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Patients with kidney transplant failure have a high risk of hospitalization and death due to infection. The optimal use of immunosuppressants after transplant failure remains uncertain and clinical practice varies widely.

This prospective cohort study enrolled patients within 21 days of starting dialysis after transplant failure in 16 Canadian centers. Immunosuppressant medication use, death, hospitalized infection, rejection of the failed allograft, and anti-HLA panel reactive antibodies were determined at 1, 3, 6, and 12 months and and then twice yearly until death, repeat transplantation, or loss to follow-up.

The 269 study patients were followed for a median of 558 days. There were 33 deaths, 143 patients hospitalized for infection, and 21 rejections. Most patients (65%) continued immunosuppressants, 20% continued prednisone only, and 15% discontinued all immunosuppressants. In multivariable models, patients who continued immunosuppressants had a lower risk of death (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.17 to 0.93) and were not at increased risk of hospitalized infection (HR, 1.81; 95% CI, 0.82 to 4.0) compared with patients who discontinued all immunosuppressants or continued prednisone only. The mean class I and class II panel reactive antibodies increased from 11% to 27% and from 25% to 47%, respectively, but did not differ by immunosuppressant use. Continuation of immunosuppressants was not protective of rejection of the failed allograft (HR, 0.81; 95% CI, 0.22 to 2.94).

Prolonged use of immunosuppressants >1 year after transplant failure was not associated with a higher risk of death or hospitalized infection but was insufficient to prevent higher anti-HLA antibodies or rejection of the failed allograft.

1 year after transplant failure was not associated with a higher risk of death or hospitalized infection but was insufficient to prevent higher anti-HLA antibodies or rejection of the failed allograft.

Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown.

We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'.

MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN.

FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.

FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.

Acute non-variceal upper gastrointestinal bleeding (NVUGIB) is managed by standard endoscopic combination therapy, but a few cases remain difficult and carry a high risk of persistent or recurrent bleeding. The aim of our study was to compare first-line over-the-scope-clips (OTSC) therapy with standard endoscopic treatment in these selected patients.

We conducted a prospective, randomised, controlled, multicentre study (NCT03331224). Patients with endoscopic evidence of acute NVUGIB and high risk of rebleeding (defined as complete Rockall Score ≥7) were included. Primary endpoint was clinical success defined as successful endoscopic haemostasis without evidence of recurrent bleeding.

246 patients were screened and 100 patients were finally randomised (mean of 5 cases/centre and year; 70% male, 30% female, mean age 78 years; OTSC group n=48, standard group n=52). All but one case in the standard group were treated with conventional clips. Clinical success was 91.7% (n=44) in the OTSC group compared with 73.1% (n=38) in the ST group (p=0.019), with persistent bleeding occurring in 0 vs 6 in the OTSC versus standard group (p=0.027), all of the latter being successfully managed by rescue therapy with OTSC. Recurrent bleeding was observed in four patients (8.3%) in the OTSC group and in eight patients (15.4%) in the standard group (p=0.362).

OTSC therapy appears to be superior to standard treatment with clips when used by trained physicians for selected cases of primary therapy of NVUGIB with high risk of rebleeding. Further studies are necessary with regards to patient selection to identify subgroups benefiting most from OTSC haemostasis.

NCT03331224.

