ANCA-negative granulomatosis polyangiitis: an airway emergency.

Granulomatosis polyangiitis (GPA) is an autoimmune condition causing inflammation of small blood vessels. It is a rare disorder that may affect various parts of the body. The diagnosis is often based on clinical examination, laboratory investigations and tissue biopsy. In about 10-20% of patients, the anti-neutrophilic cytoplasmic antibody (ANCA) can be negative, and histology maybe inconclusive, which can lead to diagnostic uncertainty. Failure to treat vasculitis can lead to morbidity and even mortality. We present a case report of a gentleman who was presented with an airway emergency with inflammation of the nasal cavity and subglottic involvement amounting to airway stenosis. His ANCA was negative and tissue biopsy from the subglottis was inconclusive. He underwent urgent dilatation of his airway, local therapies to the nose and was commenced on 10 cycles of cyclophosphamide. A follow-up of over 4 years has not shown any relapse of his disease clinically or biochemically. We discuss the clinical findings, diagnostic dilemma and multidisciplinary management of this life-threatening condition.

IgA vasculitis nephritis-outcomes in adult-onset disease.

OBJECTIVES: IgA vasculitis (IgAV) in adults has been relatively under-investigated. Since outcomes are worse in other forms of vasculitis with increasing age, we investigated the outcomes of IgAV comparing younger adults (18-34), middle aged adults (35-64) and elderly patients (≥64 years) focusing on kidney outcomes. METHODS: We identified patients with renal biopsy confirmed IgAV nephritis and collected data regarding clinical features and progression to end stage kidney disease (ESKD). The relationship between patient factors and ESKD was analysed by regression. RESULTS: We identified 202 cases, 34% aged 18-34, 43% aged 35-64 and 23% were elderly (>64 years). Median follow up was 44 months. Elderly patients were more likely to present with ESKD (23.9%) compared with middle aged (13.7%) and younger adults (2.9%)(χ2 11.6, p= 0.002). In patients with independent kidney function at biopsy, there was no difference in outcomes between age groups. Male gender, Black ethnicity, diabetes, histological evidence of chronic renal damage and eGFR < 30mls/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression. CONCLUSIONS: Elderly patients with IgAV are more likely to have ESKD at presentation, but there is no difference in renal survival between age groups, among those presenting with independent renal function. Renal impairment at biopsy is an independent risk factor for subsequent development of ESKD. There is significant variability in the timing of kidney biopsy and management of these patients among specialist centres. Young adults have outcomes more in keeping with childhood IgAV.

Risk Stratification to Predict Renal Survival in Anti-Glomerular Basement Membrane Disease.

SIGNIFICANCE STATEMENT: Most patients with anti-glomerular basement membrane (GBM) disease present with rapidly progressive glomerulonephritis, and more than half develop ESKD. Currently, no tools are available to aid in the prognostication or management of this rare disease. In one of the largest assembled cohorts of patients with anti-GBM disease (with 174 patients included in the final analysis), the authors demonstrated that the renal risk score for ANCA-associated vasculitis is transferable to anti-GBM disease and the renal histology is strongly predictive of renal survival and recovery. Stratifying patients according to the percentage of normal glomeruli in the kidney biopsy and the need for RRT at the time of diagnosis improves outcome prediction. Such stratification may assist in the management of anti-GBM disease. BACKGROUND: Prospective randomized trials investigating treatments and outcomes in anti-glomerular basement membrane (anti-GBM) disease are sparse, and validated tools to aid prognostication or management are lacking. METHODS: In a retrospective, multicenter, international cohort study, we investigated clinical and histologic parameters predicting kidney outcome and sought to identify patients who benefit from rescue immunosuppressive therapy. We also explored applying the concept of the renal risk score (RRS), currently used to predict renal outcomes in ANCA-associated vasculitis, to anti-GBM disease. RESULTS: The final analysis included 174 patients (out of a total of 191). Using Cox and Kaplan-Meier methods, we found that the RRS was a strong predictor for ESKD. The 36-month renal survival was 100%, 62.4%, and 20.7% in the low-risk, moderate-risk, and high-risk groups, respectively. The need for renal replacement therapy (RRT) at diagnosis and the percentage of normal glomeruli in the biopsy were independent predictors of ESKD. The best predictor for renal recovery was the percentage of normal glomeruli, with a cut point of 10% normal glomeruli providing good stratification. A model with the predictors RRT and normal glomeruli ( N ) achieved superior discrimination for significant differences in renal survival. Dividing patients into four risk groups led to a 36-month renal survival of 96.4% (no RRT, N ≥10%), 74.0% (no RRT, N <10%), 42.3% (RRT, N ≥10%), and 14.1% (RRT, N <10%), respectively. CONCLUSIONS: These findings demonstrate that the RRS concept is transferrable to anti-GBM disease. Stratifying patients according to the need for RRT at diagnosis and renal histology improves prediction, highlighting the importance of normal glomeruli. Such stratification may assist in the management of anti-GBM disease. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_02_27_JASN0000000000000060.mp3.

