Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort.

BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.

Moving and Static Faces, Bodies, Objects, and Scenes Are Differentially Represented across the Three Visual Pathways.

Models of human cortex propose the existence of neuroanatomical pathways specialized for different behavioral functions. These pathways include a ventral pathway for object recognition, a dorsal pathway for performing visually guided physical actions, and a recently proposed third pathway for social perception. In the current study, we tested the hypothesis that different categories of moving stimuli are differentially processed across the dorsal and third pathways according to their behavioral implications. Human participants (n = 30) were scanned with fMRI while viewing moving and static stimuli from four categories (faces, bodies, scenes, and objects). A whole-brain group analysis showed that moving bodies and moving objects increased neural responses in the bilateral posterior parietal cortex, parts of the dorsal pathway. By contrast, moving faces and moving bodies increased neural responses, the superior temporal sulcus, part of the third pathway. This pattern of results was also supported by a separate ROI analysis showing that moving stimuli produced more robust neural responses for all visual object categories, particularly in lateral and dorsal brain areas. Our results suggest that dynamic naturalistic stimuli from different categories are routed in specific visual pathways that process dissociable behavioral functions.

Provoked overt recognition in acquired prosopagnosia using multiple different images of famous faces.

Provoked overt recognition refers to the fact that patients with acquired prosopagnosia can sometimes recognize faces when presented in arrays of individuals from the same category (e.g., actors or politicians). We ask whether a prosopagnosic patient might experience recognition when presented with multiple different images of the same face simultaneously. Over two sessions, patient Herschel, a 66-year-old British man with acquired prosopagnosia, viewed face images individually or in arrays. On several occasions he failed to recognize single photos of an individual but successfully identified that person when the same photos were presented together. For example, Herschel failed to recognize any individual images of King Charles or Paul McCartney but recognised both in arrays of the same photos. Like reports based on category membership, overt recognition was transient and inconsistent. These findings are discussed in terms of models of covert recognition, alongside more recent research on within-person variability for face perception.

Associations with age and glomerular filtration rate in a referred population with chronic kidney disease: methods and baseline data from a UK multicentre cohort study (NURTuRE-CKD).

BACKGROUND: Chronic kidney disease (CKD) is common but heterogenous and is associated with multiple adverse outcomes. The National Unified Renal Translational Research Enterprise (NURTuRE)-CKD cohort was established to investigate risk factors for clinically important outcomes in persons with CKD referred to secondary care. METHODS: Eligible participants with CKD stages G3-4 or stages G1-2 plus albuminuria >30 mg/mmol were enrolled from 16 nephrology centres in England, Scotland and Wales from 2017 to 2019. Baseline assessment included demographic data, routine laboratory data and research samples. Clinical outcomes are being collected over 15 years by the UK Renal Registry using established data linkage. Baseline data are presented with subgroup analysis by age, sex and estimated glomerular filtration rate (eGFR). RESULTS: A total of 2996 participants was enrolled. Median (interquartile range) age was 66 (54-74) years, eGFR 33.8 (24.0-46.6) mL/min/1.73 m2 and urine albumin to creatinine ratio 209 (33-926) mg/g; 58.5% were male. Of these participants, 1883 (69.1%) were in high-risk CKD categories. Primary renal diagnosis was CKD of unknown cause in 32.3%, glomerular disease in 23.4% and diabetic kidney disease in 11.5%. Older participants and those with lower eGFR had higher systolic blood pressure and were less likely to be treated with renin-angiotensin system inhibitors (RASi) but were more likely to receive a statin. Female participants were less likely to receive a RASi or statin. CONCLUSIONS: NURTuRE-CKD is a prospective cohort of persons who are at relatively high risk of adverse outcomes. Long-term follow-up and a large biorepository create opportunities for research to improve risk prediction and to investigate underlying mechanisms to inform new treatment development.

Immunohistochemical characteristics of local sites that trigger atrial arrhythmias in response to high-frequency stimulation.

