Francesco Zaccardi

• MD
• Fellow at University of Leicester

Objectives In patients with heart failure (HF), investigate the association between symptoms recorded in routine primary care consultations and short-term (3-month) hospitalisation and mortality. Design Landmark analysis using Royston-Parmar flexible parametric survival models fitted at three different timepoints (landmarks): baseline (diagnosis d...

Background Reducing the high patient and economic burden of early readmissions after hospitalisation for heart failure (HF) has become a health policy priority of recent years. Methods An observational study linking Hospital Episode Statistics to socioeconomic and death data in England (2002-2018). All first hospitalisations with a primary dischar...

Background: Reducing the high patient and economic burden of early readmissions after hospitalisation for heart failure (HF) has become a health policy priority of recent years. Methods: An observational study linking Hospital Episode Statistics to socioeconomic and death data in England (2002-2018). All fi rst hospitalisations with a primary disch...

Background Health and key workers have elevated odds of developing severe COVID-19; it is not known, however, if this is exacerbated in those with irregular work patterns. We aimed to investigate the odds of developing severe COVID-19 in health and shift workers. Methods We included UK Biobank participants in employment or self-employed at baselin...

Background: Health and key workers are at an increased risk of developing severe COVID-19; it is not known, however, if this risk is exacerbated in those with irregular work patterns. We aimed to investigate the risk of severe COVID-19 in health and shift workers. Methods: We included UK Biobank participants in employment or self-employed at basel...

Aims/Hypotheses: Early-onset adult type 2 diabetes (diagnosed aged 18-39 years) is increasingly prevalent and associated with poor long-term outcomes. However, we hypothesised that individuals with early-onset adult type 2 diabetes are underrepresented in the prominent research trials that underpin type 2 diabetes management guidelines. Methods: W...

Aims The purpose of this study was to quantify and rank the prognostic relevance of dietary, physical activity and physical function factors in predicting all-cause and cardiovascular mortality in comparison with the established risk factors included in the European Society of Cardiology Systematic COronary Risk Evaluation (SCORE). Methods We exam...

Background Accurately predicting the risk of diabetic foot ulceration (DFU) could dramatically reduce the enormous burden of chronic wound management and amputation. Yet, the current prognostic models are unable to precisely predict DFU events. Typically, efforts have focused on individual factors like temperature, pressure, or shear rather than th...

Objectives: to evaluate the characteristics of patients with type 2 diabetes newly treated with basal insulin therapy in UK primary care setting. Methods: adults diagnosed with T2DM newly initiated with a basal insulin from January 2004 to December 2016 were identified in the Clinical Practice Research Link (CPRD). Demographic and clinical data inc...

Background and aims: Intake of red and processed meat has been associated with a higher risk of morbidity and mortality; it is unknown whether these associations are modified by overall physical health. This study examined the associations of red and processed meat consumption with all-cause, cardiovascular, and cancer mortality and investigated w...

Diabetic foot ulcers (DFUs), a micro-vascular complication, are associated with a substantial increase in morbidity and mortality. DFUs are a complicated mixture of neuropathy, peripheral arterial diseases, foot deformities, and infections. Foot infections are frequent and potentially devastating complications. Infection prospers in more than half...

Aims To review systematically and quantify the weight loss achieved through low‐ (LEDs) and very‐low‐energy diets (VLEDs) in people with type 2 diabetes mellitus (T2DM). Materials and methods Studies reporting the effects of diet‐only interventions of up to 1600 kcal/d in people with T2DM were searched in MEDLINE, EMBASE and CINAHL up to July 2018...

Background and aims: The association of beta-blockers and their selectivity with mortality and cardiovascular events in patients with and without hypoglycaemia is unknown. Methods and results: Insulin-treated patients with diabetes were identified within the UK CPRD database. All-cause deaths, cardiovascular events, and hypoglycaemic episodes we...

Aims To compare the cardiovascular efficacy and safety of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) in adults with Type 2 diabetes. Methods Electronic databases were searched from inception to 22 October 2018 for randomized controlled trials designed to assess the cardiovascular eff...

