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Lichen planus (LP) is an inflammatory disease affecting both adults and children that may present with numerous rare morphologies. LP and its many subtypes can prove difficult to treat and often leave patients with dyspigmentation. Additionally, pruritus associated with LP can be distressing to patients. The aim of this report is to highlight an uncommon subtype, annular atrophic lichen planus, which uniquely presented in a child, to emphasize the importance of early disease recognition and finally, to demonstrate successful treatment with topical monotherapy with clobetasol propionate ointment.

Vasculopathy associated with connective tissue diseases (CTD) has diverse clinical presentations and complex underlying pathology. Existing imaging techniques remain inadequate for assessing vasculopathy in CTD, particularly in earlier stages of pathogenesis. Novel imaging techniques, such as optical coherence tomography, near-infrared spectroscopy and superb microvascular imaging, demonstrate potential in monitoring disease progression at earlier stages prior to systemic complications.

African swine fever (ASF) was diagnosed for the first time in Romania in a backyard holding in Satu‐Mare County in July 2017. Since then, more than 3800 outbreaks occurred in the entire country. Disease control strategies in the backyard sector rely almost exclusively on reactive measures implemented upon appearance of clinical signs and laboratory confirmation of ASF. In our descriptive study, infection course and outbreak investigation data of 56 affected backyard holdings in Satu‐Mare County has been investigated. Early disease detection based on clinical signs appeared to be efficient. In the majority of outbreaks, ASF was detected within the first 2 weeks after the estimated virus introduction. A clinical phase of 2–8 days was observed before pigs either succumbed to the disease or control measures were implemented on affected farms. A moderate on‐farm transmissibility of ASF virus between pigs was observed. Four clusters of outbreaks were identified indicating virus perpetuation and transmission from farm to farm. To suspend infection chains, rapid intervention by isolating affected farms combined with effective biosecurity measures is required. However, due to the backyard peculiarities, quick and effective implementation of control measures has shown to be rather difficult., In our case report, infection course and outbreak investigation data of 56 affected backyard holdings in Satu‐Mare County has been investigated. Early disease detection based on clinical signs appeared to be efficient. In the majority of outbreaks, ASF was detected within the first two weeks after the estimated virus introduction.

POLE mutations, which lead to an ultramutated phenotype in colorectal cancer (CRC), have been reported as a promising marker in immunotherapy. We performed sequencing of CRC cases in Zhejiang University (ZJU) and extracted obtainable data from recently published results, including The Cancer Genome Atlas (TCGA), Japanese studies and clinical trials, to present clinical patterns of POLE driver‐mutated CRC and reveal its heterogeneity. The rate of somatic POLE driver mutations has been reported as 2.60% (ZJU cohort), 1.50% (TCGA cohort), 1.00% (Japan cohort), and 1.00% (Lancet cohort). POLE driver mutations show a clearly increased mutation burden (mean TMB: 217.98 mut/Mb in ZJU; 203.13 mut/Mb in TCGA). Based on pooled data, more than 70.00% of patients with POLE driver mutations were diagnosed before they were 55 years old and at an early disease stage (Stage 0–II >70.00%), and more than 70.00% were male. Among Asian patients, 68.40% developed POLE driver mutations in the left‐side colon, whereas 64.00% of non‐Asian patients developed them in the right‐side colon (p, POLE could be a promising marker for immunotherapy, and its heterogeneity should not be ignored. Here we present the clinical patterns and heterogeneity of POLE driver mutations so that investigators and physicians will be better equipped to design clinical trials and analyze their data.

The main objectives in Crohn's disease are to avoid disease complications and preserve the patient's quality of life. Early disease control and close monitoring with specific targets to reach might be the only way to change the disease course. In two decades, we have moved from clinical response to full remission (clinical and endoscopic remission) requiring a tight monitoring of both symptoms and objective signs of inflammation. This review summarizes the concepts of tight control and treat-to-target and their potential for disease modification.