AIMS: The response to high frequency stimulation (HFS) is used to locate putative sites of ganglionated plexuses (GPs), which are implicated in triggering atrial fibrillation (AF). To identify topological and immunohistochemical characteristics of presumed GP sites functionally identified by HFS. METHODS AND RESULTS: Sixty-three atrial sites were tested with HFS in four Langendorff-perfused porcine hearts. A 3.5 mm tip quadripolar ablation catheter was used to stimulate and deliver HFS to the left and right atrial epicardium, within the local atrial refractory period. Tissue samples from sites triggering atrial ectopy/AF (ET) sites and non-ET sites were stained with choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH), for quantification of parasympathetic and sympathetic nerves, respectively. The average cross-sectional area (CSA) of nerves was also calculated. Histomorphometry of six ET sites (9.5%) identified by HFS evoking at least a single atrial ectopic was compared with non-ET sites. All ET sites contained ChAT-immunoreactive (ChAT-IR) and/or TH-immunoreactive nerves (TH-IR). Nerve density was greater in ET sites compared to non-ET sites (nerves/cm2: 162.3 ± 110.9 vs. 69.65 ± 72.48; P = 0.047). Overall, TH-IR nerves had a larger CSA than ChAT-IR nerves (µm2: 11 196 ± 35 141 vs. 2070 ± 5841; P < 0.0001), but in ET sites, TH-IR nerves were smaller than in non-ET sites (µm2: 6021 ± 14 586 vs. 25 254 ± 61 499; P < 0.001). CONCLUSIONS: ET sites identified by HFS contained a higher density of smaller nerves than non-ET sites. The majority of these nerves were within the atrial myocardium. This has important clinical implications for devising an effective therapeutic strategy for targeting autonomic triggers of AF.

Seasonal mortality trends for hospitalised patients with acute kidney injury across England.

BACKGROUND: Incidence of acute kidney injury (AKI) is known to peak in winter months. This is likely influenced by seasonality of commonly associated acute illnesses. We set out to assess seasonal mortality trends for patients who develop AKI across the English National Health Service (NHS) and to better understand associations with patient 'case-mix'. METHODS: The study cohort included all hospitalised adult patients in England who triggered a biochemical AKI alert in 2017. We modelled the impact of season on 30-day mortality using multivariable logistic regression; adjusting for age, sex, ethnicity, index of multiple deprivation (IMD), primary diagnosis, comorbidity (RCCI), elective/emergency admission, peak AKI stage and community/hospital acquired AKI. Seasonal odds ratios for AKI mortality were then calculated and compared across individual NHS hospital trusts. RESULTS: The crude 30-day mortality for hospitalised AKI patients was 33% higher in winter compared to summer. Case-mix adjustment for a wide range of clinical and demographic factors did not fully explain excess winter mortality. The adjusted odds ratio of patients dying in winter vs. summer was 1.25 (1.22-1.29), this was higher than for Autumn and Spring vs. Summer, 1.09 (1.06-1.12) and 1.07 (1.04-1.11) respectively and varied across different NHS trusts (9 out of 90 centres outliers). CONCLUSION: We have demonstrated an excess winter mortality risk for hospitalised patients with AKI across the English NHS, which could not be fully explained by seasonal variation in patient case-mix. Whilst the explanation for worse winter outcomes is not clear, unaccounted differences including 'winter-pressures' merit further investigation.

Centre variation in mortality following post-hospitalization acute kidney injury: analysis of a large national cohort.

BACKGROUND: Routine monitoring of outcomes for patients with acute kidney injury (AKI) is important to drive ongoing quality improvement in patient care. In this study we describe the development of a case mix-adjusted 30-day mortality indicator for patients with post-hospitalization AKI (PH-AKI) across England to facilitate identification of any unwarranted centre variation in outcomes. METHODS: We utilized a routinely collected national dataset of biochemically detected AKI cases linked with national hospitals administrative and mortality data. A total of 250 504 PH-AKI episodes were studied across 103 National Health Service hospital trusts between January 2017 and December 2018. Standardized mortality ratios (SMRs) were calculated for each trust using logistic regression, adjusting for age, sex, primary diagnosis, comorbidity score, AKI severity, month of AKI and admission method. RESULTS: The mean 30-day mortality rate was high, at 28.6%. SMRs for 23/103 trusts were classed as outliers, 12 above and 11 below the 95% confidence limits. Patients with PH-AKI had mortality rates >5 times higher than the overall hospitalized population in 90/136 diagnosis groups and >10 times higher in 60/136 groups. Presentation at trusts with a co-located specialist nephrology service was associated with a lower mortality risk, as was South Asian or Black ethnicity. Deprivation, however, was associated with higher mortality. CONCLUSIONS: This is the largest multicentre analysis of mortality for patients with biochemically ascertained PH-AKI to date, demonstrating once again the considerable risk associated with developing even mild elevations in serum creatinine. Mortality rates varied considerably across centres and those identified as outliers will now need to carefully interrogate local care pathways to understand and address the reasons for this, with national policy required to tackle the identified health disparities.

