Prevalence of autosomal dominant polycystic kidney disease in the European Union.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease, but estimates of its prevalence vary by >10-fold. The objective of this study was to examine the public health impact of ADPKD in the European Union (EU) by estimating minimum prevalence (point prevalence of known cases) and screening prevalence (minimum prevalence plus cases expected after population-based screening). METHODS: A review of the epidemiology literature from January 1980 to February 2015 identified population-based studies that met criteria for methodological quality. These examined large German and British populations, providing direct estimates of minimum prevalence and screening prevalence. In a second approach, patients from the 2012 European Renal Association‒European Dialysis and Transplant Association (ERA-EDTA) Registry and literature-based inflation factors that adjust for disease severity and screening yield were used to estimate prevalence across 19 EU countries (N = 407 million). RESULTS: Population-based studies yielded minimum prevalences of 2.41 and 3.89/10 000, respectively, and corresponding estimates of screening prevalences of 3.3 and 4.6/10 000. A close correspondence existed between estimates in countries where both direct and registry-derived methods were compared, which supports the validity of the registry-based approach. Using the registry-derived method, the minimum prevalence was 3.29/10 000 (95% confidence interval 3.27-3.30), and if ADPKD screening was implemented in all countries, the expected prevalence was 3.96/10 000 (3.94-3.98). CONCLUSIONS: ERA-EDTA-based prevalence estimates and application of a uniform definition of prevalence to population-based studies consistently indicate that the ADPKD point prevalence is <5/10 000, the threshold for rare disease in the EU.

mRNA vaccination in people over 80 years of age induces strong humoral immune responses against SARS-CoV-2 with cross neutralization of P.1 Brazilian variant.

Age is the major risk factor for mortality after SARS-CoV-2 infection and older people have received priority consideration for COVID-19 vaccination. However, vaccine responses are often suboptimal in this age group and few people over the age of 80 years were included in vaccine registration trials. We determined the serological and cellular response to spike protein in 100 people aged 80-96 years at 2 weeks after the second vaccination with the Pfizer BNT162b2 mRNA vaccine. Antibody responses were seen in every donor with high titers in 98%. Spike-specific cellular immune responses were detectable in only 63% and correlated with humoral response. Previous SARS-CoV-2 infection substantially increased antibody responses after one vaccine and antibody and cellular responses remained 28-fold and 3-fold higher, respectively, after dual vaccination. Post-vaccine sera mediated strong neutralization of live Victoria infection and although neutralization titers were reduced 14-fold against the P.1 variant first discovered in Brazil they remained largely effective. These data demonstrate that the mRNA vaccine platform delivers strong humoral immunity in people up to 96 years of age and retains broad efficacy against the P.1 variant of concern.

Hummingbird Study: a study protocol for a multicentre exploratory trial to assess the acceptance and performance of a digital medicine system in adults with schizophrenia, schizoaffective disorder or first-episode psychosis.

INTRODUCTION: In patients with schizophrenia, medication adherence is important for relapse prevention, and effective adherence monitoring is essential for treatment planning. A digital medicine system (DMS) has been developed to objectively monitor patient adherence and support clinical decision making regarding treatment choices. This study assesses the acceptance and performance of the DMS in adults with schizophrenia, schizoaffective disorder or first-episode psychosis and in healthcare professionals (HCPs). METHODS/ANALYSIS: This is a multicentre, 8-week, single-arm, open-label pragmatic trial designed using coproduction methodology. The study will be conducted at five National Health Service Foundation Trusts in the UK. Patients 18-65 years old with a diagnosis of schizophrenia, schizoaffective disorder or first-episode psychosis will be eligible. HCPs (psychiatrists, care coordinators, nurses, pharmacists), researchers, information governance personnel, clinical commissioning groups and patients participated in the study design and coproduction. Intervention employed will be the DMS, an integrated system comprising an oral sensor tablet coencapsulated with an antipsychotic, non-medicated wearable patch, mobile application (app) and web-based dashboard. The coencapsulation product contains aripiprazole, olanzapine, quetiapine or risperidone, as prescribed by the HCP, with a miniature ingestible event marker (IEM) in tablet. On ingestion, the IEM transmits a signal to the patch, which collects ingestion and physical activity data for processing on the patient's smartphone or tablet before transmission to a cloud-based server for viewing by patients, caregivers and HCPs on secure web portals or mobile apps. ETHICS AND DISSEMINATION: Approval was granted by London - City and East Research Ethics Committee (REC ref no 18/LO/0128), and clinical trial authorisation was provided by the Medicines and Healthcare products Regulatory Agency. Written informed consent will be obtained from every participant. The trial will be compliant with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines and the Declaration of Helsinki. TRIAL REGISTRATION NUMBER: NCT03568500; EudraCT2017-004602-17; Pre-results.