A case report is a narrative that describes, for medical, scientific or educational purposes, a medical problem experienced by one or more patients. Case reports written without guidance from reporting standards are insufficiently rigorous to guide clinical practice or to inform clinical study design. Develop, disseminate and implement systematic reporting guidelines for case reports. We used a three-phase consensus process consisting of (1) premeeting literature review and interviews to generate items for the reporting guidelines, (2) a face-to-face consensus meeting to draft the reporting guidelines and (3) postmeeting feedback, review and pilot testing, followed by finalisation of the case report guidelines. This consensus process involved 27 participants and resulted in a 13-item checklist-a reporting guideline for case reports. The primary items of the checklist are title, key words, abstract, introduction, patient information, clinical findings, timeline, diagnostic assessment, therapeutic interventions, follow-up and outcomes, discussion, patient perspective and informed consent. We believe the implementation of the CARE (CAse REport) guidelines by medical journals will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports will inform clinical study design, provide early signals of effectiveness and harms, and improve healthcare delivery.

The past decade has seen a dramatic expansion of the field of prodromal PD. Ten years ago, there were only six known prodromal markers of disease, none of which had more than two studies documenting diagnostic value. We now have at least 16 markers, with as many as 10 prospective studies for a single marker. This review summarizes the major advances over the last decade and speculates about the advances we will see in the decade to come. The most notable advances over the last decade came through the study of high-risk cohorts (REM sleep behavior disorder and later genetic and autonomic cohorts), the generation of more representative population-based cohorts for studying prodromal PD, major advances in neuroimaging of early disease stages, the emerging likelihood that tissue biopsy will be able to diagnose prodromal PD, and the coalescence of prodromal markers into discrete criteria. As the next decade dawns, we await increasing precision of sensitivity and specificity estimates of known markers, the discovery of new biomarkers of prodromal disease, improvements in diagnosis using combined methods/criteria (with increasing recognition of prodromal PD as one stage of the full PD spectrum), and ultimately the development of neuroprotective therapy that can be provided at the earliest stages of disease. © 2019 International Parkinson and Movement Disorder Society.

Early classification of time series is valuable in many real‐world applications such as early disease prediction, early disaster prediction, and patient monitoring where data are generated...

Angewandte Chemie. International Edition, 57 (28), ISSN:1433-7851, ISSN:1521-3773, ISSN:0570-0833

Objective Early identification of patients unlikely to achieve good long‐term disease control with anti–tumor necrosis factor therapy in axial spondyloarthritis (SpA) and psoriatic arthritis (PsA) is important for physicians following treat‐to‐target recommendations. Here we assess associations between disease activity or clinical response during the first 12 weeks of treatment and attainment of treatment targets at week 48 in axial SpA and PsA patients receiving certolizumab pegol. Methods The relationship between disease activity or clinical response during the first 12 weeks of treatment and achievement of week‐48 targets (for axial SpA: inactive disease based on Ankylosing Spondylitis Disease Activity Score [ASDAS] using the C‐reactive protein [CRP] level, or Bath Ankylosing Spondylitis Disease Activity Index 5.1 at week 12, compared to 73% of patients (57 of 78) with DAS28‐CRP

The success rate of the pharmaceutical research and development (RD) for dementia drugs has been abysmally low, in the last two decades. Also low has been the number of pipeline drugs in development, compared to other therapy areas. However, the rationale of early terminations has not been reported in the majority of trials. These are key findings of the recently published pharmaceutical pipeline analysis by the UK-based Office of Health Economics (OHE). Our understanding of main challenges include (1) the significant gaps of knowledge in the nosology and complexity of the underpinning biological mechanisms of the commonest, not familial, forms of late onset dementias; (2) low signal-to-noise ratio, notwithstanding the lack of validated biomarkers as entry and/or end-point criteria; (3) recruitment and retention, particularly in the asymptomatic and early disease stages. A number of current and future strategies aimed at ameliorating drug development are outlined and discussed.