Deep hashing for global registration of untracked 2D laparoscopic ultrasound to CT.

PURPOSE: The registration of Laparoscopic Ultrasound (LUS) to CT can enhance the safety of laparoscopic liver surgery by providing the surgeon with awareness on the relative positioning between critical vessels and a tumour. In an effort to provide a translatable solution for this poorly constrained problem, Content-based Image Retrieval (CBIR) based on vessel information has been suggested as a method for obtaining a global coarse registration without using tracking information. However, the performance of these frameworks is limited by the use of non-generalisable handcrafted vessel features. METHODS: We propose the use of a Deep Hashing (DH) network to directly convert vessel images from both LUS and CT into fixed size hash codes. During training, these codes are learnt from a patient-specific CT scan by supplying the network with triplets of vessel images which include both a registered and a mis-registered pair. Once hash codes have been learnt, they can be used to perform registration with CBIR methods. RESULTS: We test a CBIR pipeline on 11 sequences of untracked LUS distributed across 5 clinical cases. Compared to a handcrafted feature approach, our model improves the registration success rate significantly from 48% to 61%, considering a 20 mm error as the threshold for a successful coarse registration. CONCLUSIONS: We present the first DH framework for interventional multi-modal registration tasks. The presented approach is easily generalisable to other registration problems, does not require annotated data for training, and may promote the translation of these techniques.

Use of Virtual Reality for Pediatric Cardiac Critical Care Simulation.

Simulation is a key component of training in the pediatric cardiac intensive care unit (CICU), a complex environment that lends itself to virtual reality (VR)-based simulations. However, VR has not been previously described for this purpose. Two simulations were developed to test the use of VR in simulating pediatric CICU clinical scenarios, one simulating junctional ectopic tachycardia and low cardiac output syndrome, and the other simulating acute respiratory failure in a patient with suspected coronavirus disease 2019. Six attending pediatric cardiac critical care physicians were recruited to participate in the simulations as a pilot test of VR's feasibility for educational and practice improvement efforts in this highly specialized clinical environment. All participants successfully navigated the VR environment and met the critical endpoints of the two clinical scenarios. Qualitative feedback was overall positive with some specific critiques regarding limited realism in some mechanical aspects of the simulation. This is the first described use of VR in pediatric cardiac critical care simulation.

Vessel segmentation for automatic registration of untracked laparoscopic ultrasound to CT of the liver.

