Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, ...but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available.
Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification.
We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234).
We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU.
We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.
Multisystem inflammatory syndrome in children (MIS-C) is a recently identified entity in association with COVID-19. AKI has been widely reported in patients with primary COVID-19 infection. However, ...there is a paucity of literature regarding renal injury in MIS-C. We aim to characterize AKI in MIS-C in this cohort identified at a major children's hospital in New York City during the COVID-19 pandemic.
We conducted a retrospective cohort study of children 0-20 years old admitted to Morgan Stanley Children's Hospital (MSCH) between April 18th and September 23rd, 2020. Patients were included if they met criteria for MIS-C on the basis of CDC guidelines. All patients were evaluated for the presence of AKI, and AKI was staged according to KDIGO criteria.
Of the 57 children who met inclusion criteria, 46% (26 of 57) were found to have AKI. The majority of patients (58%; 15 of 26) were classified as KDIGO stage 1. AKI was present upon admission in 70% of those identified. All patients had resolution of AKI at discharge, with 61% achieving recovery by day 2. One patient required dialysis. When compared with those without renal injury, the AKI cohort was older (
<0.001) and had higher median peak values of CRP (
<0.001), IL-6 (
=0.02), ferritin (
<0.001), and procalcitonin (
=0.02). More patients with AKI had left ventricular systolic dysfunction (
<0.001) and lymphopenia (
=0.01) when compared with those without AKI. No differences in body mass index or sex were found.
Although children with MIS-C may develop AKI, our study suggests that most experience mild disease, swift resolution, and promising outcome. Older age, increased inflammation, and left ventricular systolic dysfunction may be risk factors. Our study highlights the substantial differences in epidemiology and outcomes between AKI associated with pediatric MIS-C versus primary COVID-19 infection.
Background
Medullary sponge kidney (MSK) disease predisposes patients to recurrent nephrolithiasis, which affects one in every 5000 people in the United States.
Methods
We report a rare case of a ...pediatric recipient of a living donor MSK transplant and discuss considerations when discussing risks and benefits of accepting MSK allografts for this population.
Results
The recipient was admitted due to concerns for nephrolithiasis, hydronephrosis, and urinary tract infection at 1‐month post‐transplant. The hydronephrosis was resolved by surgical removal of an encrusted ureteral stent; this was followed by supplementation with oral medications to prevent future episodes of nephrolithiasis. The recipient did not have any further episodes after this as seen at a 1‐year follow‐up. The donor has remained well through this period.
Conclusions
With increasing organ shortages, the use of variety of donors may need to be considered to enlarge the organ pool.
The diagnosis and management of proteinuric kidney diseases such as focal segmental glomerulosclerosis (FSGS) are challenging. Genetics holds the promise to improve clinical decision making for these ...diseases; however, it is often performed too late to enable timely clinical action and it is not implemented within routine outpatient nephrology visits.
We sought to test the implementation and feasibility of clinical rapid genome sequencing (GS) in guiding decision making in patients with proteinuric kidney disease in real-time and embedded in the outpatient nephrology setting.
We enrolled 10 children or young adults with biopsy-proven FSGS (9 cases) or minimal change disease (1 case). The mean age at enrollment was 16.2 years (range 2–30). The workflow did not require referral to external genetics clinics but was conducted entirely during the nephrology standard-of-care appointments. The total turn-around-time from enrollment to return-of-results and clinical decision averaged 21.8 days (12.4 for GS), which is well within a time frame that allows clinically relevant treatment decisions. A monogenic or APOL1-related form of kidney disease was diagnosed in 5 of 10 patients. The genetic findings resulted in a rectified diagnosis in 6 patients. Both positive and negative GS findings determined a change in pharmacological treatment. In 3 patients, the results were instrumental for transplant evaluation, donor selection, and the immunosuppressive treatment. All patients and families received genetic counseling.
Clinical GS is feasible and can be implemented in real-time in the outpatient care to help guiding clinical management. Additional studies are needed to confirm the cost-effectiveness and broader utility of clinical GS across the phenotypic and demographic spectrum of kidney diseases.
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The utility of exome sequencing for most constitutional disorders in adults is unclear. In this study, exome sequencing in 3315 patients with chronic kidney disease yielded a genetic diagnosis in 307 ...cases (9.3%), with clinically important management implications for 89% of those reviewed.
