Potential impact of NOTCH1 activation on venetoclax sensitivity in chronic lymphocytic Leukaemia: In vitro insights and clinical implications.

Despite significant progress in treating chronic lymphocytic leukaemia (CLL), resistance to therapy remains challenging. NOTCH1 activation, common in CLL, confers adverse prognosis. This study explores the impact of NOTCH1 signalling on venetoclax sensitivity in vitro. Although NOTCH1 activation minimally impaired the susceptibility of CLL cells to venetoclax, ex vivo cell competition studies reveal that cells with constitutive NOTCH1 activation outgrew their wild-type counterparts in the presence of ongoing venetoclax exposure. Our findings suggest that while NOTCH1 activation is insufficient to confer venetoclax refractoriness, there is enhanced potential for cells with NOTCH1 activation to escape and thus become fully resistant to venetoclax.

Comparison of eGFR Equations to Guide Dosing of Medications for Kidney Transplant Recipients.

BACKGROUND: Clinicians caring for kidney transplant recipients (KTRs) most commonly use estimated glomerular filtration rate (eGFR) to guide medication dosing as it is the most readily available measure of kidney function. Which eGFR equations provide the most accurate medication dosing guidance for KTRs remains uncertain. METHODS: We studied 415 stable KTRs in Canada and New Zealand. Participants completed same-day measurements of creatinine and cystatin C and measured GFR (diethylenetriaminepentaacetic acid). Chronic Kidney Disease Epidemiology Collaboration, European Kidney Function Consortium, and transplant-specific eGFR equations were compared with both Cockcroft-Gault creatinine clearance (CrCl) and measured GFR. eGFR equations were assessed both indexed to a standardized body surface area (BSA) of 1.73 m2 (milliliter per minute per 1.73 m2, as is conventional reporting from most clinical laboratories) and nonindexed (milliliter per minute) accounting for actual BSA. The primary outcome was the proportion of medication dosing discordance relative to Cockcroft-Gault CrCl or measured GFR for 8 commonly prescribed medications. Stratified analyses were performed on the basis of obesity status. RESULTS: Nonindexed eGFR equations (milliliter per minute) resulted in substantially lower medication dosing discordance compared with indexed eGFR equations (milliliter per minute per 1.73 m2). These findings were most pronounced among KTRs with obesity, in whom underdosing was frequent. When compared with Cockcroft-Gault CrCl, the lowest proportion of discordance was found with the nonindexed 2023 transplant-specific equation. When compared with measured GFR, the lowest proportion of discordance was found with the nonindexed 2021 Chronic Kidney Disease Epidemiology CollaborationCr/CysC equation. CONCLUSIONS: Nonindexed eGFR values accounting for actual BSA should be used by clinicians for medication dosing in KTRs. These findings may inform KT providers about which eGFR equations provide the safest, most accurate medication dosing guidance for KTRs.

Sociodemographic differences in nutrition labels effect on Chilean and Mexican youth / Diferencias sociodemográficas en el efecto de las etiquetas nutricionales en las adolescentes de Chile y México / Diferenças sociodemográficas no efeito da rotulagem nutricional em adolescentes chilenos e mexicanos

ABSTRACT Objective. To examine sociodemographic differences in the awareness, understanding, use and effect of nutrition labels among Mexican and Chilean youth. Methods. Online surveys among youth (10-17 years) were obtained in 2019 (n=2631). Participants reported their awareness, understanding, and use of their country-specific nutrition facts tables (NFT) and front-of-pack labels (FOPL) (Chile: warning labels [WLs]; Mexico: guideline daily amounts [GDA]). Additionally, participants reported their perceived healthfulness of a sweetened fruit drink after viewing one of six versions of it with different FOPL (no-label control, Health Star Rating, WLs, GDAs, Traffic Light, or Nutri-Score) during an experimental task. Results. Higher self-reported nutrition knowledge was associated with higher NFT and FOPL awareness, understanding, and use, except for WL use. WLs were the most effective FOPL in decreasing the perceived healthfulness of the sweetened fruit drink compared to a no-label condition and other FOP labels. In Chile, the effect of GDA differed by income adequacy, while in Mexico Nutri-Score differed by age. Conclusions. Results suggest that nutrition label awareness, use, understanding, and impact differ across demographics, favoring higher income and nutrition knowledge. Despite this, WLs are likely to have a positive impact on nutrition-related knowledge and behaviors among Mexican and Chilean youth, independently of their socio-demographic groups.

