Pinching dynamics, extensional rheology, and stringiness of saliva substitutes.

Saliva substitutes are human-made formulations extensively used in medicine, food, and pharmaceutical research to emulate human saliva's biochemical, tribological, and rheological properties. Even though extensional flows involving saliva are commonly encountered in situations such as swallowing, coughing, sneezing, licking, drooling, gleeking, and blowing spit bubbles, rheological evaluations of saliva and its substitutes in most studies rely on measured values of shear viscosity. Natural saliva possesses stringiness or spinnbarkeit, governed by extensional rheology response, which cannot be evaluated or anticipated from the knowledge of shear rheology response. In this contribution, we comprehensively examine the rheology of twelve commercially available saliva substitutes using torsional rheometry for rate-dependent shear viscosity and dripping-onto-substrate (DoS) protocols for extensional rheology characterization. Even though most formulations are marketed as having suitable rheology, only three displayed measurable viscoelasticity and strain-hardening. Still, these too, failed to emulate the viscosity reduction with the shear rate observed for saliva or match perceived stringiness. Finally, we explore the challenges in creating saliva-like formulations for dysphagia patients and opportunities for using DoS rheometry for diagnostics and designing biomimetic fluids.

Ultrathin Micellar Foam Films of Sodium Caseinate Protein Solutions.

Sodium caseinates (NaCas), derived from milk proteins called caseins, are often added to food formulations as emulsifiers, foaming agents, and ingredients for producing dairy products. In this contribution, we contrast the drainage behavior of single foam films made with micellar NaCas solutions with well-established features of stratification observed for the micellar sodium dodecyl sulfate (SDS) foam films. In reflected light microscopy, the stratified SDS foam films display regions with distinct gray colors due to differences in interference intensity from coexisting thick-thin regions. Using IDIOM (interferometry digital imaging optical microscopy) protocols we pioneered for mapping nanotopography of foam films, we showed that drainage via stratification in SDS films proceeds by the expansion of flat domains that are thinner than surrounding by a concentration-dependent step-size, and nonflat features (nanoridges and mesas) form at the moving front. Furthermore, stratifying SDS foam films show stepwise thinning, such that the step-size and terminal film thickness decrease with concentration. Here we visualize the nanotopography in protein films with high spatiotemporal resolution using IDIOM protocols to address two long-standing questions. Do protein foam films formulated with NaCas undergo drainage via stratification? Are thickness transitions and variations in protein foam films determined by intermicellar interactions and supramolecular oscillatory disjoining pressure? In contrast with foam films containing micellar SDS, we find that micellar NaCas foam films display just one step, nonflat and noncircular domains that expand without forming nanoridges and a terminal thickness that increases with NaCas concentration. We infer that the differences in adsorbing and self-assembling unimers triumph over any similarities in the structure and interactions of their micelles.

Rheology and dispensing of real and vegan mayo: the chickpea or egg problem.

The rheology, stability, texture, and taste of mayonnaise, a dense oil-in-water (O/W) emulsion, are determined by interfacially active egg lipids and proteins. Often mayonnaise is presented as a challenging example of an egg-based food material that is hard to emulate using plant-based or vegan ingredients. In this contribution, we characterize the flow behavior of animal-based and plant-based mayo emulsions, seeking to decipher the signatures that make the real mayonnaise into such an appetizing complex fluid. We find that commercially available vegan mayos can emulate the apparent yield stress and shear thinning of yolk-based mayonnaise by the combined influence of plant-based proteins (like those extracted from chickpeas) and polysaccharide thickeners. However, we show that the dispensing and dipping behavior of egg-based and vegan mayos display striking differences in neck shape, sharpness, and length. The ratio of apparent extensional to shear yield stress value is found to be larger than the theoretically predicted square root of three for all mayo emulsions. The analysis of neck radius evolution of these extension thinning yield stress fluids reveals that even when the power law exponent governing the intermediate pinching dynamics is similar to the exponent obtained from the shear flow curve, the terminal pinching dynamics show strong local effects, possibly influenced by interstitial fluid properties, finite drop size and deformations, and capillarity.

