugated BAs than wild type in their liver but similar concentrations of glycine-conjugated BAs and higher microbially conjugated BAs. Furthermore, the BA pool in Baat-/- was enriched in a variety of unusual BAs that were putatively sourced from cysteamine conjugation with subsequent oxidation and methylation of the sulfur group mimicking taurine. Antibiotic treatment of KO mice indicated the microbiome was not the likely source of the unusual conjugations, instead, the unique BAs in KO animals were likely derived from the peroxisomal acyltransferases Acnat1 and Acnat2, which are duplications of Baat in the mouse genome that are inactivated in humans. This study demonstrates that BA conjugation is important for early life development of mice.

Longitudinal effects of growth restriction on the murine gut microbiome and metabolome.

Undernutrition-induced growth restriction in the early stages of life increases the risk of chronic disease in adulthood. Although metabolic impairments have been observed, few studies have characterized the gut microbiome and gut-liver metabolome profiles of growth-restricted animals during early-to-mid-life development. To induce growth restriction, mouse offspring were either born to gestational undernutrition (GUN) or suckled from postnatal undernutrition (PUN) dams fed a protein-restricted diet (8% protein) or control diet (CON; 20% protein) until weaning at postnatal age of 21 days (PN21). At PN21, all mice were fed the CON diet until adulthood (PN80). Livers were collected at PN21 and PN80, and fecal samples were collected weekly starting at PN21 (postweaning week 1) until PN80 (postweaning week 5) for gut microbiome and metabolome analyses. PUN mice exhibited the most alterations in gut microbiome and gut and liver metabolome compared with CON mice. These mice had altered fecal microbial ß-diversity (P = 0.001) and exhibited higher proportions of Bifidobacteriales [linear mixed model (LMM) P = 7.1 × 10-6), Clostridiales (P = 1.459 × 10-5), Erysipelotrichales (P = 0.0003), and lower Bacteroidales (P = 4.1 × 10-5)]. PUN liver and fecal metabolome had a reduced total bile acid pool (P < 0.01), as well as lower abundance of riboflavin (P = 0.003), amino acids [i.e., methionine (P = 0.0018), phenylalanine (P = 0.0015), and tyrosine (P = 0.0041)], and higher excreted total peptides (LMM P = 0.0064) compared with CON. Overall, protein restriction during lactation permanently alters the gut microbiome into adulthood. Although the liver bile acids, amino acids, and acyl-carnitines recovered, the fecal peptides and microbiome remained permanently altered into adulthood, indicating that inadequate protein intake in a specific time frame in early life can have an irreversible impact on the microbiome and fecal metabolome.NEW & NOTEWORTHY Undernutrition-induced early-life growth restriction not only leads to increased disease risk but also permanently alters the gut microbiome and gut-liver metabolome during specific windows of early-life development.

Calculated versus measured albumin-creatinine ratio to predict kidney failure and death in people with chronic kidney disease.

Albumin-to-creatinine ratio (ACR), the preferred method to quantify proteinuria, can be calculated from urine dipstick protein or protein-to-creatinine ratio (PCR). The performance of calculated vs. measured ACR in predicting kidney failure and death without kidney failure in people with chronic kidney disease (CKD) is unknown. Here, we used population-based data from Alberta, Canada, to identify adults with incident moderate-severe CKD (sustained for more than 90 days) from 2008-04-01 to 2017-03-31, who had same-day measures of ACR and urine dipstick (ACR-dipstick cohort) or PCR (ACR-PCR cohort) in the two years before cohort entry. We followed participants until 2019-03-31 and trained competing risk models of kidney failure and death without kidney failure including age, sex, estimated glomerular filtration rate, diabetes, cardiovascular disease, and either measured or calculated ACR. Model performance was tested in cohorts created using the same algorithm in Manitoba, Canada. The ACR-dipstick and ACR-PCR cohorts included 18,731 and 4,542 people (training cohorts) and 821 and 1,831 people (testing cohorts), respectively. In internal and external testing, there was closer agreement between predictions based on measured vs. PCR-calculated ACR than between those based on measured vs. dipstick-calculated ACR. The dipstick-calculated ACR had higher Brier scores than measured ACR from year three for both outcomes, indicating worsening calibration. Models including measured or calculated ACR had similar discrimination: year one-to-five area under the receiver operating characteristic curve of 83-89% for kidney failure and 69-75% for mortality. Thus, if confirmed in different ethnic groups, calculated ACR can be used for risk predictions when the measured ACR is not available. PCR-calculated ACR may have superior performance to dipstick-calculated ACR.

