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The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. The growing scale and persistence of humanitarian crises constitute a critical problem for nation-states, aid organizations, and crisis-affected people around the world. Many in the fields of disaster response and humanitarian aid continue to focus on material aid, providing essential supplies and services during these crises, followed by restoration of physical infrastructure. We believe decision-makers and aid workers are overlooking the pivotal nature of horizontal and vertical ties within and between communities. Using qualitative and quantitative data from Uganda and Nigeria we show how social capital matters even during the most severe humanitarian crises. Through interviews and regression analyses based on survey data, we find that deeper reservoirs of bridging social capital are significantly associated with the preparedness of individuals affected by the terror group Boko Haram in Nigeria and that bonding and linking social capital are correlated to positive resilience outcomes for individuals affected by foodinsecurity stresses in the Karamoja region of Uganda. Our paper brings a number of concrete policy recommendations for aid agencies, decision-makers, and residents alike, especially for agencies willing to invest in building social infrastructure in affected or vulnerable populations

Implementation of the seventh amendment to the EU Cosmetics Directive has driven much research into suitable in vitro alternative assays to support satisfactory risk assessments. One such assay is the reconstructed skin micronucleus (RSMN) assay. First reported in 2006, further development occurred and a standard protocol was published in 2011. To evaluate and optimise the assay at Covance Laboratories, we tested nine chemicals [4-nitrophenol (4-NP), cyclohexanone (CH), 2-ethyl-1,3-hexanediol (2-EHD), methyl methansulfonate (MMS), mitomycin C (MMC), ethyl nitrosourea (ENU), benzo[a]pyrene (BaP), cyclophosphamide (CPA) and vinblastine (VIN)] using the EpiDerm™ 3D skin model (MatTek Corporation®, IVLSL, Bratislava, Slovakia) and compared the data using the standard 48-h treatment regimen and also an emerging 72-h treatment protocol. The EpiDerm™ tissue has reportedly some metabolic capacity but data using 48-h treatments has provided mixed results. Our investigations demonstrate that the two chemicals requiring metabolic activation (BaP and CPA) were negative following the 48-h protocol but were clearly positive following 72-h treatment. Furthermore, Replication Index (RI) data showed higher RI values in vehicle control treatments (indicating increased cell division) across the treatment set following 72-h treatments. A general greater magnitude of micronucleus (MN) induction was also observed following test chemical treatment. These data suggest that the 72-h treatment protocol is more suitable as a standard approach for the detection of clastogenic, aneugenic and metabolically activated chemicals in the RSMN assay. For further assay optimisation, we compare the statistical power of scoring cells from duplicate or triplicate cultures per treatment concentration and provide recommendations.

Background Social isolation is associated with CHD mortality but evidence of association with incident CHD is mixed. We prospectively examined this association in the Million Women Study (MWS) and UK Biobank (UKB). Methods 481,946 MWS and 456,612 UKB participants reported on social isolation (living alone, little contact with family/friends/groups). Excluding those reporting previous CHD or stroke, participants were followed for incident CHD using linkage to hospital admission and death records. Cox regression yielded relative risks (RR) by 3 levels of social isolation, adjusted for relevant confounders. Results During 7 years follow-up in the MWS and UKB, there were 42,402 first coronary heart disease events in total (of which 1,834 were fatal without an associated hospital admission). After adjustment, social isolation was not associated with hospital admission for first CHD events (combined RR for both studies: RR = 1.01, 95% CI: 0.98–1.04). However, the risk of fatal first CHD events without an associated hospital admission was substantially higher in the most isolated group than the least isolated group (1.86 [1.63–2.12]) This association with fatal first CHD events was driven by the association with living alone. Conclusions Social isolation was not associated with increased risk of first CHD hospital admissions but was associated with increased risk of death from CHD. Key messages Social isolation is likely not a risk factor for developing CHD, but people living alone may be at greater risk of dying from a coronary event than those not living alone.

