Association between Proton Pump Inhibitors, Immune Checkpoint Inhibitors, and Acute Kidney Injury: A Nested Case-Control Study.

BACKGROUND: An association between proton pump inhibitor (PPI) use and an increased risk of acute kidney injury (AKI) has been confirmed. This study aimed to evaluate the effects of PPI use on the risk of AKI in patients with cancer who were administered immune checkpoint inhibitors (ICIs), a class of drugs used in cancer treatment, and in those who were not. METHODS: We used a database provided by the Health, Clinic, and Education Information Evaluation Institute, which included demographic data, diagnoses, prescriptions, and laboratory results. We conducted a nested case-control study of 38,930 patients with cancer who were new PPI or ICI users and had no history of AKI before cohort entry. The odds ratio (OR) for AKI was estimated using conditional logistic regression models. RESULTS: During a mean follow-up of 8.3 months, 5,870 cases of AKI were identified (incidence rate, 21.9/100 person-years). Compared to never or past PPI use without ICI use, the adjusted ORs of AKI for current PPI use without ICI use, past or never PPI use with prior ICI use, current PPI use with prior ICI use were 1.82 (95% CI, 1.67 to 2.00), 1.47 (95% CI, 1.17 to 1.86), or 2.13 (95% CI, 1.42 to 3.20), respectively. The risk of AKI in patients treated with both PPIs and ICIs was not higher than the additional or multiplication of the risks in those who were treated with PPIs or ICIs alone. CONCLUSIONS: This study reinforces the association between PPIs and ICIs use and the increased risk of AKI. Although the interaction between the two drug classes was not detected, these findings highlight the need for careful monitoring and evaluation of kidney function in patients treated with PPIs and ICIs.

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease. METHODS: We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

AI-MARRVEL - A Knowledge-Driven AI System for Diagnosing Mendelian Disorders.

BACKGROUND: Diagnosing genetic disorders requires extensive manual curation and interpretation of candidate variants, a labor-intensive task even for trained geneticists. Although artificial intelligence (AI) shows promise in aiding these diagnoses, existing AI tools have only achieved moderate success for primary diagnosis. METHODS: AI-MARRVEL (AIM) uses a random-forest machine-learning classifier trained on over 3.5 million variants from thousands of diagnosed cases. AIM additionally incorporates expert-engineered features into training to recapitulate the intricate decision-making processes in molecular diagnosis. The online version of AIM is available at https://ai.marrvel.org. To evaluate AIM, we benchmarked it with diagnosed patients from three independent cohorts. RESULTS: AIM improved the rate of accurate genetic diagnosis, doubling the number of solved cases as compared with benchmarked methods, across three distinct real-world cohorts. To better identify diagnosable cases from the unsolved pools accumulated over time, we designed a confidence metric on which AIM achieved a precision rate of 98% and identified 57% of diagnosable cases out of a collection of 871 cases. Furthermore, AIM's performance improved after being fine-tuned for targeted settings including recessive disorders and trio analysis. Finally, AIM demonstrated potential for novel disease gene discovery by correctly predicting two newly reported disease genes from the Undiagnosed Diseases Network. CONCLUSIONS: AIM achieved superior accuracy compared with existing methods for genetic diagnosis. We anticipate that this tool may aid in primary diagnosis, reanalysis of unsolved cases, and the discovery of novel disease genes. (Funded by the NIH Common Fund and others.).

Visualization of intracellular ATP dynamics in different nephron segments under pathophysiological conditions using the kidney slice culture system.