Background The aim was to investigate whether preoperative weight loss results in improved clinical outcomes in surgical patients with clinically significant obesity. Methods This was a systematic review and aggregate data meta‐analysis of RCTs and cohort studies. PubMed, MEDLINE, Embase and CINAHL Plus databases were searched from inception to Fe...

Emerging evidence suggests that sauna bathing is associated with reduced risk of cardiovascular and all-cause mortality events. However, the biochemical pathways by which sauna bathing might confer its effects on cardiovascular function are not certain. We aimed to study the acute effects of Finnish sauna bathing on various blood-based cardiovascul...

Aims/hypothesis: In the context of increasing prevalence of diabetes in elderly people with multimorbidity, intensive glucose control may increase the risk of severe hypoglycaemia, potentially leading to death. While rising trends of severe hypoglycaemia rates have been reported in some European, North American and Asian countries, the global burd...

Background and aims: To investigate the association of body mass index with all-cause, cardiovascular and cancer mortality in individuals with and without diabetes. Methods and results: We used data on 490,852 participants from the UK Biobank, with linkage to national mortality data between 2006 and 2016. Using Cox regression, we calculated haza...

Objective: To assess the association between frequency of sauna bathing and risk of future stroke. Methods: Baseline habits of sauna bathing were assessed in 1,628 adult men and women aged 53-74 years (mean age, 62.7 years) without a known history of stroke in the Finnish Kuopio Ischemic Heart Disease prospective cohort study. Three sauna bathin...

OBJECTIVE: To assess the association between frequency of sauna bathing and risk of future stroke. METHODS: Baseline habits of sauna bathing were assessed in 1,628 adult men and women aged 53-74 years (mean age, 62.7 years) without a known history of stroke in the Finnish Kuopio Ischemic Heart Disease prospective cohort study. Three sauna bathing...

Background and aims: Meta-analyses of randomised controlled trials (RCTs) have suggested a possible benefit of statin treatment on the risk of venous thromboembolism (VTE), with potential differences by type and dose of statins. We aimed to assess differences among statins and to investigate the relationship between risk of VTE and reduction of LD...

Emerging evidence suggests beneficial effects of sauna bathing on the cardiovascular system. However, the effects of sauna bathing on parameters of cardiovascular function and blood-based biomarkers are uncertain. We aimed to investigate whether sauna bathing induces changes in arterial stiffness, blood pressure (BP), and several blood-based biomar...

Aims: To assess the evidence supporting the choice of third-line agents in adults with inadequately controlled type 2 diabetes. Materials and methods: We searched RCTs published between Jan 2000 and July 2017 reporting data on cardiometabolic outcomes and hypoglycaemia for glucose-lowering agents added to metformin-based dual treatments. Data we...

Intelligence has previously been associated with mortality, although it is unclear whether the inverse association is independent of other related cognitive factors, such as information processing, or of measures related to physical health, such as cardiorespiratory fitness. We investigate whether fluid intelligence, reaction time and cardiorespira...

Background Heat therapy has been suggested to improve cardiovascular function. However, the effects of hot sauna exposure on arterial compliance and the dynamics of blood flow and pressure have not been well documented. Thus, we investigated the short-term effects of sauna bathing on arterial stiffness and haemodynamics. Design The design was an e...

Introduction: Brachial Artery Ultrasound Imaging (BAUI), measuring flow-mediated dilatation (FMD), is an established in vivo research model of endothelial dysfunction, but technical challenges limit its clinical application. A novel tonometric alternative, Pulse Wave Amplitude Analysis (PWAA), derives FMD via an automated algorithm, and may be a us...

A total of 230 670 women and 190 057 men free from prevalent cancer and cardiovascular disease were included from UK Biobank. Usual walking pace was self-defined as slow, steady/average or brisk. Handgrip strength was assessed by dynamometer. Cox-proportional hazard models were adjusted for social deprivation, ethnicity, employment, medications, al...

Purpose: We aimed to assess the associations of oxygen uptake at aerobic threshold (VO2 at AT) with cardiovascular and all-cause mortality. Design: VO2 at AT was assessed in 1,663 middle-aged men in a cohort study. Hazard ratios (HRs) were calculated for sudden cardiac death (SCD), fatal coronary heart disease (CHD) and cardiovascular disease (C...

