The integrated care model: facilitating initiation of or transition to home dialysis.

A proportion of end-stage kidney disease (ESKD) patients require kidney replacement therapy to maintain clinical stability. Home dialysis therapies offer convenience, autonomy and potential quality of life improvements, all of which were heightened during the COVID-19 pandemic. While the superiority of specific modalities remains uncertain, patient choice and informed decision-making remain crucial. Missed opportunities for home therapies arise from systemic, programmatic and patient-level barriers. This paper introduces the integrated care model which prioritizes the safe and effective uptake of home therapies while also emphasizing patient-centered care, informed decision-making, and comprehensive support. The integrated care framework addresses challenges in patient identification, assessment, eligibility determination, education and modality transitions. Special considerations for urgent dialysis starts are discussed, acknowledging the unique barriers faced by this population. Continuous quality improvement is emphasized, with the understanding that local challenges may require tailored solutions. Overall, the integrated care model aims to create a seamless and beneficial transition to home dialysis therapies, promoting flexibility and improved quality of life for ESKD patients globally.

Untargeted metabolomics and metagenomics reveal signatures for intramammary ceftiofur treatment and lactation stage in the cattle hindgut.

The gut microbiota in cattle is essential for protein, energy, and vitamin production and hence, microbiota perturbations can affect cattle performance. This study evaluated the effect of intramammary (IMM) ceftiofur treatment and lactation stage on the functional gut microbiome and metabolome. Forty dairy cows were enrolled at dry-off. Half received IMM ceftiofur and a non-antibiotic teat sealant containing bismuth subnitrate (cases), while the other half received the teat sealant (controls). Fecal samples were collected before treatment at dry off, during the dry period (weeks 1 and 5) and the first week after calving (week 9). Shotgun metagenomic sequencing was applied to predict microbial metabolic pathways whereas untargeted metabolomics was used identify polar and nonpolar metabolites. Compared to controls, long-term changes were observed in the cows given ceftiofur, including a lower abundance of microbial pathways linked to energy production, amino acid biosynthesis, and other vital molecules. The metabolome of treated cows had elevated levels of stachyose, phosphatidylethanolamine diacylglycerol (PE-DAG), and inosine a week after the IMM ceftiofur application, indicating alterations in microbial fermentation, lipid metabolism, energy, and cellular signaling. Differences were also observed by sampling, with cows in late lactation having more diverse metabolic pathways and a unique metabolome containing higher levels of histamine and histamine-producing bacteria. These data illustrate how IMM ceftiofur treatment can alter the functionality of the hindgut metabolome and microbiome. Understanding how antibiotics and lactation stages, which are each characterized by unique diets and physiology, impact the function of resident microbes is critical to define normal gut function in dairy cattle.

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.

Alloying and Doping Control in the Layered Metal Phosphide Thermoelectric CaCuP.

We recently identified CaCuP as a potential low cost, low density thermoelectric material, achieving zT = 0.5 at 792 K. Its performance is limited by a large lattice thermal conductivity, κL, and by intrinsically large p-type doping levels. In this paper, we address the thermal and electronic tunability of CaCuP. Isovalent alloying with As is possible over the full solid solution range in the CaCuP1-xAsx series. This leads to a reduction in κL due to mass fluctuations but also to a detrimental increase in p-type doping due to increasing Cu vacancies, which prevents zT improvement. Phase boundary mapping, exploiting small deviations from 1:1:1 stoichiometry, was used to explore doping tunability, finding increasing p-type doping to be much easier than decreasing the doping level. Calculation of the Lorenz number within the single parabolic band approximation leads to an unrealistic low κL for highly doped samples consistent with the multiband behavior in these materials. Overall, CaCuP and slightly Cu-enriched CaCu1.02P yield the best performance, with zT approaching 0.6 at 873 K.

Shifts in the functional capacity and metabolite composition of the gut microbiome during recovery from enteric infection.