Vascular access for lipid apheresis: a challenge in young children with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (hoFH) is a rare genetic disorder leading to extremely increased LDL-cholesterol (LDL-C), resulting in high cardiovascular risk in early childhood. Lipid apheresis (LA) is an effective treatment and should be started as early as possible to prevent premature cardiovascular events. As peripheral punctures in children can be challenging due to small vessels and anxiety, this study aimed to evaluate feasibility and safety of central venous catheters (CVCs) as vascular access for LA in young children with hoFH. METHODS: Retrospective analysis (2016-2019) on four children with hoFH aged 3-5 years, performing weekly or biweekly LA with a CVC. RESULTS: LDL-C decreased by> 60%. In three children, the use of a permanent CVC for 698, 595, and 411 days, respectively, avoided difficult peripheral access, without the occurrence of occlusion or thrombosis. Unfortunately, one child had recurrent CVC-related infections and needed an arteriovenous fistula from the age of 5. Although the mean dwell time per catheter was 212 days, there were, as expected, severe side effects of early catheter infections with sepsis and accidental self-removal. Starting LA at an early age improved or stabilized carotid intima-media thickness (IMT) in three children. However, IMT did increase in one child caused by intolerance to peripheral punctures and LA interruption. CONCLUSIONS: Permanent CVCs are a viable temporary access choice for LA in young children with hoFH until peripheral venipuncture is practicable. The risk of CVC-related infections needs to be taken into account.

Genome Resources for Seven Fungal Isolates That Cause Dollar Spot Disease in Turfgrass, Including Clarireedia jacksonii and C. monteithiana.

Fungi in the genus Clarireedia are widespread and destructive pathogens of grasses worldwide, and are best known as the causal agents of dollar spot disease in turfgrass. Here, we report genome assemblies of seven Clarireedia isolates, including ex-types of the two most widespread species, Clarireedia jacksonii and C. monteithiana. These datasets provide a valuable resource for ongoing studies of the dollar spot pathogens that include population diversity, host-pathogen interactions, marker development, and disease control.

Effects of Alanyl-Glutamine Treatment on the Peritoneal Dialysis Effluent Proteome Reveal Pathomechanism-Associated Molecular Signatures.

Peritoneal dialysis (PD) is a modality of renal replacement therapy in which the high volumes of available PD effluent (PDE) represents a rich source of biomarkers for monitoring disease and therapy. Although this information could help guide the management of PD patients, little is known about the potential of PDE to define pathomechanism-associated molecular signatures in PD.We therefore subjected PDE to a high-performance multiplex proteomic analysis after depletion of highly-abundant plasma proteins and enrichment of low-abundance proteins. A combination of label-free and isobaric labeling strategies was applied to PDE samples from PD patients (n = 20) treated in an open-label, randomized, two-period, cross-over clinical trial with standard PD fluid or with a novel PD fluid supplemented with alanyl-glutamine (AlaGln).With this workflow we identified 2506 unique proteins in the PDE proteome, greatly increasing coverage beyond the 171 previously-reported proteins. The proteins identified range from high abundance plasma proteins to low abundance cellular proteins, and are linked to larger numbers of biological processes and pathways, some of which are novel for PDE. Interestingly, proteins linked to membrane remodeling and fibrosis are overrepresented in PDE compared with plasma, whereas the proteins underrepresented in PDE suggest decreases in host defense, immune-competence and response to stress. Treatment with AlaGln-supplemented PD fluid is associated with reduced activity of membrane injury-associated mechanisms and with restoration of biological processes involved in stress responses and host defense.Our study represents the first application of the PDE proteome in a randomized controlled prospective clinical trial of PD. This novel proteomic workflow allowed detection of low abundance biomarkers to define pathomechanism-associated molecular signatures in PD and their alterations by a novel therapeutic intervention.

Association between timing of dialysis initiation and clinical outcomes in the paediatric population: an ESPN/ERA-EDTA registry study.