Taking resuscitation decisions in the nursing home setting.

The way decisions about resuscitation are made in A&E departments is not the same as in nursing homes for older people. This article discusses prompt appropriate decision-making regarding resuscitation in the nursing home setting.

Understanding the physical and emotional impact of early-stage ADPKD: experiences and perspectives of patients and physicians.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder; however, at the time this research was conducted, no disease-modifying treatment was currently available. Medical texts often describe early-stage disease (Stages 1 and 2) as asymptomatic, but there is evidence from patients of considerable physical and emotional effects. METHODS: In-depth interviews were conducted with 80 ADPKD patients, 72 nephrologists and 85 primary care physicians (PCPs) from nine European countries to explore the experience and impact of early-stage ADPKD. Interviews were transcribed, translated and analysed centrally using thematic analysis. An additional 600 physicians completed standardised online questionnaires to investigate perceptions of symptom severity and management of early-stage ADPKD. RESULTS: Eighty-eight per cent of patients with early-stage disease reported physical symptoms including pain, fatigue, breathlessness, weakness and a general malaise. However, 24% of nephrologists and 16% of PCPs perceived that the patients with early-stage disease did not experience any physical symptoms at all. There was a greater awareness of the emotional impact of disease, but this was still underestimated when compared with patient-reported experiences, which highlighted widespread feelings of loss, uncertainty and fear. Patients and physicians experienced frustration due to the lack of treatment options, especially in the long latent period. For many patients, the inability to affect their disease course whilst living with a diagnosis resulted in feelings of hopelessness, helplessness and depression. Physicians identified a need for improved cooperation between health-care professionals, and increased psychological support for patients. CONCLUSIONS: Early-stage ADPKD can have a significant physical and emotional impact on patients. Whilst some physicians have an awareness of patient experience during early-stage disease, most underestimate the impact of ADPKD. Both patients and physicians are negatively affected by their inability to alter disease progression.

Factor X inhibitors.

Factor X plays a central role in coagulation, being the point of convergence of the extrinsic and intrinsic pathways of blood clotting. It may also act as one of the links between the coagulation and inflammatory pathways. These findings suggest that factor X may represent an attractive target for a new antithrombotic drug. Indeed, a factor X inhibitor, fondaparinux, has already been approved for clinical use to prevent post-operative deep vein thrombosis. Factor X inhibitors are also being evaluated for use in the treatment of the acute coronary syndromes, pulmonary embolism and deep vein thrombosis. Oral factor X inhibitors are also being developed, which may be of use in the outpatient prevention and/or treatment of stroke and thromboembolism.

Thrombogenesis and endothelial damage/dysfunction in peripheral artery disease. Relationship to ethnicity and disease severity.

Peripheral artery disease (PAD) and intermittent claudication are common in men aged over 55 years. Once the diagnosis has been made, very few patients suffer from a deterioration of the disease. Those that do deteriorate tend to do so due to thrombosis of an affected artery. It is apparent that the disruption in the vessel wall accounts for some of the cause of the thrombosis but blood constituents also play a role. We hypothesized that levels of soluble P-selectin (sP-sel, a marker of platelet activation), von Willebrand factor (vWf, an index of endothelial damage/dysfunction), tissue factor (TF, a coagulation protein involved in the 'extrinsic' coagulation pathway) and fibrinogen would be abnormally elevated in relation to disease severity and correlated with each other, and related to ethnicity, in a multiethnic population of patients with PAD. To test this hypothesis, we studied 234 patients (80% white, 7% Indo-Asian, 13% Afro-Caribbean) with confirmed PAD [ankle brachial pressure index (ABPI)< or =0.8] and 50 healthy controls. All of the indices studied were increased in patients over controls (p<0.05). None of the indices of the hypercoagulable state were significantly different between the three ethnic groups studied. Patients with ischaemic rest pain were shown to have higher levels of plasma fibrinogen (p<0.001) although none of the other prothrombotic markers were increased in this group. Furthermore, fibrinogen was higher in cases whose ABPI was below the median (<0.52) when compared to those less severely affected, with an inverse correlation between fibrinogen and ABPI (Spearman, r=-0.178, p=0.009). In conclusion, we found a prothrombotic state in patients with PAD with increased levels of markers of endothelial damage/dysfunction, platelet activation and thrombosis, which may contribute to the pathogenesis of this condition. However, disease severity was only related to plasma fibrinogen levels.