PURPOSE Measuring gliomas is a time-intensive process with significant inter-rater variability in post-surgical residual tumor and resection cavities. This likely contributes to the delayed assessment of progression and in-field recurrences from radiation. Automated segmentation of pre and post-treatment gliomas could reduce inter-rater variability and increase workflow efficiency for routine longitudinal radiographic assessment and treatment planning. We evaluated whether a 3D neural network is comparable to expert assessment of pre and post-treatment diffuse gliomas tissue types and resection cavities. METHODS A retrospective cohort of 647 MRIs of patients with diffuse gliomas (average 55.1 years, 45% female, 396 pre-treatment and 251 post-treatment, median 237 days post-surgery) from The Cancer Imaging Archive were stratified by operation status and tumor grade and randomly split into training (536) and testing (111) samples. T1, T1-post-contrast, T2, and FLAIR images were registered, skull-stripped, and interpolated to 1x1x1. Four classes — edema/infiltrative/post-treatment changes (ED), enhancing tissue (ET), necrotic core (NCR), and resection cavities (RC) — were manually segmented by an expert neuroradiologist. Using these segmentations and the four input image modalities, a nnU-Net, a state-of-the-art 3D U-Net convolutional neural network, was trained to predict segmentations of the four classes. RESULTS Segmentation performance in the test set for the ED, ET, and RC classes was at the level of inter-rater reliability with median Dice scores ranging from 0.85 to 1 and relative volume errors ranging from -0.05 to 0.02. There was a near-perfect correlation between manually segmented and predicted total lesion volumes (r2 values ranging from 0.95 to 0.98 among classes). CONCLUSIONS Accurate, automated volumetric quantification of diffuse glioma tissue volumes may improve response assessment in clinical trials and reduce provider burden and errors in measurement.

OBJECTIVES The intermediate-term all-cause mortality rate of real-world patients with multivessel disease (MVD) treated with percutaneous coronary intervention (PCI) with new-generation drug-eluting stents or coronary artery bypass grafting (CABG) remains unknown. We sought to compare the intermediate-term all-cause mortality rates of real-world patients with MVD including left main stem disease, treated with CABG or PCI. METHODS All consecutive all-comer patients with MVD undergoing CABG or PCI with second/third generation drug-eluting stents from 2007 to 2015 in Harefield Hospital, UK were included in this study. The revascularization modality was based on heart team discussions. Primary outcome was all-cause mortality. Mean follow-up of the study was 3.3 years. Cox regression analysis and propensity matching were used. RESULTS Of 6383 patients with MVD, 4230 underwent CABG, whereas 2153 had PCI with new-generation stents. In the CABG group, the mean age was 66.4 ± 10 years, whereas in the PCI group it was 65.3 ± 12.1 years (P CONCLUSIONS In this contemporary cohort of real-world patients with MVD, CABG was associated with increased intermediate-term survival compared to PCI with new-generation drug-eluting stents.

The in vitro micronucleus (IVMN) test was endorsed for regulatory genotoxicity testing with adoption of the Organisation for Economic Co-operation and Development (OECD) test guideline (TG) 487 in 2010. This included two equally acceptable options for extended treatment in the absence of metabolic activation: a treatment for 1.5–2.0 cell cycles with harvest at the end of treatment (Option A) or treatment for 1.5–2.0 cell cycles followed by recovery for 1.5–2.0 cell cycles prior to harvest (Option B). Although no preferences were discussed, TG 487 cautions that Option B may not be appropriate for stimulated lymphocytes where exponential growth may be declining at 96 h after phytohaemagglutinin (PHA) stimulation. Following revision of TG 487 in 2014 and 2016, emphasis has been placed on using Option A. Given the purpose of the IVMN assay is to determine both clastogenic and aneugenic potential, the authors believe the assay is compromised if an extended treatment with recovery is not included for sensitive detection of certain classes of chemical. In this study, average generation time (via bromodeoxyuridine incorporation) of human peripheral blood lymphocytes (HPBL) was measured up to 144 h after PHA stimulation. In addition, the HPBL micronucleus (MN) assay was performed using Option A and B treatment schedules. Cytotoxicity (replication index) and MN induction were determined following treatment with 14 chemicals. The data demonstrate that lymphocytes actively divide beyond 96 h after PHA stimulation. Furthermore, MN induction was only observed with some aneugenic chemicals and nucleoside analogues in HPBLs following extended treatment with a recovery period. For the majority of chemicals tested the magnitude of MN induction was generally greater and MN induction was observed across a wider concentration range following the Option B treatment schedule. In addition, steep concentration-related toxicity following treatment without recovery is more common, making selection of suitable concentrations (within regulatory toxicity limits) for MN analysis challenging.

