Choosing fluids to reduce the risks of acute electrolyte disturbances in children after a kidney transplant.

Intravenous (i.v.) fluid therapy is critically important in pediatric kidney transplantation. Because of the high volumes given perioperatively, transplant recipients can develop significant electrolyte abnormalities depending on the types of fluids used. Current practices in pediatric transplantation aim to balance risks of hyponatremia from traditionally used hypotonic fluids, such as 0.45% sodium chloride, against hyperchloremia and acidosis associated with isotonic 0.9% sodium chloride. Using the balanced solution Plasma-Lyte 148 as an alternative might mitigate these risks.

Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS: BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS: Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION: Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection.

Neurological disorders are often debilitating conditions with no cure. The majority of current therapies are palliative rather than disease-modifying; therefore, new strategies for treating neurological disorders are greatly needed. mRNA-based therapeutics have great potential for treating such neurological disorders; however, challenges with delivery have limited their clinical potential. Lipid nanoparticles (LNPs) are a promising delivery vector for the brain, given their safer toxicity profile and higher efficacy. Despite this, very little is known about LNP-mediated delivery of mRNA into the brain. Here, we employ MC3-based LNPs and successfully deliver Cre mRNA and Cas9 mRNA/Ai9 sgRNA to the adult Ai9 mouse brain; greater than half of the entire striatum and hippocampus was found to be penetrated along the rostro-caudal axis by direct intracerebral injections of MC3 LNP mRNAs. MC3 LNP Cre mRNA successfully transfected cells in the striatum (∼52% efficiency) and hippocampus (∼49% efficiency). In addition, we demonstrate that MC3 LNP Cas9 mRNA/Ai9 sgRNA edited cells in the striatum (∼7% efficiency) and hippocampus (∼3% efficiency). Further analysis demonstrates that MC3 LNPs mediate mRNA delivery to multiple cell types including neurons, astrocytes, and microglia in the brain. Overall, LNP-based mRNA delivery is effective in brain tissue and shows great promise for treating complex neurological disorders.

Interactions Between Donor Age and 12-Month Estimated Glomerular Filtration Rate on Allograft and Patient Outcomes After Kidney Transplantation.

Reduced estimated glomerular filtration rate (eGFR) at 12-months after kidney transplantation is associated with increased risk of allograft loss, but it is uncertain whether donor age and types modify this relationship. Using Australia and New Zealand registry data, multivariable Cox proportional modelling was used to examine the interactive effects between donor age, types and 12-month eGFR on overall allograft loss. We included 11,095 recipients (4,423 received live-donors). Recipients with lowest 12-month eGFR (<30 ml/min/1.73 m2) experienced the greatest risk of allograft loss, with adjusted HR [95% CI) of 2.65 [2.38-2.95] compared to eGFR of 30-60 ml/min/1.73 m2; whereas the adjusted HR for highest eGFR (>60 ml/min/1.73 m2) was 0.67 [0.62-0.74]. The association of 12-month eGFR and allograft loss was modified by donor age (but not donor types) where a higher risk of allograft loss in recipients with lower compared with higher 12-month eGFR being most pronounced in the younger donor age groups (p < 0.01). Recipients with eGFR <30 ml/min/1.73 m2 12-months after transplantation experienced ≥2.5-fold increased risk of overall allograft loss compared to those with eGFR of >60 ml/min/1.73 m2, and the magnitude of the increased risk is most marked among recipients with younger donors. Careful deliberation of other factors including donor age when considering eGFR as a surrogate for clinical endpoints is warranted.

Patient and center characteristics associated with kidney transplant outcomes: a binational registry analysis.