While enteric pathogens have been widely studied for their roles in causing foodborne infection, their impacts on the gut microbial community have yet to be fully characterized. Previous work has identified notable changes in the gut microbiome related to pathogen invasion, both taxonomically and genetically. Characterization of the metabolic landscape during and after enteric infection, however, has not been explored. Consequently, we investigated the metabolome of paired stools recovered from 60 patients (cases) during and after recovery from enteric bacterial infections (follow-ups). Shotgun metagenomics was applied to predict functional microbial pathways combined with untargeted metametabolomics classified by Liquid Chromatography Mass Spectrometry. Notably, cases had a greater overall metabolic capacity with significantly higher pathway richness and evenness relative to the follow-ups (p<0.05). Metabolic pathways related to central carbon metabolism, amino acid metabolism, and lipid and fatty acid biosynthesis were more highly represented in cases and distinct signatures for menaquinone production were detected. By contrast, the follow-up samples had a more diverse metabolic landscape with enhanced richness of polar metabolites (p<0.0001) and significantly greater richness, evenness, and overall diversity of nonpolar metabolites (p<0.0001). Although many metabolites could not be annotated with existing databases, a marked increase in certain clusters of metabolites was observed in the follow-up samples when compared to the case samples and vice versa. These findings suggest the importance of key metabolites in gut health and recovery and enhance understanding of metabolic fluctuations during enteric infections.

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.

Decline of a distinct coral reef holobiont community under ocean acidification.

BACKGROUND: Microbes play vital roles across coral reefs both in the environment and inside and upon macrobes (holobionts), where they support critical functions such as nutrition and immune system modulation. These roles highlight the potential ecosystem-level importance of microbes, yet most knowledge of microbial functions on reefs is derived from a small set of holobionts such as corals and sponges. Declining seawater pH - an important global coral reef stressor - can cause ecosystem-level change on coral reefs, providing an opportunity to study the role of microbes at this scale. We use an in situ experimental approach to test the hypothesis that under such ocean acidification (OA), known shifts among macrobe trophic and functional groups may drive a general ecosystem-level response extending across macrobes and microbes, leading to reduced distinctness between the benthic holobiont community microbiome and the environmental microbiome. RESULTS: We test this hypothesis using genetic and chemical data from benthic coral reef community holobionts sampled across a pH gradient from CO2 seeps in Papua New Guinea. We find support for our hypothesis; under OA, the microbiome and metabolome of the benthic holobiont community become less compositionally distinct from the sediment microbiome and metabolome, suggesting that benthic macrobe communities are colonised by environmental microbes to a higher degree under OA conditions. We also find a simplification and homogenisation of the benthic photosynthetic community, and an increased abundance of fleshy macroalgae, consistent with previously observed reef microbialisation. CONCLUSIONS: We demonstrate a novel structural shift in coral reefs involving macrobes and microbes: that the microbiome of the benthic holobiont community becomes less distinct from the sediment microbiome under OA. Our findings suggest that microbialisation and the disruption of macrobe trophic networks are interwoven general responses to environmental stress, pointing towards a universal, undesirable, and measurable form of ecosystem changed. Video Abstract.

Predicting the risks of kidney failure and death in adults with moderate to severe chronic kidney disease: multinational, longitudinal, population based, cohort study.