BACKGROUNDMedullary sponge kidney (MSK) disease predisposes patients to recurrent nephrolithiasis, which affects one in every 5000 people in the United States. METHODSWe report a rare case of a ...pediatric recipient of a living donor MSK transplant and discuss considerations when discussing risks and benefits of accepting MSK allografts for this population. RESULTSThe recipient was admitted due to concerns for nephrolithiasis, hydronephrosis, and urinary tract infection at 1-month post-transplant. The hydronephrosis was resolved by surgical removal of an encrusted ureteral stent; this was followed by supplementation with oral medications to prevent future episodes of nephrolithiasis. The recipient did not have any further episodes after this as seen at a 1-year follow-up. The donor has remained well through this period. CONCLUSIONSWith increasing organ shortages, the use of variety of donors may need to be considered to enlarge the organ pool.
Social interactions have large effects on individual physiology and fitness. In the immediate sense, social stimuli are often highly salient and engaging. Over longer time scales, competitive ...interactions often lead to distinct social ranks and differences in physiology and behavior. Understanding how initial responses lead to longer-term effects of social interactions requires examining the changes in responses over time. Here we examined the effects of social interactions on transcriptomic signatures at two times, at the end of a 45-minute interaction and 4 hours later, in female Polistes fuscatus paper wasp foundresses. Female P. fuscatus have variable facial patterns that are used for visual individual recognition, so we separately examined the transcriptional dynamics in the optic lobe and the non-visual brain. Results demonstrate much stronger transcriptional responses to social interactions in the non-visual brain compared to the optic lobe. Differentially regulated genes in response to social interactions are enriched for memory-related transcripts. Comparisons between winners and losers of the encounters revealed similar overall transcriptional profiles at the end of an interaction, which significantly diverged over the course of 4 hours, with losers showing changes in expression levels of genes associated with aggression and reproduction in paper wasps. On nests, subordinate foundresses are less aggressive, do more foraging and lay fewer eggs compared to dominant foundresses and we find losers shift expression of many genes in the non-visual brain, including vitellogenin, related to aggression, worker behavior, and reproduction within hours of losing an encounter. These results highlight the early neurogenomic changes that likely contribute to behavioral and physiological effects of social status changes in a social insect.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The human pelvic canal (true pelvis) functions to support the abdominopelvic organs and serves as a passageway for reproduction (females). Previous research suggests that these two functions work ...against each other with the expectation that the supportive role results in a narrower pelvic midplane, while fetal passage necessitates a larger opening. In this research, we examine how gut size relates to the size and shape of the true pelvis, which may have implications on how gut size can influence pelvic floor integrity. Pelves and in vivo gut volumes were measured from CT scans of 92 adults (48 female, 44 male). The true pelvis was measured at three obstetrical planes (inlet, midplane, outlet) using 11 3D landmarks. CT volumetry was used to obtain an individual's gut size. Gut volume was compared to the pelvic planes using multiple regression to evaluate the relationship between gut size and the true pelvis. We find that, in males, larger gut sizes are associated with increased mediolateral canal dimensions at the inlet and midplane. In females, we find that larger gut sizes are associated with more medially-projecting ischial spines and an anteroposteriorly longer outlet. We hypothesize that the association of larger guts with increased canal width in males and increased outlet length in females are adaptations to create adequate space for the gut, while more medially projecting ischial spines reduce the risk of pelvic floor disorders in females, despite its possible spatial consequences for fetal passage.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human epidermal growth factor receptor 2 (HER2), a member of the ERBB family of tyrosine kinase receptors, has emerged as a therapeutic target of interest for non-small cell lung cancer (NSCLC) in ...recent years. Activating HER2 alterations in NSCLC include gene mutations, gene amplifications, and protein overexpression. In particular, the HER2 exon 20 mutation is now a well clinically validated biomarker. Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations. This remains an unmet clinical need, as HER2 alterations are present in 7–27% of de novo NSCLC and may serve as a resistance mechanism in up to 10% of EGFR mutated NSCLC. There has been an influx of research on antibody–drug conjugates (ADCs), monoclonal antibodies, and tyrosine kinase inhibitors (TKIs) with mixed results. The most promising therapies are ADCs (trastuzumab-deruxtecan) and novel TKIs targeting exon 20 mutations (poziotinib, mobocertinib and pyrotinib); both have resulted in meaningful anti-tumor efficacy in HER2 mutated NSCLC. Future studies on HER2 targeted therapy will need to define the specific HER2 alteration to better select patients who will benefit, particularly for HER2 amplification and overexpression. Given the variety of HER2 targeted drugs, sequencing of these agents and optimizing combination therapies will depend on more mature efficacy data from clinical trials and toxicity profiles. This review highlights the challenges of diagnosing HER2 alterations, summarizes recent progress in novel HER2-targeted agents, and projects next steps in advancing treatment for the thousands of patients with HER2 altered NSCLC.
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