Formation of massive black holes in rapidly growing pre-galactic gas clouds.

The origin of the supermassive black holes that inhabit the centres of massive galaxies remains unclear1,2. Direct-collapse black holes-remnants of supermassive stars, with masses around 10,000 times that of the Sun-are ideal seed candidates3-6. However, their very existence and their formation environment in the early Universe are still under debate, and their supposed rarity makes modelling their formation difficult7,8. Models have shown that rapid collapse of pre-galactic gas (with a mass infall rate above some critical value) in metal-free haloes is a requirement for the formation of a protostellar core that will then form a supermassive star9,10. Here we report a radiation hydrodynamics simulation of early galaxy formation11,12 that produces metal-free haloes massive enough and with sufficiently high mass infall rates to form supermassive stars. We find that pre-galactic haloes and their associated gas clouds that are exposed to a Lyman-Werner intensity roughly three times the intensity of the background radiation and that undergo at least one period of rapid mass growth early in their evolution are ideal environments for the formation of supermassive stars. The rapid growth induces substantial dynamical heating13,14, amplifying the Lyman-Werner suppression that originates from a group of young galaxies 20 kiloparsecs away. Our results strongly indicate that the dynamics of structure formation, rather than a critical Lyman-Werner flux, is the main driver of the formation of massive black holes in the early Universe. We find that the seeds of massive black holes may be much more common than previously considered in overdense regions of the early Universe, with a co-moving number density up to 10-3 per cubic megaparsec.

Acute interstitial nephritis with podocyte foot-process effacement complicating Plasmodium falciparum infection.

BACKGROUND: Malarial acute renal failure (MARF) is a component of the severe malaria syndrome, and complicates 1-5% of malaria infections. This form of renal failure has not been well characterized by histopathology. CASE PRESENTATION: A 44 year-old male presented to the emergency department with a 5-day history of fever and malaise after returning from Nigeria. A blood film was positive for Plasmodium falciparum. His creatinine was 616 µmol/L coming from a normal baseline of 89 µmol/L. He had a urine protein:creatinine ratio of 346 mg/mmol (4.4 g/L). He required dialysis. A renal biopsy showed acute interstitial nephritis with podocyte foot-process effacement. He was treated with artesunate and his renal function improved. At 1 year follow-up his creatinine had plateaued at 120 µmol/L with persistent low-grade proteinuria. CONCLUSION: Acute interstitial nephritis and podocyte foot-process effacement might be under-recognized lesions in MARF. Studying the mechanisms of MARF could give insight into the immunopathology of severe malaria.

Experience and confidence in vaginal breech and twin deliveries among obstetric trainees and new specialists in Australia and New Zealand.

BACKGROUND: The number of vaginal breech and twin deliveries may be insufficient for adequate training. OBJECTIVE: To determine whether advanced trainees and new Fellows in obstetrics are gaining adequate experience and confidence in vaginal breech and twin deliveries. METHODS: An online survey was emailed to registered Royal Australia and New Zealand College of Obstetrics and Gynaecology (RANZCOG) advanced trainees and new Fellows (Years 1-5). This survey asked about their experience, confidence and whether they intend to perform vaginal breech and twin deliveries as specialists. RESULTS: The survey was sent to 703 advanced trainees (162) and Fellows (541) and answered by 217 (31.7%). Experience and confidence in vaginal breech and twin deliveries increased with the number of procedures performed (P < 0.001) in both groups and were significantly higher among Fellows. Despite the level of experience, 100% of respondents felt confident in managing vaginal twin deliveries with or without supervision, whereas 14.9% of respondents did not feel confident in managing vaginal breech deliveries. Intention to offer these procedures in their practice depended on confidence levels, and there was a significant difference between twins and breech. Overall, 87.3% of respondents intended to offer vaginal twin deliveries in their practice, while only 32.7% intended to offer vaginal breech deliveries. CONCLUSION: Confidence in complex vaginal deliveries increases with increasing number of procedures performed and a significant proportion of trainees and Fellows consider they do not have sufficient experience. The association between confidence and intention to offer these procedures is stronger in twins than in breech deliveries.

Posttransplant Lymphoproliferative Disorders in Irish Renal Transplant Recipients: Insights From a National Observational Study.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) are a common malignancy after renal transplantation with a high incidence of PTLD described in the first posttransplant year. We sought to determine incidence and risk determinants of PTLD in Irish kidney transplant recipients. METHODS: Retrospective observational study of 1996 adult first kidney transplant recipients between 1991 and 2010 in the Republic of Ireland. Recipients were cross-referenced with the National Cancer Registry to determine incidence of PTLD. Kaplan-Meier analysis was performed for PTLD-free survival, allograft survival, and patient survival after PTLD. Cox proportional hazards models were used to identify independent risk factors for PTLD in our population. RESULTS: We identified 31 cases of PTLD during the study period. Histological subgroups included: early lesions (n = 1); polymorphic PTLD (n = 1); monomorphic PTLD (n = 27), Hodgkin disease (n = 2). Median time to PTLD diagnosis was 8.3 (range, 1.2-13.9) years. Cumulative incidence (95% CI) of PTLD at 1, 2, 3, 5, 10, and 15 years was 0%, 0.16% (0.05-0.5%), 0.21% (0.08-0.57%), 0.21% (0.08-0.57%), 1.76% (1.15-2.69%), and 3.07% (2.1-4.43%), respectively. Allograft survival after PTLD diagnosis was 94.4% (66.6-99.2%) at 5 years. Patient survival after PTLD diagnosis was 64% at 1 year, 53% at 2 years, 48% at 5 years, and 37% at 10 years. No risk factors for PTLD were identified. CONCLUSIONS: We found a paucity of early onset PTLD in our cohort with no cases in the first posttransplant year. Potential contributing factors included a high prevalence of previous Epstein-Barr virus exposure and a relatively low immunological risk profile in our recipient cohort compared with prior studies. Further studies are required to reevaluate the epidemiology of PTLD in the modern era of transplant immunosuppression.

