Clinical and pathological findings of SARS-CoV-2 infection and concurrent IgA nephropathy: a case report.

BACKGROUND: Since the Coronavirus Disease 2019 (COVID-19) outbreak, there is accumulating data on the clinical characteristics, treatment strategies and prognosis of COVID-19 in patients with concurrent renal disease. Postmortem investigations reveal renal involvement in COVID-19, and most recently, several biopsy researches reveal that acute tubular injury, as well as glomerular nephropathy such as collapsing glomerulopathy were common histological findings. However, to our best knowledge, there is limited data regarding IgA nephropathy in the setting of COVID-19. CASE PRESENTATION: In the present case, we report a 65-year old Chinese woman who presented with dark-colored urine, worsening proteinuria and decreased renal function after COVID-19 infection. She received a renal biopsy during COVID-19 infection. The renal biopsy revealed IgA nephropathy without any evidence for SARS-Cov-2. The findings suggest that the renal abnormalities were a consequence of exacerbation of this patient's underlying glomerular disease after COVID-19 infection. After a regimen of 3-day course of glucocorticoid and angiotensin II receptor blocker therapy, the patient recovered and remained stable upon follow-up. CONCLUSIONS: It is important to consider the underlying glomerular disease exacerbation as well as virus induced injury when dealing with renal abnormalities in patients with COVID-19. A kidney biopsy may be indicated to exclude a rapidly progressive glomerular disease.

Urban and rural Chinese adolescents' judgments and reasoning about personal and group jurisdiction.

This research applied social domain theory to illuminate reasoning about the perceived legitimacy and limits of group decision making (majority rule) among adolescents from urban and rural China (N = 160). Study 1 revealed that adolescents from both urban and rural China judged group decision making as acceptable for both social conventional and prudential issues, but not for personal issues or those that entailed possible harmful coercion of others. Study 2 revealed that personal jurisdiction develops later for rural than urban adolescents for certain issues (democratic rights to political participation and choice of friends). Results indicate that reasoning about group and personal jurisdiction in a non-Western society (China) is influenced by social domain, age, and environmental setting (modern vs. traditional).

Minimal Change Disease After First Dose of Pfizer-BioNTech COVID-19 Vaccine: A Case Report and Review of Minimal Change Disease Related to COVID-19 Vaccine.

RATIONALE: While severe complications are generally uncommon with novel coronavirus disease 2019 (COVID-19) vaccine, there has been a steady increase in the number of patients presenting with nephrotic syndrome and acute kidney injury after the administration of COVID-19 vaccine. Physicians should be made aware of minimal change disease as a potential complication associated with COVID-19 vaccine. PRESENTING CONCERNS: A 60-year-old male without significant past medical history presented with new onset of nephrotic syndrome approximately 10 days after his first dose of Pfizer-BioNTech COVID-19 vaccine. Laboratory findings showed hypoalbuminemia (20 g/L), elevated urine albumin/creatinine ratio (668 mg/mmol), and elevated creatinine of 116 µmol/L from a baseline of 79 µmol/L. DIAGNOSIS: A diagnostic kidney biopsy was performed 6 weeks after the onset of the edema and approximately 8 weeks after his first dose of Pfizer-BioNTech COVID-19 vaccine. The kidney biopsy findings were consistent with minimal change disease with focal acute tubular injury. INTERVENTIONS: The patient was treated conservatively with ramipril 10 mg and furosemide 80 mg daily 5 weeks after the onset of swelling. Prednisone 1 mg/kg was initiated immediately when the kidney biopsy result became available (approximately 6 weeks after the onset of edema). OUTCOMES: The patient remitted with rapid weight loss starting 2 weeks post prednisone initiation. NOVEL FINDINGS: De novo minimal change disease with acute tubular injury is a kidney manifestation following the administration of Pfizer-BioNTech COVID-19 vaccine. Minimal change disease is potentially a rare complication of Pfizer-BioNTech COVID-19 vaccine.