Background and Aims The relationship between platelet indices and glucose control may differ in type 1 (T1DM) and type 2 (T2DM) diabetes. We aimed to investigate differences in the mean platelet volume (MPV), platelet count, and platelet mass among patients with T1DM, T2DM, and healthy controls and to explore associations between these platelet ind...

Background: Sauna bathing is associated with reduced cardiovascular risk, but the mechanisms underlying this beneficial effect are not entirely understood. We aimed to assess the relationship between sauna bathing and risk of incident hypertension. Methods: Frequency of sauna bathing was ascertained using questionnaires in the Kuopio Ischemic He...

Aims/hypothesis: Hospital admissions for hypoglycaemia represent a significant burden on individuals with diabetes and have a substantial economic impact on healthcare systems. To date, no prognostic models have been developed to predict outcomes following admission for hypoglycaemia. We aimed to develop and validate prediction models to estimate...

We thank Loke and Mattishent for their commentary on our paper investigating risk factors for hospitalisation for hypoglycaemia in England.(1, 2) In their editorial, they further underlined the challenges we recognised in the manuscript over the use of administrative databases for epidemiological research and, in particular, for identifying potenti...

Aims: To evaluate risk factors for hospital admissions for hypoglycaemia and compare length of hospitalization, inpatient mortality and hospital readmission between hypoglycaemia- and non-hypoglycaemia-related admissions. Materials and methods: We used all admissions for hypoglycaemia in individuals with diabetes to English NHS hospital trusts b...

Aims/hypothesis: The relationship between BMI and mortality has been extensively investigated in the general population; however, it is less clear in people with type 2 diabetes. We aimed to assess the association of BMI with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. Methods: We searched electronic data...

Background: Oxygen uptake (VO2) at ventilatory threshold (VT), is a cardiopulmonary exercise testing parameter which may be a proxy for peak VO2. We aimed to assess the associations of VO2 at VT with sudden cardiac death (SCD), fatal coronary heart disease (CHD) and cardiovascular disease (CVD), and all-cause mortality. Methods and results: VO2...

Background: It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria five years after a diagnosis of screen-detected diabetes within the ADDITION-Europe study, a pragmatic cardiovascular outcome tria...

BACKGROUND: It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria five years after a diagnosis of screen-detected diabetes within the ADDITION-Europe study, a pragmatic cardiovascular outcome trial...

Aims: To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in subjects with type 2 diabetes MATERIALS AND METHODS: We electronically searched, up to June 3(rd) , 2016, published randomised clinical trials lasting between 24 and 32 weeks and comparing a GLP-1RA (albiglutide, dulaglutide, twice-daily (EBID) and once...

Background Smoking is associated with increased macrovascular and microvascular complications in people with diabetes. In addition to other concomitant vascular perturbations, it also seems to influence the cardiometabolic parameters, which may partly explain the accelerated rate of vascular complications in smokers with diabetes. While smoking ces...

Introduction: Cardiorespiratory fitness (CRF) is independently and inversely associated with cardiovascular outcomes. Oxygen uptake (VO2) at aerobic thresholds, which can be defined at submaximal exercise levels, is a proxy for CRF. However, the association of VO2 at aerobic thresholds, with fatal cardiovascular events and all-cause mortality has n...

Aim: Low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c), which are components of total cholesterol, have each been suggested to be linked to the risk of sudden cardiac death (SCD). However, the relationship between LDL-c/HDL-c ratio and the risk of SCD has not been previously investigated. We aimed to asse...

Glucagon like peptide-1 receptor agonists (GLP-1RAs) are a new class of injectable agent used in the management of type 2 diabetes (T2DM). In the UK, NICE approved the use of GLP-1RAs in combination with metformin and sulphonylurea in people with T2DM whose glycaemic control is above target (≥7.5%, 58 mmol/mol) and body mass index (BMI) ≥35 kg/m² w...

