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Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Introduction Pharmacy students are significantly less likely than medical students to seek on-campus mental health services, though barriers are not well known. This study's objective is to expand on perceived barriers to seeking care for mental health concerns among doctor of pharmacy students in the United States. Methods An institutional review board-exempt, online survey was disseminated to eight pharmacy programs' students assessing mental health barriers to care, resource interest, attitudes towards treatment, and stigma. Quantitative data were analyzed aggregately and by gender, program type, employment status, and education year. Free-text response analysis used thematic coding. Results Common barriers to care included lack of time (20.2%), financial support or resources (13.2%), and preferring to solve the issue independently (13.2%). About half agreed their programs had sufficient resources to support mental health (58.4%). Suggested resources included on-site counselors (14.5%), pet therapy (13.4%), and wellness activities (12.3%). Students reported high rates of perceived internal stigma, yet low rates of stigma towards others. No significant differences were found among employment status or program type, but first-year students had more positive attitudes towards mental health treatment. Females were significantly more likely to agree mental health treatment was effective and less likely to view someone differently who received treatment. Conclusions Common barriers to care included lack of time, finances or resources, and concerns of being viewed differently. Additionally, substantial stigma exists, particularly public perception and concern for negative impact on future opportunities. Programs should take initiative to understand students' needs and interest in support services.

A common complaint of older adults is difficulty understanding speech, particularly in challenging listening conditions. Accumulating evidence suggests that these difficulties may reflect a loss and/or dysfunction of auditory nerve (AN) fibers. We used a novel approach to study age-related changes in AN structure and several measures of AN function, including neural synchrony, in 58 older adults and 42 younger adults. AN activity was measured in response to an auditory click (compound action potential; CAP), presented at stimulus levels ranging from 70 to 110 dB pSPL. Poorer AN function was observed for older than younger adults across CAP measures at higher but not lower stimulus levels. Associations across metrics and stimulus levels were consistent with age-related AN disengagement and AN dyssynchrony. High-resolution T2-weighted structural imaging revealed age-related differences in the density of cranial nerve VIII, with lower density in older adults with poorer neural synchrony. Individual differences in neural synchrony were the strongest predictor of speech recognition, such that poorer synchrony predicted poorer recognition of time-compressed speech and poorer speech recognition in noise for both younger and older adults. These results have broad clinical implications and are consistent with an interpretation that age-related atrophy at the level of the AN contributes to poorer neural synchrony and may explain some of the perceptual difficulties of older adults.SIGNIFICANCE STATEMENTDifferences in auditory nerve (AN) pathophysiology may contribute to the large variations in hearing and communication abilities of older adults. However, current diagnostics focus largely on the increase in detection thresholds, which is likely because of the absence of indirect measures of AN function in standard clinical test batteries. Using novel metrics of AN function, combined with estimates of AN structure and auditory function, we identified age-related differences across measures that we interpret to represent age-related reductions in AN engagement and poorer neural synchrony. Structure-function associations are consistent with an explanation of AN deficits that arise from age-related atrophy of the AN. Associations between neural synchrony and speech recognition suggest that individual and age-related deficits in neural synchrony contribute to speech recognition deficits.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by growth of kidney cysts and glomerular filtration rate (GFR) decline. Metformin was found to impact cystogenesis in preclinical models of polycystic disease, is generally considered safe and may be a promising candidate for clinical investigation in ADPKD. In this phase 2 two-year trial, we randomly assigned 97 patients, 18-60 years of age, with ADPKD and estimated GFR over 50 ml/min/1.73 m2, in a 1:1 ratio to receive metformin or placebo twice daily. Primary outcomes were medication safety and tolerability. Secondary outcomes included estimated GFR decline, and total kidney volume growth. Thirty-eight metformin and 39 placebo participants still received study product at 24-months. Twenty-one participants in the metformin arm reduced drug dose due to inability to tolerate, compared with 14 in the placebo arm (not significant). Proportions of participants experiencing serious adverse events was similar between the groups. The Gastrointestinal Symptoms Rating Scale score was low at baseline and did not significantly change over time. The annual change for estimated GFR was -1.71 with metformin and -3.07 ml/min/1.73m2 per year with placebo (mean difference 1.37 {-0.70, 3.44} ml/min/1.73m2), while mean annual percent change in height-adjusted total kidney volume was 3.87% in metformin and 2.16% per year in placebo, (mean difference 1.68% {-2.11, 5.62}). Thus, metformin in adults with ADPKD was found to be safe and tolerable while slightly reducing estimated GFR decline but not to a significant degree. Hence, evaluation of efficacy requires a larger trial, with sufficient power to detect differences in endpoints.

Introduction Because of phenotypic overlap between monogenic urinary stone diseases (USD), gene-specific analyses can result in missed diagnoses. We used targeted next generation sequencing (tNGS), including known and candidate monogenic USD genes, to analyze suspected primary hyperoxaluria (PH) or Dent disease (DD) patients genetically unresolved (negative; N) after Sanger analysis of the known genes. Cohorts consisted of 285 PH (PHN) and 59 DD (DDN) families. Methods Variants were assessed using disease-specific and population databases plus variant assessment tools and categorized using the American College of Medical Genetics (ACMG) guidelines. Prior Sanger analysis identified 47 novel PH or DD gene pathogenic variants. Results Screening by tNGS revealed pathogenic variants in 14 known monogenic USD genes, accounting for 45 families (13.1%), 27 biallelic and 18 monoallelic, including 1 family with a copy number variant (CNV). Recurrent genes included the following: SLC34A3 (n = 13), CLDN16 (n = 8), CYP24A1 (n = 4), SLC34A1 (n = 3), SLC4A1 (n = 3), APRT (n = 2), CLDN19 (n = 2), HNF4A1 (n = 2), and KCNJ1 (n = 2), whereas ATP6V1B1, CASR, and SLC12A1 and missed CNVs in the PH genes AGXT and GRHPR accounted for 1 pedigree each. Of the 48 defined pathogenic variants, 27.1% were truncating and 39.6% were novel. Most patients were diagnosed before 18 years of age (76.1%), and 70.3% of biallelic patients were homozygous, mainly from consanguineous families. Conclusion Overall, in patients suspected of DD or PH, 23.9% and 7.3% of cases, respectively, were caused by pathogenic variants in other genes. This study shows the value of a tNGS screening approach to increase the diagnosis of monogenic USD, which can optimize therapies and facilitate enrollment in clinical trials., Graphical abstract