PURPOSE: Registration of Laparoscopic Ultrasound (LUS) to a pre-operative scan such as Computed Tomography (CT) using blood vessel information has been proposed as a method to enable image-guidance for laparoscopic liver resection. Currently, there are solutions for this problem that can potentially enable clinical translation by bypassing the need for a manual initialisation and tracking information. However, no reliable framework for the segmentation of vessels in 2D untracked LUS images has been presented. METHODS: We propose the use of 2D UNet for the segmentation of liver vessels in 2D LUS images. We integrate these results in a previously developed registration method, and show the feasibility of a fully automatic initialisation to the LUS to CT registration problem without a tracking device. RESULTS: We validate our segmentation using LUS data from 6 patients. We test multiple models by placing patient datasets into different combinations of training, testing and hold-out, and obtain mean Dice scores ranging from 0.543 to 0.706. Using these segmentations, we obtain registration accuracies between 6.3 and 16.6 mm in 50% of cases. CONCLUSIONS: We demonstrate the first instance of deep learning (DL) for the segmentation of liver vessels in LUS. Our results show the feasibility of UNet in detecting multiple vessel instances in 2D LUS images, and potentially automating a LUS to CT registration pipeline.

Cervical screening uptake and rates of cervical dysplasia in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis.

OBJECTIVES: To compare cervical screening attendance and cytology (high- and low-grade cervical dysplasia [HGCD and LGCD]) between women with RA and the English general population and between biologic DMARD (bDMARD)-naïve and exposed women. METHODS: The British Society for Rheumatology Biologics Register for RA (BSRBR-RA), a national prospective study of RA treatment outcomes, was linked to the National Health Service Cervical Screening Programme, providing data for 12 785 women to compare with national screening data. Rates of HGCD/LGCD were compared with rates of negative smears using risk difference calculations between BSRBR-RA and national statistics. Within the BSRBR-RA, coverage was compared between those with low and high physical disability scores, while coverage and cytology results were compared between bDMARD-naïve and -exposed RA patients. RESULTS: The mean 5 year screening coverage was significantly higher in BSRBR-RA (83%) compared with the general population (79%), but lower in women with high disability (78%) compared with lesser disability (85%). Risk differences for HGCD were lower in the BSRBR-RA compared with national statistics, whereas risk differences for LGCD were higher. There was no statistically significant difference in the rates of HGCD or LGCD between bDMARD-exposed and -naïve women. CONCLUSION: This first-ever British analysis of cervical screening rates in RA has shown that women with RA have higher screening rates than the general population. Disability negatively impacts attendance, but treatment type does not. Women with RA did not have an increased risk of HGCD compared with national statistics, which was also not influenced by bDMARD exposure.

Drugs for Primary Prevention of Atherosclerotic Cardiovascular Disease: An Overview of Systematic Reviews.

IMPORTANCE: The Million Hearts initiative emphasizes ABCS (aspirin for high-risk patients, blood pressure [BP] control, cholesterol level management, and smoking cessation). Evidence of the effects of drugs used to achieve ABCS has not been synthesized comprehensively in the prevention of primary atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE: To compare the efficacy and safety of aspirin, BP-lowering therapy, statins, and tobacco cessation drugs for fatal and nonfatal ASCVD outcomes in primary ASCVD prevention. EVIDENCE REVIEW: Structured search of the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), MEDLINE, EMBASE, and PROSPERO International Prospective Systematic Review Trial Register to identify systematic reviews published from January 1, 2005, to June 17, 2015, that reported the effect of aspirin, BP-lowering therapy, statin, or tobacco cessation drugs on ASCVD events in individuals without prevalent ASCVD. Additional studies were identified by searching the reference lists of included systematic reviews, meta-analyses, and health technology assessment reports. Reviews were selected according to predefined criteria and appraised for methodologic quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool (range, 0-11). Studies were independently reviewed for key participant and intervention characteristics. Outcomes that were meta-analyzed in each included review were extracted. Qualitative synthesis was performed, and data were analyzed from July 2 to August 13, 2015. FINDINGS: From a total of 1967 reports, 35 systematic reviews of randomized clinical trials were identified, including 15 reviews of aspirin, 4 reviews of BP-lowering therapy, 12 reviews of statins, and 4 reviews of tobacco cessation drugs. Methodologic quality varied, but 30 reviews had AMSTAR ratings of 5 or higher. Compared with placebo, aspirin (relative risk [RR], 0.90; 95% CI, 0.85-0.96) and statins (RR, 0.75; 95% CI, 0.70-0.81) reduced the risk for ASCVD. Compared with placebo, BP-lowering therapy reduced the risk for coronary heart disease (RR, 0.84; 95% CI, 0.79-0.90) and stroke (RR, 0.64; 95% CI, 0.56-0.73). Tobacco cessation drugs increased the odds of continued abstinence at 6 months (odds ratio range, 1.82 [95% CI, 1.60-2.06] to 2.88 [95% CI, 2.40-3.47]), but the direct effects on ASCVD were poorly reported. Aspirin increased the risk for major bleeding (RR, 1.54; 95% CI, 1.30-1.82), and statins did not increase overall risk for adverse effects (RR, 1.00; 95% CI, 0.97-1.03). Adverse effects of BP-lowering therapy and tobacco cessation drugs were poorly reported. CONCLUSIONS AND RELEVANCE: This overview demonstrates high-quality evidence to support aspirin, BP-lowering therapy, and statins for primary ASCVD prevention and tobacco cessation drugs for smoking cessation. Treatment effects of each drug can be used to enrich discussions between health care professionals and patients in primary ASCVD prevention.