Transcranial Magnetic Stimulation and the Understanding of Behavior.

The development of the use of transcranial magnetic stimulation (TMS) in the study of psychological functions has entered a new phase of sophistication. This is largely due to an increasing physiological knowledge of its effects and to its being used in combination with other experimental techniques. This review presents the current state of our understanding of the mechanisms of TMS in the context of designing and interpreting psychological experiments. We discuss the major conceptual advances in behavioral studies using TMS. There are meaningful physiological and technical achievements to review, as well as a wealth of new perceptual and cognitive experiments. In doing so we summarize the different uses and challenges of TMS in mental chronometry, perception, awareness, learning, and memory.

Face learning via brief real-world social interactions induces changes in face-selective brain areas and hippocampus.

Making new acquaintances requires learning to recognise previously unfamiliar faces. In the current study, we investigated this process by staging real-world social interactions between actors and the participants. Participants completed a face-matching behavioural task in which they matched photographs of the actors (whom they had yet to meet), or faces similar to the actors (henceforth called foils). Participants were then scanned using functional magnetic resonance imaging (fMRI) while viewing photographs of actors and foils. Immediately after exiting the scanner, participants met the actors for the first time and interacted with them for 10 min. On subsequent days, participants completed a second behavioural experiment and then a second fMRI scan. Prior to each session, actors again interacted with the participants for 10 min. Behavioural results showed that social interactions improved performance accuracy when matching actor photographs, but not foil photographs. The fMRI analysis revealed a difference in the neural response to actor photographs and foil photographs across all regions of interest (ROIs) only after social interactions had occurred. Our results demonstrate that short social interactions were sufficient to learn and discriminate previously unfamiliar individuals. Moreover, these learning effects were present in brain areas involved in face processing and memory.

Theta-burst TMS of lateral occipital cortex reduces BOLD responses across category-selective areas in ventral temporal cortex.

Human visual cortex contains three scene-selective regions in the lateral, medial and ventral cortex, termed the occipital place area (OPA), medial place area (MPA) and parahippocampal place area (PPA). Using functional magnetic resonance imaging (fMRI), all three regions respond more strongly when viewing visual scenes compared with isolated objects or faces. To determine how these regions are functionally and causally connected, we applied transcranial magnetic stimulation to OPA and measured fMRI responses before and after stimulation, using a theta-burst paradigm (TBS). To test for stimulus category-selectivity, we presented a range of visual categories (scenes, buildings, objects, faces). To test for specificity of any effects to TBS of OPA we employed two control conditions: Sham, with no TBS stimulation, and an active TBS-control with TBS to a proximal face-selective cortical region (occipital face area, or OFA). We predicted that TBS to OPA (but not OFA) would lead to decreased responses to scenes and buildings (but not other categories) in other scene-selective cortical regions. Across both ROI and whole-volume analyses, we observed decreased responses to scenes in PPA as a result of TBS. However, these effects were neither category specific, with decreased responses to all stimulus categories, nor limited to scene-selective regions, with decreases also observed in face-selective fusiform face area (FFA). Furthermore, similar effects were observed with TBS to OFA, thus effects were not specific to the stimulation site in the lateral occipital cortex. Whilst these data are suggestive of a causal, but non-specific relationship between lateral occipital and ventral temporal cortex, we discuss several factors that could have underpinned this result, such as the differences between TBS and online TMS, the role of anatomical distance between stimulated regions and how TMS effects are operationalised. Furthermore, our findings highlight the importance of active control conditions in brain stimulation experiments to accurately assess functional and causal connectivity between specific brain regions.

The Human Posterior Superior Temporal Sulcus Samples Visual Space Differently From Other Face-Selective Regions.

