Primary Hepatic Melanoma: A Diagnostic Surprise.

Melanoma is a relatively rare malignancy with a highly aggressive biological behavior. Metastases to other sites, like lymph nodes and liver are common, but primary hepatic melanoma is a rarity with poor survival ranging from months to few years. Diagnosis of primary hepatic melanoma via clinical features and imaging technology is difficult because of its ambiguous features. Here, we present a 26-year-old North Indian woman admitted in the department of gastrointestinal surgery at our tertiary care hospital with the complaint of pain in the abdomen for a month associated with the loss of appetite and subsequent weight loss. The liver function tests were within normal limits and viral markers were negative. The triple-phase computed tomography scan of abdomen showed significant hepatomegaly and two well-defined lesions in both lobes of the liver. Histopathological evaluation was performed on the core liver biopsies submitted from the liver lesions. A malignant tumor with abundant black intracytoplasmic pigment was identified. Immunohistochemistry proved the tumor to be melanoma. The detailed clinical history, laboratory, and radiological investigations were acquired and analyzed to rule out a metastatic lesion of the same. A final diagnosis of primary hepatic melanoma was thus rendered. Primary hepatic melanoma is extremely uncommon and has been rarely reported. Preoperative diagnosis is challenging due to low index of suspicion and nonspecific clinical features. In this case report, we discuss the clinicopathological features of primary hepatic melanoma and review the literature so as to increase the awareness and improve our understanding of the disease.

Regulated regeneration of adipose tissue in lipodystrophic Agpat2-null mice partially ameliorates hepatic steatosis.

Both humans and mice with congenital generalized lipodystrophy due to AGPAT2 deficiency develop diabetes mellitus, insulin resistance, and hepatic steatosis, which have been attributed to the near total loss of adipose tissue (AT). Here, we show that regulated AT regeneration in doxycycline (dox)-fed Tg-AT-hAGPAT2;mAgpat2-/- mice partially ameliorates hepatic steatosis at 12 weeks of age and causes reduced expression of genes involved in hepatic de novo lipogenesis despite partial (∼30-50%) AT regeneration compared to that in wild-type mice. Compared to chow-fed Tg-AT-hAGPAT2;mAgpat2-/- mice, those fed dox diet had markedly reduced serum insulin levels, suggesting an improvement in insulin resistance. Interestingly, the fasting plasma glucose levels in dox-fed Tg-AT-hAGPAT2;mAgpat2-/- mice were no different than those in chow-fed wild-type mice. Indirect calorimetry revealed normalization in the energy balance of dox-fed Tg-AT-hAGPAT2;mAgpat2-/- mice compared to that in chow-fed mice. This study's findings suggest that partial AT regeneration in lipodystrophic mice can ameliorate metabolic derangements.

Adipose-specific overexpression of human AGPAT2 in mice causes increased adiposity and mild hepatic dysfunction.

AGPAT2, a critical enzyme involved in the biosynthesis of phospholipids and triacylglycerol (TAG), is highly expressed in adipose tissue (AT). Whether overexpression of AGPAT2 in AT will result in increased TAG synthesis (obesity) and its metabolic complications remains unknown. We overexpressed human AGPAT2 specifically in AT using the adiponectin promoter and report increased mass of subcutaneous, gonadal, and brown AT in wild-type mice. Unexpectedly, overexpression of hAGPAT2 did not change the pattern of phospholipid or TAG concentration of the AT depots. Although there is an increase in liver weight, plasma aspartate aminotransferase, and plasma insulin at various time points of the study, it did not result in significant liver dysfunction. Despite increased adiposity in the Tg-AT-hAGPAT2;mAgpat2+/+ mice, there was no significant increase in TAG concentration of AT. Therefore, this study suggests a role of AGPAT2 in the generation of AT, but not for adipocyte TAG synthesis.

Early-onset diabetes mellitus as a presenting feature of Werner's syndrome in an Indian family.