OBJECTIVE: To train and test a super learner strategy for risk prediction of kidney failure and mortality in people with incident moderate to severe chronic kidney disease (stage G3b to G4). DESIGN: Multinational, longitudinal, population based, cohort study. SETTINGS: Linked population health data from Canada (training and temporal testing), and Denmark and Scotland (geographical testing). PARTICIPANTS: People with newly recorded chronic kidney disease at stage G3b-G4, estimated glomerular filtration rate (eGFR) 15-44 mL/min/1.73 m2. MODELLING: The super learner algorithm selected the best performing regression models or machine learning algorithms (learners) based on their ability to predict kidney failure and mortality with minimised cross-validated prediction error (Brier score, the lower the better). Prespecified learners included age, sex, eGFR, albuminuria, with or without diabetes, and cardiovascular disease. The index of prediction accuracy, a measure of calibration and discrimination calculated from the Brier score (the higher the better) was used to compare KDpredict with the benchmark, kidney failure risk equation, which does not account for the competing risk of death, and to evaluate the performance of KDpredict mortality models. RESULTS: 67 942 Canadians, 17 528 Danish, and 7740 Scottish residents with chronic kidney disease at stage G3b to G4 were included (median age 77-80 years; median eGFR 39 mL/min/1.73 m2). Median follow-up times were five to six years in all cohorts. Rates were 0.8-1.1 per 100 person years for kidney failure and 10-12 per 100 person years for death. KDpredict was more accurate than kidney failure risk equation in prediction of kidney failure risk: five year index of prediction accuracy 27.8% (95% confidence interval 25.2% to 30.6%) versus 18.1% (15.7% to 20.4%) in Denmark and 30.5% (27.8% to 33.5%) versus 14.2% (12.0% to 16.5%) in Scotland. Predictions from kidney failure risk equation and KDpredict differed substantially, potentially leading to diverging treatment decisions. An 80-year-old man with an eGFR of 30 mL/min/1.73 m2 and an albumin-to-creatinine ratio of 100 mg/g (11 mg/mmol) would receive a five year kidney failure risk prediction of 10% from kidney failure risk equation (above the current nephrology referral threshold of 5%). The same man would receive five year risk predictions of 2% for kidney failure and 57% for mortality from KDpredict. Individual risk predictions from KDpredict with four or six variables were accurate for both outcomes. The KDpredict models retrained using older data provided accurate predictions when tested in temporally distinct, more recent data. CONCLUSIONS: KDpredict could be incorporated into electronic medical records or accessed online to accurately predict the risks of kidney failure and death in people with moderate to severe CKD. The KDpredict learning strategy is designed to be adapted to local needs and regularly revised over time to account for changes in the underlying health system and care processes.

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.

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.

The impact of the Starting dialysis on Time, At home on the Right Therapy (START) project on the use of peritoneal dialysis.

BACKGROUND: Peritoneal dialysis (PD) is actively promoted, but increasing PD utilisation is difficult. The objective of this study was to determine if the Starting dialysis on Time, At Home, on the Right Therapy (START) project was associated with an increase in the proportion of dialysis patients receiving PD within 6 months of starting therapy. METHODS: Consecutive patients over age 18, with end-stage kidney failure, who started dialysis between 1 April 2015 and 31 March 2018 in the province of Alberta, Canada. Programmes were provided with high-quality data about the individual steps in the process of care that drive PD utilisation that were used to identify problem areas, design and implement interventions to address them, and then evaluate whether those interventions had impact. The primary outcome was the proportion of patients receiving PD within 6 months of starting dialysis. Secondary outcomes included hospitalisation, death or probability of transfer to haemodialysis (HD). Interrupted time series methodology was used to evaluate the impact of the quality improvement initiative on the primary and secondary outcomes. RESULTS: A total of 1962 patients started dialysis during the study period. Twenty-seven per cent of incident patients received PD at baseline, and there was a 5.4% (95% confidence interval: 1.5-9.2) increase in the use of PD in the province immediately after implementation. There were no changes in the rates of hospitalisation, death or probability of transfer to HD after the introduction of START. CONCLUSIONS: The approach used in the START project was associated with an increase in the use of PD in a setting with high baseline utilisation.

Risk Factors for Developing Low Estimated Glomerular Filtration Rate and Albuminuria in Living Kidney Donors.

Rationale & Objective: Chronic kidney disease is associated with significant morbidity and mortality in the general population, but little is known about the incidence and risk factors associated with developing low estimated glomerular filtration rate (eGFR) and moderate-severe albuminuria in living kidney donors following nephrectomy. Study Design: Retrospective, population-based cohort study. Setting & Participants: Kidney donors in Alberta, Canada. Exposure: Donor nephrectomy between May 2001 and December 2017. Outcome: Two eGFR measurements <45 mL/min/1.73 m2 or 2 measurements of moderate or severe albuminuria from 1-year postdonation onwards that were at least 90 days apart. Analytical Approach: Associations between potential risk factors and the primary outcome were assessed using Cox proportional hazard regression analyses. Results: Over a median follow-up period of 8.6 years (IQR, 4.7-12.6 years), 47 of 590 donors (8.0%) developed sustained low eGFR or moderate-severe albuminuria with an incidence rate of 9.2 per 1,000 person-years (95% confidence interval, 6.6-11.8). The median time for development of this outcome beyond the first year after nephrectomy was 2.9 years (IQR, 1.4-8.0 years). Within the first 4 years of follow-up, a 5 mL/min/1.73 m2 lower predonation eGFR increased the hazard of developing postdonation low eGFR or moderate-severe albuminuria by 26% (adjusted HR, 1.26; 95% CI, 1.10-1.44). Furthermore, donors were at higher risk of developing low eGFR or albuminuria if they had evidence of predonation hypertension (adjusted HR, 2.52; 95% CI, 1.28-4.96) or postdonation diabetes (adjusted HR, 4.72; 95% CI, 1.54-14.50). Limitations: We lacked data on certain donor characteristics that may affect long-term kidney function, such as race, smoking history, and transplant-related characteristics. Conclusions: A proportion of kidney donors at an incidence rate of 9.2 per 1,000 person-years will develop low eGFR or albuminuria after donation. Donors with lower predonation eGFR, predonation hypertension, and postdonation diabetes are at increased risk of developing this outcome.