RESUMEN Objetivo. Examinar las diferencias sociodemográficas por lo que respecta al conocimiento, la comprensión, el uso y el efecto de las etiquetas nutricionales en adolescentes de México y Chile. Métodos. En el 2019 se efectuó una encuesta en línea en adolescentes (10 a 17 años) (n=2631). Los participantes indicaron su conocimiento, comprensión y uso de los cuadros de información nutricional y los etiquetados frontales específicos de los empaques de su país (en el caso de Chile, las etiquetas de advertencia, y en el de México, las guías diarias de alimentación (GDA). Asimismo, se llevó a cabo un experimento en el que los participantes indicaron su percepción de lo saludable que era una bebida de fruta azucarada después de ver una de sus seis versiones con diferentes etiquetas frontales en los envases (control sin etiqueta, calificación de producto saludable mediante estrellas Health Star, etiquetas de advertencia, GDA, colores del semáforo, o sistema Nutri-Score). Resultados. El autorreporte de un mayor conocimiento sobre nutrición por parte de los participantes se asoció a un mayor conocimiento, comprensión y uso de los cuadros de información nutricional y los sistemas de etiquetado frontal, excepto en el caso del uso de las etiquetas de advertencia. Las etiquetas de advertencia fueron el sistema de etiquetado frontal más eficaz para reducir la percepción saludable del producto con respecto a la bebida de fruta azucarada, en comparación con la ausencia de etiqueta y el resto de los etiquetados frontales. En Chile, el efecto de las GDA variaba en función de la adecuación del ingreso, mientras que en México el efecto del Nutri-Score difería según la edad. Conclusiones. Los resultados sugieren que el conocimiento, el uso, la comprensión y el efecto de las etiquetas nutricionales difieren entre los distintos grupos demográficos, de tal manera que son más favorables en las personas con mayores ingresos y conocimientos de nutrición. A pesar de esto, es probable que las etiquetas de advertencia tengan un impacto positivo sobre los conocimientos y los comportamientos relacionados con la nutrición en los adolescentes de México y Chile, con independencia de los grupos sociodemográficos de los que forman parte.

RESUMO Objetivo. Analisar diferenças sociodemográficas em termos de conhecimento, compreensão, uso e efeito da rotulagem nutricional entre adolescentes mexicanos e chilenos. Métodos. Foram realizadas pesquisas on-line entre adolescentes de 10 a 17 anos ao longo de 2019 (n=2631). Os participantes relataram que conheciam, compreendiam e usavam as tabelas de informação nutricional e a rotulagem frontal de embalagens específicas de seus respectivos países (Chile: rotulagem de advertência; México: valores diários de referência). Além disso, os participantes relataram sua percepção sobre a saudabilidade de um suco de fruta adoçado depois de ver uma de seis versões diferentes de rotulagem frontal (controle sem rótulo, Health Star Rating, rótulos de advertência, valores diários de referência, semáforo nutricional ou Nutri-Score) durante uma tarefa experimental. Resultados. Um maior conhecimento autodeclarado sobre nutrição foi associado a maior conhecimento, compreensão e uso de tabelas de informação nutricional e rotulagem frontal, com exceção do uso de rótulos de advertência. Os rótulos de advertência foram o tipo de rotulagem frontal mais efetivo para reduzir a percepção de saudabilidade do suco de fruta adoçado em comparação com o controle sem rótulo e outros tipos de rotulagem frontal. No Chile, o efeito dos valores diários de referência variou de acordo com a renda, enquanto no México o Nutri-Score variou de acordo com a idade. Conclusões. Os resultados sugerem que o conhecimento, a compreensão, o uso e o impacto da rotulagem nutricional variam de acordo com fatores demográficos, favorecendo uma renda mais alta e conhecimento sobre nutrição. Apesar disso, é provável que os rótulos de advertência tenham um impacto positivo sobre o conhecimento e os comportamentos relativos à nutrição entre adolescentes mexicanos e chilenos, independentemente do grupo sociodemográfico a que pertencem.

Ependymoma-like tumor with mesenchymal differentiation (ELTMD) with ZFTA:NCOA1 fusion: A diagnostic challenge.