BACKGROUND: There is no consensus regarding the timing of dialysis therapy initiation for end-stage kidney disease (ESKD) in children. As studies investigating the association between timing of dialysis initiation and clinical outcomes are lacking, we aimed to study this relationship in a cohort of European children who started maintenance dialysis treatment. METHODS: We used data on 2963 children from 21 different countries included in the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry who started renal replacement therapy before 18 years of age between 2000 and 2014. We compared two groups according to the estimated glomerular filtration rate (eGFR) at start: eGFR ≥8 mL/min/1.73 m2 (early starters) and eGFR <8 mL/min/1.73 m2 (late starters). The primary outcomes were patient survival and access to transplantation. Secondary outcomes were growth and cardiovascular risk factors. Sensitivity analyses were performed to account for selection- and lead time-bias. RESULTS: The median eGFR at the start of dialysis was 6.1 for late versus 10.5 mL/min/1.73 m2 for early starters. Early starters were older [median: 11.0, interquartile range (IQR): 5.7-14.5 versus 9.4, IQR: 2.6-14.1 years]. There were no differences observed between the two groups in mortality and access to transplantation at 1, 2 and 5 years of follow-up. One-year evolution of height standard deviation scores was similar among the groups, whereas hypertension was more prevalent among late initiators. Sensitivity analyses resulted in similar findings. CONCLUSIONS: We found no evidence for a clinically relevant benefit of early start of dialysis in children with ESKD. Presence of cardiovascular risk factors, such as high blood pressure, should be taken into account when deciding to initiate or postpone dialysis in children with ESKD, as this affects the survival.

Hemodialysis vascular access and subsequent transplantation: a report from the ESPN/ERA-EDTA Registry.

BACKGROUND: Current guidelines advocate use of arteriovenous fistula (AVF) over central venous catheter (CVC) for children starting hemodialysis (HD). European data on current practice, determinants of access choice and switches, patient survival, and access to transplantation are limited. METHODS: We included incident patients from 18 European countries who started HD from 2000 to 2013 for whom vascular access type was reported to the ESPN/ERA-EDTA Registry. Data were evaluated using descriptive statistics, logistic and Cox regression models, and cumulative incidence competing risk analysis. RESULTS: Three hundred ninety-three (55.1%) of 713 children started HD with a CVC and were more often females, younger, had more often an unknown diagnosis, glomerulonephritis, or vasculitis, and lower hemoglobin and height-SDS at HD initiation. AVF patients were 91% less likely to switch to a second access, and two-year patient survival was 99.6% (CVC, 97.2%). Children who started with an AVF were less likely to receive a living donor transplant (adjusted HR, 0.30; 95% CI, 0.16-0.54) and more likely to receive a deceased donor transplant (adjusted HR, 1.50; 95% CI, 1.17-1.93), even after excluding patients who died or were transplanted in the first 6 months. CONCLUSIONS: CVC remains the most frequent type of vascular access in European children commencing HD. Our results suggest that the choice for CVC is influenced by the time of referral, rapid onset of end-stage renal disease, young age, and an expected short time to transplantation. The role of vascular access type on the pattern between living and deceased donation in subsequent transplantation requires further study.

Data Sharing: A New Editorial Initiative of the International Committee of Medical Journal Editors. Implications for the Editors' Network.

The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship- emphasizing the importance of responsibility and accountability-, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors' Network of the European Society of Cardiology.

Anterior ischemic optic neuropathy in pediatric peritoneal dialysis: risk factors and therapy.

BACKGROUND: Sudden blindness caused by anterior ischemic optic neuropathy (AION) is a rare complication for patients undergoing peritoneal dialysis (PD). Prognosis is generally poor, with AION commonly resulting in permanent visual loss. METHODS: We first describe four case reports of children with AION during PD treatment. We then review ten additional AION cases reported in the literature and compare these 14 affected patients with a control cohort of 59 non-affected patients in the Vienna PD registry. RESULTS: Significant risk factors for AION were identified as median age (4 vs. 27 months; p < 0.001), autosomal recessive polycystic kidney disease (28.6 vs. 3.4%; p = 0.01), anephric status (53.8 vs. 6.8%; p < 0.001) and low to normal blood pressure evidenced by the number of patients having to be treated with antihypertensive medications (14.3 vs. 62.7%; p = 0.01). Severe hypovolemia was reported in 50% of all cases. Outcome was visual loss with optic atrophy in nine patients; five patients had a good visual outcome. The major difference in treatment was a rapid bolus of saline within 12 h after the initial symptoms. CONCLUSIONS: Young age, autosomal recessive polycystic kidney disease, anephric status and hypotension are substantial risk factors for AION. Early hospitalization with vascular refilling within a few hours following onset of blindness leads to improved visual outcome.

