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.

Visual neuroscience: A brain area tuned for processing social interactions.

Socialising with others is part of everyday life. A new study demonstrates that a brain area specialised for visual body perception is attuned to processing social interactions between two people. Intriguingly, this area is lateralised in the left hemisphere.

Individual differences in internal models explain idiosyncrasies in scene perception.

According to predictive processing theories, vision is facilitated by predictions derived from our internal models of what the world should look like. However, the contents of these models and how they vary across people remains unclear. Here, we use drawing as a behavioral readout of the contents of the internal models in individual participants. Participants were first asked to draw typical versions of scene categories, as descriptors of their internal models. These drawings were converted into standardized 3d renders, which we used as stimuli in subsequent scene categorization experiments. Across two experiments, participants' scene categorization was more accurate for renders tailored to their own drawings compared to renders based on others' drawings or copies of scene photographs, suggesting that scene perception is determined by a match with idiosyncratic internal models. Using a deep neural network to computationally evaluate similarities between scene renders, we further demonstrate that graded similarity to the render based on participants' own typical drawings (and thus to their internal model) predicts categorization performance across a range of candidate scenes. Together, our results showcase the potential of a new method for understanding individual differences - starting from participants' personal expectations about the structure of real-world scenes.

Visual neuroscience: A specialised neural pathway for social perception.

Humans are an intensely social species. Our daily lives depend on understanding the behaviour and intentions of the people around us. A new study identifies a neural pathway specialised for interpreting the physical actions that we use to understand others.

TMS disruption of the lateral prefrontal cortex increases neural activity in the default mode network when naming facial expressions.

Recognizing facial expressions is dependent on multiple brain networks specialized for different cognitive functions. In the current study, participants (N = 20) were scanned using functional magnetic resonance imaging (fMRI), while they performed a covert facial expression naming task. Immediately prior to scanning thetaburst transcranial magnetic stimulation (TMS) was delivered over the right lateral prefrontal cortex (PFC), or the vertex control site. A group whole-brain analysis revealed that TMS induced opposite effects in the neural responses across different brain networks. Stimulation of the right PFC (compared to stimulation of the vertex) decreased neural activity in the left lateral PFC but increased neural activity in three nodes of the default mode network (DMN): the right superior frontal gyrus, right angular gyrus and the bilateral middle cingulate gyrus. A region of interest analysis showed that TMS delivered over the right PFC reduced neural activity across all functionally localised face areas (including in the PFC) compared to TMS delivered over the vertex. These results suggest that visually recognizing facial expressions is dependent on the dynamic interaction of the face-processing network and the DMN. Our study also demonstrates the utility of combined TMS/fMRI studies for revealing the dynamic interactions between different functional brain networks.

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.

Identifying the cortical face network with dynamic face stimuli: A large group fMRI study.

Functional magnetic resonance imaging (fMRI) studies have identified a network of face-selective regions distributed across the human brain. In the present study, we analyzed data from a large group of gender-balanced participants to investigate how reliably these face-selective regions could be identified across both cerebral hemispheres. Participants ( N =52) were scanned with fMRI while viewing short videos of faces, bodies, and objects. Results revealed that five face-selective regions: the fusiform face area (FFA), posterior superior temporal sulcus (pSTS), anterior superior temporal sulcus (aSTS), inferior frontal gyrus (IFG) and the amygdala were all larger in the right than in the left hemisphere. The occipital face area (OFA) was larger in the right hemisphere as well, but the difference between the hemispheres was not significant. The neural response to moving faces was also greater in face-selective regions in the right than in the left hemisphere. An additional analysis revealed that the pSTS and IFG were significantly larger in the right hemisphere compared to other face-selective regions. This pattern of results demonstrates that moving faces are preferentially processed in the right hemisphere and that the pSTS and IFG appear to be the strongest drivers of this laterality. An analysis of gender revealed that face-selective regions were typically larger in females ( N =26) than males ( N =26), but this gender difference was not statistically significant.

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.

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.

Long-Term Outcomes in IgA Nephropathy.

BACKGROUND: IgA nephropathy can progress to kidney failure, and risk assessment soon after diagnosis has advantages both for clinical management and the development of new therapeutics. We present relationships among proteinuria, eGFR slope, and lifetime risks for kidney failure. METHODS: The IgA nephropathy cohort (2299 adults and 140 children) of the UK National Registry of Rare Kidney Diseases (RaDaR) was analyzed. Patients enrolled had a biopsy-proven diagnosis of IgA nephropathy plus proteinuria >0.5 g/d or eGFR <60 ml/min per 1.73 m 2 . Incident and prevalent populations and a population representative of a typical phase 3 clinical trial cohort were studied. Analyses of kidney survival were conducted using Kaplan-Meier and Cox regression. eGFR slope was estimated using linear mixed models with random intercept and slope. RESULTS: The median (Q1, Q3) follow-up was 5.9 (3.0, 10.5) years; 50% of patients reached kidney failure or died in the study period. The median (95% confidence interval [CI]) kidney survival was 11.4 (10.5 to 12.5) years; the mean age at kidney failure/death was 48 years, and most patients progressed to kidney failure within 10-15 years. On the basis of eGFR and age at diagnosis, almost all patients were at risk of progression to kidney failure within their expected lifetime unless a rate of eGFR loss ≤1 ml/min per 1.73 m 2 per year was maintained. Time-averaged proteinuria was significantly associated with worse kidney survival and more rapid eGFR loss in incident, prevalent, and clinical trial populations. Thirty percent of patients with time-averaged proteinuria of 0.44 to <0.88 g/g and approximately 20% of patients with time-averaged proteinuria <0.44 g/g developed kidney failure within 10 years. In the clinical trial population, each 10% decrease in time-averaged proteinuria from baseline was associated with a hazard ratio (95% CI) for kidney failure/death of 0.89 (0.87 to 0.92). CONCLUSIONS: Outcomes in this large IgA nephropathy cohort are generally poor with few patients expected to avoid kidney failure in their lifetime. Significantly, patients traditionally regarded as being low risk, with proteinuria <0.88 g/g (<100 mg/mmol), had high rates of kidney failure within 10 years.