Female pattern hair loss (FPHL) is a common non-scarring alopecia characterized by widening of the midline hair part at the crown (vertex). In 1977, Ludwig developed a scale that graded the degree of visible vertex hair thinning from I (least severe) to III (most severe). However, by the time patients exhibit the full manifestations of 'Ludwig I', they have already lost a significant volume of hair. Although current therapies may realistically halt progression of hair loss, improvements in hair density is often more limited. Identification and grading of FPHL at an earlier stage is desirable to institute appropriate therapy before significant hair loss has occurred and to enable monitoring over time.To generate consensus guidance for the recognition and quantification of FPHL that can be used in the clinic.Nine clinicians from Europe, North America and Australia experienced in the management of FPHL developed this scale by consensus.We propose a three-point severity scale (termed the FPHL Severity Index (FPHL-SI)) that combines validated measures of hair shedding, midline hair density and scalp trichoscopy criteria to produce a total FPHL-SI score (maximum score = 20). The score is designed to grade FPHL severity over time, while being sufficiently sensitive to identify early disease. A score of 0-4 makes FPHL unlikely; a score of 5-9 would indicate early-stage FPHL, with higher scores indicating greater disease severity.As a starting point for further public debate, we employ criteria already used in clinical practice to generate a pragmatic FPHL grading system (FPHL-SI) of sufficient sensitivity to identify and monitor early FPHL changes. This may have to be further optimized after systematic validation in clinical practice.

Early diagnosis, standardized treatment, and regular monitoring are the clinical treatment principle of rheumatoid arthritis (RA). The overarching principles and recommendations of treat-to-target (T2T) in RA advocate remission as the optimum aim, especially for patients with very early disease who are initiating therapy with anti-RA medications. However, traditional anti-RA drugs cannot selectively target the inflammatory areas and may cause serious side effects due to its short biological half-life and poor bioavailability. These limitations have significantly driven the research and application of nanomaterial-based drugs in theranostics of RA. Nanomedicines have appropriate sizes and easily modified surfaces which can enhance their biological compatibility and prolong circulation time of drug-loading systems in vivo. Traditional T2T regimens cannot evaluate the efficacy of drugs in real time, while clinical drug nanosizing can realize the integration of diagnosis and treatment of RA. This review bridges clinically proposed T2T concepts and nanomedicine in an integrated system for RA early-stage diagnosis and treatment. The most advanced progress in various nanodrug delivery systems for theranostics of RA is summarized, establishing a clear path and a new perspective for further optimization of T2T. Finally, the key facing challenges are discussed and prospects are addressed.

Understanding HIV incidence, the rate at which new infections occur in populations, is critical for tracking and surveillance of the epidemic. In this article, we derive methods for determining sample sizes for cross-sectional surveys to estimate incidence with sufficient precision. We further show how to specify sample sizes for two successive cross-sectional surveys to detect changes in incidence with adequate power. In these surveys biomarkers such as CD4 cell count, viral load, and recently developed serological assays are used to determine which individuals are in an early disease stage of infection. The total number of individuals in this stage, divided by the number of people who are uninfected, is used to approximate the incidence rate. Our methods account for uncertainty in the durations of time spent in the biomarker defined early disease stage. We find that failure to account for this uncertainty when designing surveys can lead to imprecise estimates of incidence and underpowered studies. We evaluated our sample size methods in simulations and found that they performed well in a variety of underlying epidemics. Code for implementing our methods in R is available with this article at the Biometrics website on Wiley Online Library.