ATP depletion plays a central role in the pathogenesis of kidney diseases. Recently, we reported spatiotemporal intracellular ATP dynamics during ischemia reperfusion (IR) using GO-ATeam2 mice systemically expressing an ATP biosensor. However, observation from the kidney surface did not allow visualization of deeper nephrons or accurate evaluation of ATP synthesis pathways. Here, we established a novel ATP imaging system using slice culture of GO-ATeam2 mouse kidneys, evaluated the ATP synthesis pathway, and analyzed intracellular ATP dynamics using an ex vivo IR-mimicking model and a cisplatin nephropathy model. Proximal tubules (PTs) were found to be strongly dependent on oxidative phosphorylation (OXPHOS) using the inhibitor oligomycin A, whereas podocytes relied on both OXPHOS and glycolysis using phloretin an active transport inhibitor of glucose. We also confirmed that an ex vivo IR-mimicking model could recapitulate ATP dynamics in vivo; ATP recovery in PTs after reoxygenation varied depending on anoxic time length, whereas ATP in distal tubules (DTs) recovered well even after long-term anoxia. After cisplatin administration, ATP levels in PTs decreased first, followed by a decrease in DTs. An organic cation transporter 2 inhibitor, cimetidine, suppressed cisplatin uptake in kidney slices, leading to better ATP recovery in PTs, but not in DTs. Finally, we confirmed that a mitochondria protection reagent (Mitochonic Acid 5) delayed the cisplatin-induced ATP decrease in PTs. Thus, our novel system may provide new insights into the energy dynamics and pathogenesis of kidney disease.

Oxytocin homogenizes horse group organization.

The oxytocinergic system has been suggested to make up an important part of the endocrine basis of group cohesion. However, controlled studies in open-group settings have not been performed. We here investigated the impact of exogenous intranasal oxytocin on the group-level social organization of 5 groups of horses (N = 58; 12 mares and 46 geldings) through GPS tracking and social network analysis. We find oxytocin flattened social differentiation across levels. Most strikingly, oxytocin did not simply reinforce existing bonds but selectively shifted social preferences toward homogenization - individuals and pairs who otherwise rarely associated spent more time close together, while individuals and pairs with the highest baseline association instead spent more time further apart. This resulted in a more distributed structure and lower clustering coefficient at the network level. These effects reinforce and extend oxytocin's role in collective behavior, social organization, and the evolution of group-based sociality across taxa.

Cholecystocutaneous Fistula Associated with Edwardsiella tarda as a Result of Aggressive Lymphoma Development.

A cholecystocutaneous fistula is a type of external biliary fistula that occurs when there is an abnormal connection between the gallbladder and skin. We report the first case of a cholecystocutaneous fistula that occurred in association with the development of lymphoma in the gallbladder. A 76-year-old woman who was under observation for follicular lymphoma with a low tumor burden presented with fatigue and abdominal pain. Imaging studies revealed cholecystitis associated with an abdominal subcutaneous abscess, and lymphoma transformation was confirmed by a lymph node biopsy. Edwardsiella tarda was cultured from both the abdominal subcutaneous abscess and percutaneous transhepatic gallbladder drainage, demonstrating cholecystocutaneous fistula, and open cholecystectomy revealed lymphoma cell infiltration into the gallbladder. Our case showed unique complications, and its successful management was associated with aggressive lymphoma development.

Dominant missense variants in SREBF2 are associated with complex dermatological, neurological, and skeletal abnormalities.

PURPOSE: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation. METHODS: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences of SREBF2 variants on SREBP pathway function. RESULTS: We observed reduced LD formation, endoplasmic reticulum expansion, accumulation of aberrant lysosomes, and deficits in SREBP2 target gene expression in fibroblasts from an affected individual, indicating that the SREBF2 variant inhibits SREBP pathway activation. Using our fly model, we discovered that SREBF2 variants fail to induce LD production and act in a dominant-negative manner, which can be rescued by overexpression of S1P. CONCLUSION: Taken together, these data reveal a mechanism by which SREBF2 pathogenic variants that disrupt the S1P cleavage motif cause disease via dominant-negative antagonism of S1P, limiting the cleavage of S1P targets, including SREBP1 and SREBP2.

Expression pattern of Runt-related transcription factor (RUNX) family members and the role of RUNX1 during kidney development.