Ependymal tumors are classified based on their location, histology, and molecular characteristics. Supratentorial ependymomas (ST-EPNs) are a group of circumscribed supratentorial gliomas, which usually have pathogenic fusions involving either zinc finger translocation associated (ZFTA) (formerly C11orf95) or YAP1. A subtype of ependymoma was recently described and labeled ependymoma-like tumors with mesenchymal differentiation (ELTMDs). We describe a case of a 5-year-old boy who presented with a right frontal tumor. The diagnosis was challenging, and a correct diagnosis could only be reached after reanalysis of methylation data with a more recent version of the classifier and RNA fusion testing, which revealed ZFTA:NCOA1 (nuclear receptor coactivator 1) fusion. There are only a handful of cases of this entity, which is being reported for its rarity and the diagnostic challenge it poses.

Implementation of DNA Methylation Array Profiling in Pediatric Central Nervous System Tumors: The AIM BRAIN Project: An Australian and New Zealand Children's Haematology/Oncology Group Study.

DNA methylation array profiling for classifying pediatric central nervous system (CNS) tumors is a valuable adjunct to histopathology. However, unbiased prospective and interlaboratory validation studies have been lacking. The AIM BRAIN diagnostic trial involving 11 pediatric cancer centers in Australia and New Zealand was designed to test the feasibility of routine clinical testing and ran in parallel with the Molecular Neuropathology 2.0 (MNP2.0) study at Deutsches Krebsforschungszentrum (German Cancer Research Center). CNS tumors from 269 pediatric patients were prospectively tested on Illumina EPIC arrays, including 104 cases co-enrolled on MNP2.0. Using MNP classifier versions 11b4 and 12.5, we report classifications with a probability score ≥0.90 in 176 of 265 (66.4%) and 213 of 269 (79.2%) cases, respectively. Significant diagnostic information was obtained in 130 of 176 (74%) for 11b4, and 12 of 174 (7%) classifications were discordant with histopathology. Cases prospectively co-enrolled on MNP2.0 gave concordant classifications (99%) and score thresholds (93%), demonstrating excellent test reproducibility and sensitivity. Overall, DNA methylation profiling is a robust single workflow technique with an acceptable diagnostic yield that is considerably enhanced by the extensive subgroup and copy number profile information generated by the platform. The platform has excellent test reproducibility and sensitivity and contributes significantly to CNS tumor diagnosis.

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome.

BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.

A multi-institutional retrospective pooled outcome analysis of molecularly annotated pediatric supratentorial ZFTA-fused ependymoma.

Background: ZFTA-RELA (formerly known as c11orf-RELA) fused supratentorial ependymoma (ZFTAfus ST-EPN) has been recognized as a novel entity in the 2016 WHO classification of CNS tumors and further defined in the recent 2021 edition. ZFTAfus ST-EPN was reported to portend poorer prognosis when compared to its counterpart, YAP1 ST-EPN in some previously published series. The aim of this study was to determine the treatment outcome of molecularly confirmed and conventionally treated ZFTAfus ST-EPN patients treated in multiple institutions. Methods: We conducted a retrospective analysis of all pediatric patients with molecularly confirmed ZFTAfus ST-EPN patients treated in multiple institutions in 5 different countries (Australia, Canada, Germany, Switzerland, and Czechia). Survival outcomes were analyzed and correlated with clinical characteristics and treatment approaches. Results: A total of 108 patients were collated from multiple institutions in 5 different countries across three continents. We found across the entire cohort that the 5- and 10-year PFS were 65% and 63%, respectively. The 5- and 10-year OS of this cohort of patients were 87% and 73%. The rates of gross total resection (GTR) were high with 84 out of 108 (77.8%) patients achieving GTR. The vast majority of patients also received post-operative radiotherapy, 98 out of 108 (90.7%). Chemotherapy did not appear to provide any survival benefit in our patient cohort. Conclusion: This is the largest study to date of contemporaneously treated molecularly confirmed ZFTAfus ST-EPN patients which identified markedly improved survival outcomes compared to previously published series. This study also re-emphasizes the importance of maximal surgical resection in achieving optimal outcomes in pediatric patients with supratentorial ependymoma.

In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma.