Background: Evidence on the role of lifestyle factors in relation to multimorbidity, especially in elderly populations, is scarce. We assessed the association between five lifestyle factors and incident multimorbidity (presence of ≥2 chronic conditions) in an English cohort aged ≥50 years. Methods: We used data from waves 4, 5, and 6 of the Engl...

The serum TXB2 (sTXB2) assay reflects the pharmacodynamics of platelet inhibition by low-dose aspirin. However, different studies reported variable sTXB2 values. sTXB2 assay requires whole blood incubation at 37 °C as a condition for optimal thrombin generation, arachidonic acid release and its metabolism by platelet cyclooxygenase-1 to form TXA2....

Few studies have investigated long-term changes in cardiorespiratory fitness (CRF), defined by indirect measures of CRF, and all-cause mortality. We aimed to investigate whether long-term change in CRF, as assessed by the gold standard method of respiratory gas exchange during exercise, is associated with all-cause mortality. A population-based sam...

Aims: Charcot Neuroarthropathy (CN) is a disabling complication, culminating in bone destruction and involving joints and articular cartilage with high inflammatory environment. Its real pathogenesis is unknown yet. In autoinflammatory diseases, as rheumatoid arthritis, characterized by inflammation and joints involvement, autoantibodies against p...

Video capsule endoscopy (VCE) is a noninvasive diagnostic tool used to observe the small intestinal mucosa. We report a case of a 57-year-old woman with T2DM, treated with continuous subcutaneous insulin infusion using second-generation OmniPod patch pump, undergoing VCE (Given M2A; VCE Ltd, Yoqneam, Israel) for melena and anemia. During VCE, an ab...

Background: Studies in the USA and Canada have reported increasing or stable rates of hospital admissions for hypoglycaemia. Some data from small studies are available for other countries. We aimed to gather information about long-term trends in hospital admission for hypoglycaemia and subsequent outcomes in England to help widen understanding for...

Aims: To assess the comparative efficacy and safety of SGLT2 inhibitors in adults with type 2 diabetes. Materials and methods: We electronically searched up to November 3, 2015, randomised controlled trials (≥24 weeks) including canagliflozin, dapagliflozin, or empagliflozin. Data were collected for cardiometabolic and safety outcomes and synthe...

Background: We tested the hypothesis that selected exercise heart rate responses, specifically those providing indices of autonomic dysfunction, may be associated with incident type 2 diabetes in 2231 apparently healthy men with normal baseline fasting glucose levels. Methods: Heart rate reserve was calculated as the difference between the maxim...

Multimorbidity has become one of the main challenges in the recent years for patients, health care providers and the health care systems globally. However, literature describing the burden of multimorbidity in the elderly population, especially longitudinal trends is very limited. Physical activity is recommended as one of the main lifestyle change...

There is limited knowledge on the relationship between kidney function and incidence of atrial fibrillation. Thus, this prospective study was designed to evaluate whether various biomarkers of kidney function are associated to the risk of atrial fibrillation. The study population consisted of 1840 subjects (615 women and 1225 men) aged 61-82 years....

Background: Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of type 2 diabetes. Purpose: To summarize evidence for the cardiometabolic efficacy and adverse effects of once-weekly GLP-1RAs in adults with type 2 diabetes. Data sources: Electronic databases (PubMed, Web of Science, Cochrane Central...

Background: Inflammatory markers such as C-reactive protein (CRP) and interleukin-6 have been linked with an increased risk of sudden cardiac death (SCD), but the relationship between fibrinogen and SCD is uncertain. We aimed to assess the association between fibrinogen and SCD. Methods: Plasma fibrinogen was measured at baseline in a prospectiv...

Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose me...

Platelet activation is persistently enhanced and its inhibition by low-dose aspirin is impaired in type 2 diabetes mellitus (T2DM). We investigated in vivo thromboxane (TX) and prostacyclin (PGI2) biosynthesis and their determinants, as well as aspirin responsiveness in young adult subjects with type 1 diabetes mellitus (T1DM) without overt cardiov...