The purpose of this study was to understand the risk of developing kidney disease in living kidney donors after donation. We followed 590 donors in Alberta, Canada for almost 9 years. Approximately 8% of donors developed reduced kidney function (low estimated glomerular filtration rate) or increased protein in the urine (albuminuria). Donors with lower kidney function before donation, hypertension before donation, or diabetes after donation had a higher likelihood of experiencing these kidney outcomes. This research provides important insights to patients and health care providers to better support the long-term kidney health of living kidney donors.

Revisiting Solid-Solid Phase Transitions in Sodium and Potassium Tetrafluoroborate for Thermal Energy Storage.

In situ synchrotron powder X-ray diffraction (PXRD) study was conducted on sodium and potassium tetrafluoroborate (NaBF4 and KBF4) to elucidate structural changes across solid-solid phase transitions over multiple heating-cooling cycles. The phase transition temperatures from diffraction measurements are consistent with the differential scanning calorimetry data (∼240 °C for NaBF4 and ∼290 °C for KBF4). The crystal structure of the high-temperature (HT) NaBF4 phase was determined from synchrotron PXRD data. The HT disordered phase of NaBF4 crystallizes in the hexagonal, space group P63/mmc (no. 194) with a = 4.98936(2) Å, c = 7.73464(4) Å, V = 166.748(2) Å3, and Z = 2 at 250 °C. Density functional theory molecular dynamics (MD) calculations imply that the P63/mmc is indeed a stable structure for rotational NaBF4. MD simulations reproduce the experimental phase sequence upon heating and indicate that F atoms are markedly more mobile than K and B atoms in the disordered state. Thermal expansion coefficients for both phases were determined from high-precision lattice parameters at elevated temperatures, as obtained from Rietveld refinement of the PXRD data. Interestingly, for the HT-phase of NaBF4, the structure (upon heating) contracts slightly in the a-b plane but expands in the c direction such that overall thermal expansion is positive. Thermal conductivities at room temperature were measured, and the values are 0.8-1.0 W m-1 K-1 for NaBF4 and 0.55-0.65 W m-1 K-1 for KBF4. The thermal conductivity and diffusivity showed a gradual decrease up to the transition temperature and then rose slightly. Both materials show good thermal and structural stabilities over multiple heating/cooling cycles.

Proton Pump Inhibitors Use in Kidney Transplant Recipients: A Population-Based Study.