The study of the relationships between pre-cancer and cancer and identification of early driver mutations is becoming increasingly important as the value of molecular markers of early disease and personalised drug targets is recognized, especially now the extent of clonal heterogeneity in fully invasive disease is being realized. It has been assumed that pre-cancerous lesions exhibit a fairly passive progression to invasive disease; the degree to which they, too, are heterogeneous is unknown. We performed ultra-deep sequencing of thousands of selected mutations, together with copy number analysis, from multiple, matched pre-invasive lesions, primary tumours and metastases from five patients with oral cancer, some with multiple primary tumours presenting either synchronously or metachronously, totalling 75 samples. This allowed the clonal relationships between the samples to be observed for each patient. We expose for the first time the unexpected variety and complexity of the relationships between this group of oral dysplasias and their associated carcinomas and, ultimately, the diversity of processes by which tumours are initiated, spread and metastasize. Instead of a series of genomic precursors of their adjacent invasive disease, we have shown dysplasia to be a distinct dynamic entity, refuting the belief that pre-cancer and invasive tumours with a close spatial relationship always have linearly related genomes. We show that oral pre-cancer exhibits considerable subclonal heterogeneity in its own right, that mutational changes in pre-cancer do not predict the onset of invasion, and that the genomic pathway to invasion is neither unified nor predictable. Sequence data from this study have been deposited in the European Nucleotide Archive, Accession No. PRJEB6588.

Epidemic agent-based models (ABMs) simulate individuals in artificial societies that are capable of movement, interaction, and transmitting disease among themselves. ABMs have been used to study the spread of disease at various spatial and temporal scales ranging from small communities to the world, over days, months, and years. The representations of space and time often vary between different epidemic ABMs and can be influenced by factors such as the size of a modeled population, computational requirements, population environments, and disease-related data. The influence that the representations of space and time have on epidemic ABMs is difficult to assess. Here we show that the finest representations of space and time—termed spatial and temporal granularities (STGs)—in a parsimonious ABM affect speed, intensity, and spatial spread of a synthetic disease. Specifically, we found disease spread faster and more intensely as spatial granularity is coarsened, whereas disease spread slower and less intensely as temporal granularity is coarsened in a parsimonious ABM. Our study is the first to use the same epidemic ABM to examine the influence of STGs. Our results demonstrate that STGs influence ABM dynamics including early disease burnout and that an interrelationship exists between the coarsening of STGs and the speed and intensity at which disease spreads. Our parsimonious ABM is extended based on a structured community model and we found STGs also influence ABM dynamics in a more realistic context that includes hierarchical movement. Broadly, our study serves as a basis for further inquiry toward the influence of space–time representations on more realistic models that include multiscale mobility, routine movements (e.g., commuting), and heterogeneous population distributions.

In this review, we discuss the application of mouse models to the identification and pre-clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large-scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross-species comparative 'omics-based approaches to this problem. We highlight recent progress in modelling late-stage disease using mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection.

While the FEV1 had been recognized as an excellent indicator of disability, it is not very sensitive to early and mild disease. In cystic fibrosis (CF) small airway disease is believed to be one of the early hallmarks and indices such as the FEF25-75 and FEF75 have been proposed as sensitive markers of early disease. The site of early disease in asthma is not as well worked out. Recently a study of more than 20,000 spirometries found that neither of these indices added anything to the FEV1 /FVC but that study was not disease specific and contained both adults and children and the adults were the most numerous. To see if this would be true in children, 1,175 spirograms from children 6 to 18 years of age with CF or asthma whose FEV1 and FVC were above the lower limit of normal were taken from sequential studies. The data expressed in z scores was plotted with either the FEF25-75 or FEF75 plotted against FEV1 /FVC. In both diseases, but particularly in asthma, the FEV1 /FVC was more likely to be abnormal than either of the other two indices for suggesting that for children, early, or mild disease will be more apparent using the FEV1 /FVC than any other index.

The possibility to detect biomarkers of adult disease in early life and particularly in newborns holds enormous promise for early disease detection and prevention. Early detection of disease or potential for future disease would allow for prevention or amelioration of disease before overt symptoms develop, by lifestyle modifications, appropriate medication and monitoring. It is now increasingly important to develop the technologies that allow dried blood spots (DBS) to be utilized for protein-based studies. The use of DBS in proteome wide association studies (PWAS) may in turn allow for detection of major diseases of adulthood at the earliest possible time. This review focuses on the utility of DBS in proteomics, the main challenges, as well as the latest approaches for overcoming those, facilitating the use of DBS for detection of major diseases of adulthood at the earliest possible time.