Runt-related transcription factor (RUNX) family members play critical roles in the development of multiple organs. Mammalian RUNX family members, consisting of RUNX1, RUNX2, and RUNX3, have distinct tissue-specific expression and function. In this study, we examined the spatiotemporal expression patterns of RUNX family members in developing kidneys and analyzed the role of RUNX1 during kidney development. In the developing mouse kidney, RUNX1 protein was strongly expressed in the ureteric bud (UB) tip and weakly expressed in the distal segment of the renal vesicle (RV), comma-shaped body (CSB), and S-shaped body (SSB). In contrast, RUNX2 protein was restricted to the stroma, and RUNX3 protein was only expressed in immune cells. We also analyzed the expression of RUNX family members in the cynomolgus monkey kidney. We found that expression patterns of RUNX2 and RUNX3 were conserved between rodents and primates, whereas RUNX1 was only expressed in the UB tip, not in the RV, CSB, or SSB of cynomolgus monkeys, suggesting a species differences. We further evaluated the roles of RUNX1 using two different conditional knockout mice: Runx1f/f:HoxB7-Cre and Runx1f/f:R26-CreERT2 and found no abnormalities in the kidney. Our findings showed that RUNX1, which is mainly expressed in the UB tip, is not essential for kidney development.

Effects of focal cortical cooling on somatosensory evoked potentials in rats.

Although the focal brain cooling technique is widely used to examine brain function, the effects of cortical temperature at various levels on sensory information processing and neural mechanisms remain underexplored. To elucidate the mechanisms of temperature modulation in somatosensory processing, this study aimed to examine how P1 and N1 deflections of somatosensory evoked potentials (SEPs) depend on cortical temperature and how excitatory and inhibitory inputs contribute to this temperature dependency. SEPs were generated through electrical stimulation of the contralateral forepaw in anesthetized rats. The SEPs were recorded while cortical temperatures were altered between 17-38 °C either without any antagonists, with a gamma-aminobutyric acid type A (GABAA) receptor antagonist (gabazine), with an aminomethylphosphonic acid (AMPA) receptor antagonist (NBQX), or with an N-Methyl-D-aspartic acid (NMDA) receptor antagonist ([R]-CPP). The effects of different gabazine concentrations (0, 1, and 10 µM) were examined in the 35-38 °C range. The P1/N1 amplitudes and their peak-to-peak differences plotted against cortical temperature showed an inverted U relationship with a maximum at approximately 27.5 °C when no antagonists were administered. The negative correlation between these amplitudes and temperatures of ≥ 27.5 °C plateaued after gabazine administration, which occurred progressively as the gabazine concentration increased. In contrast, the correlation remained negative after the administration of NBQX and (R)-CPP. These results suggest that GABAergic inhibitory inputs contribute to the negative correlation between SEP amplitude and cortical temperature around the physiological cortical temperature.

Deep learning for automatic facial detection and recognition in Japanese macaques: illuminating social networks.

Individual identification plays a pivotal role in ecology and ethology, notably as a tool for complex social structures understanding. However, traditional identification methods often involve invasive physical tags and can prove both disruptive for animals and time-intensive for researchers. In recent years, the integration of deep learning in research has offered new methodological perspectives through the automatisation of complex tasks. Harnessing object detection and recognition technologies is increasingly used by researchers to achieve identification on video footage. This study represents a preliminary exploration into the development of a non-invasive tool for face detection and individual identification of Japanese macaques (Macaca fuscata) through deep learning. The ultimate goal of this research is, using identification done on the dataset, to automatically generate a social network representation of the studied population. The current main results are promising: (i) the creation of a Japanese macaques' face detector (Faster-RCNN model), reaching an accuracy of 82.2% and (ii) the creation of an individual recogniser for the Kojima Island macaque population (YOLOv8n model), reaching an accuracy of 83%. We also created a Kojima population social network by traditional methods, based on co-occurrences on videos. Thus, we provide a benchmark against which the automatically generated network will be assessed for reliability. These preliminary results are a testament to the potential of this approach to provide the scientific community with a tool for tracking individuals and social network studies in Japanese macaques.