Background: Kidney transplant recipients are commonly prescribed proton-pump inhibitors (PPIs), but due to concern for polypharmacy, chronic use should be limited. Objective: The objective was to describe PPI use in kidney transplant recipients beyond their first year of transplant to better inform and support deprescribing initiatives. Design: We conducted a retrospective, population-based cohort study using linked health care databases. Setting: This study was conducted in Alberta, Canada. Patients: We included all prevalent adult, kidney-only transplant recipients between April 2008 and December 2017 who received their transplant between May 2002 and December 2017. Measurements: The primary outcome was ongoing or new PPI use and patterns of use, including frequency and duration of therapy, and assessment of indication for PPI use. Methods: We ascertained baseline characteristics, covariate information, and outcome data from the Alberta Kidney Disease Network (AKDN). We compared recipients with evidence of a PPI prescription in the 3 months prior to study entry to those with a histamine-2-receptor antagonist (H2Ra) fill and those with neither. Results: We identified 1823 kidney transplant recipients, of whom 868 (48%) were on a PPI, 215 (12%) were on an H2Ra, and 740 (41%) were on neither at baseline. Over a median follow-up of 5.4 years (interquartile range [IQR] = 2.6-9.3), there were almost 45 000 unique PPI prescriptions dispensed, the majority (80%) of which were filled by initial PPI users. Recipients who were on a PPI at baseline would spend 91% (IQR = 70-98) of their graft survival time on a PPI in follow-up, and nephrologists were the main prescribers. We identified an indication for ongoing PPI use in 54% of recipients with the most common indication being concurrent antiplatelet use (26%). Limitations: Our kidney transplant recipients have access to universal health care coverage which may limit generalizability. We identified common gastrointestinal indications for PPI use but did not include rare conditions due to concerns about the validity of diagnostic codes. In addition, symptoms suggestive of reflux may not be well coded as the focus of follow-up visits is more likely to focus on kidney transplant. Conclusions: Many kidney transplant recipients are prescribed a PPI at, or beyond, the 1-year post-transplant date and are likely to stay on a PPI in follow-up. Almost half of the recipients in our study did not have an identifiable indication for ongoing PPI use. Nephrologists frequently prescribe PPIs to kidney transplant recipients and should be involved in deprescribing initiatives to reduce polypharmacy.

Contexte: On prescrit couramment des inhibiteurs de la pompe à protons (IPP) aux receveurs d'une greffe rénale; une pratique qui devrait cependant être limitée en raison de préoccupations liées à la polypharmacie. Objectif: Décrire l'utilisation des IPP chez les receveurs d'une greffe rénale au-delà de la première année post-greffe, afin de mieux informer et de soutenir les initiatives de déprescription. Type d'étude: Étude de cohorte populationnelle rétrospective réalisée à partir des bases de données couplées du système de santé. Cadre: Alberta, Canada. Sujets: Nous avons recueilli les données d'avril 2008 à décembre 2017 de tous les adultes qui avaient reçu un rein seulement entre mai 2002 et décembre 2017. Mesures: Le principal critère de jugement était la prise continue ­ ou une nouvelle ordonnance ­ d'IPP et les modalités d'utilisation, notamment la fréquence et la durée du traitement, ainsi que l'indication pour la prescription d'IPP. Méthodologie: Nous avons vérifié les caractéristiques initiales, les informations covariées et les données sur les résultats colligées dans l'Alberta Kidney Disease Network (AKDN). Nous avons comparé des receveurs présentant des preuves d'une prescription d'IPP au cours des trois mois précédant l'entrée dans l'étude à des patients avec une ordonnance d'antagonistes des récepteurs de l'histamine-2 (aRH2), ainsi qu'à des patients n'ayant aucune de ces prescriptions. Résultats: Nous avons identifié 1 823 receveurs d'une greffe rénale; 868 (48 %) recevaient un IPP, 215 (12 %) recevaient un aRH2 et 740 (41 %) ne recevaient aucun traitement à l'inclusion. Au cours d'un suivi médian de 5,4 ans (intervalle interquartile [IIQ]: 2,6-9,3), près de 45 000 ordonnances uniques d'IPP ont été délivrées, dont la majorité (80 %) avait été remplie par des utilisateurs initiaux d'IPP. Les receveurs qui prenaient des IPP à l'inclusion avaient passé 91 % (IIQ: 70-98) de leur temps de survie du greffon à prendre un IPP durant la période de suivi, et ces médicaments avaient été majoritairement prescrits par des néphrologues. Une indication justifiant l'utilisation continue d'un IPP était présente chez 54 % des receveurs; la plus courante étant l'utilisation concomitante d'un agent antiplaquettaire (26 %). Limites: Les receveurs inclus dans notre étude ont accès à une couverture médicale universelle, ce qui peut limiter la généralisabilité des résultats. Nous avons repéré des indications gastro-intestinales courantes pour l'utilisation d'IPP, mais nous n'avons pas inclus les affections rares en raison de préoccupations concernant la validité des codes diagnostiques. Aussi, les symptômes évocateurs d'un reflux pourraient ne pas être bien codés, car les visites de suivi sont plus susceptibles de porter sur la transplantation rénale. Conclusion: De nombreux receveurs d'une greffe rénale se voient encore prescrire un IPP dans l'année suivant la transplantation, ou au-delà, et sont susceptibles de continuer d'en prendre pendant le suivi. Près de la moitié des receveurs de notre étude n'avaient pas d'indication clairement identifiable de prendre un IPP en continu. Les néphrologues prescrivent fréquemment des IPP aux receveurs d'une greffe rénale et devraient être impliqués dans les initiatives de déprescription visant à réduire la polypharmacie.