Neuroimaging studies show that ventral face-selective regions, including the fusiform face area (FFA) and occipital face area (OFA), preferentially respond to faces presented in the contralateral visual field (VF). In the current study we measured the VF response of the face-selective posterior superior temporal sulcus (pSTS). Across 3 functional magnetic resonance imaging experiments, participants viewed face videos presented in different parts of the VF. Consistent with prior results, we observed a contralateral VF bias in bilateral FFA, right OFA (rOFA), and bilateral human motion-selective area MT+. Intriguingly, this contralateral VF bias was absent in the bilateral pSTS. We then delivered transcranial magnetic stimulation (TMS) over right pSTS (rpSTS) and rOFA, while participants matched facial expressions in both hemifields. TMS delivered over the rpSTS disrupted performance in both hemifields, but TMS delivered over the rOFA disrupted performance in the contralateral hemifield only. These converging results demonstrate that the contralateral bias for faces observed in ventral face-selective areas is absent in the pSTS. This difference in VF response is consistent with face processing models proposing 2 functionally distinct pathways. It further suggests that these models should account for differences in interhemispheric connections between the face-selective areas across these 2 pathways.

Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling.

We describe a human and large animal Langendorff experimental apparatus for live electrophysiological studies and measure the electrophysiological changes due to gap junction uncoupling in human and porcine hearts. The resultant ex vivo intact human and porcine model can bridge the translational gap between smaller simple laboratory models and clinical research. In particular, electrophysiological models would benefit from the greater myocardial mass of a large heart due to its effects on far-field signal, electrode contact issues and motion artefacts, consequently more closely mimicking the clinical setting. Porcine (n = 9) and human (n = 4) donor hearts were perfused on a custom-designed Langendorff apparatus. Epicardial electrograms were collected at 16 sites across the left atrium and left ventricle. A total of 1 mM of carbenoxolone was administered at 5 ml/min to induce cellular uncoupling, and then recordings were repeated at the same sites. Changes in electrogram characteristics were analysed. We demonstrate the viability of a controlled ex vivo model of intact porcine and human hearts for electrophysiology with pharmacological modulation. Carbenoxolone reduces cellular coupling and changes contact electrogram features. The time from stimulus artefact to (-dV/dt)max increased between baseline and carbenoxolone (47.9 ± 4.1-67.2 ± 2.7 ms) indicating conduction slowing. The features with the largest percentage change between baseline and carbenoxolone were fractionation + 185.3%, endpoint amplitude - 106.9%, S-endpoint gradient + 54.9%, S point - 39.4%, RS ratio + 38.6% and (-dV/dt)max - 20.9%. The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically induced pro-arrhythmic substrates.

The Superior Temporal Sulcus Is Causally Connected to the Amygdala: A Combined TBS-fMRI Study.

Nonhuman primate neuroanatomical studies have identified a cortical pathway from the superior temporal sulcus (STS) projecting into dorsal subregions of the amygdala, but whether this same pathway exists in humans is unknown. Here, we addressed this question by combining theta burst transcranial magnetic stimulation (TBS) with fMRI to test the prediction that the STS and amygdala are functionally connected during face perception. Human participants (N = 17) were scanned, over two sessions, while viewing 3 s video clips of moving faces, bodies, and objects. During these sessions, TBS was delivered over the face-selective right posterior STS (rpSTS) or over the vertex control site. A region-of-interest analysis revealed results consistent with our hypothesis. Namely, TBS delivered over the rpSTS reduced the neural response to faces (but not to bodies or objects) in the rpSTS, right anterior STS (raSTS), and right amygdala, compared with TBS delivered over the vertex. By contrast, TBS delivered over the rpSTS did not significantly reduce the neural response to faces in the right fusiform face area or right occipital face area. This pattern of results is consistent with the existence of a cortico-amygdala pathway in humans for processing face information projecting from the rpSTS, via the raSTS, into the amygdala. This conclusion is consistent with nonhuman primate neuroanatomy and with existing face perception models. SIGNIFICANCE STATEMENT: Neuroimaging studies have identified multiple face-selective regions in the brain, but the functional connections between these regions are unknown. In the present study, participants were scanned with fMRI while viewing movie clips of faces, bodies, and objects before and after transient disruption of the face-selective right posterior superior temporal sulcus (rpSTS). Results showed that TBS disruption reduced the neural response to faces, but not to bodies or objects, in the rpSTS, right anterior STS (raSTS), and right amygdala. These results are consistent with the existence of a cortico-amygdala pathway in humans for processing face information projecting from the rpSTS, via the raSTS, into the amygdala. This conclusion is consistent with nonhuman primate neuroanatomy and with existing face perception models.