NCT03331224.This response to Evans et al encourages broader consideration of what constitutes disability, extending beyond a protagonist's capabilities toward society's fuller chorus. Three avenues are submitted to encourage this. First, Engel's biopsychosocial paradigm of health can be helpfully applied to the question of identity in general, and disability in particular. Second, the philosophy of language (and of naming) gives useful insight into the pitfalls of trying to define disability via descriptions of capability. Third, Kennedy's critique 'Unmasking Medicine' offers a sociopolitical view that builds on Foucault and Illich allowing us to recognise that it matters who judges who, as disabled, and on what grounds. Alongside this, I suggest alternative views first, on the authors' liberal use of bell curves in the depiction of disability and second, on their terminology of capacity spaces.In the UK, it has been proposed that alongside the current advice to abstain from alcohol completely in pregnancy, there should be increased screening of pregnant women for alcohol consumption in order to prevent instances of fetal alcohol spectrum disorder. The Scottish Intercollegiate Guidelines Network published guidelines in 2019 recommending that standardised screening questionnaires and associated use of biomarkers should be considered to identify alcohol exposure in pregnancy. This was followed in 2020 by the National Institute for Health and Care Excellence Draft Quality Standard, which recommended that pregnant women should have information on their alcohol consumption recorded throughout their pregnancy and this information transferred to the child's health records. Most recently, Public Health England has stated that the alcohol intake of all women should be recorded throughout pregnancy, not just at the initial booking appointment and that tools such as blood biomarkers and meconium testing should be researched in order to determine true prevalence rates of alcohol in pregnancy. We argue that this proposed enhanced screening undermines women's autonomy and their legal right to be sufficiently informed to consent to screening. We argue that there is no evidence that this kind of screening will result in a reduction of fetal harm and there is a danger that undermining the autonomy of women and the trust relationship between women and healthcare professionals may even increase harm to future children.Chronic exposure to environmental pollutants is a major contributor to the development and progression of obstructive airway diseases, including asthma and COPD. Understanding the mechanisms underlying the development of obstructive lung diseases upon exposure to inhaled pollutants will lead to novel insights into the pathogenesis, prevention and treatment of these diseases. The respiratory epithelial lining forms a robust physicochemical barrier protecting the body from inhaled toxic particles and pathogens. Inhalation of airborne particles and gases may impair airway epithelial barrier function and subsequently lead to exaggerated inflammatory responses and airway remodelling, which are key features of asthma and COPD. In addition, air pollutant-induced airway epithelial barrier dysfunction may increase susceptibility to respiratory infections, thereby increasing the risk of exacerbations and thus triggering further inflammation. In this review, we discuss the molecular and immunological mechanisms involved in physical barrier disruption induced by major airborne pollutants and outline their implications in the pathogenesis of asthma and COPD. We further discuss the link between these pollutants and changes in the lung microbiome as a potential factor for aggravating airway diseases. Understanding these mechanisms may lead to identification of novel targets for therapeutic intervention to restore airway epithelial integrity in asthma and COPD.Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder characterised by reduced levels of circulating alpha-1 antitrypsin and an increased risk of lung and liver disease. Recent reviews of AATD have focused on diagnosis, epidemiology and clinical management; comprehensive reviews examining disease burden are lacking. Therefore, we conducted literature reviews to investigate the AATD disease burden for patients, caregivers and healthcare systems. Embase, PubMed and Cochrane libraries were searched for AATD publications from database inception to June 2021, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. selleck inhibitor Most published AATD studies were small and short in duration, with variations in populations, designs, measures and outcomes, complicating cross-study comparisons. AATD was associated with significant pulmonary and hepatic morbidity. COPD, emphysema and bronchiectasis were common lung morbidities, where smoking was a key risk factor. Fibrosis and steatosis were the most common liver complications reported in patients with a PiZ allele. Health status analyses suggested a poorer quality of life for AATD patients diagnosed with COPD versus those with non-AATD-associated COPD. The burden for caregivers included loss of personal time due to caring responsibilities, stress and anxiety. AATD was also associated with high direct medical costs and healthcare resource utilisation.

To determine the effects of electronic cigarettes (e-cigarettes) as a therapeutic intervention compared to nicotine replacement therapy (NRT) on nicotine abstinence.

Two authors independently searched the PubMed, Embase, PsycInfo and Cochrane Central Register of Controlled Trials databases for articles published up to and including 10 July 2021. We included randomised controlled trials (RCTs) in which nicotine e-cigarettes were compared to NRT among current cigarette users. The primary outcome was abstaining from all nicotine-delivery devices. Secondary outcomes were 1) allocated product use (e-cigarettes or NRT) among successful cigarette quitters and 2) quitting cigarettes at the end of the trial using fixed-effect Mantel-Haenszel models.

We included four RCTs representing 1598 adult participants (51.0% females). The mean age of participants in these studies ranged from 41 to 54 years, while average baseline smoking ranged from 14 to 21 cigarettes per day. Compared to NRT, e-cigarette use was associated with lower nicotine abstinence rates at the longest follow-up (risk ratio 0.