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.

The Association of Intra-Abdominal Adhesions with Peritoneal Dialysis Catheter-Related Complications.

BACKGROUND: This study investigated the association of intra-abdominal adhesions with the risk of peritoneal dialysis (PD) catheter complications. METHODS: Individuals undergoing laparoscopic PD catheter insertion were prospectively enrolled from eight centers in Canada and the United States. Patients were grouped based on the presence of adhesions observed during catheter insertion. The primary outcome was the composite of PD never starting, termination of PD, or the need for an invasive procedure caused by flow restriction or abdominal pain. RESULTS: Seven hundred and fifty-eight individuals were enrolled, of whom 201 (27%) had adhesions during laparoscopic PD catheter insertion. The risk of the primary outcome occurred in 35 (17%) in the adhesion group compared with 58 (10%) in the no adhesion group (adjusted HR, 1.64; 95% confidence interval [CI], 1.05 to 2.55) within 6 months of insertion. Lower abdominal or pelvic adhesions had an adjusted HR of 1.80 (95% CI, 1.09 to 2.98) compared with the no adhesion group. Invasive procedures were required in 26 (13%) and 47 (8%) of the adhesion and no adhesion groups, respectively (unadjusted HR, 1.60: 95% CI, 1.04 to 2.47) within 6 months of insertion. The adjusted odds ratio for adhesions for women was 1.65 (95% CI, 1.12 to 2.41), for body mass index per 5 kg/m 2 was 1.16 (95% CI, 1.003 to 1.34), and for prior abdominal surgery was 8.34 (95% CI, 5.5 to 12.34). Common abnormalities found during invasive procedures included PD catheter tip migration, occlusion of the lumen with fibrin, omental wrapping, adherence to the bowel, and the development of new adhesions. CONCLUSIONS: People with intra-abdominal adhesions undergoing PD catheter insertion were at higher risk for abdominal pain or flow restriction preventing PD from starting, PD termination, or requiring an invasive procedure. However, most patients, with or without adhesions, did not experience complications, and most complications did not lead to the termination of PD therapy.

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.

Implementing a Formalized Risk-Based Approach to Determine Candidacy for Multidisciplinary CKD Care: A Descriptive Cohort Study.

Background: The kidney failure risk equation (KFRE) can be used to predict progression to end-stage kidney disease in a clinical setting. Objective: Evaluate implementation of a formalized risk-based approach in nephrologists' outpatient clinics and multidisciplinary chronic kidney disease (CKD) clinics to determine candidacy for multidisciplinary care, and the impact of CKD care selection on clinical outcomes. Design: Population-based descriptive cohort study. Setting: Alberta Kidney Care South. Patients: Adults attending or considered for a multidisciplinary CKD clinic between April 1, 2017, and March 31, 2019. Measurements: Exposure-The course of CKD care assigned by the nephrologist: management at multidisciplinary CKD clinic; management by a nephrologist or primary care physician. Primary Outcome-CKD progression, defined as commencement of kidney replacement therapy (KRT). Secondary Outcomes-Death, emergency department visits, and hospitalizations. Methods: We linked operational data from the clinics (available until March 31, 2019) with administrative health and laboratory data (available until March 31, 2020). Comparisons among patient groups, courses of care, and clinical settings with negative binomial regression count models and calculated unadjusted and fully adjusted incidence rate ratios. For the all-cause death outcome, we used Cox survival models to calculate unadjusted and fully adjusted hazard ratios. Results: Of the 1748 patients for whom a KFRE was completed, 1347 (77%) remained in or were admitted to a multidisciplinary CKD clinic, 310 (18%) were managed by a nephrologist only, and 91 (5%) were referred back for management by their primary care physician. There was a much higher kidney failure risk among patients who remained at or were admitted to a multidisciplinary CKD clinic (median 2-year risk of 34.7% compared with 3.6% and 0.8% who remained with a nephrologist or primary care physician, respectively). None of the people managed by their primary care physician alone commenced KRT, while only 2 (0.6%) managed by a nephrologist without multidisciplinary CKD care commenced KRT. The rates of emergency department visits, hospitalizations, and death were lower in those assigned to management outside the multidisciplinary CKD clinics when compared with those managed in the multidisciplinary care setting. Limitations: The follow-up period may not have been long enough to determine outcomes, and potentially limited generalizability given variability of care in multidisciplinary clinics. Conclusions: Our findings indicate that a portion of patients can be directed to less resource-intensive care without a higher risk of adverse events. Trial registration: Not applicable.