Prevalence and Risk Factors for Fatigue in Adults With Inflammatory Bowel Disease: A Systematic Review With Meta-Analysis.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic relapsing and remitting disease with high morbidity, substantial health care costs, and increasing incidence. Fatigue is one of the most common symptoms that impacts quality of life and is a leading concern for patients with IBD. The aim of this study was to determine the global prevalence, risk factors, and impact of fatigue in adults with IBD. METHODS: A systematic review and meta-analysis was conducted. Data were retrieved from Medline, Embase, CINAHL, and PsycINFO from database inception to October 2019. A pooled prevalence of fatigue was calculated using a random-effects model. Stratified meta-analyses explored sources of between-study heterogeneity. Study quality was assessed using an adapted checklist from Downs and Black. RESULTS: The search yielded 4524 studies, of which 20 studies were included in the systematic review and meta-analysis. Overall, the studies were of good quality. The pooled prevalence of fatigue was 47% (95% confidence interval, 41%-54%), though between-study heterogeneity was high (I2 = 98%). Fatigue prevalence varied significantly by the definition of fatigue (chronic: 28%; high: 48%; P < .01) and disease status (active disease: 72%; remission: 47%; P < .01). Sleep disturbance, anxiety, depression, and anemia were the most commonly reported fatigue-related risk factors. CONCLUSIONS: The prevalence of fatigue in adults with IBD is high, emphasizing the importance of additional efforts to manage fatigue to improve the care and quality of life for patients with IBD.

Learning representations of microbe-metabolite interactions.

Integrating multiomics datasets is critical for microbiome research; however, inferring interactions across omics datasets has multiple statistical challenges. We solve this problem by using neural networks (https://github.com/biocore/mmvec) to estimate the conditional probability that each molecule is present given the presence of a specific microorganism. We show with known environmental (desert soil biocrust wetting) and clinical (cystic fibrosis lung) examples, our ability to recover microbe-metabolite relationships, and demonstrate how the method can discover relationships between microbially produced metabolites and inflammatory bowel disease.

Microbiome-wide association studies link dynamic microbial consortia to disease.

Rapid advances in DNA sequencing, metabolomics, proteomics and computational tools are dramatically increasing access to the microbiome and identification of its links with disease. In particular, time-series studies and multiple molecular perspectives are facilitating microbiome-wide association studies, which are analogous to genome-wide association studies. Early findings point to actionable outcomes of microbiome-wide association studies, although their clinical application has yet to be approved. An appreciation of the complexity of interactions among the microbiome and the host's diet, chemistry and health, as well as determining the frequency of observations that are needed to capture and integrate this dynamic interface, is paramount for developing precision diagnostics and therapies that are based on the microbiome.

NSAID prescriptions in kidney transplant recipients.

BACKGROUND: Guidelines recommend that non-steroidal anti-inflammatory drugs (NSAIDs) be avoided in kidney transplant recipients due to potential nephrotoxicity. It is unclear whether physicians are following these recommendations. METHODS: We conducted a retrospective cohort study of adult kidney transplant recipients from 2008 to 2017 in Alberta, Canada. We determined the frequency and prescriber of NSAID prescriptions, the proportion with serum creatinine and potassium testing post-fill, and the incidence of acute kidney injury (AKI, serum creatinine increase of ≥ 50% or ≥ 26.5 µmol/L from baseline) and hyperkalemia (potassium ≥ 5.5 mmol/L) within 14 and 30 days. RESULTS: Of the 1730 kidney transplant recipients, 189 (11%) had at least one NSAID prescription over a median follow-up of 5 years (IQR 2-9) (280 unique prescriptions). The majority were prescribed by family physicians (67%). Approximately 25% and 50% of prescriptions had serum creatinine and potassium testing within 14 and 30 days, respectively. Of those with lab measurements within 14 days, 13% of prescriptions were associated with AKI and 5% had hyperkalemia. CONCLUSIONS: Contrary to guidelines, one in 10 kidney transplant recipients are prescribed an NSAID, and most do not get follow-up testing of graft function and hyperkalemia. These findings call for improved education of patients and primary care providers.