Introduction: Ependymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who survive treatment often suffer long-term neurological side effects as a result of therapy. It is evident that there is a need for safer, more effective treatments for pediatric EPN patients. There are ten distinct subgroups of EPN, each with their own molecular and prognostic features. To identify and facilitate the testing of new treatments for EPN, in vivo laboratory models representative of the diverse molecular subtypes are required. Here, we describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of posterior fossa A (PFA) EPN, derived from a metastatic cranial lesion. Methods: Patient and PDOX tumors were analyzed using immunohistochemistry, DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. Results: Both patient and PDOX tumors classified as PFA EPN by methylation profiling, and shared similar histological features consistent with this molecular subgroup. RNA sequencing revealed that gene expression patterns were maintained across the primary and metastatic tumors, as well as the PDOX. Copy number profiling revealed gains of chromosomes 7, 8 and 19, and loss of chromosomes 2q and 6q in the PDOX and matched patient tumor. No clinically significant single nucleotide variants were identified, consistent with the low mutation rates observed in PFA EPN. Overexpression of EZHIP RNA and protein, a common feature of PFA EPN, was also observed. Despite the aggressive nature of the tumor in the patient, this PDOX was unable to be maintained past two passages in vivo. Discussion: Others who have successfully developed PDOX models report some of the lowest success rates for EPN compared to other pediatric brain cancer types attempted, with loss of tumorigenicity not uncommon, highlighting the challenges of propagating these tumors in the laboratory. Here, we discuss our collective experiences with PFA EPN PDOX model generation and propose potential approaches to improve future success in establishing preclinical EPN models.

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology.

The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.

Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions.

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.

Social determinants of health and the transition from advanced chronic kidney disease to kidney failure.

BACKGROUND: The transition from chronic kidney disease (CKD) to kidney failure is a vulnerable time for patients, with suboptimal transitions associated with increased morbidity and mortality. Whether social determinants of health are associated with suboptimal transitions is not well understood. METHODS: This retrospective cohort study included 1070 patients with advanced CKD who were referred to the Ottawa Hospital Multi-Care Kidney Clinic and developed kidney failure (dialysis or kidney transplantation) between 2010 and 2021. Social determinant information, including education level, employment status and marital status, was collected under routine clinic protocol. Outcomes surrounding suboptimal transition included inpatient (versus outpatient) dialysis starts, pre-emptive (versus delayed) access creation and pre-emptive kidney transplantation. We examined the association between social determinants of health and suboptimal transition outcomes using multivariable logistic regression. RESULTS: The mean age and estimated glomerular filtration rate were 63 years and 18 ml/min/1.73 m2, respectively. Not having a high school degree was associated with higher odds for an inpatient dialysis start compared with having a college degree {odds ratio [OR] 1.71 [95% confidence interval (CI) 1.09-2.69]}. Unemployment was associated with higher odds for an inpatient dialysis start [OR 1.85 (95% CI 1.18-2.92)], lower odds for pre-emptive access creation [OR 0.53 (95% CI 0.34-0.82)] and lower odds for pre-emptive kidney transplantation [OR 0.48 (95% CI 0.24-0.96)] compared with active employment. Being single was associated with higher odds for an inpatient dialysis start [OR 1.44 (95% CI 1.07-1.93)] and lower odds for pre-emptive access creation [OR 0.67 (95% CI 0.50-0.89)] compared with being married. CONCLUSIONS: Social determinants of health, including education, employment and marital status, are associated with suboptimal transitions from CKD to kidney failure.

Screening screeners: calculating classification indices using correlations and cut-points.

Given the recent push for universal screening, it is important to take into account how well a screener identifies children at risk for reading problems as well as how screener and sample information contribute to this classification. Picking the best cut-point for a particular sample and screening goal can be challenging given that test manuals often report classification information for a specific cut-point and sample base rate which may not generalize to other samples. By assuming a bivariate normal distribution, it is possible to calculate all of the classification information for a screener based on the correlation between the screener and outcome, the cut-point on the outcome (i.e., the base rate in the sample), and the cut-point on the screener. We provide an example with empirical data to validate these estimation procedures. This information is the basis for a free online tool that provides classification information for a given correlation between screener and outcome and cut-points on each. Results show that the correlation between screener and outcome needs to be greater than .9 (higher than observed in practice) to obtain good classification. These findings are important for researchers, administrators, and practitioners because current screeners do not meet these requirements. Since a correlation is dependent on the reliability of the measures involved, we need screeners with better reliability and/or multiple measures to increase reliability. Additionally, we demonstrate the impact of base rate on positive predictive power and discuss how gated screening can be useful in samples with low base rates.

