Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesio11See Editorial by Haas,P. 1188.

Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion.BackgroundSeveral entities or variants within focal segmental glomerulosclerosis (FSGS) have been described, but their changes with time and interrelationships are undetermined.MethodsChanges with time were studied in two series of segmental sclerosing lesions in the nephrotic syndrome, one of 22 specimens from ten patients in a trial, the other of 176 specimens from 121 consecutive patients.ResultsThe earliest lesions were probably all at the tubular origin, equivalent to the tip variant of FSGS. In some patients, lesions remained at this site, but progression to renal failure was accompanied by morphologic progression, with development of lesions at various sites, equivalent to FSGS, not otherwise specified (NOS). Progression was more likely if there were large lesions, abnormal mesangium, and extensive acute tubular damage. Patients with lesions at the tubular origin at presentation had a shorter duration of symptoms and less chronic renal damage than those with multiple lesions, were more likely to have a complete response of the nephrotic syndrome, and were less likely to progress to renal failure. Recurrent nephrotic syndrome occurred in 12 of 14 allografts at risk, and was usually accompanied by lesions at the tubular origin, then multiple lesions.ConclusionAt least some patients with FSGS (NOS) have evolved from the tip variant. The tip variant has been considered a distinct entity. Another interpretation is that it includes two conditions, one an early form of classic FSGS, and the other closely related to minimal change nephropathy (MCN), equivalent to the glomerular tip lesion as originally defined

Polyclonal and Monoclonal Antibodies for Treating Acute Rejection Episodes in Kidney Transplant Recipients

Background: Registry data shows that between 15-35% kidney recipients will undergo treatment for at least one episode of acute rejection within the first post transplant year. Treatment options include pulsed steroid therapy, the use of an antibody preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the US, 61.4% patients with an acute rejection episode received steroids, 20.4% received an antibody preparation and 18.2% received both. Objectives: To determine the benefits and harms of mono- or polyclonal antibodies (Ab) used to treat acute rejection in kidney transplant recipients. Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library, issue 2, 2005), MEDLINE (1966-June 2005), EMBASE (1980-June 2005), and the specialised register of the Cochrane Renal Group (June 2005). Selection criteria: Randomised controlled trials (RCTs) in all languages comparing all mono- and polyclonal antibody preparations, given in combination with any other immunosuppressive agents, for the treatment of acute graft rejection, when compared to any other treatment for acute rejection. Data collection and analysis: Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as relative risk (RR) with 95% confidence intervals (CI). Main results: Twenty one trials (49 reports, 1387 patients) were identified. Trials were generally small, incompletely reported, especially for potential harms, and did not define outcome measures adequately. Fourteen trials (965 patients) compared therapies for first rejection episodes. Ab was better than steroid in reversing rejection (RR 0.57, 95% CI 0.38 to 0.87) and preventing graft loss (death censored RR 0.74, CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection or death at one year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection. There was no benefit of muromonab-CD3 over ATG or ALG in either reversing rejection, preventing subsequent rejection, preventing graft loss or death. Authors' conclusions: In reversing first rejection, any antibody is better than steroid and also prevents graft loss, but subsequent rejection and patient survival are not significantly different. In reversing steroid-resistant rejection the effects of different antibodies are also not significantly different. Given the clinical problem caused by acute rejection, data are very sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed

Patient-reported outcome measures used in patients with primary sclerosing cholangitis: a systematic review

Abstract Background Primary Sclerosing Cholangitis (PSC) is a rare chronic, cholestatic liver condition in which patients can experience a range of debilitating symptoms. Patient reported outcome measures (PROMs) could provide a valuable insight into the impact of PSC on patient quality of life and symptoms. A previous review has been conducted on the quality of life instruments used in liver transplant recipients. However, there has been no comprehensive review evaluating PROM use or measurement properties in PSC patients’ to-date. The aim of the systematic review was to: (a) To identify and categorise which PROMs are currently being used in research involving the PSC population (b) To investigate the measurement properties of PROMs used in PSC. Methods A systematic review of Medline, EMBASE and CINAHL, from inception to February 2018, was undertaken. The methodological quality of included studies was assessed using the Consensus-based Standards for selection of health Measurement Instruments (COSMIN) checklist. Results Thirty-seven studies were identified, which included 36 different PROMs. Seven PROMs were generic, 10 disease-specific, 17 symptom-specific measures and 2 measures on dietary intake. The most common PROMs were the Short form-36 (SF-36) (n = 15) and Chronic liver disease questionnaire (CLDQ) (n = 6). Only three studies evaluated measurement properties, two studies evaluated the National Institute of Diabetes Digestive and Kidney Diseases Liver Transplant (NIDDK-QA) and one study evaluated the PSC PRO; however, according to the COSMIN guidelines, methodological quality was poor for the NIDDK-QA studies and fair for the PSC PRO study. Conclusion A wide variety of PROMs have been used to assess health-related quality of life and symptom burden in patients with PSC; however only two measures (NIDDK-QA and PSC PRO) have been formally validated in this population. The newly developed PSC PRO requires further validation in PSC patients with diverse demographics, comorbidities and at different stages of disease; however this is a promising new measure with which to assess the impact of PSC on patient quality of life and symptoms

Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis.