This registry-based study evaluated the contribution of center characteristics to kidney transplant outcomes in adult first kidney transplant recipients in Australia and New Zealand between 2004 and 2014. Primary outcomes were mortality and graft failure, and secondary outcomes were transplant complications. Overall, 6970 transplants from 17 centers were included. For deceased donor transplants, 5-year patient and graft survival rates varied considerably (81.0-93.9% and 72.2-88.3%, respectively). Variations in mortality and graft failure were partially reduced after adjustment for patient characteristics (1% and 20% reductions) and more markedly reduced after adjustment for center characteristics (41% and 55% reductions). For living donor transplants, 5-year patient and graft survival rates varied (89.7-100% and 79.2-96.9%, respectively). Centers with high average total ischemic times (>14 h) were associated with higher mortality for both deceased (adjusted hazard ratio [(AHR] 2.24, 95% CI 1.21-4.13) and living donor transplants (AHR 1.76, 95% CI 1.02-3.04). Small center size (<35 new kidney transplants/year) was associated with a lower hazard of mortality for living donor kidney transplants (AHR 0.48, 95% CI 0.28-0.81). No center characteristic was associated with graft failure. The appreciable variations in deceased donor kidney transplant recipient and graft survival outcomes across centers were attributable to center effects.

Comparison of graft and patient outcomes following kidney transplantation in extended hour and conventional haemodialysis patients.

AIM: Differences in early graft function between kidney transplant recipients previously managed with either haemodialysis (HD) or peritoneal dialysis are well described. However, only two single-centre studies have compared graft and patient outcomes between extended hour and conventional HD patients, with conflicting results. METHODS: This study compared the outcomes of all extended hour (≥24 h/week) and conventional HD patients transplanted in Australia and New Zealand between 2000 and 2014. The primary outcome was delayed graft function (DGF), defined in an ordinal manner as either a spontaneous fall in serum creatinine of less than 10% within 24 h, or the need for dialysis within 72 h following transplantation. Secondary outcomes included the requirement for dialysis within 72 h post-transplant, acute rejection, estimated glomerular filtration rate at 12 months, death-censored graft failure, all-cause and cardiovascular mortality, and a composite of graft failure and mortality. RESULTS: A total of 4935 HD patients (378 extended hour HD, 4557 conventional HD) received a kidney transplant during the study period. Extended hour HD was associated with an increased likelihood of DGF compared with conventional HD (adjusted proportional odds ratio 1.33; 95% confidence interval 1.06-1.67). There was no significant difference between extended hour and conventional HD in terms of any of the secondary outcomes. CONCLUSION: Compared to conventional HD, extended hour HD was associated with DGF, although long-term graft and patient outcomes were not different.

Effects of Renal Impairment and Hemodialysis on the Pharmacokinetics and Safety of the Glecaprevir and Pibrentasvir Combination in Hepatitis C Virus-Negative Subjects.

Hepatitis C virus (HCV) infection is an independent risk factor for developing chronic renal impairment and end-stage renal disease. Limited treatment options are available for HCV genotype 2, 3, 5, and 6 infections in patients with an estimated glomerular filtration rate (eGFR) of <30 ml/min. Glecaprevir and pibrentasvir are active against all six major HCV genotypes, are primarily excreted in the bile, and have minimal renal elimination. Therefore, combined treatment with these direct-acting antivirals may be useful for patients with HCV infection and chronic kidney disease. A phase 1, multicenter, open-label study evaluated the effects of renal impairment on the pharmacokinetics and safety of glecaprevir-pibrentasvir. In substudy 1, 38 subjects with stage 2 to 5 chronic kidney disease who were not on dialysis or who had normal renal function received single doses of the combination of 300 mg glecaprevir and 120 mg pibrentasvir. In substudy 2, 8 subjects requiring hemodialysis received single doses of the combination of 300 mg glecaprevir and 120 mg pibrentasvir under dialysis and nondialysis conditions. Regression analyses demonstrated increased glecaprevir and pibrentasvir plasma exposures, as determined by the area under the curve, with decreasing renal function, up to 56% and 46%, respectively, in subjects with an eGFR of <15 ml/min/1.73 m2 In dialysis-dependent subjects, glecaprevir and pibrentasvir exposures were similar (≤18% difference) when study drugs were administered before hemodialysis or on a nondialysis day. Adverse events were mostly mild, with the most common being self-limited fatigue (3 subjects). The study findings support the clinical evaluation of glecaprevir-pibrentasvir without dose adjustment in HCV-infected subjects with renal impairment. (This study has been registered at ClinicalTrials.gov under registration number NCT02442258.).