Performance of the 2021 Race-Free CKD-EPI Creatinine- and Cystatin C-Based Estimated GFR Equations Among Kidney Transplant Recipients.

RATIONALE & OBJECTIVE: Race-free estimated glomerular filtration rate (eGFR) equations incorporating creatinine with and without cystatin C were recently developed and recommended for routine use. However, the performance of these equations among kidney transplant recipients (KTRs) remains unknown. STUDY DESIGN: Cross-sectional study to validate the 2021 race-free Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) eGFR equation based on creatinine alone (eGFRcr) or based on creatinine and cystatin C (eGFRcr-cys) among KTRs. SETTING & PARTICIPANTS: KTRs in stable condition (N = 415) from Canada and New Zealand with same-day measurements of creatinine, cystatin C, and glomerular filtration rate (GFR) using radiolabeled diethylenetriaminepentaacetic acid. TESTS COMPARED: The 2009 CKD-EPI eGFRcr, 2021 CKD-EPI eGFRcr, 2012 CKD-EPI eGFRcr-cys, 2021 CKD-EPI eGFRcr-cys, 2012 CKD-EPI eGFRcys, and Modification of Diet in Renal Disease (MDRD) Study eGFR equations were compared with measured GFR. OUTCOMES: Bias, precision, accuracy, and correct classification by CKD stage. Bias was defined as the difference between estimated and measured GFR. Precision was represented by the interquartile range. Accuracy was defined as the percentages of participants with eGFRs within 10%/20%/30% (P10/P20/P30) of measured GFR, root mean square error, and mean absolute error. RESULTS: 87% of patients studied were White, 3% Black, and 10% other races. Mean measured GFR was 53 ± 19 (SD) mL/min/1.73 m2. The 2009 and 2021 CKD-EPI eGFRcr equations demonstrated similar median bias (-2.3 vs -0.2 mL/min/1.73 m2, respectively), precision (14.5 vs 14.9 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/65%/84% vs 33%/63%/84%). The 2012 and 2021 CKD-EPI eGFRcr-cys equations also demonstrated similar median bias (-3.6 vs 0.3 mL/min/1.73 m2, respectively), precision (13.3 vs 14.3 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/63%/80% vs 32%/67%/83%). No clear difference in performance was detected between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations among KTRs. The proportion of correct classification by CKD stage was similar across all eGFR equations. LIMITATIONS: Moderate sample size, few patients had a GFR <30 mL/min/1.73 m2, and the large majority of patients were White. CONCLUSIONS: Among KTRs, the 2021 race-free CKD-EPI eGFR equations perform similarly to the previous CKD-EPI equations that included race correction terms. No significant difference in performance was observed between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations in the kidney transplant population.

Evaluation of novel glomerular filtration rate estimation equations in adolescents and young adults with type 1 diabetes.

AIMS: Individuals with type 1 diabetes (T1D) are at an increased risk of chronic kidney disease making estimation of glomerular filtration rate (eGFR) an important component of diabetes care. Which eGFR equation is most appropriate to use in patients with T1D during the transition to adult care is unclear. We, therefore, sought to evaluate the performance of five eGFR equations in adolescents and young adults with T1D. METHODS: Measured iohexol-based glomerular filtration rate was compared to the Chronic Kidney Disease and Epidemiology Collaboration (CKD-EPI) eGFR, Chronic Kidney Disease in Children (CKiD) eGFR, and three recently developed age-adjusted versions of these in 53 patients with T1D and preserved GFR using bias, precision, and accuracy. RESULTS: The best performance was found in the sex-dependent CKiD equation (bias: -0.8, accuracy: 11.8 ml/min/1.73 m2). Bias and accuracy (26.4 and 26.8 ml/min/1.73 m2) were worst in the CKD-EPI equation. Age-dependent adjustment improved performance for this equation (bias: 5.3, accuracy: 13.4 ml/min/1.73 m2), but not for the CKiD equation (bias: 15.5, accuracy: 18.8 ml/min/1.73 m2). CONCLUSION: Age-adjustment improved performance for the CKD-EPI equation, but not for the CKiD equation. The sex-adjusted CKiD equation performed best out of all equations.

The Clinical Trial Treatment Train.