BACKGROUND: Insulin resistance is associated with cardiovascular disease risk and worsened kidney function. Patients with CKD have higher levels of insulin resistance. Elevated levels of copeptin (a surrogate for vasopressin levels) have been associated with an increased incidence and progression of CKD, and with incident diabetes mellitus. The purpose of our study was to examine the relationship between insulin resistance, copeptin, and CKD. METHODS: We performed a cross-sectional study to investigate if insulin resistance was associated with higher copeptin levels in nondiabetic patients with stage 3–4 CKD versus controls. We measured plasma copeptin levels and used data from 52 patients with stage 3–4 CKD and 85 controls (eGFR ≥60 ml/min per 1.73 m(2)) enrolled in the Insulin Resistance in Chronic Kidney Disease (IRCKD) study. We then used a multivariable linear-regression model to assess the independent relationship between peripheral or hepatic insulin resistance and copeptin across levels of eGFR. RESULTS: We found that in patients with CKD (eGFR of 30–60 ml/min per 1.73 m(2)), but not in controls, peripheral insulin resistance was significantly correlated with higher levels of log copeptin (r=−0.21, P=0.04). In patients with CKD, when adjusted for age, sex, BMI, serum osmolality, log IL6, and log leptin/adiponectin ratio, each 1 SD decrease in insulin sensitivity was associated with a 39% increase in serum copeptin levels. The relationship between hepatic insulin resistance, copeptin, and eGFR is similar between controls and patients with reduced eGFR. CONCLUSION: Peripheral insulin resistance is associated with elevated copeptin levels in nondiabetic patients with stage 3–4 CKD. Further research into how the interaction between peripheral insulin resistance and elevated vasopressin affects CKD progression could be of interest.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. However, if and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. Here we address this question with a “cystic extracellular vesicles/exosomes theory”. We show that cystic cell derived extracellular vesicles and urinary exosomes derived from ADPKD patients promote cyst growth in Pkd1 mutant kidneys and in 3D cultures. This is achieved by: 1) downregulation of Pkd1 gene expression and upregulation of specific miRNAs, resulting in the activation of PKD associated signaling pathways in recipient renal epithelial cells and tissues; 2) the activation of fibroblasts; and 3) the induction of cytokine expression and the recruitment of macrophages to increase renal inflammation in cystic kidneys. Inhibition of exosome biogenesis/release with GW4869 significantly delays cyst growth in aggressive and milder ADPKD mouse models, suggesting that targeting exosome secretion has therapeutic potential for ADPKD., Autosomal dominant polycystic kidney disease is characterized by the formation of cysts in the kidney. Here the authors show that cystic extracellular vesicles/exosomes play a critical role in regulating the biology and function of adjacent cells, including renal epithelial cells, fibroblasts and macrophages, and contribute to renal cyst growth.

Introduction Loss-of-function variants in the CYP24A1 gene cause a rare hereditary disease characterized by reduced 24-hydroxylase enzyme activity, increased serum 1,25-dihydroxycholecalciferol levels, hypercalcemia, hypercalciuria, and nephrocalcinosis and/or nephrolithiasis. Kidney cysts in patients with CYP24A1 deficiency were first reported in a single case study from our center. However, a possible association between CYP24A1 deficiency and kidney cysts has not been described. Methods Retrospective analysis of patients with confirmed or suspected CYP24A1 deficiency and available kidney imaging. Results Among 16 patients with confirmed pathogenic variants, 38% were male and 31% were children, the median age at genetic confirmation was 38 years (range 1–66), and none had a family history of cystic kidney disease. Medullary and/or corticomedullary junction cysts were present in all cases. The median age at first detected cyst was 37 years (range 3–60). The mean and median number of cysts per patient were 5.3 and 2.5 (range 1–37), respectively. Four of 5 further patients with suspected but unconfirmed pathogenic variants had cysts. The number of cysts ≥5 mm in size was above the 97.5th percentile of an age- and sex-matched control population in 55% and 67% of patients with confirmed and suspected pathogenic variants, respectively. At least 1 cyst (≥5 mm in size) was found in 80% of children with confirmed CYP24A1 deficiency. Conclusions These observations strongly suggest an association between CYP24A1 deficiency and kidney cysts. Further studies are needed to evaluate the role of CYP24A1, vitamin D metabolism, and/or hypercalciuria in cyst formation, and whether cysts exacerbate chronic kidney disease or modify nephrocalcinosis and stone risk.

Stereotactic body radiation therapy (SBRT) is an emerging locoregional treatment (LRT) modality used in the management of patients with hepatocellular carcinoma (HCC). The decision to treat HCC with LRT is evaluated in a multidisciplinary setting, and the specific LRT chosen depends on the treatment intent, such as bridge-to-transplant, down-staging to transplant, definitive/curative treatment, and/or palliation, as well as underlying patient clinical factors. Accurate assessment of treatment response is necessary in order to guide clinical management in these patients. Patients who undergo LRT need continuous imaging evaluation to assess treatment response and to evaluate for recurrence. Thus, an accurate understanding of expected post-SBRT imaging findings is critical to avoid misinterpreting normal post-treatment changes as local progression or viable tumor. SBRT-treated HCC demonstrates unique imaging findings that differ from HCC treated with other forms of LRT. In particular, SBRT-treated HCC can demonstrate persistent APHE and washout on short-term follow-up imaging. This brief review summarizes current evidence for the use of SBRT for HCC, including patient population, SBRT technique and procedure, tumor response assessment on contrast-enhanced cross-sectional imaging with expected findings, and pitfalls in treatment response evaluation.

Background and Aims Gastric intestinal metaplasia with dysplasia (GIM-D) that is visible as a discrete limited lesion on endoscopy is readily treated using endoscopic mucosal resection or endoscopic submucosal dissection. However, there are few options for more extensive and invisible dysplasia. Ablating a wide swath of tissue with argon plasma coagulation or radiofrequency ablation can be challenging and carries risks, including postprocedure ulceration. Liquid nitrogen spray cryotherapy is an established treatment for dysplasia in Barrett’s esophagus, but its use for GIM-D has not been previously reported. Methods Three patients with intramucosal adenocarcinoma and GIM-D underwent a total of 10 sessions of spray cryotherapy. In all cases, spray cryotherapy was performed after passing an orogastric decompression tube into the stomach for active suctioning. Ablations were performed in cycles of 20 to 40 seconds, with at least 45 seconds between cycles to allow for tissue thawing. Between 2 and 7 ablations were performed during each procedure. Before each procedure, Sydney protocol biopsy specimens were obtained. No patient reported any postprocedure adverse events. Results The first patient underwent 3 sessions of spray cryotherapy; there was no evidence of GIM-D after 1 session, no evidence of gastric intestinal metaplasia after 3 sessions, and no recurrence after 29 months. The second patient underwent 5 sessions of spray cryotherapy; after 1 session there was no adenocarcinoma, and at 14 months there was only GIM-D. The third patient underwent 2 spray cryotherapy sessions, and after 1 session there was gastric intestinal metaplasia but no GIM-D. Conclusions Very few treatment modalities exist for extensive GIM-D. We present 3 cases in which off-label spray cryotherapy was used to treat extensive high-grade dysplasia with good treatment effect and patient tolerance. This adds to the body of literature supporting spray cryotherapy as a safe, well-tolerated, and effective treatment for extensive GIM-D., Video Video 1 A series of cases are presented of patients with diffuse intestinal metaplasia with dysplasia treated with liquid nitrogen spray cryotherapy, along with the key steps to performing successful spray cryotherapy.