In Reply We thank both Kivimäki et al and Epstein and Shoenfeld for their comments about the association of sauna bathing and fatal cardiovascular events. We agree that observational studies cannot establish causality of the relationship given that the potential for residual confounding or reverse causation cannot be totally eliminated, as discusse...

We read with great interest the recent article by Nolan et al. (1) in which the authors, summarizing previous basic and pathophysiological research, propose the concept of insulin resistance (IR) as a protective mechanism in overweight/obese subjects with type 2 diabetes. As a consequence of this premise, they argue against intensive insulin treatm...

Background: Little is known about the relationship between metabolic syndrome and sudden cardiac death (SCD). We examined the association of metabolic syndrome, as defined by World Health Organization (WHO), International Diabetes Federation (IDF), National Cholesterol Education Program (NCEP) and American Heart Association (AHA) - IDF interim cri...

Aims: To investigate the association between cardiorespiratory fitness (CRF) and type 2 diabetes mellitus (T2DM) in a cohort of middle-age Finnish men and to summarise the current evidence in a meta-analysis of prospective studies. Methods: CRF was measured at baseline in a random population-based sample of 2520 subjects by assessing oxygen upta...

In nondiabetic individuals, low values of fasting plasma glucose (FPG) have been associated with an increased risk of cardiovascular events. Identification of the potential mechanisms behind this association could help to elucidate the relationship between glycaemia and cardiovascular disease. We aimed to determine the association between FPG and v...

The efficacy of antiplatelet drugs may differ in specific patient subgroups. We aimed to assess the efficacy and safety of the P2Y12 inhibitors clopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor according to diabetes status, age, gender, body mass index, and body weight. Randomized clinical trials (RCTs) of P2Y12 inhibitors reporting in...

Introduction: Previous observational studies have shown conflicting results between plasma K+ concentrations and risk of type 2 diabetes. To help clarify the evidence we aimed to determine whether an association existed between serum K+ and glucose regulation within a UK multiethnic population. Methods: Participants were recruited as part of the...

Previous prospective studies showing a positive association between serum calcium and incidence of type 2 diabetes mellitus (T2DM) have relied on total calcium or an indirect estimate of active, ionized calcium (iCa). We aimed to assess this relationship using a direct measurement of iCa. iCa and cardiometabolic risk factors were measured in a popu...

Sauna bathing is a health habit associated with better hemodynamic function; however, the association of sauna bathing with cardiovascular and all-cause mortality is not known. To investigate the association of frequency and duration of sauna bathing with the risk of sudden cardiac death (SCD), fatal coronary heart disease (CHD), fatal cardiovascul...

Background Platelet activation contributes to cardiovascular disease (CVD), the main complication of type 2 diabetes mellitus (T2DM) and pre-diabetic conditions. Mean platelet volume (MPV) is an easy-to-measure platelet parameter which has been associated with CVD. We sought to assess MPV, platelet distribution width (PDW), and platelet count in T2...

Background And Aims The association between fructosamine and cardiovascular complications is not well established. We sought to evaluate whether serum fructosamine may be a risk factor for cardiovascular and all-cause mortality in nondiabetic subjects. Methods And Results Fructosamine and other cardiovascular risk factors were measured in a sample...

The aim of this study was to determine whether serum fructosamine is associated with the risk of type 2 diabetes mellitus (T2DM) in a cohort of middle-age Finnish men. Fructosamine and other cardiometabolic risk factors were measured in a sample of 2,520 subjects from the population-based Kuopio Ischemic Heart Disease study. Associations between ba...

Whether glucose and insulin are differently associated with the risk of coronary heart disease (CHD) mortality is unclear. We aimed to estimate the association between insulin resistance (estimated by the homeostasis model assessment for insulin resistance, HOMA-IR), fasting serum insulin (FI) and fasting plasma glucose (FPG) with incident CHD mort...

Thromboxane (TX) A2 is a pro-thrombotic prostanoid synthesized by activated platelets, biotransformed into 11-dehydro-TXB2, measurable in urines. Eleven-dehydro-TXB2 excretion is increased in high risk cardiovascular diseases; however, this cardiovascular biomarker awaits validation in large trials. The need of large urine volume (8 - 10 mL) and th...