The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package ('Mykrobe predictor') that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S. aureus, the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n=470). For M. tuberculosis, our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n=1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes

Peace and Justice through a Feminist Lens: Gender Justice and the Women’s Court for the Former Yugoslavia

Post-conflict interventions to ‘deal with’ violent pasts have moved from exception to global norm. Early efforts to achieve peace and justice were critiqued as ‘gender-blind’—for failing to address sexual and gender-based violence, and neglecting the gender-specific interests and needs of women in transitional settings. The advent of UN Security Council resolutions on ‘Women, Peace and Security’ provided a key policy framework for integrating both women and gender issues into transitional justice processes and mechanisms. Despite this, gender justice and equality in (post-)conflict settings remain largely unachieved. This article explores efforts to attain gender-just peace in post-conflict Bosnia and Herzegovina (BiH). It critically examines the significance of a recent ‘bottom-up’ truth-telling project—the Women’s Court for the former Yugoslavia—as a locally engaged approach to achieving justice and redress for women impacted by armed conflict. Drawing on participant observation, documentary analysis, and interviews with women activists, the article evaluates the successes and shortcomings of responding to gendered forms of wartime violence through truth-telling. Extending Nancy Fraser’s tripartite model of justice to peacebuilding contexts, the article advances notions of recognition, redistribution and representation as crucial components of gender-just peace. It argues that recognizing women as victims and survivors of conflict, achieving a gender-equitable distribution of material and symbolic resources, and enabling women to participate as agents of transitional justice processes are all essential for transforming the structural inequalities that enable gender violence and discrimination to materialize before, during, and after conflict

Heterogeneity of injury in vasculitis: influence of anti neutrophil cytoplasm antibody IgG subclass and endothelial susceptibility.

This study examined IgG subclass in ANCA associated vasculitis and glomerular endothelial cell (GEC) phenotype predisposes to injury. Using the flow model, interaction of neutrophils with normal immunoglobulin subclasses was compared to interaction with subclasses of ANCA IgG. Neutrophils were captured by normal IgG3>IgG1>IgG2/IgG4. Blockade of CD32 affected IgG3, CD16, IgG1/2. Neutrophils exposed to soluble ANCA IgG1/3 adhered to cytokine-activated endothelial cells, as did IgG4, not previously thought to bind constitutively expressed CD16/CD32. Fc blockade reduced binding. GEC were compared with human umbilical vein endothelial cells. Surface VCAM-1 was reduced on GEC and GEC demonstrated reduced leukocyte capture. RNA array analysis demonstrated a reduction in the GEC gene responsible for post translational modification of VCAM-1 to a sialoglycoprotein. VCAM-1 expression by GEC may be a protective mechanism to reduce inflammatory responses, potentially disrupted in disease. ANCA subclass and endothelial phenotype are important vasculitis pathogenesis: this may be useful in designing targeted therapy reducing overall immunsuppressive load. Additionally modification of specific adhesion molecule profiles on endothelial cells may enable alteration of conditions of one vascular bed whilst reducing impact on unaffected sites

Malignancy is increased in ANCA-associated vasculitis

Objective. In the light of previous reports of an association between malignancy and renal vasculitis, we aimed to investigate the association of malignancy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, either Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA), and compare it with the general population and disease control groups comprising patients with systemic lupus erythematosus (SLE) or Henoch–Schönlein purpura (HSP). Methods. A retrospective review of 200 consecutive patients with WG or MPA was performed. Malignancies preceding or concurrent with vasculitis were recorded and the incidence of malignancy was compared with those in a population of 129 patients with HSP, 333 patients with SLE and a normal population in the West Midlands of the UK. Results. Twenty patients had a diagnosis of malignancy, 14 had MPA and six had WG. Patients with ANCA-associated vasculitis had an increased risk of malignancy compared with HSP patients, of whom six patients had malignancy (relative risk 0.85, confidence interval 0.69–1.05; P 0.034), or SLE patients, of whom five patients had malignancy (relative risk 0.31, 95% confidence interval 0.14–0.7; P<0.0001). The rate of malignancy compared with an age-matched control group was increased in patients with ANCA-associated vasculitis and HSP (ANCA-associated vasculitis, relative risk 6.02, 95 % confidence interval 3.72–9.74; HSP, relative risk 5.25, 95 % confidence interval 2.4–11.5). The presence of ANCA was not predictive of malignancy. Conclusion. In conclusion, patients with ANCA-associated vasculitis have an increased risk of preceding or concurren