DNA damage and alterations in DNA damage response (DDR) signaling could be one of the molecular mechanisms mediating focal kidney cyst formation in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that markers of DNA damage and DDR signaling are increased in human and experimental ADPKD. In the human ADPKD transcriptome, the number of up-regulated DDR-related genes was increased by 16.6-fold compared with that in normal kidney, and by 2.5-fold in cystic compared with that in minimally cystic tissue (P 0.0001). In end-stage human ADPKD tissue, γ-H2A histone family member X (H2AX), phosphorylated ataxia telangiectasia and radiation-sensitive mutant 3 (Rad3)-related (pATR), and phosphorylated ataxia telangiectasia mutated (pATM) localized to cystic kidney epithelial cells. In vitro, pATR and pATM were also constitutively increased in human ADPKD tubular cells (WT 9-7 and 9-12) compared with control (HK-2). In addition, extrinsic oxidative DNA damage by hydrogen peroxide augmented γ-H2AX and cell survival in human ADPKD cells, and exacerbated cyst growth in the three-dimensional Madin-Darby canine kidney cyst model. In contrast, DDR-related gene expression was only transiently increased on postnatal day 0 in Pkd1

Background: Aortic dilation, stiffening, and dissection are common and potentially lethal complications of Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), which involve abnormal transforming growth factor beta (TGF-β) signalling. The relation of aortic dimensions, stiffness, and biomarker levels is unknown. The objective of this study was to measure aortic dimensions, stiffness, TGF-β and matrix metalloproteinase (MMP) levels, and endothelial function in patients with MFS, and to compare TGF-β levels in patients with MFS receiving different therapeutic regimens. Methods: This was a cohort study of 40 MFS and 4 LDS patients and 87 control participants. Aortic dimension and stiffness indexes, including pulse wave velocity (PWV), were measured using echocardiography and Doppler. Total and free TGF-β and MMP blood levels were measured using Quantikine (R&D Systems, Inc, Minneapolis, MN) and Quanterix (Billerica, MA) kits. Endothelial function was measured using brachial artery flow-mediated dilation. Results: PWV was increased in patients with MFS. There were increased MMP-2 levels in those with MFS but no increase in free or total TGF-β or MMP-9 levels compared with control participants. There was no difference in TGF-β levels between MFS patients receiving no medications, angiotensin receptor blockers, and β-blockers. PWV correlated most strongly with age. Endothelial function showed premature gradual decline in patients with MFS. Conclusions: Despite the increased PWV, monitoring aortic stiffness or TGF-β levels would not be helpful in patients with MFS. TGF-β levels were not increased and the increased MMP-2 levels suggest consideration of a different therapeutic target. Résumé: Contexte: La dilatation, la rigidification et la dissection de l’aorte sont des complications fréquentes et parfois mortelles du syndrome de Marfan (SM) et du syndrome de Loeys-Dietz (SLD), qui sont tous deux dûs à une anomalie de la voie de signalisation du facteur de croissance transformant bêta (TGF-β). On ne connaît pas la relation entre les dimensions et la rigidité de l’aorte et la présence de biomarqueurs. Notre étude visait à mesurer les dimensions et la rigidité de l’aorte, les taux de TGF-β et de métalloprotéases matricielles (MMP) et la fonction endothéliale chez des patients atteints du SM, et à les comparer aux taux de TGF-β observés chez des patients également atteints de SM, mais recevant un autre traitement. Méthodologie: Il s’agissait d’une étude de cohorte menée auprès de 40 patients atteints du SM et de quatre patients atteints du SLD, ainsi que de 87 témoins. Les indices des dimensions et de la rigidité aortiques, y compris la vitesse d’onde de pouls (VOP), ont été mesurés par échocardiographie et par échographie Doppler. Les taux sanguins de TGF-β et de MMP totaux et libres ont été mesurés à l’aide de trousses Quantikine (R&D Systems, Inc, Minneapolis, MN) et Quanterix (Billerica, MA). La fonction endothéliale a été mesurée par dilatation liée au flux dans l’artère brachiale. Résultats: La VOP était plus élevée chez les patients atteints du SM. On a aussi observé une hausse des taux de MMP-2 chez les patients atteints de SM, mais aucune augmentation des taux de TGF-β ou de MMP-9 libres ou totaux comparativement aux témoins. Il n’y avait pas de différence entre les taux de TGF-β chez les patients atteints de SM ne recevant aucun traitement, ceux qui prenaient un antagoniste des récepteurs de l’angiotensine et ceux qui prenaient un bêtabloquant. La VOP été plus fortement corrélée avec l’âge. La fonction endothéliale a affiché un déclin progressif prématuré chez les patients atteints du SM. Conclusions: Malgré l’augmentation de la VOP, il ne semble pas utile de surveiller la rigidité aortique ni les taux de TGF-β en cas de SM. Les taux de TGF-β n’étaient pas plus élevés chez les patients atteints du SM, et la hausse des taux de MMP-2 indique qu’il conviendrait de choisir une autre cible thérapeutique.

We recently encountered concern about the safety of bariatric surgery for a patient with cystinuria. Bariatric surgery procedures include those that cause malabsorption, like the Roux-en-Y gastric bypass procedure, and restrictive operations, such as the sleeve gastrectomy. These procedures produce beneficial effects on health and life expectancy, though whether kidney stones are prevented, as well as promoted, is not established. Although the importance of body weight to metabolic stone activity in patients with cystinuria is not established, the patient's physicians were concerned about whether any bariatric surgery procedure would affect her ability to drink sufficient quantities of water in order to reduce stone activity. Here we report the experience of a genetically defined patient with cystinuria who underwent a gastric sleeve procedure. In the months after the procedure, she lost 45 kg, though with time she regained 23 kg of that loss. She was able to maintain a urine volume of 4.0 L per day and has had no stone recurrence.

Transarterial radioembolization with yttrium-90 microspheres is an established therapy for hepatocellular carcinoma. Post-procedural imaging is important for the assessment of both treatment response and procedural complications. A variety of challenging treatment-specific imaging phenomena complicate imaging assessment, such as changes in tumoral size, tumoral and peritumoral enhancement, and extrahepatic complications. A review of the procedural steps, emerging variations, and timelines for post-treatment tumoral and extra-tumoral imaging changes are presented, which may aid the reporting radiologist in the interpretation of post-procedural imaging. Furthermore, a description of post-procedural complications and their significance is provided.