Immunoglobulin-A Vasculitis With Renal Involvement in a Patient With COVID-19: A Case Report and Review of Acute Kidney Injury Related to SARS-CoV-2.

RATIONALE: Acute kidney injury is a common complication of COVID-19 and is associated with significantly increased mortality. The most frequent renal biopsy finding with SARS-CoV-2 infection is acute tubular injury; however, new onset glomerular diseases have been reported. The development of persistent urinary abnormalities in patients with COVID-19 should prompt consideration for renal biopsy to rule out glomerulonephritis. PRESENTING CONCERNS: A 30-year-old man with no prior medical history presented to the emergency department with symptoms of COVID-19 and new onset painful purpuric rash, arthralgia, and abdominal pain. SARS-CoV-2 infection was confirmed with nucleic acid testing and laboratory investigations revealed preserved renal function with dysmorphic hematuria and nephrotic range proteinuria. DIAGNOSIS: A skin biopsy of the purpuric rash was performed, which demonstrated leukocytoclastic vasculitis. Renal biopsy revealed focally crescentic and segmentally necrotizing IgA nephropathy. Overall, given the clinical syndrome of glomerulonephritis with purpuric rash, arthralgia, and abdominal pain, the presentation is most in keeping with a diagnosis of IgA vasculitis in the setting of COVID-19. INTERVENTIONS: The patient was treated conservatively for COVID-19 in the community. A 7-day course of prednisone was started for the vasculitic rash. IgA nephropathy was managed conservatively with blood pressure control and RAAS blockade with losartan. OUTCOMES: With conservative management, the patient's COVID-19 symptoms resolved completely and he did not require hospital admission. Following prednisone therapy, the patient's rash, arthralgia, and abdominal pain improved. However, despite resolution of COVID-19, hematuria and proteinuria persisted. With the initiation of RAAS blockade, renal function remained stable and proteinuria improved dramatically at 6 weeks. NOVEL FINDINGS: De novo glomerulonephritis is a renal manifestation of SARS-CoV-2 infection beyond acute tubular injury. IgA vasculitis appears to be a rare complication of COVID-19.

Differential fracture response to traumatic brain injury suggests dominance of neuroinflammatory response in polytrauma.

Polytraumatic injuries, specifically long bone fracture and traumatic brain injury (TBI), frequently occur together. Clinical observation has long held that TBI can accelerate fracture healing, yet the complexity and heterogeneity of these injuries has produced conflicting data with limited information on underlying mechanisms. We developed a murine polytrauma model with TBI and fracture to evaluate healing in a controlled system. Fractures were created both contralateral and ipsilateral to the TBI to test whether differential responses of humoral and/or neuronal systems drove altered healing patterns. Our results show increased bone formation after TBI when injuries occur contralateral to each other, rather than ipsilateral, suggesting a role of the nervous system based on the crossed neuroanatomy of motor and sensory systems. Analysis of the humoral system shows that blood cell counts and inflammatory markers are differentially modulated by polytrauma. A data-driven multivariate analysis integrating all outcome measures showed a distinct pathological state of polytrauma and co-variations between fracture, TBI and systemic markers. Taken together, our results suggest that a contralateral bone fracture and TBI alter the local neuroinflammatory state to accelerate early fracture healing. We believe applying a similar data-driven approach to clinical polytrauma may help to better understand the complicated pathophysiological mechanisms of healing.

Clear cell papillary renal cell carcinoma as part of histologically discordant multifocal renal cell carcinoma: A case report and review of literature.