Introduction Percutaneous edge-to-edge mitral repair is a safe treatment method for functional (FMR) and degenerative (DMR) mitral regurgitation. Iatrogenic mitral stenosis remains a concern and periprocedural transoesophageal echocardiography is essential for real-time monitoring of mean mitral pressure gradient (intra-MMPG) and to guide clip deployment. Purpose Published data suggests intra-MMPG predicts clinical outcome and mortality only in DMR patients. We sought to validate these findings in a large high-volume UK center cohort with prolonged follow-up and further explore its use to predict mortality in functional MR patients. Methods All consecutive patients who underwent edge-to-edge mitral repair between 2010 and 2020 were analysed. The intra-MMPG and the severity of MR grade from the transoesophageal echocardiogram post-clip deployment (intra-MRgrade) were collected. Statistical analysis using covariates before and after edge-to-edge repair were compared using paired tests and cox regression models were used to assess the relationship of covariates with all-cause mortality. p Results We analysed data from 246 consecutive patients, 65% were men and mean age was 76±11 years. Pre-procedure LVEF was 49±15%, TAPSE was 16±6 mm, severity of MR was 3.8±0.5, 80% had NYHA III/IV and 45% had FMR. Post procedure, there was a significant reduction in severity of MR grade (3.8±0.5 to 1.7±0.8; p Patients were followed-up for a median of 1021 days (inter-quartile range 289 to 1555) during which 76 patients died. Multivariate survival analysis (see table) showed that the increase in intra-MMPG was independently associated with mortality for FMR, but not for DMR. Furthermore, higher intra-MRgrade was associated with mortality for FMR patients only. Conclusion Intraprocedural mean mitral pressure gradient (intra-MMPG) predicts mortality in percutaneous mitral edge-to-edge repair for FMR, but not for DMR, herby challenging previously published data. Funding Acknowledgement Type of funding source: None

Background Percutaneous mitral leaflet repair (PMVR) is a safe and effective alternative to conventional surgery in high-risk patients with both degenerative (DMR) and functional (FMR) mitral regurgitation. We present an analysis of a large cohort of consecutive patients treated with PMVR at a high-volume UK centre. Purpose We sought to analyse the outcomes of a group of patients undergoing PMVR over a 7-year period at a single centre, where surgery had been excluded. We hypothesised that the long-term mortality in this group would be high and would differ depending on the aetiology of MR. Methods We identified 246 consecutive patients over the duration of the PMVR programme, where follow up and pre-procedural data were available. We collected baseline characteristics including age at procedure, left ventricular ejection fraction (LVEF), left ventricular indexed diastolic volumes (LVEDVi) and aetiology of MR. Post procedural data included MR at end of procedure, all-cause mortality and duration of follow up. Results Baseline characteristics for the group, as a whole, were as follows: mean age 76±11 years, 170 (69%) male, DMR 136 (55%) vs. FMR 110 (45%), LVEF 49±15%. Baseline data by aetiology subgroup: mean age DMR 80±9 vs. FMR 71±11 (p Conclusions This analysis of consecutive “real world” patients demonstrates encouraging survival outcome at a mean of 3 years after PMVR, regardless of MR aetiology. DMR patients tended to be older but with lower LVEDVi and significantly higher LVEF. These data compare favourably with the published literature, where mortality for mixed and similarly high-risk populations at 12 months averages approximately 20–25%. Mortality in our FMR group at 3 years was also similar to that seen in the recently published COAPT study at 2 years. We have demonstrated that PMVR is a safe option for our cohort of unselected high-risk patients presenting with either degenerative or functional MR. We hypothesise that the absence of survival difference could relate to the younger age of FMR patients despite the significantly lower baseline LVEF and higher ventricular volumes. This analysis encourages the more routine use of PMVR for FMR in the UK, where currently only DMR is commissioned. Funding Acknowledgement Type of funding source: None