Parents' understanding of medication at discharge and potential harm in children with medical complexity.

OBJECTIVE: Children with medical complexity (CMC) are among the most vulnerable patient groups. This study aimed to evaluate their prevalence and risk factors for medication misunderstanding and potential harm (PH) at discharge. DESIGN AND SETTING: Cross-sectional study at a tertiary care centre. STUDY POPULATION: CMC admitted at Medical University of Vienna between May 2018 and January 2019. INTERVENTION: CMC and caregivers underwent a structured interview at discharge; medication understanding and PH for adverse events were assessed by a hybrid approach. MAIN OUTCOME MEASURES: Medication misunderstanding rate; PH. RESULTS: For 106 included children (median age 9.6 years), a median number of 5.0 (IQR 3.0-8.0) different medications were prescribed. 83 CMC (78.3%) demonstrated at least one misunderstanding, in 33 CMC (31.1%), potential harm was detected, 5 of them severe. Misunderstandings were associated with more medications (r=0.24, p=0.013), new prescriptions (r=0.23, p=0.019), quality of medication-related communication (r=-0.21, p=0.032), low level of education (p=0.013), low language skills (p=0.002) and migratory background (p=0.001). Relative risk of PH was 2.27 times increased (95% CI 1.23 to 4.22) with new medications, 2.14 times increased (95% CI 1.10 to 4.17) with migratory background. CONCLUSION: Despite continuous care at a tertiary care centre and high level of subjective satisfaction, high prevalence of medication misunderstanding with relevant risk for PH was discovered in CMC and their caregivers. This demonstrates the need of interventions to improve patient safety, with stratification of medication-related communication for high-risk groups and a restructured discharge process focusing on detection of misunderstandings ('unknown unknowns').

Life outcomes after paediatric kidney transplantation: a qualitative, biographical study in long-term survivors.

OBJECTIVE: The objective of this study was to analyse the narrative life stories of children with end-stage kidney disease (ESKD) and their families to determine how health professionals can effectively support these children to achieve better life outcomes. DESIGN: Qualitative narrative biographic study. SETTING: We invited every long-term survivor of paediatric kidney transplants and their families at the Medical University of Vienna between 2008 and 2013 to participate in this study. PARTICIPANTS: Nineteen patients (women: n=8, 42%) and 34 family members (women: n=22, 65%) were interviewed. The patients had a mean age of 7.6 (SD±5.6) years at the time of transplantation and 22.2 (SD±5.4) at the time of interview. MAIN OUTCOMES MEASURES: A qualitative narrative biographical analysis was combined with computational structured topic models using the Latent Dirichlet Allocation. RESULTS: The overarching finding was the desire for normality in daily life in long-term survivors and their families but with different perceptions of what normality looks like and predominance of this aspect evolving. Different strategies were used by patients (focused on their advancement) and caregivers (normality for all family members). Siblings played a major role in supporting survivors' social inclusion. CONCLUSIONS: The strong desire for normality confirms recent findings of the Standardised Outcomes in Nephrology Group initiative, which proposes survival and life participation as core outcomes in children with chronic kidney disease. Our study should be a starting point for an international effort to identify typologies and stratified interventions for children with ESKD and their families, particularly siblings.

SARS-CoV-2 trends in Italy, Germany and Portugal and school opening during the period of Omicron variant dominance: A quasi experimental study in the EuCARE project.

OBJECTIVES: We investigated the impact of school reopening on SARS-CoV-2 transmission in Italy, Germany, and Portugal in autumn 2022 when the Omicron variant was prevalent. METHODS: A prospective international study was conducted using the case reproduction number (Rc) calculated with the time parametrization of Omicron. For Germany and Italy, staggered difference-in-differences analysis was employed to explore the causal relationship between school reopening and Rc changes, accounting for varying reopening dates. In Portugal, interrupted time series analysis was used due to simultaneous school reopenings. Multivariable models were adopted to adjust for confounders. RESULTS: In Italy and Germany, post-reopening Rc estimates were significantly lower compared to those from regions/states that had not yet reopened at the same time points, both in the student population (overall average treatment effect for the treated subpopulation [O-ATT]: -0.80 [95% CI: -0.94;-0.66] for Italy; O-ATT-0.30 [95% CI: -0.36;-0.23] for Germany) and the adult population (O-ATT: -0.04 [95% CI: -0.07;-0.01] for Italy; O-ATT: -0.07 [95% CI: -0.11;-0.03] for Germany). In Portugal, there was a significant decreasing trend in Rc following school reopenings compared to the pre-reopening period (sustained effect: -0.03 [95% CI: -0.04; -0.03] in students; -0.02 [95% CI: -0.03; -0.02] in adults). CONCLUSIONS: We found no evidence of a causal relationship between school reopenings in autumn 2022 and Omicron SARS-CoV-2 transmission.