The Clinical Trial Treatment Train Ms. Christine Cissy White received a diagnosis of high-grade serous ovarian cancer in August 2019 at 52 years of age. Her experiences as a clinical trial participant and the uncertainties of living with cancer are recounted in this Patient Platform.

Assessment of kidney function: clinical indications for measured GFR.

In the vast majority of cases, glomerular filtration rate (GFR) is estimated using serum creatinine, which is highly influenced by age, sex, muscle mass, body composition, severe chronic illness and many other factors. This often leads to misclassification of patients or potentially puts patients at risk for inappropriate clinical decisions. Possible solutions are the use of cystatin C as an alternative endogenous marker or performing direct measurement of GFR using an exogenous marker such as iohexol. The purpose of this review is to highlight clinical scenarios and conditions such as extreme body composition, Black race, disagreement between creatinine- and cystatin C-based estimated GFR (eGFR), drug dosing, liver cirrhosis, advanced chronic kidney disease and the transition to kidney replacement therapy, non-kidney solid organ transplant recipients and living kidney donors where creatinine-based GFR estimation may be invalid. In contrast to the majority of literature on measured GFR (mGFR), this review does not include aspects of mGFR for research or public health settings but aims to reach practicing clinicians and raise their understanding of the substantial limitations of creatinine. While including cystatin C as a renal biomarker in GFR estimating equations has been shown to increase the accuracy of the GFR estimate, there are also limitations to eGFR based on cystatin C alone or the combination of creatinine and cystatin C in the clinical scenarios described above that can be overcome by measuring GFR with an exogenous marker. We acknowledge that mGFR is not readily available in many centres but hope that this review will highlight and promote the expansion of kidney function diagnostics using standardized mGFR procedures as an important milestone towards more accurate and personalized medicine.

Antiviral antibody responses to systemic administration of an oncolytic RNA virus: the impact of standard concomitant anticancer chemotherapies.

BACKGROUND: Oncolytic reovirus therapy for cancer induces a typical antiviral response to this RNA virus, including neutralizing antibodies. Concomitant treatment with cytotoxic chemotherapies has been hypothesized to improve the therapeutic potential of the virus. Chemotherapy side effects can include immunosuppression, which may slow the rate of the antiviral antibody response, as well as potentially make the patient more vulnerable to viral infection. METHOD: Reovirus neutralizing antibody data were aggregated from separate phase I clinical trials of reovirus administered as a single agent or in combination with gemcitabine, docetaxel, carboplatin and paclitaxel doublet or cyclophosphamide. In addition, the kinetics of individual antibody isotypes were profiled in sera collected in these trials. RESULTS: These data demonstrate preserved antiviral antibody responses, with only moderately reduced kinetics with some drugs, most notably gemcitabine. All patients ultimately produced an effective neutralizing antibody response. CONCLUSION: Patients' responses to infection by reovirus are largely unaffected by the concomitant drug treatments tested, providing confidence that RNA viral treatment or infection is compatible with standard of care treatments.

Raman Spectroscopy of Liquid-Based Cervical Smear Samples as a Triage to Stratify Women Who Are HPV-Positive on Screening.

The role of persistent high-risk human papillomavirus (HPV) infection in the development of cervical precancer and cancer is now well accepted, and HPV testing has recently been introduced for primary cervical screening. However, the low specificity of HPV DNA testing can result in large numbers of women with an HPV-positive result, and additional triage approaches are needed to avoid over-referral to colposcopy and overtreatment. The aim of this study was to assess Raman spectroscopy as a potential triage test to discriminate between transient and persistent HPV infection. HPV DNA status and mRNA status were confirmed in ThinPrep® cervical samples (n = 60) using the Cobas 4800 and APTIMA HPV test, respectively. Raman spectra were recorded from single-cell nuclei and subjected to partial least squares discriminant analysis (PLSDA). In addition, the PLSDA classification model was validated using a blinded independent test set (n = 14). Sensitivity of 85% and specificity of 92% were achieved for the classification of transient and persistent HPV infection, and this increased to 90% sensitivity and 100% specificity when mean sample spectra were used instead of individual cellular spectra. This study showed that Raman spectroscopy has potential as a triage test for HPV-positive women to identify persistent HPV infection.

Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2.

The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-XL, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic "p5" pocket identified in BCL-XL. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-XL. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-XL and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC50)) and displaying mechanism-based killing in cells engineered to depend on BCL-XL for survival.