Successful outcome of pregnancy in patients with anti-neutrophil cytoplasm antibody-associated small vessel vasculitis.

Pregnancy in patients with anti-neutrophil cytoplasm antibody-associated vasculitis is reportedly associated with a high risk of fetal and maternal complications. Here we describe the outcome of pregnancies in patients with granulomatosis with polyangiitis and microscopic polyangiitis at five centers in the United Kingdom using a retrospective case review of all women who became pregnant following diagnosis. We report 15 pregnancies in 13 women resulting in 15 live births including one twin pregnancy and 13 singleton pregnancies. One patient had an unplanned pregnancy and a first trimester miscarriage while taking methotrexate. All other pregnancies were planned following a minimum of 6 months clinical remission. Eleven successful pregnancies were delivered vaginally at full term, whereas three were delivered by cesarean section. All infants were healthy with no neonatal complications on their initial health check within the first 24 h of delivery and no evidence of neonatal vasculitis. One relapse occurred during pregnancy and was successfully treated with an increased dose of azathioprine and corticosteroids, intravenous immunoglobulin, and plasma exchange therapy. One patient developed tracheal crusting and subglottic stenosis of infective etiology in the third trimester requiring tracheal debridement post delivery. No patient had a relapse in the first 12 months postpartum. Thus, successful pregnancy outcomes can occur following planned pregnancy in women in sustained remission on non-teratogenic therapies.

Urinary protein selectivity in nephrotic syndrome and pregnancy: resurrection of a biomarker when renal biopsy is contraindicated.

Significant proteinuria in pregnancy can indicate the presence of serious conditions requiring investigation and treatment. The nephrotic syndrome in pregnancy presents a multitude of difficulties and is a relative contraindication of renal biopsy, particularly in the third trimester. We present a case of nephrotic syndrome of unknown cause presenting at 33 weeks of pregnancy. With renal biopsy contraindicated, we used the urine protein selectivity test, a largely discarded test predicting steroid-responsive nephrotic syndrome, to help inform the decision to give steroids. This led to a successful clinical outcome including the avoidance of neonatal ICU care for baby.

Increasing prevalence of methicillin resistance in serious ocular infections caused by Staphylococcus aureus in the United States: 2000 to 2005.

PURPOSE: To report the nationwide prevalence of methicillin resistance in serious ocular infections involving Staphylococcus aureus and profile in vitro antimicrobial susceptibility of S aureus from ocular isolates over time. SETTING: Mount Sinai School of Medicine, New York, New York, USA. METHODS: Data on S aureus submitted to The Surveillance Network (TSN) by more than 200 laboratories in the United States from January 2000 to December 2005 were reviewed. The prevalence of methicillin resistance in S aureus ocular infections and in vitro susceptibility to antibiotic agents commonly used to treat or prevent ocular infections were determined. RESULTS: The proportion of S aureus infections culture-positive for methicillin-resistant S aureus (MRSA) increased from 29.5% in 2000 to 41.6% in 2005. The MRSA ocular isolates were multidrug resistant; that is, in vitro resistance to 3 antibiotic agents or more, including all fluoroquinolones tested. CONCLUSIONS: Multidrug-resistant MRSA is increasing in serious ocular infections. Based on the rate of increase in the TSN database, MRSA cultures from serious ocular infections could be more common than methicillin-susceptible S aureus within 2 to 3 years. Large-scale national surveillance programs are needed to monitor in vitro antimicrobial resistance trends in ocular isolates.