Summary At the time of diagnosis primary cutaneous lymphomas are limited to the skin. T-cell lymphomas represent at least two thirds of all primary cutaneous lymphomas with mycosis fungoides and Sezary syndrome being the most frequent entities. A precise staging based on clinical, histological, immunohistological and molecular biological criteria is crucial for selecting the appropriate therapy. Since curative treatment is only possible in exceptional cases, the aim of any therapy is to achieve healing of the skin lesions, minimizing relapses, preventing progression and maintaining the quality of life. While in early disease stages skin-directed therapy is being used, in later stages systemic treatments become more important. This work aims to provide an overview of established and new therapies for the treatment of mycosis fungoides and Sezary syndrome.

Although most of the statistical methods for diagnostic studies focus on disease processes with binary disease status, many diseases can be naturally classified into three ordinal diagnostic categories, that is normal, early stage, and fully diseased. For such diseases, the volume under the ROC surface (VUS) is the most commonly used index of diagnostic accuracy. Because the early disease stage is most likely the optimal time window for therapeutic intervention, the sensitivity to the early diseased stage has been suggested as another diagnostic measure. For the purpose of comparing the diagnostic abilities on early disease detection between two markers, it is of interest to estimate the confidence interval of the difference between sensitivities to the early diseased stage. In this paper, we present both parametric and non-parametric methods for this purpose. An extensive simulation study is carried out for a variety of settings for the purpose of evaluating and comparing the performance of the proposed methods. A real example of Alzheimer's disease (AD) is analyzed using the proposed approaches.

We estimate how the effect of antiretroviral treatment depends on the time from HIV-infection to initiation of treatment, using observational data. A major challenge in making inferences from such observational data arises from biases associated with the nonrandom assignment of treatment, for example bias induced by dependence of time of initiation on disease status. To address this concern, we develop a new class of Structural Nested Mean Models (SNMMs) to estimate the impact of time of initiation of treatment after infection on an outcome measured a fixed duration after initiation, compared to the effect of not initiating treatment. This leads to a SNMM that models the effect of multiple dosages of treatment on a time-dependent outcome, in contrast to most existing SNNMs, which focus on the effect of one dosage of treatment on an outcome measured at the end of the study. Our identifying assumption is that there are no unmeasured confounders. We illustrate our methods using the observational Acute Infection and Early Disease Research Program (AIEDRP) Core01 database on HIV. The current standard of care in HIV-infected patients is Highly Active Anti-Retroviral Treatment (HAART); however, the optimal time to start HAART has not yet been identified. The new class of SNNMs allows estimation of the dependence of the effect of 1 year of HAART on the time between estimated date of infection and treatment initiation, and on patient characteristics. Results of fitting this model imply that early use of HAART substantially improves immune reconstitution in the early and acute phase of HIV-infection.

Background Esophagectomy with gastric pull-up is the optimal treatment for patients with resectable esophageal cancer. Although the morbidity and mortality of an esophagectomy is reduced, the long-term outcome remains poor. The aim of this study was to evaluate the 10-year survival of a standardized multidisciplinary therapy concept for esophageal cancer. Methods Between 1989 and 1999, 114 patients were treated for esophageal cancer at the University of Essen. All patients underwent an en-bloc esophagectomy with systematic lymphadenectomy. Patients with locally advanced disease (stage III) received neoadjuvant therapy. All patients were followed-up for 10 years or more or until death. Results The 3-year survival was 35%, the 5-year survival 25%, and the 10-year survival was 18%. The recurrence rate was 44% with a median time of 13 months. There was no significant difference in survival between patients with locally advanced disease who received neoadjuvant therapy and patients with early disease (stadium I + II) who underwent surgery alone. Of the patients who achieved 10-year survival, 60% had locally advanced disease and received neoadjuvant therapy. Conclusion Patients with locally advanced disease, managed by a multidisciplinary treatment strategy, achieved a similar long-term survival to patients with early disease (stadium I + II). J. Surg. Oncol. 2012; 105:284–287. © 2011 Wiley Periodicals, Inc.