Ischemic heart disease is the leading cause of death worldwide and is frequently comorbid with chronic kidney disease. Physiological communication is known to occur between the heart and the kidney. Although primary dysfunction in either organ can induce dysfunction in the other, a clinical entity known as cardiorenal syndrome, mechanistic details are lacking. Here, we used a model of experimental myocardial infarction (MI) to test effects of chronic cardiac ischemia on acute and chronic kidney injury. Surprisingly, chronic cardiac damage protected animals from subsequent acute ischemic renal injury, an effect that was accompanied by evidence of chronic kidney hypoxia. The protection observed post-MI was similar to protection observed in a separate group of healthy animals housed in ambient hypoxic conditions prior to kidney injury, suggesting a common mechanism. There was evidence that chronic cardiac injury activates renal hypoxia-sensing pathways. Increased renal abundance of several glycolytic enzymes following MI suggested that a shift toward glycolysis may confer renal ischemic preconditioning. In contrast, effects on chronic renal injury followed a different pattern, with post-MI animals displaying worsened chronic renal injury and fibrosis. These data show that although chronic cardiac injury following MI protected against acute kidney injury via activation of hypoxia-sensing pathways, it worsened chronic kidney injury. The results further our understanding of cardiorenal signaling mechanisms and have implications for the treatment of heart failure patients with associated renal disease. NEW & NOTEWORTHY Experimental myocardial infarction (MI) protects from subsequent ischemic acute kidney injury but worsens chronic kidney injury. Observed protection from ischemic acute kidney injury after MI was accompanied by chronic kidney hypoxia and increased renal abundance of hypoxia-inducible transcripts. These data support the idea that MI confers protection from renal ischemic injury via chronic renal hypoxia and activation of downstream hypoxia-inducible signaling pathways.

Introduction Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth and a loss of functioning renal mass, but a decline in glomerular filtration rate (GFR) and onset of end-stage renal disease (ESRD) occur late in the disease course. There is therefore a great need for early prognostic biomarkers in this disorder. Methods We measured baseline serum fibroblast growth factor 23 (FGF23) levels in 192 patients with ADPKD from the Consortium for Radiologic Imaging Studies of PKD (CRISP) cohort that were followed for a median of 13 years and tested the association between FGF23 levels and change over time in height-adjusted total kidney volume (htTKV), GFR, and time to the composite endpoints of ESRD, death, and doubling of serum creatinine. Results Patients in the highest quartile for baseline FGF23 level had a higher rate of increase in htTKV (0.95% per year, P = 0.0016), and faster rate of decline in GFR (difference of −1.03 ml/min/1.73 m2 per year, P = 0.005) compared with the lowest quartile, after adjusting for other covariates, including htTKV and genotype. The highest quartile of FGF23 was also associated with a substantial increase in risk for the composite endpoint of ESRD, death, or doubling of serum creatinine (hazard ratio [HR] of 2.45 in the fully adjusted model, P = 0.03). Conclusion FGF23 is a prognostic biomarker for disease progression and clinically important outcomes in ADPKD, and has additive value to established imaging and genetic biomarkers., Graphical abstract

[English] This study determined if supplementation with pantothenic acid (PA) for 16 weeks could increase skeletal muscle coenzyme A (CoASH) content and exercise performance. Trained male cyclists (n = 14) were matched into control or PA (6 g·day1) groups. At 0, 4, 8, and 16 weeks, subjects performed an incremental time to exhaustion cycle with muscle biopsies taken prior to and following exercise. Prolonged PA supplementation did not change skeletal muscle CoASH and acetyl- CoA contents or exercise performance. Novelty: Supplementation with pantothenic acid for 16 weeks had no effect on skeletal muscle CoASH and acetyl-CoA content or exercise performance in trained male cyclists. [French] Cette étude détermine si une supplémentation en acide pantothénique (« PA ») pendant 16 semaines peut augmenter la teneur en coenzyme A (« CoASH ») du muscle squelettique et la performance à l’exercice. Les cyclistes masculins entraînés (n = 14) sont appariés dans des groupes témoins ou PA (6 g·jour−1). Aux semaines 0, 4, 8 et 16, les sujets effectuent un exercice incrémental de pédalage au cours duquel on mesure la durée jusqu’à épuisement ; des biopsies musculaires sont prélevées avant et après l’exercice. Une supplémentation prolongée en PA ne modifie pas les teneurs en CoASH et en acétyl-CoA du muscle squelettique ni la performance à l’exercice. [Traduit par la Rédaction]

Introduction Cystic expansion damaging the parenchyma is thought to lead to end-stage kidney disease (ESKD) in autosomal dominant polycystic kidney disease (ADPKD). Here we characterized genotypic and phenotypic attributes of ADPKD at time of ESKD. Methods This is a retrospective cross-sectional study of patients with ADPKD with ESKD evaluated at Mayo Clinic with available abdominal computed tomography (CT) or magnetic resonance imaging (MRI). Kidney volumes were measured (total kidney volume adjusted for height [HtTKV]), Mayo Image Class (MIC) calculated, ADPKD genotype determined, and clinical and laboratory features obtained from medical records. Results Differences in HtTKV at ESKD were associated with patient age and sex; older patients and women had smaller HtTKV at ESKD. HtTKV at ESKD was observed to be 12.3% smaller with each decade of age (P < 0.01); but significant only in women (17.8%, P < 0.01; men 6.9%, P = 0.06). Patients with onset of ESKD at 61 years had different characteristics, with a shift from youngest to oldest in male to female enrichment, MIC from 1D/1E to 1B/1C, likely fully penetrant PKD1 mutations from 95% to 42%, and presence of macrovascular disease from 8% to 40%. Macrovascular disease was associated with smaller kidneys in female patients. Conclusion HtTKV at ESKD was smaller with advancing age in patients with ADPKD, particularly in women. These novel findings provide insight into possible underlying mechanisms leading to ESKD, which differ between younger and older individuals. Cystic growth is the predominant mechanism in younger patients with ESKD, whereas aging-related factors, including vascular disease, becomes potentially important as patients age., Graphical abstract

Objective To evaluate levonorgestrel 52 mg intrauterine system (IUS) expulsion risk by menstrual cycle day of insertion (days 1–8 vs days 9 and beyond) in women using the IUS for noncontraceptive indications. Study design We performed a retrospective cohort study of patients with a levonorgestrel IUS inserted for the management of noncontraceptive, gynecologic conditions at Kaiser Permanente-Hawaii between January 2009 and December 2010. We used multivariable logistic regression models to estimate the likelihood of IUS expulsion adjusting for demographic and clinical factors and a Kaplan-Meier curve for survival analysis. Results Of 176 patients identified, insertion occurred in 42 patients in cycle days 1 to 8 and 87 patients after day 8. Patient follow-up within the Kaiser system ranged from 1 to 71 months. Thirty-nine (22%) patients experienced expulsion, 16 (38%) and 15 (17%) for the 2 timing groups, respectively. Expulsion was more likely if the IUS placement occurred during the menstrual cycle days 1 to 8 (adjusted odds ratio 3.57 [95% confidence interval 1.13, 11.31]), which was consistent with the Kaplan-Meier analysis (p = 0.008). Conclusion Levonorgestrel IUS expulsion among women using the IUS for noncontraceptive indications occurred more frequently if insertion occurred during the first eight days of the menstrual cycle. Implications In women planning to use the levonorgestrel IUS to treat gynecologic conditions such as abnormal uterine bleeding, dysmenorrhea, and endometrial hyperplasia, providers should consider waiting until after cycle day 8 to perform insertion.