The benefits of smaller care homes is not a new discovery.

It is dispiriting to note the finding that people with dementia thrive in smaller care homes (clinical digest September 26). This is a classic lost opportunity. In 1988, the Griffiths report recommended that care homes have no more than 21 residents.

'we get the care that we pay for'.

The financial difficulties faced by the Southern Cross care homes group raise questions about the stability of the long-term care model. Since the late 1980s, long-stay hospitals have closed and the care of older people has been taken up mostly by the private sector.

Trust in my colleagues has been shaken by mid staffs.

The Francis report into the failings at Mid Staffordshire NHS Foundation Trust makes for shocking reading. It is clear that there was a failure of management and nursing involving a culture shift, rather than simply a lack of resources. There was a lack of compassion and of basic nursing responsibilities that had nothing to do with understaffing.

Vascular endothelial growth factor and tissue factor in patients with established peripheral artery disease: a link between angiogenesis and thrombogenesis?

Increasing evidence points towards a prothrombotic state in atherosclerosis and its manifestations, such as peripheral artery disease (PAD), which is associated with thrombosis-related complications, such as acute limb ischaemia, graft thrombosis and stroke. We hypothesized that the increased risk of thrombogenesis in PAD may be related to abnormal angiogenesis and, thus, an increased risk of future vascular disease. To test this hypothesis, we measured plasma levels of tissue factor (TF) and related levels to indices of angiogenesis, that is vascular endothelial growth factor (VEGF) and its soluble receptor sFlt-1. We studied 234 patients (145 males; mean age 68.6+/-10 years) with proven PAD (ankle brachial pressure index <0.8) and compared them with 50 healthy controls. Levels of VEGF ( P =0.001) and TF ( P =0.043) were increased in patients compared with controls. There were significant correlations between VEGF and TF levels in both patients (Spearman r =0.351, P <0.001) and healthy controls (Spearman r =0.335, P =0.017). Amongst PAD patients, levels of VEGF were related to gender, with women having higher levels than men. There was no difference in the levels of sFlt-1 between the patients and controls, or between the subgroups of patients. There were however significant correlations between the levels of sFlt-1 and TF (Spearman r =0.268, P <0.001) and between sFlt-1 and VEGF (Spearman r =0.499, P <0.001). In conclusion, patients suffering from proven PAD have higher plasma levels of TF and VEGF compared with controls, with a significant correlation between the two. This suggests a link between the hypercoagulable state in PAD and the process of angiogenesis.

Alterations of thrombogenesis, endothelial damage and oxidative stress with reperfusion during femoral artery bypass surgery for peripheral vascular disease.

Peripheral vascular disease (PVD) is a significant cause of cardiovascular morbidity. We hypothesised that there would be significant alterations of thrombogenesis, platelet activation and endothelial damage, which could be associated with abnormal oxidative stress during femoral artery bypass surgery for PVD, where the femoral artery is cross-clamped (causing acute ischaemia) and reperfused (following revascularisation). To test this hypothesis, we measured sequential changes in von Willebrand factor (vWF, and index of endothelial damage/dysfunction), tissue factor (TF, an index of thrombogenesis) and soluble P-selectin (sP-sel, an index of platelet activation) as well as lipid hydroperoxides (LPO, an index of oxidative stress) in 28 consecutive patients undergoing elective peripheral artery bypass surgery. Mean baseline vWF and sP-sel levels in PVD patients (before clamping) were significantly higher compared with age- and sex-matched controls (unpaired t test, both p < 0.05), but there were no significant differences in TF and LPO levels. There was a correlation between TF and vWF (Spearman's, r = 0.374, p = 0.05), as well as between sP-sel and vWF at the start of surgery (r = 0.467, p = 0.012). The patients undergoing peripheral artery bypass surgery had a mean femoral artery clamp time of 28 min (standard deviation 14 min; range 11-65 min). There were no significant overall changes in sP-sel, vWF, TF and LPO with femoral artery cross-clamping and reperfusion (repeated measures ANOVA, p = NS). In conclusion, we found that during ischaemia-reperfusion during peripheral arterial bypass surgery, thrombogenesis (as measured by plasma TF) and oxidative damage (as measured by LPO) within the affected leg does not increase in the immediate perioperative period. Further studies are required to assess the mechanism(s) of ischaemia-reperfusion injury in PVD, and the contributory role(s) of the endothelium and platelets.