Cyclodextrin-crosslinked poly(acrylic acid): adhesion and controlled release of diflunisal and fluconazole from solid dosage forms.

The controlled release of diflunisal and fluconazole from tablets made of novel polymers, poly(acrylic acid) (PAA) crosslinked with either ß-cyclodextrin (ßCD) or hydroxypropyl-ßCD (HPßCD), was investigated and Carbopol 934P (Carbopol) was used as a highly crosslinked PAA for comparison. Diflunisal strongly associates with ßCD-PAA and HPßCD-PAA polymers (Ka of 486 and 6,055 M(-1) respectively); thus, it was physically mixed into the conjugates and also precomplexed to identify whether decomplexation has any influence on release kinetics. Fluconazole has poor complexing ability (Ka of 34 M(-1) with HPßCD-PAA); thus, it was only tested as a physical mixture. Swelling and adhesion studies were conducted on all tablet combinations and adhesivity of the CD-PAA polymer tablets was maintained. Diflunisal release was much slower from HPßCD-PAA tablets than from ßCD-PAA, suggesting that a higher degree of complexation retards release. The precomplexed diflunisal release was also slower than the physically mixed diflunisal of the corresponding conjugate. The release closely followed zero-order kinetics for HPßCD-PAA, but was more sigmoidal for ßCD-PAA and especially Carbopol. Conversely, poorly associating fluconazole released in almost exactly the same way across both polymers and Carbopol, indicating that the release kinetics of poorly associating drugs are not influenced by the presence of cyclodextrins. In view of the varying profiles and release rates shown with diflunisal for the different polymers, the fluconazole data support the concept that adequate complexation can indeed modulate the release kinetics of drugs.

Flow-induced alignment of protein nanofibril dispersions.

HYPOTHESIS: Protein nanofibrils (PNF) resulting from the self-assembly of proteins or peptides can present structural ordering triggered by numerous factors, including the shear flow. We hypothesize that i) depending on the contour length of the PNF and the magnitude of the shear rate applied to the PNF dispersion, they exhibit specific orientation, and ii) it is possible to predict the alignment of PNF by establishing a flow-alignment relationship. Understanding such a relationship is pivotal to improving the fundamental knowledge and application of fibril systems. EXPERIMENTS: We use ß-lactoglobulin PNF aqueous dispersions with different average contour lengths but equal persistence lengths. We employ simple shear-dominated microfluidic devices with state-of-the-art imaging techniques: flow-induced birefringence (FIB) and micro-particle image velocimetry (µ-PIV), to probe the effect of shear flow on PNF alignment. FINDINGS: We provide an empirical relationship connecting the birefringence Δn (quantifying the extent of PNF alignment), and the Péclet number Pe (correlating the shear rate of the flow relative to the rotational diffusion of PNF) to understand the flow-alignment behavior of PNF under shear-dominated flows. Furthermore, we assess the alignment and flow profile of PNF at both high and low flow rates. The length of PNF emerges as a controlling parameter capable of modulating PNF alignment at specific shear rates. Our results shed new insights into the hydrodynamic behavior of PNF, which is highly relevant to various industrial processes involving the fibril systems.

Alanyl-glutamine dipeptide restores the cytoprotective stress proteome of mesothelial cells exposed to peritoneal dialysis fluids.