Characterisation of re-entrant circuit (or rotational activity) in vitro using the HL1-6 myocyte cell line.

Fibrillation is the most common arrhythmia observed in clinical practice. Understanding of the mechanisms underlying its initiation and maintenance remains incomplete. Functional re-entries are potential drivers of the arrhythmia. Two main concepts are still debated, the "leading circle" and the "spiral wave or rotor" theories. The homogeneous subclone of the HL1 atrial-derived cardiomyocyte cell line, HL1-6, spontaneously exhibits re-entry on a microscopic scale due to its slow conduction velocity and the presence of triggers, making it possible to examine re-entry at the cellular level. We therefore investigated the re-entry cores in cell monolayers through the use of fluorescence optical mapping at high spatiotemporal resolution in order to obtain insights into the mechanisms of re-entry. Re-entries in HL1-6 myocytes required at least two triggers and a minimum colony area to initiate (3.5 to 6.4 mm2). After electrical activity was completely stopped and re-started by varying the extracellular K+ concentration, re-entries never returned to the same location while 35% of triggers re-appeared at the same position. A conduction delay algorithm also allows visualisation of the core of the re-entries. This work has revealed that the core of re-entries is conduction blocks constituted by lines and/or groups of cells rather than the round area assumed by the other concepts of functional re-entry. This highlights the importance of experimentation at the microscopic level in the study of re-entry mechanisms.

TMS demonstrates that both right and left superior temporal sulci are important for facial expression recognition.

Prior studies demonstrate that a face-responsive region in the posterior superior temporal sulcus (pSTS) is involved in facial expression recognition. Although this region can be identified in both hemispheres, studies more commonly report it in the right hemisphere. However, the extent to which expression recognition is lateralised in pSTS remains unclear. In the current study, we used transcranial magnetic stimulation (TMS) to systematically compare the causal contribution of the right pSTS (rpSTS) with the left pSTS (lpSTS) during facial expression recognition. TMS was delivered over the functionally localised rpSTS, lpSTS and the control vertex site while participants (N = 30) performed an expression matching task and a control object matching task. TMS delivered over the rpSTS impaired expression recognition more than TMS delivered over the lpSTS. Crucially, TMS delivered over the rpSTS and lpSTS impaired task performance more than TMS delivered over the control site. TMS had no effect on the control task. This causally demonstrates that while task disruption was greater in the rpSTS, both the rpSTS and the lpSTS were engaged in facial expression recognition. Our results indicate that cognitive functions that are seemingly lateralised in neuroimaging studies, still rely on computations performed in both hemispheres for optimum task performance.

Normal acquisition of expertise with greebles in two cases of acquired prosopagnosia.

Face recognition is generally thought to rely on different neurocognitive mechanisms than most types of objects, but the specificity of these mechanisms is debated. One account suggests the mechanisms are specific to upright faces, whereas the expertise view proposes the mechanisms operate on objects of high within-class similarity with which an observer has become proficient at rapid individuation. Much of the evidence cited in support of the expertise view comes from laboratory-based training experiments involving computer-generated objects called greebles that are designed to place face-like demands on recognition mechanisms. A fundamental prediction of the expertise hypothesis is that recognition deficits with faces will be accompanied by deficits with objects of expertise. Here we present two cases of acquired prosopagnosia, Herschel and Florence, who violate this prediction: Both show normal performance in a standard greeble training procedure, along with severe deficits on a matched face training procedure. Herschel and Florence also meet several response time criteria that advocates of the expertise view suggest signal successful acquisition of greeble expertise. Furthermore, Herschel's results show that greeble learning can occur without normal functioning of the right fusiform face area, an area proposed to mediate greeble expertise. The marked dissociation between face and greeble expertise undermines greeble-based claims challenging face-specificity and indicates face recognition mechanisms are not necessary for object recognition after laboratory-based training.

Algorithms to guide ambulance clinicians in the management of emergencies in patients with implanted rotary left ventricular assist devices.