BACKGROUND: Diabetes mellitus (DM) in children and adolescents is typically caused by type 1 DM, followed by type 2 DM and maturity-onset diabetes of the young (MODY). We report an unusual Asian Indian family in which three members presented with DM at ages 15, 20, and 30, but not fitting the typical clinical picture of type 1 DM, type 2 DM, or MODY. The primary objective was to elucidate the molecular genetic basis of DM in this family. METHODS: The proband, a 22-year-old man, had short stature, gray hair, osteoporosis, and markedly reduced subcutaneous fat on the body, especially on the extremities along with acanthosis nigricans, and developed myxoid malignant peripheral nerve sheath tumor. Detailed family history revealed multiple loops of consanguinity. The proband underwent whole-genome sequencing, and seven relatives underwent whole-exome sequencing. RESULTS: The proband and three additional family members were found to have the homozygous c.561A>G nucleotide variant of WRN RecQ-like helicase (WRN) gene consistent with the diagnosis of Werner's syndrome. The c.561A>G variant induces a new splicing site on exon 6 resulting in a truncated WRN protein, p.Lys187Trpfs*13. CONCLUSION: Our report brings to attention the onset of DM during childhood or early adulthood in patients with Werner's syndrome who typically develop type 2 DM around the age of 30-40 years. Presence of consanguinity among parents, dysmorphic features, and malignancy should prompt consideration of diagnosis of Werner's syndrome.

Effect of Intensive Blood Pressure Control on Kidney Outcomes: Long-Term Electronic Health Record-Based Post-Trial Follow-Up of SPRINT.

BACKGROUND: Intensive BP lowering in the Systolic Blood Pressure Intervention Trial (SPRINT) produced acute decreases in kidney function and higher risk for AKI. We evaluated the effect of intensive BP lowering on long-term changes in kidney function using trial and outpatient electronic health record (EHR) creatinine values. METHODS: SPRINT data were linked with EHR data from 49 (of 102) study sites. The primary outcome was the total slope of decline in eGFR for the intervention phase and the post-trial slope of decline during the observation phase using trial and outpatient EHR values. Secondary outcomes included a ≥30% decline in eGFR to <60 ml/min per 1.73 m 2 and a ≥50% decline in eGFR or kidney failure among participants with baseline eGFR ≥60 and <60 ml/min per 1.73 m 2 , respectively. RESULTS: EHR creatinine values were available for a median of 8.3 years for 3041 participants. The total slope of decline in eGFR during the intervention phase was -0.67 ml/min per 1.73 m 2 per year (95% confidence interval [CI], -0.79 to -0.56) in the standard treatment group and -0.96 ml/min per 1.73 m 2 per year (95% CI, -1.08 to -0.85) in the intensive treatment group ( P < 0.001). The slopes were not significantly different during the observation phase: -1.02 ml/min per 1.73 m 2 per year (95% CI, -1.24 to -0.81) in the standard group and -0.85 ml/min per 1.73 m 2 per year (95% CI, -1.07 to -0.64) in the intensive group. Among participants without CKD at baseline, intensive treatment was associated with higher risk of a ≥30% decline in eGFR during the intervention (hazard ratio, 3.27; 95% CI, 2.43 to 4.40), but not during the postintervention observation phase. In those with CKD at baseline, intensive treatment was associated with a higher hazard of eGFR decline only during the intervention phase (hazard ratio, 1.95; 95% CI, 1.03 to 3.70). CONCLUSIONS: Intensive BP lowering was associated with a steeper total slope of decline in eGFR and higher risk for kidney events during the intervention phase of the trial, but not during the postintervention observation phase.

Taurolidine/Heparin Lock Solution and Catheter-Related Bloodstream Infection in Hemodialysis: A Randomized, Double-Blind, Active-Control, Phase 3 Study.