BACKGROUND: Multifocal renal cell carcinoma of different histological subtypes within a single kidney is rare. We report a recently classified clear cell (tubulo) papillary renal cell carcinoma as part of an unusual case of multifocal renal cell carcinoma of discordant histological subtypes. RESULTS: A 57 year-old-man was found to have multiple renal tumors and cysts on imaging and underwent a laparoscopic left radical nephrectomy. Pathological review showed multifocal renal cell carcinoma (clear cell (tubulo) papillary, clear cell and papillary renal cell carcinomas and papillary adenomas). Morphology of clear cell papillary renal cell carcinoma was supported by immunohistochemical profile (CK7+, HMWK+, CAIX+, AMACR-, CD10-, TFE3-). CONCLUSIONS: This is the first report of clear cell papillary renal cell carcinoma as part of multifocal renal cell carcinoma of different histological subtypes. Related lineage of clear cell renal cell carcinoma and papillary renal cell carcinoma is supported by the highest prevalence of their combination within multifocal renal cell carcinoma of different histological subtypes along with their molecular interconnection. Clear cell papillary renal cell carcinoma may be uniquely placed between clear cell and papillary renal cell carcinomas since it shows morphological features intermediate between clear cell and papillary renal cell carcinoma along with overlapping but unique immunohistochemical profile. Clear cell papillary renal cell carcinoma may be molecularly related to clear cell and papillary renal cell carcinomas since the tumors overexpress markers of HIF pathway activation with normal/elevated VHL mRNA expression and some tumors show losses of chromosome 3. Due to the overlapping morphology, it is possible that cases of clear cell papillary renal cell carcinoma may have been misclassified as papillary or clear cell renal cell carcinoma in the literature, incorrectly increasing their reported prevalence. Identification of multifocal RCCs may be related to the extent of pathological sampling.

Comparison of HER2 Dual-Color and Fluorescence In Situ Hybridization in Breast Cancer: A Cohort Study Emphasizing Equivocal Cases.

OBJECTIVES: Human epidermal growth factor receptor 2 (HER2; ERBB2 gene) is of prognostic and predictive significance in breast carcinoma. Both fluorescence in situ hybridization (FISH) and dual-color in situ hybridization (DISH) methods are available. DISH and FISH are highly concordant in validation studies, but differences may be more prevalent in the equivocal range. Our goal was to compare FISH and DISH on a cohort enriched for equivocal cases, with respect to HER2 determination. METHODS: The cohort was enriched for equivocal (2+) cases. DISH and FISH were evaluated using standard protocols and the results compared with respect to HER2 status, HER2 copy number, and HER2/chromosome 17 (Chr17) ratio. RESULTS: In total, 109 cases were identified. The agreement rate of DISH with FISH was 74%. The mean ± SD HER2/Chr17 ratio by DISH was 1.63 ± 0.08 vs 1.59 ± 0.26 by FISH (P = .45). The mean ± SD HER2 copy number by DISH was 4.56 ± 0.45 vs 4.75 ± 1.08 by FISH (P = .004). Individual signals were more easily resolved using FISH in cases with higher copy numbers. CONCLUSIONS: In our cohort enriched for equivocal cases, the numerical values of HER2 copy number were significantly lower using DISH, resulting in discordances. Although DISH is a valid method, variations with FISH may be expected in high-equivocal cases and in quality assurance activities.

Docosahexaenoic acid and palmitic acid reciprocally modulate monocyte activation in part through endoplasmic reticulum stress.

Palmitic acid (C16:0) and TLR2 ligand induce, but docosahexaenoic acid (DHA) inhibits monocyte activation. C16:0 and TLR2 or TLR4 ligand induce certain ER stress markers; thus, we determined whether ER stress induced by these agonists is sufficient to induce monocyte activation, and whether the ER stress is inhibited by DHA which is known to inhibit C16:0- or ligand-induced TLR activation. Monocyte activation and ER stress were assessed by TLR/inflammasome-induced IL-1ß production, and phosphorylation of IRE-1 and eIF2 and expression of CHOP, respectively in THP-1 cells. TLR2 ligand Pam3CSK4 induced phosphorylation of eIF2, but not phosphorylation of IRE-1 and CHOP expression. LPS also induced phosphorylation of both IRE-1 and eIF2 but not CHOP expression suggesting that TLR2 or TLR4 ligand, or C16:0 induces different ER stress responses. C16:0-, Pam3CSK4-, or LPS-induced IL-1ß production was inhibited by 4-phenylbutyric acid, an inhibitor of ER stress suggesting that IL-1ß production induced by these agonists is partly mediated through ER stress. Among two ER stress-inducing molecules, thapsigargin but not tunicamycin led to the expression of pro-IL-1ß and secretion of IL-1ß. Thus, not all types of ER stress are sufficient to induce inflammasome-mediated IL-1ß secretion in monocytes. Although both C16:0 and thapsigargin-induced IL-1ß secretion was inhibited by DHA, only C16:0-mediated ER stress was responsive to DHA. These findings suggest that the anti-inflammatory effects of DHA are at least in part mediated through modulating ER homeostasis and that the propensity of ER stress can be differentially modulated by the types of dietary fat we consume.