A Randomized Controlled Trial of an Intensive Nutrition Intervention Versus Standard Nutrition Care to Avoid Excess Weight Gain After Kidney Transplantation: The INTENT Trial.

OBJECTIVE: Excessive weight gain is common after kidney transplantation and increases cardiovascular risk. The aim of this randomized controlled trial was to determine whether an intensive nutrition and exercise intervention delivered alongside routine post-transplant care would reduce post-transplant weight gain. DESIGN: Single-blind, randomized controlled trial. SUBJECTS AND SETTING: Adult kidney transplant recipients at a regional transplant center were recruited during routine outpatient clinic visits in the first month after transplant. Patients with a body mass index >40 kg/m2 or <18.5 kg/m2, severe malnutrition, or ongoing medical complications were excluded. INTERVENTION: Participants were randomized to intensive nutrition intervention (individualized nutrition and exercise counselling; 12 dietitian visits; 3 exercise physiologist visits over 12 months) or to standard nutrition care (guideline based; 4 dietitian visits). MAIN OUTCOME MEASURES: The primary outcome was weight at 6 months after transplant adjusted for baseline weight, obesity, and gender, analyzed using analysis of covariance. The secondary outcomes included body composition, biochemistry, quality of life, and physical function. RESULTS: Thirty-seven participants were randomized to the intensive intervention (n = 19) or to standard care (n = 18); one intensive group participant withdrew before baseline. Weight increased between baseline, 6 and 12 months (78.0 ± 13.7 [standard deviation], 79.6 ± 13.0 kg, 81.6 ± 12.9 kg; mean change 4.6% P < .001) but at 6 months did not differ significantly between the groups: 77.0 ± 12.4 kg (intensive); 82.2 ± 13.4 kg (standard); difference in adjusted means 0.4 kg (95% confidence interval: -2.2 to 3.0 kg); analysis of covariance P = .7. No between-group differences in secondary outcomes were observed. Across the whole cohort, total body protein and physical function (gait speed, sit to stand, grip strength, physical activity, and quality of life [all but 2 domains]) improved. However, adverse changes were seen for total body fat, HbA1c, and fasting glucose across the cohort. CONCLUSIONS: Kidney transplant recipients in the first year after transplant did not benefit from an intensive nutrition intervention compared with standard nutrition care, although weight gain was relatively modest in both groups.

Spontaneous glomerular mesangial lesions in common marmoset monkeys (Callithrix jacchus): a benign non-progressive glomerulopathy.

BACKGROUND: Common marmosets are known to develop an IgM glomerulopathy, which has been linked with 'wasting marmoset' syndrome. This study investigated renal pathology in a colony of marmosets, with and without weight loss. METHODS: Renal histology, immunofluorescence, and electron microscopy were performed on marmosets euthanized for research or for weight loss. Serum and urine biochemistry were measured during life and at euthanasia. RESULTS: Histology from 25 adult marmosets (19 research and 6 weight loss) showed mesangial expansion in the majority of glomeruli. Mesangial changes correlated with electron-dense deposits and IgM deposition by immunofluorescence; negligible other pathology was seen. Glomerular basement membrane thickness appeared increased compared to reported human measurements. Low-grade proteinuria was present in all animals, but did not progress. Renal function was normal in all animals. CONCLUSIONS: Marmosets develop a glomerulopathy characterized by mesangial expansion, IgM deposition, and proteinuria. This is a benign occurrence and not specifically associated with weight loss.

The effect of intensive nutrition interventions on weight gain after kidney transplantation: protocol of a randomised controlled trial.