Background Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone disease in the first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. This study characterized clinical manifestations of PH3 across the decades of life in comparison with PH1 and PH2. Methods Clinical information was obtained from the Rare Kidney Stone Consortium PH Registry (PH1, n = 384; PH2, n = 51; PH3, n = 62). Results PH3 patients presented with symptoms at a median of 2.7 years old compared with PH1 (4.9 years) and PH2 (5.7 years) (P = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients, while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared with PH1 and PH2 (1.1 versus 1.6 and 1.5 mmol/day/1.73 m2, respectively, P Conclusions Patients with all forms of PH experience lifelong stone events, often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer-term follow-up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.

Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71–83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.

Thyroidectomy is one of the most common procedures performed in head and neck surgery. The quality of online resources for thyroidectomy is unknown. We aim to evaluate search trends and online resource quality regarding thyroidectomy.Cross-sectional analysis.Websites appearing on Google search.The first 30 Google websites for thyroidectomy were reviewed, excluding research, video, and restricted sites. Search patterns were obtained with Google Trends. Quality was measured by readability (Flesch Reading Ease and Flesch-Kinkaid Grade Level), understandability and actionability (Patient Education Materials Assessment Tool), and clinical practice guideline (CPG) compatibility. Fleiss kappa interrater reliability analysis was performed for 2 raters.Twenty-one sites were evaluated. Search popularity for thyroidectomy has increased since 2004. Median reading ease was 42.2 (range, 15.4-62.7) on a scale from 1 to 100, with 100 indicating maximum readability. Median reading grade level was 12 (range, 7-16). Thyroidectomy resources were poorly understandable (median, 66%; range, 21%-88%) and actionable (median, 10%; range, 0%-60%). Median CPG compatibility was 4 out of 5 (range, 0-5). Interrater reliability ranged from substantial to moderate for understandability (0.78), actionability (0.57), and CPG compatibility (0.58), withOnline resources about thyroidectomy vary in quality and reliability and are written at grade levels above the average reading level of the public. Providers should be aware of existing resources and work to create education resources that meet universal health literacy guidelines. The framework provided in this article may also serve as a guide and provide tangible steps that providers can take to help patients access care.

During the COVID-19 pandemic, research on "cytokine storms" has been reinvigorated in the field of infectious disease, but it also has particular relevance to cancer research. Interleukin-6 (IL-6) has emerged as a key component of the immune response to SARS-CoV-2, such that the repurposing of anti-IL-6 therapeutics for COVID-19 is now a major line of investigation, with several ongoing clinical trials. We lay a framework for understanding the role of IL-6 in the context of cancer research and COVID-19 and suggest how lessons learned from cancer research may impact SARS-CoV-2 research and vice versa.

The recent coronavirus disease 19 (COVID-19) crisis has resulted in an economic downturn and the implementation of policies such as social distancing and shelter-in-place.1 In light of these events, the US government has passed the Coronavirus Preparedness and Response Supplemental Appropriations Act. This act relaxed Health Insurance Portability and Accountability Act regulations and instituted new avenues of revenue for telehealth, including (1) real-time audio-video technology communication; (2) store-and-forward technology, which collects data to be later transmitted via virtual check-ins, email, or other digital applications; and (3) verbal/audio-only communication without images or prerecorded videos.2 Moreover, latest polls have found that around two-thirds of patients are willing to try telehealth because of the pandemic.3 These factors have allowed physicians to provide virtual care for patients who are receptive to such technology while adhering to newly instituted policies. The various treatment options for keratinocyte carcinomas (KCs)—surgery, radiation, lasers, curettage and electrodesiccation, photodynamic therapy, intralesional chemotherapy, and cryotherapy—require in-person office visits for implementation.4 Currently, effective treatment options for KCs that allow for entirely no in-person visits are unknown or limited. The combination of topical antitumor agents (imiquimod 5% cream [IMI], 5-fluorouracil 2% solution [5-FU], and tretinoin 0.1% cream [TRET]) with limited cryotherapy was found to be efficacious in the treatment of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).5 With the recent institution of social distancing, we evaluated the use of store-and-forward technology with this combination (IMI/5-FU/TRET) for the treatment of KCs that required no in-office patient visits.

Background Aortic stiffness is an important marker of cardiovascular risk and is elevated in children and adolescents with congenital heart disease (CHD) compared with healthy children; however, in children with CHD, little is known about the interaction between aortic stiffness and physical activity—a key determinant of aortic stiffness. Methods For this cross-sectional cohort study, we recruited children and adolescents aged 9-16 years with moderate-to-complex CHD from British Columbia Children's Hospital and travelling partnership clinics across the province of British Columbia and the Yukon territory. Mean daily minutes of moderate-to-vigorous physical activity were objectively assessed using an ActiGraph accelerometer worn over the right hip during waking hours for 7 days. Aortic pulse wave velocity (cm/s) was measured using standard 2-dimensional echocardiography and Doppler ultrasound. Results Participants (n = 104, 61% male; 85% consent rate) had a mean (standard deviation) age of 12.4 (2.4) years. Daily moderate-to-vigorous physical activity was 46.7 (20.0) minutes/d, with 25% meeting guidelines of ≥ 60 minutes of moderate-to-vigorous physical activity per day. Mean (standard deviation) aortic pulse wave velocity was 490.5 (161.9) cm/s, which was not significantly different between cardiac diagnoses. Higher levels of moderate-to-vigorous physical activity were associated with lower aortic pulse wave velocity (r = −0.226, P = 0.021). Conclusion In children and adolescents with CHD, higher levels of physical activity are associated with better vascular function. Given this association, promoting physical activity should be a high priority in the care of children and adolescents with CHD.

Background: Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-neurotensin (Pro-NT) was associated with metabolic diseases and predicted incident CVD and mortality. However, Pro-NT regulation in CKD and its potential role linking CKD and mortality have not been investigated, so far. Methods: In a central lab, circulating Pro-NT was quantified in three independent cohorts comprising 4715 participants (cohort 1: patients with CKD; cohort 2: general population study; and cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. In a 4th independent cohort, serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was further investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice. Results: Pro-NT significantly increased with deteriorating renal function (P < 0.001). In meta-analysis of cohorts 1–3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (P ≤ 0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-cause mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, P = 0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals. Conclusions: Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD.

Endoscopic ultrasound (EUS)-guided drainage procedures are an increasingly utilized minimally invasive alternative to percutaneous or surgical management strategies, having been shown to decrease recovery time, cost, and duration of hospital stay. The current mainstay of EUS-guided drainage procedures is in pancreatic and peripancreatic collections in pancreatitis. Recent technological advancements and the development of specialized stents have allowed for novel applications in a growing variety of clinical scenarios, including biliary obstruction, cholecystitis and gastrointestinal obstruction. An overview is provided of standard EUS-guided lumen-apposing metal stent (LAMS) management in pancreatic collections, including the expected radiologic findings and appropriate post-treatment sequelae. Relevant parameters to report include presence of a walled-off collection, collection contents, proximity of the target collection to the gastrointestinal lumen, intervening vascular structures or vascular malformations, and presence of regional cystic structures. Novel stent applications in biliary and gastrointestinal drainage are summarized and examples are provided, including choledochoduodenostomy in biliary obstruction, cholecystogastrostomy in cholecystitis, and jejunogastrostomy in focal gastrointestinal obstruction. Finally, a pictorial review of imaging findings of complications including perforation, hemorrhage, displacement, occlusion, migration and mistargeting is provided. Minimally invasive EUS-guided endoluminal stenting is utilized in a growing variety of clinical applications. Radiologist familiarity with common and novel applications of EUS-guided stenting is invaluable in determining suitability for endoscopic management, evaluating treatment response and identifying potential complications.

Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.

Introduction Few studies have examined the role of medication-related factors in psychiatric readmissions. Our objective was to characterize the medication regimen complexity index (MRCI) and assess its association with psychiatric hospital readmission frequency and time to readmission in a high-utilizer psychiatric cohort. Methods Adult patients admitted between July 2012 and March 2014 were identified if discharged from an inpatient psychiatry service with greater than or equal to 5 psychiatric readmissions or at least one 30-day readmission. Complexity of the medication regimen was determined using a validated MRCI electronic capture tool. Results One hundred sixty-eight patients were included. Average MRCI for all readmissions was 7.09 for psychotropic medications, 5.90 for other prescription medications, 2.98 for over the counter, and 16.00 for total medications. Ages greater than 65 years old and female sex were associated with higher total MRCI scores. Average MRCI for psychotropic medications and average psychotropic medication count, along with depression diagnosis, were found to be significantly associated with average time between each readmission but not with readmission frequency. An average total MRCI score greater than 19.7, when broken down by percentiles, was associated with a shorter time to readmission. Discussion Psychotropic regimen complexity, psychotropic medication count, total MRCI greater than 19.7, and a diagnosis of depression may contribute to a shorter time to readmission in adult psychiatric patients with a history of frequent readmissions. Future studies are needed to confirm findings and evaluate clinical significance and impact.

Background: Three-dimensional (3D) printing is a new technology capable of producing patient-specific 3D cardiac models. Methods: A cross-sectional survey of pediatric cardiologists was conducted. Members of the Canadian Pediatric Cardiology Association and Congenital Cardiac Interventional Study Consortium were invited to participate. A questionnaire was distributed using Research Electronic Data Capture between May and September 2019. Results were analyzed using descriptive statistics, Fisher exact test, and odds ratio. Results: A total of 71 pediatric cardiologists responded. Some 85% (60/71) agreed that patient-specific 3D printed cardiac models are a beneficial tool in treating children with congenital heart disease (CHD); 80% of those (48/60) believe 3D models facilitate communication with colleagues; 49% (35/71) of respondents had access to 3D printing technology; and 77% (27/35) of those were using models for clinical care. Access differed according to geographic location (P = 0.004). Of respondents, Americans were 5.5 times more likely (confidence interval, 1.6-19.2) than Canadians to have access to 3D printing technology. The primary reason for lack of access was financial barriers (50%, 18/36). In clinical practice, surgical planning is the primary use of models (96%, 26/27), followed by interventional catheterization planning (52%, 14/27). Double outlet right ventricle was the most commonly modelled lesion (70%, 19/27). Conclusion: 3D printing is a new technology that is beneficial in the care of children with CHD. Access to 3D printing varies by geographic location. In pediatric cardiology, 3D models are primarily used for procedural planning for CHD lesions with complex 3D spatial relationships. Résumé: Contexte: L’impression en trois dimensions (3D) est une nouvelle technologie permettant de produire des modèles cardiaques 3D sur mesure pour chaque patient. Méthodologie: Une enquête transversale a été menée auprès de cardiologues-pédiatres. Les membres de l’Association canadienne de cardiologie pédiatrique et du Congenital Cardiac Interventional Study Consortium ont été invités à y participer. À cette fin, un questionnaire a été diffusé au moyen de l’outil REDCap (Research Electronic Data Capture) de mai à septembre 2019. Les résultats ont été analysés au moyen de techniques de statistique descriptive, du test exact de Fisher et du rapport de cotes. Résultats: Au total, 71 cardiologues-pédiatres ont répondu au questionnaire. Environ 85 % (60/71) des répondants convenaient que les modèles cardiaques personnalisés à chaque patient et produits par impression 3D sont utiles pour traiter les enfants atteints d’une cardiopathie congénitale; de ce nombre, 80 % (48/60) estimaient que les modèles 3D facilitent la communication entre collègues; 49 % (35/71) avaient accès à la technologie d’impression 3D et, parmi eux, 77 % (27/35) se servaient de modèles pour prodiguer des soins cliniques. L’accès variait selon l’emplacement géographique (p = 0,004). Parmi les répondants, les médecins situés aux États-Unis étaient 5,5 fois plus susceptibles (intervalle de confiance : 1,6-19,2) que les médecins canadiens d’avoir accès à la technologie d’impression 3D. Les ressources financières constituaient le principal obstacle à l’accès à cette technologie (50 %, 18/36). Dans la pratique clinique, les modèles sont surtout utilisés pour planifier les interventions chirurgicales (96 %, 26/27) et le cathétérisme interventionnel (52 %, 14/27). Le ventricule droit à double issue était particulièrement modélisé (70 %, 19/27). Conclusion: L’impression 3D est une nouvelle technologie utile pour soigner les enfants présentant une cardiopathie congénitale. L’accès à cette technologie varie selon l’emplacement géographique. En cardiologie-pédiatrie, les modèles 3D sont surtout utilisés pour planifier les interventions relatives à des cardiopathies congénitales complexes sur le plan tridimensionnel.

Children with congenital heart disease (CHD) are at-risk for both COVID-19 and secondary cardiovascular outcomes. Their increased cardiovascular risk may be mitigated through physical activity, but public health measures implemented for COVID-19 can make physical activity challenging. We objectively measured the impact of the COVID-19 pandemic on physical activity, continuously measured by FitbitTM step-counts, in children with CHD. Step-counts were markedly lower in late March and early April 2020, compared to 2019 and to early March 2020. It is vital to understand how precautions for COVID-19 will impact the health of children with CHD, especially if they persist long-term., Brief Summary Children with congenital heart disease (CHD) are a vulnerable population at-risk for severe infection with COVID-19; they also have increased cardiovascular risk. Physical activity is important for their health. We have observed a significant decline in physical activity in late March and early April, compared to 2019 and to earlier in 2020, associated with COVID-19 public health measures.