Use and misuse of waterfall plots.

BACKGROUND: "Waterfall plots" are used to describe changes in tumor size observed in clinical studies. Here we assess criteria for generation of waterfall plots and the impact of measurement error in generating them. METHODS: We reviewed published waterfall plots to investigate variability in criteria used to define them. We then compared waterfall plots generated by different observers for 24 patients enrolled in a completed phase I study of solid tumors with available computed tomography (CT) scans. Tumor measurements were made independently from CT scans according to Response Evaluation Criteria in Solid Tumors 1.1 by four board-certified radiologists and four medical oncologists. Interobserver variability was quantified and compared with reference measurements reported for the phase 1 study. All statistical tests were two-sided. RESULTS: There was substantial variability in criteria used to generate published waterfall plots. In the internal study, the results were statistically significantly different between all eight readers (P = .01, variance = 197.1, SD = 14.0) and between the oncologists (P = .01, variance = 319.0, SD = 17.9), but not between the radiologists (P = .68, variance = 70.8, SD = 8.4). Different observers classified one to five patients as having a partial response and 12-19 patients as having stable disease. Similar variability in categorization of response was observed when these error rates were applied to published waterfall plots. CONCLUSION: Waterfall plots are subject to substantial variability in criteria used to define them and are influenced by measurement errors; they should be generated by trained radiologists. Caution should be exercised when interpreting results of waterfall plots in the context of clinical trials.

The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs.

PURPOSE: Registration of new anticancer drugs is usually based on results of randomized controlled trials (RCTs) showing improved efficacy when compared with standard therapy. There is relatively less emphasis on toxicity. In our study, we analyze serious toxicities of newly approved anticancer drugs reported in pivotal RCTs used for drug registration. PATIENTS AND METHODS: We identified RCTs evaluating agents for the treatment of solid tumors approved by the US Food and Drug Administration between 2000 and 2010. Odds ratios (OR) and 95% CI were computed for three end points of safety and tolerability: treatment-related death, treatment-discontinuation related to toxicity, and grade 3 or 4 adverse events (AEs). These were then pooled in a meta-analysis. Correlations between these end points and the hazard ratios for overall survival (OS) and progression-free survival (PFS) were also assessed. RESULTS: Thirty-eight RCTs were analyzed. Compared with control groups, the odds of toxic death was greater for new agents (OR, 1.40; 95% CI, 1.15 to 1.70; P < .001) as were the odds of treatment-discontinuation (OR, 1.33; 95% CI, 1.22 to 1.45, P < .001). Grade 3 or 4 AEs (OR, 1.52; 95% CI, 1.35 to 1. 71; P < .001) were also more common with new agents, especially nonhematologic AEs such as diarrhea, skin reactions, and neuropathy. There were no significant correlations between safety end points and OS or PFS. CONCLUSION: New anticancer agents that lead to improvements in time-to-event end points also increase morbidity and treatment-related mortality. The balance between efficacy and toxicity may be less favorable in clinical practice because of selection of fewer patients with good performance status and limited comorbidities. Patients' baseline health characteristics should be considered when choosing therapy.