BACKGROUND: Weight gain and obesity are common after kidney transplantation, particularly during the first year. Obesity is a risk factor for the development of new-onset diabetes after transplantation, and is associated with reduced graft survival. There is a lack of evidence for effective interventions to prevent weight gain after kidney transplantation. METHODS/DESIGN: The effect of INTEnsive Nutrition interventions on weight gain after kidney Transplantation (INTENT) trial is a single-blind (outcomes assessor), randomised controlled trial to assess the effect of intensive nutrition interventions, including exercise advice, on weight gain and metabolic parameters in the first year after transplantation. Participants will be randomised during the first post-transplant month to either standard care (four visits with a renal dietitian over twelve months) or intensive nutrition intervention (eight visits with a renal dietitian over the first six months, four visits over the second six months, and three visits over the first six months with an exercise physiologist). In the intensive intervention group, nutrition counselling will be provided using motivational interviewing techniques to encourage quality engagement. Collaborative goal setting will be used to develop personalised nutrition care plans. Individualised advice regarding physical activity will be provided by an exercise physiologist. The primary outcome of the study is weight at six months after transplant, adjusted for baseline (one month post-transplant) weight, obesity and gender. Secondary outcomes will include changes in weight and other anthropometric measures over 12 months, body composition (in vivo neutron activation analysis, total body potassium, dual-energy X-ray absorptiometry, and bioelectrical impedance), biochemistry (fasting glucose, lipids, haemoglobin A1c and insulin), dietary intake and nutritional status, quality of life, and physical function. DISCUSSION: There are currently few randomised clinical trials of nutrition interventions after kidney transplantation. The INTENT trial will thus provide important data on the effect of intensive nutrition interventions on weight gain after transplant and the associated metabolic consequences. Additionally, by assessing changes in glucose metabolism, the study will also provide data on the feasibility of undertaking larger multi-centre trials of nutrition interventions to reduce the incidence or severity of diabetes after transplantation. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number: ACTRN12614000155695.

Patients' administration preferences: progesterone vaginal insert (Endometrin®) compared to intramuscular progesterone for Luteal phase support.

BACKGROUND: Administration of exogenous progesterone for luteal phase support has become a standard of practice. Intramuscular (IM) injections of progesterone in oil (PIO) and vaginal administration of progesterone are the primary routes of administration. This report describes the administration preferences expressed by women with infertility that were given progesterone vaginal insert (PVI) or progesterone in oil injections (PIO) for luteal phase support during fresh IVF cycles. METHODS: A questionnaire to assess the tolerability, convenience, and ease of administration of PVI and PIO given for luteal phase support was completed by infertile women diagnosed with PCOS and planning to undergo IVF. The women participated in an open-label study of highly purified human menopausal gonadotropins (HP-hMG) compared with recombinant FSH (rFSH) given for stimulation of ovulation. RESULTS: Most women commented on the convenience and ease of administration of PVI, while a majority of women who administered IM PIO described experiencing pain. In addition, their partners often indicated that they had experienced at least some anxiety regarding the administration of PIO. The most distinguishing difference between PVI and PIO in this study was the overall patient preference for PVI. Despite the need to administer PVI either twice a day or three times a day, 82.6% of the patients in the PVI group found it "very" or "somewhat convenient" compared with 44.9% of women in the PIO group. CONCLUSIONS: The results of this comprehensive, prospective patient survey, along with findings from other similar reports, suggest that PVI provides an easy-to-use and convenient method for providing the necessary luteal phase support for IVF cycles without the pain and inconvenience of daily IM PIO. Moreover, ongoing pregnancy rates with the well-tolerated PVI were as good as the pregnancy rates with PIO. TRIAL REGISTRATION: ClinicalTrial.gov, NCT00805935.

Clinical comparison of ovarian stimulation and luteal support agents in patients undergoing GnRH antagonist IVF cycles.