Aims CT calcium scoring (CTCS) and CT cardiac angiography (CTCA) are widely used in patients with stable chest pain to exclude significant coronary artery disease (CAD). We aimed to resolve uncertainty about the prevalence of obstructive coronary artery disease and long-term outcomes in patients with a zero-calcium score (ZCS). Methods and results Consecutive patients with stable cardiac symptoms referred for CTCS or CTCS and CTCA from chest pain clinics to a tertiary cardiothoracic centre were prospectively enrolled. In those with a ZCS, the prevalence of obstructive CAD on CTCA was determined. A follow-up for all-cause mortality was obtained from the NHS tracer service. A total of 3914 patients underwent CTCS of whom 2730 (69.7%) also had a CTCA. Half of the patients were men (50.3%) with a mean age of 56.9 years. Among patients who had both procedures, a ZCS was present in 52.2%, with a negative predictive value of 99.5% for excluding ≥70% stenosis on CTCA. During a mean follow-up of 5.2 years, the annual event rate was 0.3% for those with ZCS compared with 1.2% for CS ≥1. The presence of non-calcified atheroma on CTCA in patients with ZCS did not affect the prognostic value (P = 0.98). Conclusion In patients with stable symptoms and a ZCS, obstructive CAD is rare, and prognosis over the long-term is excellent, regardless of whether non-calcified atheroma is identified. A ZCS could reliably be used as a ‘gatekeeper’ in this patient cohort, obviating the need for further more expensive tests.

Background parkrun is an international organisation which hosts free, weekly volunteer-led, running events. More than 300,000 people participate across 21 countries each week. The present study investigates how access to, and participation in, parkrun events varies across England. We go on to make policy recommendations for new parkrun event locations, in order to maximise geographical access and participation whilst taking account of the impact on inequalities. Methods We combined location data of census areas, parkrun events and public parks in England. For the census areas, access was defined as the distance of the area’s centroid to the nearest parkrun event, and parkrun UK provided information on 2018 participation rates per area. Linear regression was used to investigate the effect of deprivation on access, and the effect of deprivation and access on utilisation. We propose a flexible algorithm for identifying optimal new parkrun event locations and provide two sample sets of recommendations. Results The median distance to the nearest parkrun event was 3.4 km, but the distribution was heavily skewed: for approximately 10% of the population, the nearest event was more than 10 km away. Despite statistical significance, the relationship between deprivation and access was very weak. However, access and deprivation had a considerable effect on participation: less deprived areas, and areas with good access had higher participation rates. The best locations for new events are contingent on what parkrun aims to maximise. We demonstrate that optimal locations for maximising equitable geographic access differ from locations for maximising participation. Conclusions Access to parkrun is generally good and is similar across socioeconomic groups, but participation is markedly higher in less deprived areas. Our algorithm can be used by parkrun to further improve access for deprived communities. However, better access alone is unlikely to reduce inequities in participation. Key messages In England, access to parkrun is generally good, and our algorithm can be used to further optimise it. However, better access alone is unlikely significantly increase participation from deprived areas.

Background Patients with acute, decompensated severe mitral regurgitation (MR) are poorly served by surgical or medical treatments and is associated with high mortality. Percutaneous edge-to-edge mitral valve repair (PMVR) with the MitraClip system is potentially a less-invasive life-saving procedure. While PMVR has demonstrated efficacy in stable patients with severe MR, there is limited evidence for its use in patients suffering from prolonged cardiogenic shock, recurrent or persistent pulmonary oedema, and haemodynamic instability. Purpose The aim of this study was to evaluate the effectiveness of emergency PMVR in haemodynamically unstable patients with decompensated MR who were unsuitable for surgical intervention. Methods We performed a retrospective review of all patients who underwent emergency PMVR from January 2015 to January 2019 in a single centre. Inclusion criteria were patients with acute decompensated severe MR and shock (defined at the time of procedure as dependence on one or more of: intravenous (IV) inotropes; afterload reduction for persistent pulmonary oedema; mechanical circulatory support; and invasive respiratory support). Outcome measures were pre- and post-procedural MR severity grade, mortality at six months, and incidence of further mitral valve intervention. Results Of 183 consecutive patients undergoing PMVR, 14 (8%) patients fulfilled the inclusion criteria. Median age was 70 (range 55–88, IQR 23), and 8 were female. At the time of admission, 7 (50%) were in cardiogenic shock and 7 were in persistent pulmonary oedema. MR was functional in 7 (50%) patients and degenerative in 7, of which 4 were secondary to acute papillary muscle rupture. All patients had Grade 4 MR at presentation and were considered too high-risk for surgery by the Heart Team. Median Euroscore II was 14.4 (8.1–54.6, IQR 9.1). Post-procedure, 13 patients (93%) of patients had Grade 3 MR or less. Eleven (79%) patients were successfully weaned from mechanical support and intravenous drugs. The remaining three patients died of persistent arrhythmia, stroke or heart failure within 4 weeks. At six-months, 9 out of 12 patients (75%) were alive and 2 were lost to follow-up. No patients underwent further mitral valve intervention. Conclusions This small case-series suggests that PMVR may be a feasible and life-saving procedure in patients presenting with acute, decompensated severe MR who were unsuitable for surgery. It was associated with reversal of cardiogenic shock and good short-term survival in the majority of patients. These patients are typically considered critically unwell with very high mortality. These promising results may inform larger, prospective studies to manage this otherwise under-served patient cohort.