Indices of thrombogenesis, endothelial damage and platelet function following percutaneous peripheral artery angiography and angioplasty for peripheral vascular disease.

We hypothesised that there would be alterations in markers of endothelial damage/dysfunction, platelet activation and thrombogenesis in patients with peripheral vascular disease (PVD) as a result of undergoing diagnostic angiography and therapeutic angioplasty. To test this hypothesis, we measured sequential changes in von Willebrand factor (vWf, an index of endothelial damage/dysfunction), tissue factor (TF, an index of thrombogenesis) and soluble P-selectin (sP-sel, an index of platelet activation) in 52 consecutive patients (32 male; mean age 69 years, SD 10) who were undergoing elective angiography and angioplasty for PVD. Patients with PVD had significantly higher vWf and sP-sel levels compared to healthy controls (both p < 0.001), but median TF levels were not significantly different (p = 0.344). In the whole group, there was a significant reduction in sP-sel levels (p < 0.001, paired t test) post-angiography/angioplasty, but no significant change in vWf and TF levels. In patients undergoing angiography only, there was a significant drop in mean sP-sel (p < 0.001, paired t test) and vWf (p = 0.044) values after the procedure, whilst TF levels were not significantly changed (p = 0.370, Mann-Whitney U test). In patients undergoing angioplasty and stent, mean sP-sel levels fell immediately after the procedure (p = 0.001, paired t test), but there were no statistically significant changes in vWf and TF-levels. In conclusion, there appears to be a reduction in plasma sP-sel levels following angioplasty and stenting for PVD, suggesting alterations in platelet physiology, which may be accompanied by some alterations in the endothelium. The possibility that these changes may have pathophysiological implications for understanding platelet and endothelial reactions to angiography and associated interventions (that is, angioplasty and stent) needs to be explored.

Assessment of endothelial damage in atherosclerotic vascular disease by quantification of circulating endothelial cells. Relationship with von Willebrand factor and tissue factor.

BACKGROUND: Increased numbers of CD146-defined circulating endothelial cells (CECs), as are present in the peripheral blood of patients suffering acute coronary syndromes, imply injury to the endothelium. Endothelial damage can also be assessed by the measurement of plasma levels of von Willebrand factor (vWf). Increased levels of procoagulant plasma tissue factor (TF), arising from monocytes/macrophages and endothelial cells, is present in atherosclerosis. We hypothesised increased CECs in patients with ischaemic rest pain (IRP) of the lower limb due to peripheral atherosclerosis and comparable to that seen in patients with acute myocardial infarction (AMI), when compared to patients with intermittent claudication (IC) or healthy controls that would correlate with vWf and TF. PATIENTS AND METHODS: We recruited 20 patients in each of four groups: (i) IRP of the lower limb; (ii) AMI; (iii) 'stable' IC; and (iv) healthy controls. CD146-expressing CECs were measured by immumomagnetic separation and counting under a fluorescence microscope; plasma vWf and TF by ELISA. RESULTS: In IRP, median (IQR) CEC levels were 3.5 (2.0-5.8) cells/ml, in IC were 1.1 (0.6-2.9) cells/ml, and in healthy controls were 1.0 (0.5-1.7) cells/ml (p<0.001). The levels of vWf (p=0.034) and TF (p=0.007) were also significantly different between the groups, with the highest levels in patients with IRP. Levels of CECs correlated with vWf (rs=0.4, p=0.002) and TF ( rs=0.296, p=0.021 ). In AMI, CEC levels were higher than those in IRP at 4.9 (3.6-8.4) cells/ml (p=0.0385). CONCLUSION: This study demonstrates evidence of direct endothelial cell injury (i.e. raised CECs) in patients with IRP that correlated with vWf and TF, but that this is less severe than in AMI.