Contexte: L'équation KFRE (Kidney Failure Risk Equation) peut être utilisée en environnement clinique pour prédire le risque d'évolution vers l'insuffisance rénale terminale (IRT). Objectif: Évaluer la mise en œuvre d'une approche structurée fondée sur le risque dans les cliniques multidisciplinaires d'insuffisance rénale chronique (IRC) et les cliniques ambulatoires des néphrologues afin de déterminer l'aptitude des patients à recevoir des soins multidisciplinaires et de mesurer l'incidence des soins d'IRC reçus sur les résultats cliniques. Conception: Étude de cohorte populationnelle descriptive. Cadre: Alberta Kidney Care South. Sujets: Adultes fréquentant ou envisageant de fréquenter une clinique multidisciplinaire d'IRC entre le 1er avril 2017 et le 31 mars 2019. Mesures: Exposition­le parcours de soins d'IRC attribué par le néphrologue ­ prise en charge en clinique multidisciplinaire d'IRC; prise en charge par un néphrologue ou un médecin de premier recours. Principaux résultats­progression de l'IRC, définie comme l'amorce d'une thérapie de remplacement rénal (TRR). Résultats secondaires­décès, visites aux urgences et hospitalisations. Méthodologie: Nous avons couplé les données opérationnelles des cliniques (disponibles jusqu'au 31 mars 2019) aux données administratives de santé et aux données de laboratoire (disponibles jusqu'au 31 mars 2020). Des modèles de régression binomiale négative et des rapports des taux d'incidence non corrigés et entièrement corrigés ont servi aux comparaisons entre les groupes de patients, les parcours de soins et les environnements cliniques. Les risques relatifs non corrigés et entièrement corrigés de décès toutes causes confondues ont été calculés à l'aide de modèles de survie de Cox. Résultats: Des 1 748 patients avec une KFRE calculée, 1 347 (77 %) sont restés ou ont été admis dans une clinique multidisciplinaire d'IRC, 310 (18 %) ont été pris en charge par un néphrologue seulement et 91 (5 %) ont été orientés pour une prise en charge par leur médecin de premier recours. Le risque d'insuffisance rénale terminale était beaucoup plus élevé chez les patients restés ou admis dans une clinique multidisciplinaire d'IRC (risque médian à 2 ans : 34,7 %) que chez ceux pris en charge par un néphrologue (3,6 %) et par un médecin de premier recours (0,8 %). Aucun patient pris en charge par un médecin de premier recours n'avait amorcé une TRR; 2 personnes (0,6 %) prises en charge par un néphrologue sans soins multidisciplinaires d'IRC avaient amorcé une TRR. Les taux de visites aux urgences, d'hospitalisations et de décès étaient plus faibles chez les patients pris en charge à l'extérieur des cliniques multidisciplinaires d'IRC comparativement à ceux pris en charge dans ces cliniques. Limites: La période de suivi n'était peut-être pas été assez longue pour déterminer les résultats. La variabilité des soins dans les cliniques multidisciplinaires pourrait également limiter la généralisation des résultats. Conclusion: Nos résultats suggèrent qu'une partie des patients pourrait être dirigée vers des soins nécessitant moins de ressources sans hausser le risque d'événements indésirables.

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.