BACKGROUND: Catheter-related bloodstream infections (CRBSIs) are one of the most prevalent, fatal, and costly complications of hemodialysis with a central venous catheter (CVC). The LOCK IT-100 trial compared the efficacy and safety of a taurolidine/heparin catheter lock solution that combines taurolidine 13.5 mg/ml and heparin (1000 units/ml) versus heparin in preventing CRBSIs in participants receiving hemodialysis via CVC. METHODS: LOCK IT-100 was a randomized, double-blind, active-control, multicenter, phase 3 study that enrolled adults with kidney failure undergoing maintenance hemodialysis via CVC from 70 US sites. Participants were randomized 1:1 to taurolidine/heparin catheter lock solution or heparin control catheter lock solution (1000 units/ml). The primary end point was time to CRBSI as assessed by a blinded Clinical Adjudication Committee. Secondary end points were catheter removal for any reason and loss of catheter patency. On the basis of a prespecified interim analysis, the Data and Safety Monitoring Board recommended terminating the trial early for efficacy with no safety concerns. RESULTS: In the full analysis population ( N =795), nine participants in the taurolidine/heparin arm ( n =397; 2%) and 32 participants in the heparin arm ( n =398; 8%) had a CRBSI. Event rates per 1000 catheter days were 0.13 and 0.46, respectively, with the difference in time to CRBSI being statistically significant, favoring taurolidine/heparin ( P < 0.001). The hazard ratio was 0.29 (95% confidence interval, 0.14 to 0.62), corresponding to a 71% reduction in risk of CRBSIs with taurolidine/heparin versus heparin. There were no significant differences between study arms in time to catheter removal for any reason or loss of catheter patency. The safety of taurolidine/heparin was comparable with that of heparin, and most treatment-emergent adverse events were mild or moderate. CONCLUSIONS: Taurolidine/heparin reduced the risk of developing a CRBSI in study participants receiving hemodialysis via CVC compared with heparin with a comparable safety profile. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study Assessing Safety & Effectiveness of a Catheter Lock Solution in Dialysis Patients to Prevent Bloodstream Infection, NCT02651428 .

Regulated adipose tissue-specific expression of human AGPAT2 in lipodystrophic Agpat2-null mice results in regeneration of adipose tissue.

Genetic loss of Agpat2 in humans and mice results in congenital generalized lipodystrophy with near-total loss of adipose tissue and predisposition to develop insulin resistance, diabetes mellitus, hepatic steatosis, and hypertriglyceridemia. The mechanism by which Agpat2 deficiency results in loss of adipose tissue remains unknown. We studied this by re-expressing human AGPAT2 (hAGPAT2) in Agpat2-null mice, regulated by doxycycline. In both sexes of Agpat2-null mice, adipose-tissue-specific re-expression of hAGPAT2 resulted in partial regeneration of both white and brown adipose tissue (but only 30%-50% compared with wild-type mice), which had molecular signatures of adipocytes, including leptin secretion. Furthermore, the stromal vascular fraction cells of regenerated adipose depots differentiated ex vivo only with doxycycline, suggesting the essential role of Agpat2 in adipocyte differentiation. Turning off expression of hAGPAT2 in vivo resulted in total loss of regenerated adipose tissue, clear evidence that Agpat2 is essential for adipocyte differentiation in vivo.

Xanthogranulomatous cholecystitis with histologic features suggestive of IgG4 related cholecystitis - A morphologic overlap with IgG4 related disease.

AIMS: Both xanthogranulomatous cholecystitis (XGC) and IgG4-related cholecystitis (IgG4-CC) are rare chronic fibroinflammatory tumefactive diseases of the gallbladder, which cause a strong confusion with resectable malignancy in view of their mass forming tendency with extension into the liver. We aim to study the histopathologic features of xanthogranulomatous cholecystitis with regard to IgG4-related cholecystitis in extended cholecystectomy specimens. METHODS AND RESULTS: Sixty cases of extended cholecystectomy with liver wedge resection, diagnosed as XGC on histopathology from January 2018 to December 2021 were retrieved from the archives. Representative sections were reviewed by two pathologists independently. Immunohistochemistry was performed for IgG4 and IgG4/IgG was derived. The cases were dichotomized in two groups on the basis of IgG4 positive plasma cells. Six cases with >50 IgG4 positive plasma cells had storiform fibrosis, IgG4/IgG ratio >0.40 and extra-cholecystic extension. Of these, 50 % had obliterative phlebitis and 66.7 % had perineural plasma cell wrapping. CONCLUSIONS: A small subset of XGC cases (~10 %) had morphologic overlap with IgG4-CC, but should not be overcalled as the diagnosis of IgG4-RD requires an integrative approach based on clinical, serologic and imaging criteria and not solely on histopathology.

Concordance between clinical outcomes in the Systolic Blood Pressure Intervention Trial and in the electronic health record.