Type I ribonucleotide reductases (RNRs) are conserved across diverse taxa and are essential for the conversion of RNA into DNA precursors. In Neurospora crassa, the large subunit of RNR (UN-24) is unusual in that it also has a nonself recognition function, whereby coexpression of Oak Ridge (OR) and Panama (PA) alleles of un-24 in the same cell leads to growth inhibition and cell death. We show that coexpressing these incompatible alleles of un-24 in N. crassa results in a high molecular weight UN-24 protein complex. A 63-amino-acid portion of the C terminus was sufficient for un-24PA incompatibility activity. Redox active cysteines that are conserved in type I RNRs and essential for their catalytic function were found to be required for incompatibility activity of both UN-24OR and UN-24PA. Our results suggest a plausible model of un-24 incompatibility activity in which the formation of a complex between the incompatible RNR proteins is potentiated by intermolecular disulfide bond formation.

Introduction Most home haemodialysis (HD) modalities are limited to home use since they are based on a single-pass (SP) technique, which requires preparation of large amounts of dialysate. We present a new dialysis method, which requires minimal dialysate volumes, continuously recycled during treatment [multipass HD (MPHD)]. Theoretical calculations suggest that MPHD performed six times weekly for 8 h/night, using a dialysate bath containing 50% of the calculated body water, will achieve urea clearances equivalent to conventional HD 4 h thrice weekly, and a substantial clearance of higher middle molecules. Methods Ten stable HD patients were dialyzed for 4 h using standard SPHD (dialysate flow 500 mL/min). Used dialysate was collected. One week later, an 8-h MPHD was performed. The dialysate volume was 50% of the calculated water volume, the dialysate inflow 500 mL/min-0.5 × ultrafiltration/min and the outflow 500 mL/min + 0.5 × ultrafiltration/min. Elimination rates of urea, creatinine, uric acid, phosphate and β2-microglobulin (B2M) and dialysate saturation were determined hourly. Results Three hours of MPHD removed 49, 54, 50, 51 and 57%, respectively, of the amounts of urea, creatinine, uric acid, phosphate and B2M that were removed by 4 h conventional HD. The corresponding figures after 8 h MPHD were 63, 78, 74, 78 and 111%. Conclusions Clearance of small molecules using MPHD 6 × 8 h/week will exceed traditional HD 3 × 4 h/week. Similarly, clearance of large molecules will significantly exceed traditional HD and HD 5 × 2.5 h/week. This modality will increase patients' freedom of movement compared with traditional home HD. The new method can also be used in the intensive care unit and for automated peritoneal dialysis.

Biographical intelligence is an established concept within Intelligence circles and is used to develop a wider picture of activities of heads of state and politicians likely to be harmful to the interests of the sovereign state collecting such data. However, to date, despite the pervasiveness of the National Intelligence Model in Britain in professionalizing the face of policing, the concept of biographical intelligence has yet to mature. This briefing paper examines this overlooked issue and in particular discusses why biographical intelligence could prove to be a useful addition to the Intelligence armoury of policing. The paper demonstrates how crime entrepreneurs can gain competitive advantage across a lifetime by exploiting existing gaps in the intelligence system and how as a result they can stay ‘one step’ ahead of the police intelligence apparatus. The constructed narrative shows up systemic flaws in the system that are still relevant and open to exploitation by resourceful and intelligent criminals.