Forming supermassive black hole seeds under the influence of a nearby anisotropic multifrequency source.

The photodissociation of H2 by a nearby anisotropic source of radiation is seen as a critical component in creating an environment in which a direct collapse black hole may form. Employing radiative transfer we model the effect of multifrequency (0.76-60 eV) radiation on a collapsing halo at high redshift. We vary both the shape of the spectrum which emits the radiation and the distance to the emitting galaxy. We use blackbody spectra with temperatures of T = 104 K and 105 K and a realistic stellar spectrum. We find that an optimal zone exists between 1 and 4 kpc from the emitting galaxy. If the halo resides too close to the emitting galaxy the photoionizing radiation creates a large H ii region which effectively disrupts the collapsing halo, too far from the source and the radiation flux drops below the level of the expected background and the H2 fraction remains too high. When the emitting galaxy is initially placed between 1 and 2 kpc from the collapsing halo, with a spectral shape consistent with a star-forming high-redshift galaxy, then a large central core forms. The mass of the central core is between 5000 and 10 000 M⊙ at a temperature of approximately 1000 K. This core is however surrounded by a reservoir of hotter gas at approximately 8000 K, which leads to mass inflow rates of the order of ∼0.1 M⊙ yr-1.

Tacrolimus trough-level variability predicts long-term allograft survival following kidney transplantation.

AIMS: The purpose of this study is to investigate tacrolimus trough-level variability from 3 to 12 months following transplantation and its association with allograft survival in renal transplant recipients. MATERIALS AND METHODS: In this observational cohort study, tacrolimus trough-level variability was used as the predictor of all-cause allograft failure (defined as return to dialysis) and patient survival (all-cause mortality). RESULTS: In total, 394 transplants were included in the analysis. Sixty-two transplants failed during the study. Tacrolimus trough-level variability across quartile groups were: Q1 median variability 12.5 %, range 4.76-15.71 % (n = 99), Q2 median variability 18.17 %, range 15.74-21.29 % (n = 96), Q3 median variability 24.63 % range 21.42-28.88 % (n = 100), Q4 median variability 36.91 %, range 28.91-81.9 % (n = 99). Higher tacrolimus trough-level variability was associated with inferior allograft survival in univariate models [hazard ratio per quartile increase (HR), 1.46, 95 % CI 1.16-1.83, p value = 0.001] and multivariate models (HR 1.36, 95 % CI 1.05-1.78, p value = 0.019). Higher tacrolimus trough-level variability was not associated with patient survival; univariate model (HR 1.25, 95 % CI 0.90-1.74, p value = 0.17), multivariate model (HR 1.25, 95 % CI 0.86-1.83, p value = 0.23). CONCLUSIONS: Inferior renal allograft survival was observed in recipients with higher variability in tacrolimus trough-levels.

Prevention of sudden cardiac death in hemodialysis patients.

One quarter of all hemodialysis patients will succumb to sudden cardiac death (SCD), a rate far exceeding that observed in the general population. A high prevalence of atherosclerotic coronary artery disease amongst patients with end-stage kidney disease (ESKD) partly explains this exaggerated risk. However, uremia and dialysis related factors are also of critical importance. Interventions aimed at preventing SCD have been inadequately studied in patients with ESKD. Data extrapolated from non-renal populations cannot necessarily be applied to hemodialysis patients, who possess relatively unique risk factors for SCD including "uremic cardiomyopathy", electrolyte shifts, fluctuations in intravascular volume and derangements of mineral and bone metabolism. Pending data derived from proposed randomized controlled clinical trials, critical appraisal of existing evidence and the selective application of guidelines developed for the general population to dialysis patients are required if therapeutic nihilism, or excessive intervention, are to be avoided. We discuss the evidence supporting a role for medical therapies, dialysis prescription refinements, revascularization procedures and electrical therapies as potential interventions to prevent SCD amongst hemodialysis patients. Based on current best available evidence, we present suggested strategies for the prevention of arrhythmia-mediated death in this highly vulnerable patient population.

C3 glomerulopathy: clinicopathologic features and predictors of outcome.

BACKGROUND AND OBJECTIVES: The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model. RESULTS: Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD. CONCLUSIONS: Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.

Re-infection following sustained virological response with a different hepatitis C virus genotype: implications for infection control policy.

We report the case of a 45-year-old haemodialysis patient who achieved a sustained virological response (SVR) following pegylated interferon therapy for hepatitis C virus (HCV) genotype 2 infection. He was subsequently cohorted with other HCV-infected dialysis patients and became re-infected with HCV genotype 3a. Epidemiological and molecular investigations identified a highly viraemic HCV genotype 3a-infected dialysis patient as the likely source of this infection. This critical incident informed a revision to local and national infection control policy regarding the dialysis management of patients who achieve an SVR following anti-viral treatment.