BACKGROUND: Randomized trials are the gold standard for generating clinical practice evidence, but follow-up and outcome ascertainment are resource-intensive. Electronic health record (EHR) data from routine care can be a cost-effective means of follow-up, but concordance with trial-ascertained outcomes is less well-studied. METHODS: We linked EHR and trial data for participants of the Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial comparing intensive and standard blood pressure targets. Among participants with available EHR data concurrent to trial-ascertained outcomes, we calculated sensitivity, specificity, positive predictive value, and negative predictive value for EHR-recorded cardiovascular disease (CVD) events, using the gold standard of SPRINT-adjudicated outcomes (myocardial infarction (MI)/acute coronary syndrome (ACS), heart failure, stroke, and composite CVD events). We additionally compared the incidence of non-CVD adverse events (hyponatremia, hypernatremia, hypokalemia, hyperkalemia, bradycardia, and hypotension) in trial versus EHR data. RESULTS: 2468 SPRINT participants were included (mean age 68 (SD 9) years; 26% female). EHR data demonstrated ≥80% sensitivity and specificity, and ≥ 99% negative predictive value for MI/ACS, heart failure, stroke, and composite CVD events. Positive predictive value ranged from 26% (95% CI; 16%, 38%) for heart failure to 52% (95% CI; 37%, 67%) for MI/ACS. EHR data uniformly identified more non-CVD adverse events and higher incidence rates compared with trial ascertainment. CONCLUSIONS: These results support a role for EHR data collection in clinical trials, particularly for capturing laboratory-based adverse events. EHR data may be an efficient source for CVD outcome ascertainment, though there is clear benefit from adjudication to avoid false positives.

Lessons learnt and future directions in managing dialysis access during the COVID 19 pandemic: Patient and provider experience in the United States.

BACKGROUND: The COVID 19 pandemic adversely impacted delivery of preventive, routine, urgent, and essential care worldwide. Dialysis access care was particularly affected due to the lack of specific guidelines regarding procedures for its creation and maintenance. Early guidance by Centers for Medicare and Medicaid was inadvertently interpreted as guidance to stop dialysis access procedures. Prompt action by professional societies was needed to furnish detailed guidance to establish essential nature of these procedures. METHODS: The American Society of Diagnostic and Interventional Nephrology (ASDIN) issued a joint statement with Vascular Access Society of the Americas (VASA) - "Maintaining Lifelines for ESKD Patients" to clearly establish the role of vascular access as a lifeline for ESKD (End Stage Kidney Disease) patients and the importance and urgency of its timely management. ASDIN also conducted a survey in mid-2020, that was administered to the ASDIN database as well as shared with the general public via the organization's social media platforms. The respondents reported their experiences in the care of dialysis access, practice patterns and the utility of the ASDIN-VASA statement during the COVID 19 pandemic. RESULTS: Of the 2030 individual surveys sent, 581 were opened and 53 (9.1%) responses were received from different parts of the country and from different practice settings. ASDIN COVID 19 triage document was frequently utilized and 83% of respondents found the document valuable. The survey also revealed multiple obstacles, including logistical and financial issues that led to significant disruption of services. CONCLUSIONS: The care of dialysis access was significantly affected in the United States during the COVID 19 pandemic due to multiple reasons. ASDIN actions provided valuable specific guidance regarding and explored barriers to dialysis access care. We describe those results and discuss strategies to prevent COVID 19 transmission with innovative strategies of providing access care. Individualized decision making is of essence when considering dialysis access procedures.

Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.

Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.

Classification of endoscopic ultrasound guided fine needle aspiration cytology of pancreatic space occupying lesions by Papanicolaou Society of Cytopathology System: A five year study.