The Role of Frequent Screening or Diagnostic Testing of Serum Cryptococcal Antigen in Liver Transplant Recipients: A Descriptive Epidemiology.

Background: Cryptococcosis is a notable infectious complication of liver transplantation. Currently, there is no recommendation for screening serum cryptococcal antigen (CrAg) levels in solid organ transplant recipients. We aimed to explore the role of serum CrAg in liver transplant recipients at an institution where posttransplant serum CrAg has been widely tested. Methods: This retrospective study was conducted at a tertiary care center in Japan. All liver transplant recipients with serum CrAg measured either for screening or for diagnostic testing at least once after transplantation between April 2005 and March 2022 were included. For participants with either a positive CrAg test result or positive culture for Cryptococcus, we manually reviewed clinical manifestations, management, and prognosis from the medical records. Results: During the study period, 12 885 serum CrAg tests (median, 16 tests per patient) were performed in 468 liver transplant recipients. The 1-year posttransplant incidence of positive serum CrAg test results and culture-proven cryptococcosis was 1.9% (9/468) and 0.6% (3/468), respectively. No patient with persistently negative serum CrAg test results showed growth of Cryptococcus in culture. Four patients had clinical manifestations consistent with cryptococcosis, of whom 2 (50.0%) started antifungal therapy promptly based on a positive serum CrAg test result. In contrast, 5 patients had no clinical manifestations. Three of the 5 (60.0%) patients did not receive antifungal therapy and remained free of clinical manifestations. Conclusions: Serum CrAg test was more sensitive than culture among liver transplant recipients and prompted early diagnosis and antifungal therapy in symptomatic patients. However, serial screening of serum CrAg in asymptomatic patients may be of little value, with the potential for false-positive results.

Exogenous oxytocin increases gaze to humans in male cats.

Although oxytocin (OT) plays a role in bonding between heterospecifics and conspecifics, the effects of OT on the formation of such interspecific social behavior have only been investigated between humans and dogs (Canis familiaris). In this study, for comparative evaluation of the effects of OT between dog-human and cat-human social interaction, we investigated the effects of exogenous OT on the behavior of domestic cats (Felis silvestris catus) toward humans. We intranasally administered OT or saline to 30 cats using a nebulizer and recorded their behavior (gaze, touch, vocalization, and proximity). The results showed an interaction between the administration condition and sex for gaze duration. Post hoc analyses revealed a significant increase in gaze in the OT condition in male cats but not in females. There were no significant differences in gaze toward owners and strangers in any condition or sex. The male-specific OT-mediated increase in gaze toward humans observed in this study differs from previous research on dogs wherein such effects were observed only in females. These findings suggest an overall effect of exogenous OT on cats' social relationship with humans as well as the possibility of different mechanisms between cat-human and dog-human relationships.

Whole organism snRNA-seq reveals systemic peripheral changes in Alzheimer's Disease fly models.

Peripheral tissues become disrupted in Alzheimer's Disease (AD). However, a comprehensive understanding of how the expression of AD-associated toxic proteins, Aß42 and Tau, in neurons impacts the periphery is lacking. Using Drosophila, a prime model organism for studying aging and neurodegeneration, we generated the Alzheimer's Disease Fly Cell Atlas (AD-FCA): whole-organism single-nucleus transcriptomes of 219 cell types from adult flies neuronally expressing human Aß42 or Tau. In-depth analyses and functional data reveal impacts on peripheral sensory neurons by Aß42 and on various non-neuronal peripheral tissues by Tau, including the gut, fat body, and reproductive system. This novel AD atlas provides valuable insights into potential biomarkers and the intricate interplay between the nervous system and peripheral tissues in response to AD-associated proteins.

A Case of C3 Nephritis With a Rare Variant of the CFHR5 Gene.