BACKGROUND: Exposure of mesothelial cells to peritoneal dialysis fluids (PDF) results in cytoprotective cellular stress responses (CSR) that counteract PDF-induced damage. In this study, we tested the hypothesis that the CSR may be inadequate in relevant models of peritoneal dialysis (PD) due to insufficient levels of glutamine, resulting in increased vulnerability against PDF cytotoxicity. We particularly investigated the role of alanyl-glutamine (Ala-Gln) dipeptide on the cytoprotective PDF stress proteome. METHODS: Adequacy of CSR was investigated in two human in vitro models (immortalized cell line MeT-5A and mesothelial cells derived from peritoneal effluent of uraemic patients) following exposure to heat-sterilized glucose-based PDF (PD4-Dianeal, Baxter) diluted with medium and, in a comparative proteomics approach, at different levels of glutamine ranging from depletion (0 mM) via physiological (0.7 mM) to pharmacological levels (8 mM administered as Ala-Gln). RESULTS: Despite severe cellular injury, expression of cytoprotective proteins was dampened upon PDF exposure at physiological glutamine levels, indicating an inadequate CSR. Depletion of glutamine aggravated cell injury and further reduced the CSR, whereas addition of Ala-Gln at pharmacological level restored an adequate CSR, decreasing cellular damage in both PDF exposure systems. Ala-Gln specifically stimulated chaperoning activity, and cytoprotective processes were markedly enhanced in the PDF stress proteome. CONCLUSIONS: Taken together, this study demonstrates an inadequate CSR of mesothelial cells following PDF exposure associated with low and physiological levels of glutamine, indicating a new and potentially relevant pathomechanism. Supplementation of PDF with pharmacological doses of Ala-Gln restored the cytoprotective stress proteome, resulting in improved resistance of mesothelial cells to exposure to PDF. Future work will study the clinical relevance of CSR-mediated cytoprotection.

Prospective Evaluation of Kidney Function in Long-Term Survivors of Pediatric CNS Tumors.

Purpose: Numerous acute effects of chemotherapeutics on kidney function are well described. However, data on the long-term effects of chemotherapy in the growing population of childhood central nervous system (CNS) tumor survivors is limited. We aimed to evaluate the kidney function of a cohort of long-term CNS tumor survivors treated with different standard chemotherapeutic regimens. Methods: Patients treated for a CNS tumor were prospectively evaluated up to 12 years after completion of their therapy. Examination of kidney function was performed during routine follow-up visits. Blood pressure and blood and urine parameters were analyzed for kidney function evaluation. Glomerular function was assessed by calculating the estimated glomerular filtration rate (eGFR), tubular functions were analyzed by measuring serum electrolytes, bicarbonate and phosphate reabsorption, and proteinuria was assessed by calculating the protein/creatinine ratio and phosphate reabsorption. Results: None of the 65 patients evaluated suffered from clinically relevant kidney impairment (eGFR < 90 mL/min/L, 73 m2). There was no association between chemotherapy dose and eGFR. Only two patients showed mild signs of tubulopathy and 11 patients were diagnosed with elevated blood pressure. Conclusion: With adequate supportive measures, such as sufficient hydration according to chemotherapy protocol guidelines, as well as avoidance or close monitoring of additional nephrotoxic medication, impaired kidney function is rare in CNS tumor survivors treated with standard chemotherapy. Nonetheless, long-term follow-up is essential for early detection of mild impairment of kidney function.

Spectrum of Atazanavir-Selected Protease Inhibitor-Resistance Mutations.

Ritonavir-boosted atazanavir is an option for second-line therapy in low- and middle-income countries (LMICs). We analyzed publicly available HIV-1 protease sequences from previously PI-naïve patients with virological failure (VF) following treatment with atazanavir. Overall, 1497 patient sequences were identified, including 740 reported in 27 published studies and 757 from datasets assembled for this analysis. A total of 63% of patients received boosted atazanavir. A total of 38% had non-subtype B viruses. A total of 264 (18%) sequences had a PI drug-resistance mutation (DRM) defined as having a Stanford HIV Drug Resistance Database mutation penalty score. Among sequences with a DRM, nine major DRMs had a prevalence >5%: I50L (34%), M46I (33%), V82A (22%), L90M (19%), I54V (16%), N88S (10%), M46L (8%), V32I (6%), and I84V (6%). Common accessory DRMs were L33F (21%), Q58E (16%), K20T (14%), G73S (12%), L10F (10%), F53L (10%), K43T (9%), and L24I (6%). A novel nonpolymorphic mutation, L89T occurred in 8.4% of non-subtype B, but in only 0.4% of subtype B sequences. The 264 sequences included 3 (1.1%) interpreted as causing high-level, 14 (5.3%) as causing intermediate, and 27 (10.2%) as causing low-level darunavir resistance. Atazanavir selects for nine major and eight accessory DRMs, and one novel nonpolymorphic mutation occurring primarily in non-B sequences. Atazanavir-selected mutations confer low-levels of darunavir cross resistance. Clinical studies, however, are required to determine the optimal boosted PI to use for second-line and potentially later line therapy in LMICs.