Antimicrobial resistance trends among sinus isolates of Streptococcus pneumoniae in the United States (2001-2005).

OBJECTIVE: To test the susceptibility of Streptococcus pneumoniae sinus isolates collected across the United States against commonly used antimicrobial agents. STUDY DESIGN AND SETTING: S. pneumoniae sinus isolates (N = 847) collected as part of the Tracking Resistance in the US Today Surveillance Program from 2001 to 2005 were tested against 8 antimicrobial agents. RESULTS: In ascending order, the relative activities (% susceptible) were penicillin (51.8%), trimethoprim/sulfamethoxazole (TMP/SMX) (57.6%), erythromycin (59.5%), cefuroxime (62.0%), amoxicillin/clavulanate (85.5%), clindamycin (86.1%), levofloxacin (99.4%), and linezolid (100%; for 2004 and 2005 respiratory seasons, only). Resistance rates over the 5 years remained generally stable, although resistance to amoxicillin/clavulanate nearly doubled (from 6.5% to 12.9%). Forty percent of isolates were resistant to >or=2 agents tested. CONCLUSIONS AND SIGNIFICANCE: Susceptibility trends among sinus S. pneumoniae isolates appear to have stabilized over the past 5 years. Resistance rates remain elevated for penicillin and macrolides, whereas the high prevalence of multidrug resistance remains a concern.

Detection of a [3Fe-4S] cluster intermediate of cytosolic aconitase in yeast expressing iron regulatory protein 1. Insights into the mechanism of Fe-S cluster cycling.

Interconversion of iron regulatory protein 1 (IRP1) with cytosolic aconitase (c-aconitase) occurs via assembly/disassembly of a [4Fe-4S] cluster. Recent evidence implicates oxidants in cluster disassembly. We investigated H(2)O(2)-initiated Fe-S cluster disassembly in c-aconitase expressed in Saccharomyces cerevisiae. A signal for [3Fe-4S] c-aconitase was detected by whole-cell EPR of aerobically grown, aco1 yeast expressing wild-type IRP1 or a S138A-IRP1 mutant (IRP1(S138A)), providing the first direct evidence of a 3Fe intermediate in vivo. Exposure of yeast to H(2)O(2) increased this 3Fe c-aconitase signal up to 5-fold, coincident with inhibition of c-aconitase activity. Untreated yeast expressing IRP1(S138D) or IRP1(S138E), which mimic phosphorylated IRP1, failed to give a 3Fe signal. H(2)O(2) produced a weak 3Fe signal in yeast expressing IRP1(S138D). Yeast expressing IRP1(S138D) or IRP1(S138E) were the most sensitive to inhibition of aconitase-dependent growth by H(2)O(2) and were more responsive to changes in media iron status. Ferricyanide oxidation of anaerobically reconstituted c-aconitase yielded a strong 3Fe EPR signal with wild-type and S138A c-aconitases. Only a weak 3Fe signal was obtained with S138D c-aconitase, and no signal was obtained with S138E c-aconitase. This, paired with loss of c-aconitase activity, strongly argues that the Fe-S clusters of these phosphomimetic c-aconitase mutants undergo more complete disassembly upon oxidation. Our results demonstrate that 3Fe c-aconitase is an intermediate in H(2)O(2)-initiated Fe-S cluster disassembly in vivo and suggest that cluster assembly/disassembly in IRP1 is a dynamic process in aerobically growing yeast. Further, our results support the view that phosphorylation of IRP1 can modulate its response to iron through effects on Fe-S cluster stability and turnover.