C3 nephropathy is a renal disease caused by the aberrant activation of the alternative complement pathway. The long-term renal prognosis of C3 nephropathy is generally poor, and elucidation of its pathogenesis is clinically important. Genetic abnormalities within complement genes, encompassing autoantibodies targeting complement components and complement factor H-related proteins (CFHRs), can lead to abnormal complement activation. CFHR5 is one of the best-known responsible genes for C3 nephritis. Moreover, the renal prognosis can vary depending on the specific type of genetic mutation. Here, we report the case of a young woman with C3 nephritis and a heterozygous rare variant, P453S, in CFHR5. The P453S variant, characterized by amino acid substitutions with a low allele frequency, was located in the region essential for CFHR5 protein function, and multiple in silico analyses were done suggesting the pathological significance of P453S. The renal function of our patient remains stable. The P453S variant might contribute to the suppression of the CFHR5 protein's function, resulting in gradual complement progression and a favorable renal prognosis.

De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is expressed in multiple tissues, including the central nervous system where it is present in neurons but not in glia. Homozygous fry LoF mutation is lethal at various developmental stages, and loss of fry in mutant clones causes defects in wings and compound eyes. We next modeled four out of the five missense variants found in affected individuals using fry knockin alleles. One variant behaves as a severe LoF variant, whereas two others behave as partial LoF variants. One variant does not cause any observable defect in flies, and the corresponding human variant is not confirmed to be de novo, suggesting that this is a variant of uncertain significance. In summary, our findings support that fry is required for proper development in flies and that the LoF variants in FRYL cause a dominant disorder with developmental and neurological symptoms due to haploinsufficiency.

Surgical outcomes and predictive value for major complications of robot-assisted radical cystectomy of real-world data in a single institution in Japan.

OBJECTIVE: The objective of the study was to describe the surgical outcome of robot-assisted radical cystectomy and predictive factors for major complications in real-world clinical practice at a single institution in Japan. METHODS: We retrospectively analyzed 208 consecutive patients undergoing robot-assisted radical cystectomy at our institution between 2019 and 2023. Patient and disease characteristics, intraoperative details, and perioperative outcomes were reviewed. Postoperative complications were defined as minor complications (Clavien-Dindo grades 1-2) or major complications (grades 3-5). Predictors of complications were examined using multivariable logistic analysis. RESULTS: Overall, 147 men and 61 women, median age 70 years (interquartile range, 62-77), were included in this study. Median operative time and estimated blood loss were 8.4 h and 185 mL, respectively; 11 patients (5%) received intraoperative blood transfusions. For urinary diversions, ileal conduit, neobladder, and cutaneous ureterostomy were performed in 153 (74%), 49 (24%), and 6 (3%) patients, respectively. Urinary diversions were primarily performed with extracorporeal urinary diversion. In total, 140 complications occurred in 111 patients (53%) within 30 days. Of these patients, 31 major complications occurred in 28 patients, and one perioperative death (0.5%) with a postoperative cardiovascular event. Multivariable analysis showed only prolonged operative time (odds ratio: 4.34, 95% confidence interval: 1.82-10.35, p < 0.01) was the independent risk factor for major complications. CONCLUSIONS: This study reports surgical outcomes at our single institution. Prolonged operative time was a significant prognostic factor for major complications. As far as we know, this study reports the largest number of robot-assisted radical cystectomy cases at a single center in Japan.

Endoscopic mastectomy followed by immediate breast reconstruction with fat grafting for breast cancer.