Advances in left ventricular assist device (LVAD) therapy have resulted in increasing numbers of adult LVAD recipients in the community. However, device failure, stroke, bleeding, LVAD thrombosis and systemic infection can be life-threatening emergencies. Currently, four LVAD systems are implanted in six UK transplant centres, each of which provides device-specific information to local emergency services. This has resulted in inconsistent availability and content of information with the risks of delayed or inappropriate decision-making. In order to improve patient safety, a consortium of UK healthcare professionals with expertise in LVADs developed universally applicable prehospital emergency algorithms. Guidance was framed as closely as possible on the standard ABCDE approach to the assessment of critically ill patients.

Facial expression recognition takes longer in the posterior superior temporal sulcus than in the occipital face area.

Neuroimaging studies have identified a face-selective region in the right posterior superior temporal sulcus (rpSTS) that responds more strongly during facial expression recognition tasks than during facial identity recognition tasks, but precisely when the rpSTS begins to causally contribute to expression recognition is unclear. The present study addressed this issue using transcranial magnetic stimulation (TMS). In Experiment 1, repetitive TMS delivered over the rpSTS of human participants, at a frequency of 10 Hz for 500 ms, selectively impaired a facial expression task but had no effect on a matched facial identity task. In Experiment 2, participants performed the expression task only while double-pulse TMS (dTMS) was delivered over the rpSTS or over the right occipital face area (rOFA), a face-selective region in lateral occipital cortex, at different latencies up to 210 ms after stimulus onset. Task performance was selectively impaired when dTMS was delivered over the rpSTS at 60-100 ms and 100-140 ms. dTMS delivered over the rOFA impaired task performance at 60-100 ms only. These results demonstrate that the rpSTS causally contributes to expression recognition and that it does so over a longer time-scale than the rOFA. This difference in the length of the TMS induced impairment between the rpSTS and the rOFA suggests that the neural computations that contribute to facial expression recognition in each region are functionally distinct.

Nuclear proteasomes carry a constitutive posttranslational modification which derails SDS-PAGE (but not CTAB-PAGE).

We report that subunits of human nuclear proteasomes carry a previously unrecognised, constitutive posttranslational modification. Subunits with this modification are not visualised by SDS-PAGE, which is used in almost all denaturing protein gel electrophoresis. In contrast, CTAB-PAGE readily visualises such modified subunits. Thus, under most experimental conditions, with identical samples, SDS-PAGE yielded gel electrophoresis patterns for subunits of nuclear proteasomes which were misleading and strikingly different from those obtained with CTAB-PAGE. Initial analysis indicates a novel modification of a high negative charge with some similarity to polyADP-ribose, possibly explaining compatibility with (positively-charged) CTAB-PAGE but not (negatively-charged) SDS-PAGE and providing a mechanism for how nuclear proteasomes may interact with chromatin, DNA and other nuclear components.

Epidemiology of patients in England and Wales with autosomal dominant polycystic kidney disease and end-stage renal failure.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end-stage renal failure (ESRF). The epidemiology of the incident ADPKD patient cohort requiring renal replacement therapy (RRT) in England and Wales has not been described. METHODS: We used a retrospective cohort design. Incident adult patients commencing RRT between 1 January 2000 and 31 December 2011 in England and Wales were identified from the UK Renal Registry. Patients were stratified into three groups based on primary renal diagnosis (PRD): (i) ADPKD, (ii) diabetes as PRD, (iii) individuals with another PRD ('other'). Baseline demographics, comorbidity, care-related measures and outcomes including patient survival are described. RESULTS: A total of 52,608 individuals started RRT during the study period, 3598 (6.8%) had ADPKD, 12,137 (23.1%) diabetes as PRD and 36,873 had another PRD diagnosis. The median age of commencing RRT was 55 years in the ADPKD group compared with 62 and 66 years in those with diabetes or 'other' PRD, respectively. The median age of starting RRT did not change within the ADPKD group over the 10-year period. Median age at death was similar across all groups. The ADPKD group had a lower hazard for all-cause mortality compared with the 'other' PRD group (adjusted hazard ratio 0.45, 95% CI 0.38-0.53). In all PRD groups, crude mortality rates had improved between 2000-06 and 2007-11. CONCLUSION: Although engaged in renal services earlier than some other patient groups, individuals with ADPKD start RRT at a younger age and this has remained unchanged over the last decade. Developing a nationwide cohort and an enhanced disease-specific dataset would facilitate a wide range of research and quality improvement initiatives to try to modify progression to ESRF and the course of RRT.