OBJECTIVE: To explore the comparative efficacy, safety, and tolerability of agents used for ovarian stimulation and luteal support when applied in a population of women undergoing in vitro fertilization (IVF) using a gonadotropin-releasing hormone (GnRH) antagonist protocol. STUDY DESIGN: A phase 4, multicenter, randomized, open-label, exploratory clinical trial was performed at 7 assisted reproductive technology centers in the United States. Subjects included 173 women aged 18-42 years with a documented history of infertility who were undergoing IVF. Subjects were randomized to treatment with highly purified human menopausal gonadotropin (HP-hMG) or recombinant human follicle-stimulating hormone (rhFSH) for ovarian stimulation and progesterone vaginal inserts (PVIs) or intramuscular injection of progesterone in oil (PIO) for luteal support. Protocols for IVF followed the standard practices of participating centers within the parameters of the study. RESULTS: Biochemical, clinical, and ongoing pregnancy rates were the main outcome measures. Ongoing pregnancy rates for individual treatment groups ranged from 44.0-46.9%. No statistically significant differences were observed in pregnancy outcomes for the comparisons of HP-hMG vs. rhFSH or PVI vs. PIO. All study medications were generally safe and well tolerated. CONCLUSION: In this study HP-hMG and rhFSH were equally effective for ovarian stimulation during GnRH antagonist IVF cycles. Both PVI and PIO are viable options for luteal support.

Decreased gonadotropin requirements in once daily compared to twice daily administration: a prospective, randomized study.

OBJECTIVE: Despite the lack of any scientific data, many ART programs split the daily gonadotropin dose during ovarian stimulation, while others give the entire dose during a single administration, usually at night. DESIGN: Prospective randomized. PATIENT(S): 213 women undergoing IVF/ICSI cycles at a single private ART center. INTERVENTION(S): Gonadotropin administration once daily compared to twice daily. MAIN OUTCOME MEASURE(S): Gonadotropin usage, clinical and ongoing PR RESULTS: There were 110 women in the once daily compared to 103 in the twice daily arm. All cycles were blastocyst transfers. There was a significantly lower FSH use in the once daily arm compared to the twice daily arm (1507.5 ± 517.5 IU vs. 1702.5 ± 622.5, P = 0.015), and a trend towards lower hMG use in the once daily arm (1342.5 ± 562.5 IU vs. 1462.5 ± 645.0, P = 0.15), without compromising clinical pregnancy rate (PR) (71.8% vs. 70.9%, P = NS) or delivery/ongoing PR (58.2% vs. 62.1%, P = NS). There were no differences in age, body mass index (BMI), peak estradiol, peak progesterone, retrieved oocytes, fertilized oocytes, number of ET, or PR. CONCLUSIONS: Once daily administration is associated with lower gonadotropin usage without compromising success rates.

Gene Therapy: The Next-Generation Therapeutics and Their Delivery Approaches for Neurological Disorders.

Neurological conditions like neurodevelopmental disorders and neurodegenerative diseases are quite complex and often exceedingly difficult for patients. Most of these conditions are due to a mutation in a critical gene. There is no cure for the majority of these neurological conditions and the availability of disease-modifying therapeutics is quite rare. The lion's share of the treatments that are available only provide symptomatic relief, as such, we are in desperate need of an effective therapeutic strategy for these conditions. Considering the current drug development landscape, gene therapy is giving us hope as one such effective therapeutic strategy. Consistent efforts have been made to develop gene therapy strategies using viral and non-viral vectors of gene delivery. Here, we have discussed both of these delivery methods and their properties. We have summarized the relative advantages and drawbacks of viral and non-viral vectors from the perspectives of safety, efficiency, and productivity. Recent developments such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated gene editing and its use in vivo have been described here as well. Given recent advancements, gene therapy shows great promise to emerge as a next-generation therapeutic for many of the neurodevelopmental and neurodegenerative conditions.

Statistical analysis plan for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): a randomised controlled trial of the effect of intravenous fluid therapy with balanced crystalloid versus saline on the incidence of delayed graft function in deceased donor kidney transplantation.