BACKGROUND: Although endoscopic mastectomy has been associated with good tolerance and enhanced patient satisfaction, limitations such as the implant or flap size for reconstruction with small incisions remain unresolved. Fat grafting (FG) can expand tissue volume with pinhole skin incisions. Herein, we evaluated the safety and efficacy of endoscopic mastectomy followed by immediate FG. METHODS: Patients who underwent endoscopic mastectomy with immediate FG reconstruction from 2015 to 2021 were retrospectively evaluated to establish surgical outcomes and prognosis. RESULTS: Twenty-three patients with clinical stage 0 or I breast cancer underwent unilateral endoscopic mastectomy with immediate FG. The median age was 45 years (41-55), and the median body mass index was 19.3 kg/m2 (15.8-26.6). Endoscopically performed procedures included skin-sparing mastectomies in 18 patients (78%) and nipple-sparing mastectomies in five patients (22%). The median procedure duration was 295 min (242-346). The median specimen weight was 133 g (71-334), and the median grafted fat volume was 200 mL (136-320). No patient required reoperation or additional procedures for complications. One patient experienced recurrence at a median follow-up of 56.1 months and underwent resection; the patient was alive without recurrence 54 months post-resection. CONCLUSION: To the best of our knowledge, this is the first report of endoscopic mastectomy with immediate FG for reconstruction. When compared with other immediate autologous reconstructions, our strategy could minimize the skin incision and procedure duration, as well as limit complications. Further prospective investigations are needed to evaluate oncological safety, surgical outcomes, and patient satisfaction.

Low serum concentrations of bevacizumab and nivolumab owing to excessive urinary loss in patients with proteinuria: a case series.

PURPOSE: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients. METHODS: Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry. RESULTS: We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase. CONCLUSION: This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.

Proteinuria frequency and subsequent renal dysfunction in bevacizumab-treated patients: a single center, retrospective, observational study.

BACKGROUND: Proteinuria is a common adverse event observed during treatment with antivascular endothelial growth factor (VEGF) antibodies. Proteinuria is a risk factor for renal dysfunction and cardiovascular complications in patients with chronic kidney disease. However, the association between anti-VEGF antibody-induced proteinuria and renal dysfunction or cardiovascular complications remains unclear. METHODS: This retrospective, observational study included patients with cancer that were treated with bevacizumab (BV) at Kyoto University Hospital (Kyoto, Japan) between January 2006 and March 2018. Adverse event rates were compared between patients who developed qualitative ≥ 2 + proteinuria and those who developed < 1 + proteinuria. Adverse events were defined as renal dysfunction (i.e., ≥ 57% decrease in the eGFR, compared to the rate at the initial treatment) and hospitalization due to BV-associated cardiovascular complications and other adverse events. RESULTS: In total, 734 patients were included in this analysis. Renal dysfunction was more common in patients with ≥ 2 + proteinuria than in those with < 1 + proteinuria (13/199, 6.5% vs. 12/535, 2.3%). Seven of these 13 patients with ≥ 2 + proteinuria had transient reversible renal dysfunction. Only four (2.0%) patients had BV-associated renal dysfunction. Of the 734 patients, six patients, 16 patients, and 13 patients were hospitalized because of the adverse events of cardiovascular complications, thromboembolisms, and cerebrovascular complications, respectively. No relationship was observed between these adverse events and proteinuria. CONCLUSION: BV treatment-induced proteinuria was not associated with renal dysfunction or other adverse events. Continuing BV with caution is a possible treatment option, even after proteinuria develops, in patients with cancer and a limited prognosis.

Teaching Social Niceties to Individuals with Autism Spectrum Disorder Using the Textual Prompt.

This study examines the effectiveness of textual prompts in acquiring social niceties in the workplace for five individuals with autism spectrum disorder. Based on the results of this study, resource- and time-efficiency interventions are discussed. The participants were taught two statements: "Do you have a minute?" and "Thank you for your time." The participants worked in a simulation setting simulating the workplace. When an opportunity for interaction with an actor acting as a supervisor or colleague was provided to the participants, they were required to use social niceties before and after the interaction. During the training, the participants were presented with a textual prompt to use social niceties. As a result, most participants were able to use social niceties compared to the baseline. However, the percentage of correct responses was not stable, and the results did not show that the participants had fully acquired social niceties. A comparison of the results of the previous study with the results of this study indicates that it is difficult to obtain sufficient efficacy from interventions using only the textual prompt.