Cells in the medial preoptic area (mPOA), arcuate nucleus (ARC), and ventromedial nucleus (VMN) that possess estrogen receptor alpha (ER alpha) mediate estradiol feedback to regulate endocrine and behavioral events during the estrous cycle. A percentage of ER alpha cells located in the ARC and VMN express somatostatin (SST) and are activated in response to estradiol. The aims of the present study were to investigate the location of c-Fos, a marker for activation, in cells containing ER alpha or SST at various times during the follicular phase and to determine whether lipopolysaccharide (LPS) administration, which leads to disruption of the luteinizing hormone (LH) surge, is accompanied by altered ER alpha and/or SST activation patterns. Follicular phases were synchronized with progesterone vaginal pessaries, and control animals were killed at 0, 16, 31, and 40 h (n = 4–6/group) after progesterone withdrawal (PW [time 0]). At 28 h, other animals received LPS (100 ng/kg) and were subsequently killed at 31 h or 40 h (n = 5/group). Hypothalamic sections were immunostained for c-Fos and ER alpha or SST. LH surges occurred only in control ewes with onset at 36.7 ± 1.3 h after PW; these animals had a marked increase in the percentage of ER alpha cells that colocalized c-Fos (%ER alpha/c-Fos) in the ARC and mPOA from 31 h after PW and throughout the LH surge. In the VMN, %ER alpha/c-Fos was higher in animals that expressed sexual behavior than in those that did not. SST cell activation in the ARC and VMN was greater during the LH surge than in other stages in the follicular phase. At 31 or 40 h after PW (i.e., 3 or 12 h after treatment, respectively), LPS decreased %ER alpha/c-Fos in the ARC and the mPOA, but there was no change in the VMN compared to that in controls. The %SST/c-Fos increased in the VMN at 31 h after PW (i.e., 3 h after LPS) with no change in the ARC compared to controls. These results indicate that there is a distinct temporal pattern of ER alpha cell activation in the hypothalamus during the follicular phase, which begins in the ARC and mPOA at least 6–7 h before the LH surge onset and extends to the VMN after the onset of sexual behavior and LH surge. Furthermore, during the surge, some of these ER alpha-activated cells may be SST-secreting cells. This pattern is markedly altered by LPS administered during the late follicular phase, indicating that the disruptive effects of this stressor are mediated by suppressing ER alpha cell activation at the level of the mPOA and ARC and enhancing SST cell activation in the VMN, leading to the attenuation of the LH surge.

The concentrations of serum immunoglobulins were correlated to the stage of disease and the proportions of peripheral blood lymphocyte subsets in 25 untreated patients with B-cell chronic lymphocytic leukemia (CLL). Diminished levels of at least one serum immunoglobulin were present in 77% of all patients with CLL and 73% of patients with Stage 0 disease. The mean concentration of IgG, IgM, and IgA decreased with advancing stage of CLL. The percentages of total T, T-helper (TH), and T-suppressor (TS) cells in the peripheral blood were less in patients with CLL than in healthy persons, but the absolute concentrations of total T, TH, and TS cells were greater in patients with CLL than controls (P less than 0.02). The absolute number of B-cells (P less than 0.01) and null cells (P less than 0.001) was also increased in patients with CLL, particularly those patients in advanced stages of CLL. These findings suggest that the hypogammaglobulinemia associated with CLL first occurs during the earliest stage of disease and may be related to the alterations in the proportion of peripheral blood lymphocytes.

The renal and vasopressin (AVP) response to a standard oral water load (20 ml/kg) was examined in a group of water-replete healthy elderly men (n = 6). Two groups, respectively, of water-replete and water-deprived young healthy volunteers acted as controls. After 2 h, the old group had excreted 41 +/- 2.4% (mean +/- SEM) of the water load compared to 100.7 +/- 8.8% in the water-replete young group and 70 +/- 3.8% in the water-deprived young group (P less than 0.01). Similarly, peak diuresis (7.01 +/- 0.48 ml/kg) and peak free-water clearance (5.7 +/- 0.48 ml/min) as determined from hourly sampling in the old group were delayed and significantly less than both young groups (P less than 0.01) (peak diuresis, young water-replete, 10.86 +/- 0.56 ml/kg, young water-deprived, 10.2 +/- 0.64 ml/kg, peak free-water clearance, young water-replete 8.4 +/- 0.72 ml/min, young water-deprived 9.5 +/- 0.88 ml/min). When these indices were adjusted for reduced creatinine clearance (Ccr) in the elderly, there was no significant difference between the young and old groups. Plasma AVP decreased similarly in all three groups following ingestion of water but there was no significant difference in mean plasma AVP between the young and old subjects throughout the study period. We therefore conclude that ability to excrete excess water promptly is impaired in healthy elderly men. This defect is due, at least in part, to an age-related reduction in glomerular filtration rate.