Targeted Training for Subspecialist Care in Children With Medical Complexity.

Background: Children with medical complexity (CMC) are prone to medical errors and longer hospital stays, while residents do not feel prepared to provide adequate medical care for this vulnerable population. No educational guidance for the training of future pediatric tertiary care specialists outside their field of expertise involving the multidisciplinary care of CMC exists. We investigated pediatric residents past educational needs and challenges to identify key learning content for future training involving care for CMC. Methods: This was a prospective mixed-methods study at a single pediatric tertiary care center. Qualitative semi-structured interviews with residents were conducted, submitted to thematic content analysis, linked to the American Board of Pediatrics (ABP) general pediatrics content outline, and analyzed with importance performance analysis (IPA). Quantitative validation was focused on key themes of pediatric nephrology within the scope of an online survey among pediatric residents and specialists. Results: A total of 16 interviews, median duration 69 min [interquartile range IQR 35], were conducted. The 280 listed themes of the ABP general pediatrics content outline were reduced to 165 themes, with 86% (theoretical) knowledge, 12% practical skills, and 2% soft skills. IPA identified 23 knowledge themes to be of high importance where improvement is necessary and deemed fruitful. Quantitative validation among 84 residents and specialists (response rate 55%) of key themes in nephrology yielded high agreement among specialists in pediatric nephrology but low interrater agreement among trainees and "trained" non-nephrologists. The occurrence of themes in the qualitative interviews and their calculated importance in the quantitative survey were highly correlated (tau = 0.57, p = 0.001). Two clusters of high importance for other pediatric specialties emerged together with a contextual cluster of frequent encounters in both in- and outpatient care. Conclusion: Regarding patient safety, this study revealed the heterogeneous aspects and the importance of training future pediatric tertiary care specialists outside their field of expertise involving the multidisciplinary care of CMC. Our results may lay the groundwork for future detailed analysis and development of training boot camps that might be able to aid the improvement of patient safety by decreasing preventable harm by medical errors, especially for vulnerable patient groups, such as CMC in tertiary care pediatrics.

Kidney Transplantation in Small Children: Association Between Body Weight and Outcome-A Report From the ESPN/ERA-EDTA Registry.

BACKGROUND: Many centers accept a minimum body weight of 10 kg as threshold for kidney transplantation (Tx) in children. As solid evidence for clinical outcomes in multinational studies is lacking, we evaluated practices and outcomes in European children weighing below 10 kg at Tx. METHODS: Data were obtained from the European Society of Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry on all children who started kidney replacement therapy at <2.5 y of age and received a Tx between 2000 and 2016. Weight at Tx was categorized (<10 versus ≥10 kg) and Cox regression analysis was used to evaluate its association with graft survival. RESULTS: One hundred of the 601 children received a Tx below a weight of 10 kg during the study period. Primary renal disease groups were equal, but Tx <10 kg patients had lower pre-Tx weight gain per year (0.2 versus 2.1 kg; P < 0.001) and had a higher preemptive Tx rate (23% versus 7%; P < 0.001). No differences were found for posttransplant estimated glomerular filtration rates trajectories (P = 0.23). The graft failure risk was higher in Tx <10 kg patients at 1 y (graft survival: 90% versus 95%; hazard ratio, 3.84; 95% confidence interval, 1.24-11.84), but not at 5 y (hazard ratio, 1.71; 95% confidence interval, 0.68-4.30). CONCLUSIONS: Despite a lower 1-y graft survival rate, graft function, and survival at 5 y were identical in Tx <10 kg patients when compared with Tx ≥10 kg patients. Our results suggest that early transplantation should be offered to a carefully selected group of patients weighing <10 kg.