The aim of this study was to investigate the severity of coronary artery disease (CAD) and the plaque composition in neuropathic type 2 diabetic subjects with and without Charcot neuroarthropathy (CN) undergoing multidetector computed tomography coronary angiography (MDCT-CA). The study was a single-center, observational, with unmatched case-contro...

In western countries, diabetes mellitus, because of macrovascular and microvascular complications related to it, is still an important cause of death. Patients with type 1 diabetes mellitus (T1DM) have a six-time higher risk of mortality than healthy patients. Since the Diabetes Control and Complications Trial (DCCT) established how an intensive th...

The thrombogenic activity of Von Willebrand factor (VWF) is proportional to its molecular size and inversely related to its proteolysis by ADAMTS-13. Oxidation of VWF severely impairs its proteolysis by the metalloprotease. This study was aimed at assessing in patients with type 1 and type 2 diabetes whether protein carbonyls, marker of oxidative s...

We read with great interest the article published in Diabetes Care by Koivikko et al. (1) showing that in patients with type 1 diabetes, spontaneous episodes of hypoglycemia are associated with reduced values of heart rate variability (HRV) parameters, indicating sympatho-vagal imbalance toward sympathetic predominance. The data by Koivikko et al....

Diabetes mellitus (DM) is a pandemics that affects more than 170 million people worldwide, associated with increased mortality and morbidity due to coronary artery disease (CAD). In type 1 (T1) DM, the main pathogenic mechanism seems to be the destruction of pancreatic β -cells mediated by autoreactive T-cells resulting in chronic insulitis, while...

Diabetes mellitus is characterized by an increased macrovascular morbidity and mortality, as well as by typical microangiopathic complications (retinopathy, nephropathy and neuropathy). Oxidative stress is considered the main cause of these complications. Indeed, it causes a complex dysregulation of cell metabolism and cell–cell homeostasis that ha...

Several studies have investigated the effects of metformin treatment in patients with type 1 diabetes mellitus (T1DM). No study has hitherto examined its effects on endothelial function in these patients. In this study we sought to evaluate the effect of metformin on endothelial function in type 1 diabetic patients. Forty-two uncomplicated T1DM pat...

Objective To assess whether reduction of heart rate (HR) has beneficial effects on endothelial function in patients with type 2 diabetes mellitus (T2DM). Design Randomised, double-blind, placebo-controlled study. Setting University hospital. Patients 66 T2DM patients without overt cardiovascular disease. Interventions Patients were randomised to re...

A restrictive lung function pattern is frequently observed in patients with diabetes mellitus (DM) and has been related to respiratory muscle dysfunction in type 1 DM or in mixed population. We aimed to verify whether such a relationship applies also to type 2 DM patients. The respiratory muscle function was explored in 75 non-smoking patients with...

Oxidative stress has become the focus of interest in most biomedical disciplines and many types of clinical research. Research on several diseases show that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart...

Interindividual variability in response to aspirin has been popularized as 'resistance'. We hypothesized that faster recovery of platelet cyclooxygenase-1 activity may explain incomplete thromboxane (TX) inhibition during the 24-h dosing interval. To characterize the kinetics and determinants of platelet cyclooxygenase-1 recovery in aspirin-treated...

We describe a case report of a patient who developed transient type 2 diabetes after a drug-induced (esomeprazole) sub-acute hepatitis. This case evidences the pathophysiological relevance, also in humans, of liver inflammation in the pathogenesis of type 2 diabetes.

We read with great interest the recent article by Leeds et al. (1) regarding the effect of the presence of celiac disease (CD) on glycometabolic parameters in type 1 diabetic subjects and, above all, on diabetes-related microvascular complications. Indeed, several epidemiological and genetic studies strongly suggest a more-than-random association b...

Several abnormalities of the respiratory function have been reported in patients with type 1 and type 2 diabetes. These abnormalities concern lung volume, pulmonary diffusing capacity, control of ventilation, bronchomotor tone, and neuroadrenergic bronchial innervation. Many hypotheses have emerged, and characteristic histological changes have been...