BACKGROUND: Delayed graft function, or the requirement for dialysis due to poor kidney function, is a frequent complication of deceased donor kidney transplantation that is associated with inferior outcomes. Intravenous fluids with a high chloride content, such as isotonic sodium chloride (0.9% saline), are widely used in transplantation but may increase the risk of poor kidney function. The primary objective of the BEST-Fluids trial is to compare the effect of a balanced low-chloride crystalloid, Plasma-Lyte 148 (Plasmalyte), versus 0.9% saline on the incidence of DGF in deceased donor kidney transplant recipients. This article describes the statistical analysis plan for the trial. METHODS AND DESIGN: BEST-Fluids is an investigator-initiated, pragmatic, registry-based, multi-centre, double-blind, randomised controlled trial. Eight hundred patients (adults and children) in Australia and New Zealand with end-stage kidney disease admitted for a deceased donor kidney transplant were randomised to intravenous fluid therapy with Plasmalyte or 0.9% saline in a 1:1 ratio using minimization. The primary outcome is delayed graft function (dialysis within seven days post-transplant), which will be modelled using a log-binomial generalised linear mixed model with fixed effects for treatment group, minimization variables, and ischaemic time and a random intercept for study centre. Secondary outcomes including early kidney transplant function (a ranked composite of dialysis duration and the rate of graft function recovery), treatment for hyperkalaemia, and graft survival and will be analysed using a similar modelling approach appropriate for the type of outcome. DISCUSSION: BEST-Fluids will determine whether Plasmalyte reduces the incidence of DGF and has a beneficial effect on early kidney transplant outcomes relative to 0.9% saline and will inform clinical guidelines on intravenous fluids for deceased donor kidney transplantation. The statistical analysis plan describes the analyses to be undertaken and specified before completion of follow-up and locking the trial databases. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12617000358347 . Prospectively registered on 8 March 2017 ClinicalTrials.gov identifier NCT03829488 . Registered on 4 February 2019.

Cognition-Enhanced Machine Learning for Better Predictions with Limited Data.

The fields of machine learning (ML) and cognitive science have developed complementary approaches to computationally modeling human behavior. ML's primary concern is maximizing prediction accuracy; cognitive science's primary concern is explaining the underlying mechanisms. Cross-talk between these disciplines is limited, likely because the tasks and goals usually differ. The domain of e-learning and knowledge acquisition constitutes a fruitful intersection for the two fields' methodologies to be integrated because accurately tracking learning and forgetting over time and predicting future performance based on learning histories are central to developing effective, personalized learning tools. Here, we show how a state-of-the-art ML model can be enhanced by incorporating insights from a cognitive model of human memory. This was done by exploiting the predictive performance equation's (PPE) narrow but highly specialized domain knowledge with regard to the temporal dynamics of learning and forgetting. Specifically, the PPE was used to engineer timing-related input features for a gradient-boosted decision trees (GBDT) model. The resulting PPE-enhanced GBDT outperformed the default GBDT, especially under conditions in which limited data were available for training. Results suggest that integrating cognitive and ML models could be particularly productive if the available data are too high-dimensional to be explained by a cognitive model but not sufficiently large to effectively train a modern ML algorithm. Here, the cognitive model's insights pertaining to only one aspect of the data were enough to jump-start the ML model's ability to make predictions-a finding that holds promise for future explorations.

Baseline Characteristics and Representativeness of Participants in the BEST-Fluids Trial: A Randomized Trial of Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation.

Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail. Methods: We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients. Results: During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences. Conclusions: BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.

Trust Miscalibration Is Sometimes Necessary: An Empirical Study and a Computational Model.

The literature on trust seems to have reached a consensus that appropriately calibrated trust in humans or machines is highly desirable; miscalibrated (i.e., over- or under-) trust has been thought to only have negative consequences (i.e., over-reliance or under-utilization). While not invalidating the general idea of trust calibration, a published computational cognitive model of trust in strategic interaction predicts that some local and temporary violations of the trust calibration principle are critical for sustained success in strategic situations characterized by interdependence and uncertainty (e.g., trust game, prisoner's dilemma, and Hawk-dove). This paper presents empirical and computational modeling work aimed at testing the predictions of under- and over-trust in an extension of the trust game, the multi-arm trust game, that captures some important characteristics of real-world interpersonal and human-machine interactions, such as the ability to choose when and with whom to interact among multiple agents. As predicted by our previous model, we found that, under conditions of increased trust necessity, participants actively reconstructed their trust-investment portfolios by discounting their trust in their previously trusted counterparts and attempting to develop trust with the counterparts that they previously distrusted. We argue that studying these exceptions of the principle of trust calibration might be critical for understanding long-term trust calibration in dynamic environments.