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.

Visual motion: Asymmetrical processing differences between the cerebral hemispheres.

Hemispheric differences speak to the functional organisation of the human brain. A new study causally demonstrates such differences are present in bilateral motion-selective areas that are early in the visual cortical hierarchy.

Measuring the response to visually presented faces in the human lateral prefrontal cortex.

Neuroimaging studies identify multiple face-selective areas in the human brain. In the current study, we compared the functional response of the face area in the lateral prefrontal cortex to that of other face-selective areas. In Experiment 1, participants (n = 32) were scanned viewing videos containing faces, bodies, scenes, objects, and scrambled objects. We identified a face-selective area in the right inferior frontal gyrus (rIFG). In Experiment 2, participants (n = 24) viewed the same videos or static images. Results showed that the rIFG, right posterior superior temporal sulcus (rpSTS), and right occipital face area (rOFA) exhibited a greater response to moving than static faces. In Experiment 3, participants (n = 18) viewed face videos in the contralateral and ipsilateral visual fields. Results showed that the rIFG and rpSTS showed no visual field bias, while the rOFA and right fusiform face area (rFFA) showed a contralateral bias. These experiments suggest two conclusions; firstly, in all three experiments, the face area in the IFG was not as reliably identified as face areas in the occipitotemporal cortex. Secondly, the similarity of the response profiles in the IFG and pSTS suggests the areas may perform similar cognitive functions, a conclusion consistent with prior neuroanatomical and functional connectivity evidence.

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.

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.

Stimulating parietal regions of the multiple-demand cortex impairs novel vocabulary learning.

Neuroimaging research demonstrated that the early stages of learning engage domain-general networks, non-specialist brain regions that process a wide variety of cognitive tasks. Those networks gradually disengage as learning progresses and learned information becomes processed in brain networks specialised for the specific function (e.g., language). In the current study, we used repetitive transcranial magnetic stimulation (rTMS) in the form of continuous theta burst stimulation (cTBS) to test whether stimulation of the bilateral parietal region of the domain-general network impairs learning new vocabulary, indicating its causal engagement in this process. Twenty participants, with no prior knowledge of Polish, learned Polish words for well-known objects across three training stages. The first training stage started with cTBS applied to either the experimental domain-general bilateral parietal site or the control bilateral precentral site. Immediately after cTBS, the vocabulary training commenced. A different set of words was learned for each site. Immediately after the training stage, participants performed a novel vocabulary test, designed to measure their knowledge of the new words and the effect of stimulation on learning. To measure stimulation effect when the words were more established in the mental lexicon, participants received additional training on the same words but without cTBS (second training stage) and then the full procedures from the first training stage were repeated (third training stage). Results demonstrated that stimulation impaired novel word learning when applied to the bilateral parietal site at the first stage of learning only. This effect was not present when newly learned words were used more proficiently in the third training stage, or at any learning stage during control site stimulation. Our results show that the bilateral parietal region of the domain-general network causally contributes to the successful learning of novel words.

Correction: Reusable snorkel masks adapted as particulate respirators.

[This corrects the article DOI: 10.1371/journal.pone.0249201.].

In vivo grafting of large engineered heart tissue patches for cardiac repair.

Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be a novel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more data are needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.5 cm × 1.5 cm × 1.5 mm) consisting of up to 20 million human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) embedded in a fibrin-based hydrogel was developed. A rabbit myocardial infarction model was then established to test for feasibility and efficacy. Our data showed that hPSC-CMs in EHTs became more aligned over 28 days and had improved contraction kinetics and faster calcium transients. Blinded echocardiographic analysis revealed a significant improvement in function in infarcted hearts that received EHTs, along with reduction in infarct scar size by 35%. Vascularization from the host to the patch was observed at week 1 and stable to week 4, but electrical coupling between patch and host heart was not observed. In vivo telemetry recordings and ex vivo arrhythmia provocation protocols showed that the patch was not pro-arrhythmic. In summary, EHTs improved function and reduced scar size without causing arrhythmia, which may be due to the lack of electrical coupling between patch and host heart.