BACKGROUND: The Mayo Clinic imaging classification of autosomal dominant polycystic kidney disease (ADPKD) uses height-adjusted total kidney volume (htTKV) and age to identify patients at highest risk for disease progression. However, this classification applies only to patients with typical diffuse cystic disease (class 1). Because htTKV poorly predicts eGFR decline for the 5%–10% of patients with atypical morphology (class 2), imaging-based risk modeling remains unresolved. METHODS: Of 558 adults with ADPKD in the HALT-A study, we identified 25 patients of class 2A with prominent exophytic cysts (class 2Ae) and 43 patients of class 1 with prominent exophytic cysts; we recalculated their htTKVs to exclude exophytic cysts. Using original and recalculated htTKVs in association with imaging classification in logistic and mixed linear models, we compared predictions for developing CKD stage 3 and for eGFR trajectory. RESULTS: Using recalculated htTKVs increased specificity for developing CKD stage 3 in all participants from 82.6% to 84.2% after adjustment for baseline age, eGFR, BMI, sex, and race. The predicted proportion of class 2Ae patients developing CKD stage 3 using a cutoff of 0.5 for predicting case status was better calibrated to the observed value of 13.0% with recalculated htTKVs (45.5%) versus original htTKVs (63.6%). Using recalculated htTKVs reduced the mean paired difference between predicted and observed eGFR from 17.6 (using original htTKVs) to 4.0 ml/min per 1.73 m(2) for class 2Ae, and from −1.7 (using original htTKVs) to 0.1 ml/min per 1.73 m(2) for class 1. CONCLUSIONS: Use of a recalculated htTKV measure that excludes prominent exophytic cysts facilitates inclusion of class 2 patients and reclassification of class 1 patients in the Mayo classification model.

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.

Background A number of clinical trials have been conducted, assessing the role of long-term (>1 year) Suppressive Antibiotic Treatment (SAT) combined with debridement, antibiotics and implant retention (DAIR) for the management of periprosthetic joint infection (PJI). However, no systematic review of the literature has been published to date to evaluate complications associated with long term antibiotic treatment and overall survivorship free from reoperation and revision for infection after DAIR for total hip and total knee PJI. Methods The US National Library of Medicine (PubMed/MEDLINE), EMBASE, and the Cochrane Database of Systematic Reviews were queried for publications from January 1980 to December 2018 utilizing keywords pertinent to total knee arthroplasty, total hip arthroplasty, periprosthetic joint infection and antibiotic suppression. Results Overall, 7 articles of low quality (level III or IV) were included in this analysis. The studies included in this systematic review included 437 cases of PJI treated surgically with DAIR and then with SAT. The overall mean infection-free rate of SAT following DAIR was 75% (318/424 patients), while the all-cause reoperation rate was 6.7%. Overall the mean rate of adverse effects associated with long term antibiotic use was 15.4% and the mean rate of adverse effects leading to discontinuation of SAT was 4.3%. There was no study to show significant differences between acute (either postoperative or haematogenous, with onset of symptoms ≤4 weeks) and chronic (onset of symptoms >4 weeks) infections and failure rates of DAIR with SAT. The literature is inconclusive on the influence of anatomic location (hip versus knee) as well as microorganism on the success rate of DAIR with SAT. Conclusions The results of this systematic review demonstrate that there is still only low-quality evidence regarding the therapeutic effect of DAIR combined with SAT, which is not enough to draw definitive conclusions. Further high-quality prospective studies are needed to better understand SAT’s efficacy and safety in a controlled fashion. Although discontinuation of antibiotic treatment due to side effects was found to be low, the high rates of adverse effects noted after DAIR with SAT demonstrate the underlying frailty and complexity of many patients with PJI, and the imperfect therapies available. While S. aureus appears to be a risk factor for increased risk of SAT failure, there is not enough data to establish which patients would benefit most from DAIR with postoperative SAT.

OBJECTIVE. Underrepresentation of women in the top hierarchy of academic medicine exists despite women comprising more than half of the medical school graduates and residency positions. The purpose of this study is to analyze and quantify the relationship of gender, research productivity, and career advancement in Canadian academic radiology departments. MATERIALS AND METHODS. Seventeen academic radiology departments with affiliated residency programs in Canada were searched for publicly available data on faculty to generate a database for gender and academic profiles of the radiologists. Bibliometric data were collected using Scopus archives. The associations of gender, academic ranks, and leadership positions were assessed, and a p value of ≤ 0.05 was defined as significant. Significant variables were analyzed using a multivariate linear regression model. RESULTS. Of 1266 faculty members, gender information and academic rank were available for 932 faculty members: 597 (64.05%) were men and 335 (35.95%) were women (χ2 = 21.82; p < 0.0001). Of a total of 563 assistant professors, 331 (58.79%) were men and 232 (41.21%) were women; of 258 associate professors, 177 (68.60%) were men and 81 (31.40%) were women; and of 111 professors, 89 (80.18%) were men and 22 (19.82%) were women. The gender gap widens at higher academic ranks, displaying a threefold drop in the ratio of women holding the rank of full professor (6.57%) compared with 14.91% male professors; 29.55% of women radiologists have first-in-command leadership positions compared with 70.45% of men. A comparable or higher h-index is noted for women Canadian radiologists after adjusting for number of citations, number of publications, and years of active research. CONCLUSION. Canadian academic radiology departments have fewer women radiologists in senior faculty and leadership positions. Our study results show that Canadian female radiologists at the professor level have more publications than their male counterparts.

Introduction: Preformed metal crowns (PMC) placed using the Hall Technique (HT) are effective for managing carious lesions in primary molars and might be tolerable and successful for children with learning disabilities (CLD), possibly avoiding the need for sedation/ anaesthesia.Aim To investigate the effectiveness of the HT for management of carious lesions in children with learning disabilities through a prospective service evaluation. Methods: Sixteen, 4-12-year-old CLD had 27 carious lesions managed using the HT and were followed-up. Outcomes were: 1) incidence of dental pain/infection; 2) success of treatment outcomes as judged by patients and parents/carers; and 3) adverse outcomes. Results: Twenty seven teeth treated with HT were followed up for five to 87 months (mean = 24) with no episodes of pain and/or infection in treated teeth. Treatment was rated as causing no discomfort in 80% of children and as successful by 98% of children; 96% of parents/carers, and 100% of dentists. Other adverse outcomes; occlusal surface perforation (n = 8; 30%). Conclusion: The HT was acceptable to, and effective in treating carious lesions in CLD who were unable to accept traditional restorative treatment. This alternative treatment option may avoid the need for general anaesthesia.

Purpose We present a case report of treatment using interstitial and surface high-dose-rate (HDR) brachytherapy for cutaneous squamous cell carcinoma (SCC) involving the interspace of the third and fourth digits. The patient refused two-ray amputation and the lesion was not amenable for external beam radiation therapy (EBRT). This is the first report detailing combined interstitial and surface HDR brachytherapy for a hand SCC. Material and methods The patient received 4050 cGy in 9 fractions, twice daily using 6 interstitial catheters and 8 Freiburg flap catheters. The clinical target was defined by MRI and ultrasound as a dorsal mass to the interspace between the heads of the third and fourth metacarpals measuring approximately 7 mm transverse × 5 mm volar-dorsal × 16 mm proximal-distal. Results The treatment resulted in radiographic and clinical tumor control. The patient retained functional use of her hand. However, there were both acute and late treatment-related side effects. Acutely, inpatient admission for pain control with a nerve block was needed. Long-term toxicity was notable for grade 2 skin necrosis treated with hyperbaric oxygen. Conclusions The first interstitial and surface HDR brachytherapy for cutaneous squamous cell carcinoma of a finger interspace for hand function preservation is presented. The initial experience revealed that brachytherapy was tolerated but with notable acute and late side effects. Treatment did result in tumor shrinkage with organ preservation and function of two rays. A larger cohort of patients will be required for additional conclusions related to long-term clinical benefits in patients who refuse ray amputation.