BACKGROUND: Majority of the pancreatic cancer patients present at an advanced stage and have poor 5 year survival rate. Thus, there is a need for early detection of pancreatic cancer with the initiation of the therapy. MATERIALS & METHODS: This is a retrospective study including all the endoscopic ultrasound guided (EUS) guided pancreatic FNAs from 2016 to 2020. The aspirate smears were analyzed and classified according to The Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSCPC). RESULTS: A total of 245 EUS guided FNAs from pancreatic lesions were included. Cyto-histological correlation was done wherever available. Category I (non diagnostic) accounted for 40 cases (16%) cases, Category II (negative) comprised of 44 cases (18%); and Category III (Atypical) had 5 cases (2%). Category IV neoplastic-benign category included 3 cases of serous cystadenoma, while neoplastic-others category included pancreatic neuroendocrine tumors (n = 21), solid pseudo-papillary neoplasms (SPEN) (n = 12) and mucinous cystic neoplasms (n = 4). A total of 7 cases (2.8%) were reported in Category V (Suspicious). A diagnosis of adenocarcinoma (Category VI) was rendered in 105 cases (42.8%) cases. Rarer types included non Hodgkins lymphoma (n = 3) and one case of primary undifferentiated carcinoma with osteoclastic giant cells. Cyto-histological correlation in all categories was available in 58 cases with 8 false negative cases. Thus overall sensitivity of EUS guided FNAC was found to be 87.8% with a diagnostic yield of 83.6% while sensitivity in diagnosing adenocarcinoma was 96.9%. CONCLUSION: The present study highlights the spectrum of EUS guided FNA of pancreatic lesions in a subset of North Indian population and classified them according to PSCPC. EUS guided FNAC is a sensitive investigation which plays a crucial role in confirming the diagnosis of pancreatic space occupying lesions (SOLs) in advanced stage.

Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.

Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features.

Global challenges with providing vascular access care during COVID era.

BACKGROUND: The COVID-19 pandemic has adversely affected health care systems and dialysis access care in the US and across the globe. Beyond the initial challenges posed by the pandemic and despite the actions taken by health care leaders/organizations/professional societies such as the "Maintaining Lifelines for ESKD Patients" joint statement, there continues to be delays in providing timely care and performing elective and emergent dialysis access procedures worldwide. The aim of this study was to assess the global challenges associated with providing dialysis vascular access care across the international vascular access community during the pandemic. METHODS: The American Society of Diagnostic and Interventional Nephrology (ASDIN) conducted an online survey in 2021, that was administered to an expert panel of dialysis vascular access specialists and global leaders spanning across the international community. The respondents who are members of ASDIN, Association of Vascular Access and InTerventionAl Renal physicians (AVATAR), Asia Pacific Society of Dialysis Access (APSDA), Peruvian Vascular Access Society (APDAV), and Australia/New Zealand Society of Interventional Nephrology (ANZSIN) reported their experiences in the care of dialysis vascular access, practice patterns, and challenges faced during the COVID pandemic. RESULTS: Of the 53 individual surveys sent, 16 were opened and 11 (69%) responses were received from across the world and from different practice settings. The survey revealed the continued challenges facing the international community, the stark disparities in care delivery, supply chain disruption and logistical, regulatory, and financial issues that the global community continues to face in the ongoing pandemic. CONCLUSIONS: The COVID19 pandemic is far from over, and the challenges and barriers to providing dialysis access care seen on the initial ASDIN survey in the US seem to extend across the globe. We describe those results and discuss options, opportunities, and innovative tools to provide dialysis and access care during these trying times.

Giant hyperplastic gastric polyp: A diagnostic dilemma!!

Gastric hyperplastic polyps (GHP) account for a majority of benign gastric polyps. Most of the GHPs are <2 cm, asymptomatic, and incidentally detected on endoscopy or radiologically. With increasing size, these polyps manifest as upper gastrointestinal bleeding, iron deficiency anemia, and gastric outlet obstruction (GOO). We report an unusual case of giant GHP simulating gastric carcinoma and posing as a diagnostic challenge for the surgeons emphasizing the diagnostic role of histopathology. A 46-year-old female presented with clinical features of progressive GOO for 1 year. Endoscopy revealed an eccentric proliferative lesion in the antrum. Computed tomography showed a polypoidal, enhancing mural thickening involving distal body and antro-pyloric region measuring 8.4 cm × 6.6 cm × 1.8 cm. Subtotal gastrectomy was done in view of clinical features of GOO and having a clinical suspicion of malignancy. Gross examination showed a giant sessile hyperplastic polyp with lobulated surface. Microscopy revealed features of a large, sessile hyperplastic polyp without any evidence of dysplasia. The patient was symptomatically relieved and is on follow-up. To conclude, giant GHPs can mimic gastric carcinoma on endoscopy and radiology. The possibility of giant GHP should be kept in mind in the presence of an intensely contrast-enhancing polypoidal lesion in the gastric antrum. Long-term endoscopic follow-up is recommended.

Discovery of MDV6058 (PF-06952229), a selective and potent TGFßR1 inhibitor: Design, synthesis and optimization.

Compound 1 is a potent TGF-ß receptor type-1 (TGFßR1 or ALK5) inhibitor but is metabolically unstable. A solvent-exposed part of this molecule was used to analogue and modulate cell activity, liver microsome stability and mouse pharmacokinetics. The evolution of SAR that led to the selection of 2 (MDV6058 / PF-06952229) as a preclinical lead compound is described.

Effect of Intensive versus Standard BP Control on AKI and Subsequent Cardiovascular Outcomes and Mortality: Findings from the SPRINT EHR Study.

Background: Adjudication of inpatient AKI in the Systolic Blood Pressure Intervention Trial (SPRINT) was based on billing codes and admission and discharge notes. The purpose of this study was to evaluate the effect of intensive versus standard BP control on creatinine-based inpatient and outpatient AKI, and whether AKI was associated with cardiovascular disease (CVD) and mortality. Methods: We linked electronic health record (EHR) data from 47 clinic sites with trial data to enable creatinine-based adjudication of AKI. Cox regression was used to evaluate the effect of intensive BP control on the incidence of AKI, and the relationship between incident AKI and CVD and all-cause mortality. Results: A total of 3644 participants had linked EHR data. A greater number of inpatient AKI events were identified using EHR data (187 on intensive versus 155 on standard treatment) as compared with serious adverse event (SAE) adjudication in the trial (95 on intensive versus 61 on standard treatment). Intensive treatment increased risk for SPRINT-adjudicated inpatient AKI (HR, 1.51; 95% CI, 1.09 to 2.08) and for creatinine-based outpatient AKI (HR, 1.40; 95% CI, 1.15 to 1.70), but not for creatinine-based inpatient AKI (HR, 1.20; 95% CI, 0.97 to 1.48). Irrespective of the definition (SAE or creatinine based), AKI was associated with increased risk for all-cause mortality, but only creatinine-based inpatient AKI was associated with increased risk for CVD. Conclusions: Creatinine-based ascertainment of AKI, enabled by EHR data, may be more sensitive and less biased than traditional SAE adjudication. Identifying ways to prevent AKI may reduce mortality further in the setting of intensive BP control.

Face-sparing Congenital Generalized Lipodystrophy Type 1 Associated With Nonclassical Congenital Adrenal Hyperplasia.

CONTEXT: Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1. CASE DESCRIPTION: We report a 21-year-old woman of European descent with CGL1 who had sparing of the facial fat and premature thelarche at birth with premature pubarche and menstrual bleeding at age 3 years. Her serum 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) after cosyntropin stimulation test, suggestive of nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. Hydrocortisone replacement therapy from age 3.5 to 10 years resulted in cessation of menstruation and growth of pubic hair, and a reduction of breast size. Sanger and whole-exome sequencing revealed compound heterozygous variants c.493-1G>C; p.(Leu165_Gln196del), and c.del366_588+534; p.(Leu123Cysfs*55) in AGPAT2 plus c.806G>C; p.(Ser269Thr) and c.844G>T; p.(Val282Leu) in CYP21A2. She developed diabetes at age 13 requiring high-dose insulin and had 7 episodes of acute pancreatitis due to extreme hypertriglyceridemia in the next 5 years. Metreleptin therapy was initiated at age 18 and after 3 years, she had remission of diabetes and hypertriglyceridemia; however, menstrual irregularity and severe hirsutism did not improve. CONCLUSION: Concomitant NCAH in this CGL1 patient was associated with precocious pubertal development and sparing of facial fat. Metreleptin therapy drastically improved her hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism.

Clinical Aspects of Dialysis Interventions: Physical and Sonographic Findings.

Physical examination (PE) of arteriovenous access remains of high clinical value and continues to be recommended by leading societies and guidelines. PE is easy to learn and perform. Once learned, examiners can provide a comprehensive arteriovenous (AV) access examination in 20 to 30 seconds. Therefore, we continue to advocate that AV access PE should be part of the training for all dialysis care providers. Similarly, ultrasound can provide important AV access evaluation and provide key information. It is relatively cheap and can be readily available at the bed side. Additionally, it is well accepted by patients, as it is not expected to be associated with pain or discomfort during the examination. We present in this review the key components of PE, signs and symptoms of AV access dysfunction, and the role of ultrasound in AV access evaluation as a complementary tool to PE.