Background/objective Blood pressure abnormalities may play an important role in macrovascular damage in type 1 diabetes. Little is known about blood pressure abnormalities and macrovascular damage in children with type 1 diabetes. Methods Children with type 1 diabetes (n = 57) for a short (3 months-2 years; n = 24) or long duration (≥5 years; n = 33) and a group of control children without diabetes (n = 29) completed 24-h ambulatory blood pressure monitoring (ABPM). Carotid intima media thickness (cIMT), a subclinical indicator of atherosclerosis, was assessed by carotid ultrasound. Results ABPM abnormalities were more prevalent (57% vs 24%, respectively), and daytime, nighttime and 24-h systolic, diastolic, and mean arterial blood pressure indices were higher in children with type 1 diabetes compared to control children. The odds estimate of an ABPM abnormality was 6.68 (95% confidence interval: 1.95, 22.9; P = .003) in children with type 1 diabetes compared to controls after adjusting for age, sex, and BMI standardized for age and sex (zBMI). An interaction between ABPM and zBMI on cIMT was observed. In children with type 1 diabetes and ABPM abnormalities, every 1 SD increase in zBMI was associated with a 0.030 mm increase in cIMT (95% confidence interval: 0.002, 0.041; P = .031). This was not observed in control children with ABPM abnormalities or in children with normal ABPM, regardless of type 1 diabetes status. Conclusions Children with type 1 diabetes have a high prevalence of ABPM abnormalities independent of disease duration and this is related to early indicators of cardiovascular damage.

Objectives This study sought to describe the initial findings from the International Pediatric Optical Coherence Tomography (OCT) registry in pediatric heart transplant recipients. Background Cardiac allograft vasculopathy (CAV) is a common cause of late graft failure and mortality in pediatric heart transplant recipients. Early diagnosis may improve outcomes. OCT is a high-resolution intravascular imaging technique that has the potential to identify CAV earlier than angiography. Methods OCT and angiography of the coronary arteries were performed in pediatric heart transplant recipients at participating centers. Demographics, clinical data, medications, episodes of rejection, and angiographically confirmed CAV were collected for each case. OCT and angiography images were analyzed in a central core imaging laboratory. Intimal thickness and intima/media cross sectional area (I/M CSA) ratios were calculated for each case. Intimal thickness ≥0.25 mm was defined as abnormal and ≥0.4 mm as severe intima thickening. I/M CSA ratio of ≥1 was defined as abnormal. OCT findings were compared to angiographic findings for each case. Results Across 3 centers, 110 cases were analyzed from 76 patients. Intimal thickening was present in 26 of 110 cases. Eleven of these cases had severe intima thickening (≥0.4 mm) and notably, angiography results were normal in 8 cases. All 5 cases with a median I/M CSA ratio of ≥2 had normal angiography. The maximal intima thickness was ≥0.25 mm in 24% and ≥0.4 mm in 10% of cases. Median I/M CSA ratio was ≥1 for 80% of cases. I/M CSA ratio was significantly higher in cases with concurrent CAV (p = 0.03). Maximal intima thickness was significantly greater in cases with current or previous rejection (p = 0.01). I/M CSA ratio was significantly lower in patients treated with statins (p = 0.01). OCT findings alone prompted a change to medical management in 17% of cases. Conclusions OCT provides important insights into coronary vascular changes not detected by angiography in pediatric transplant recipients. The use of OCT for pediatric heart transplant recipients should be further investigated, given its potential to impact the management of CAV.

Background Patients with single‐ventricle physiology who undergo the Fontan procedure are at risk for thrombotic events associated with significant morbidity and mortality. The UNIVERSE Study evaluated the efficacy and safety of a novel liquid rivaroxaban formulation, using a body weight–adjusted dosing regimen, versus acetylsalicylic acid (ASA) in children post‐Fontan. Methods and Results The UNIVERSE Study was a randomized, multicenter, 2‐part, open‐label study of rivaroxaban, in children who had undergone a Fontan procedure, to evaluate its dosing regimen, safety, and efficacy. Part A was the single‐arm part of the study that determined the pharmacokinetics/pharmacodynamics and safety of rivaroxaban in 12 participants before proceeding to part B, whereby 100 participants were randomized 2:1 to open‐label rivaroxaban versus ASA. The study period was 12 months. A total of 112 participants were enrolled across 35 sites in 10 countries. In part B, for safety outcomes, major bleeding occurred in one participant on rivaroxaban (epistaxis that required transfusion). Clinically relevant nonmajor bleeding occurred in 6% of participants on rivaroxaban versus 9% on ASA. Trivial bleeding occurred in 33% of participants on rivaroxaban versus 35% on ASA. For efficacy outcomes, 1 participant on rivaroxaban in part B had a pulmonary embolism (2% overall event rate); and for ASA, 1 participant had ischemic stroke and 2 had venous thrombosis (9% overall event rate). Conclusions In this study, participants who received rivaroxaban for thromboprophylaxis had a similar safety profile and fewer thrombotic events, albeit not statistically significant, compared with those in the ASA group. Registration URL: https://www.clinicaltrials.gov . Identifier: NCT02846532.

Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of cysts and a decline of renal function. The clinical feasibility of the number of potential disease-modifying drugs is limited by systemic adverse effects. We hypothesize that megalin, a multiligand endocytic receptor expressed in the proximal tubule, may be used to facilitate drug uptake into cysts, thereby allowing for greater efficacy and fewer side effects. Methods The cyst expression of various tubular markers, including megalin and aquaporin 2 (AQP2), was analysed by immunohistochemistry (IHC) of kidney sections from the ADPKD mouse model (PKD1RC/RC) at different post-natal ages. The endocytic function of megalin in cysts was examined by IHC of kidney tissue from mice injected with the megalin ligand aprotinin. Results Cyst lining epithelial cells expressing megalin were observed at all ages; however, the proportion decreased with age. Concomitantly, an increasing proportion of cysts revealed expression of AQP2, partial expression of megalin and/or AQP2 or no expression of the examined markers. Endocytic uptake of aprotinin was evident in megalin-positive cysts, but only in those that remained connected to the renal tubular system. Conclusions Megalin-expressing cysts were observed at all ages, but the proportion decreased with age, possibly due to a switch in tubular origin, a merging of cysts of different tubular origin and/or a change in the expression pattern of cyst lining cells. Megalin expressed in cysts was functional, suggesting that megalin-mediated endocytosis is a potential mechanism for drug targeting in ADPKD if initiated early in the disease.