The aim of the study was to construct a screening programme for disseminated histiocytic sarcoma (DHS) in Bernese Mountain dogs using diagnostic imaging and blood analysis and evaluate blood borne biomarkers as early disease detection biomarkers. Healthy Bernese Mountain dogs were screened on four occasions in an attempt to detect early disease. Eleven blood borne biomarkers were examined for their worth as early tumour biomarkers. During 2.5 years, five dogs with early DHS were identified; four of these by diagnostic imaging. No dogs developed symptomatic DHS without being detected within 6 months of the screening programme. Only serum ferritin showed potential as a blood borne marker of the disease. Median survival times for the dogs with early DHS were 226 days. Screening programmes every 6 months for Bernese Mountain dogs over 4 years of age including diagnostic imaging and ferritin measurements may identify early DHS.

SUMMARY Aims: Critically reexamine and place in perspective the most appropriate therapeutic strategies for patients noncompaction of ventricular myocardium. Results: Specific treatments are not available for the majority of patients with noncompaction of ventricular myocardium currently. Treatment of patients with noncompaction of ventricular myocardium could be similar to patients with other cardiomyopathies, especially dialated cardiomyopathy, and therefore, the primary aims of treatment are to control symptoms, disease progression, and complications, which should include appropriate treatment for heart failure, management of arrhythmias, and oral anticoagulation to prevent systemic emboli. Conclusion: Among the many challenges facing clinicians treating patients with noncompaction of ventricular myocardium are the detection of early disease, the identification of the predominant mechanism of left ventricular dysfunction, and the development of treatments that target the initiating mechanism of disease. Nevertheless, there have been major advances in our understanding of the genetic basis of noncompaction of ventricular myocardium, and recent advances in the drug therapy and nondrug therapy of noncompaction of ventricular myocardium have substantially improved the outlook for many patients. The rapid pace of current research and the development of new treatments for the management of both early and late disease augur well for the future.

As the emphasis shifts from damage mitigation to disease prevention or reversal of early disease in the oral cavity, the need for sensitive and accurate detection and diagnostic tools become more important. Many novel and emergent optical diagnostic modalities for the oral cavity are becoming available to clinicians with a variety of desirable attributes including: (i) non-invasiveness, (ii) absence of ionizing radiation, (iii) patient-friendliness, (iv) real-time information (v) repeatability, and (vi) high-resolution surface and subsurface images. In this article, the principles behind optical diagnostic approaches, their feasibility and applicability for imaging soft and hard tissues, and their potential usefulness as a tool in the diagnosis of oral mucosal lesions, dental pathologies, and other dental applications will be reviewed. The clinical applications of light-based imaging technologies in the oral cavity and of their derivative devices will be discussed to provide the reader with a comprehensive understanding of emergent diagnostic modalities.

In order to identify rate and stability of remission induced by low-dose prednisone comedication in early rheumatoid arthritis (RA), we evaluated patients with early RA (

Background Axial spondyloarthritis (axSpA) is a common inflammatory arthritis of the sacroiliac joints and the spine. The best-known and most studied form of axSpA is ankylosing spondylitis. Design In this review, we provide a brief overview of the pathophysiology of axSpA. In addition, we performed a quantitative text analysis of reviews on the pathogenesis of axSpA published in the last 10 years to establish the current consensus in various fields of research into the pathogenesis of axSpA. Results There appears to be broad consensus on genetic risk factors and the involvement of the immune system in the initiation phase of the disease although little consensus was found on which specific immune cells drive disease. Moreover, despite relatively little data available, alterations in the microbiome are commonly thought to be involved in disease. Abnormal bone formation is the most prominent pathogenic factor thought to be involved in disease progression. Conclusion So, although the pathophysiology of axSpA remains incompletely understood, the progress in recent years in several fields of research in axSpA including genetics, diagnosis, imaging and therapeutics, hold great promise for the future.

Rapid early disease prevention or precise diagnosis is almost impossible in low-resource settings. Natural ordered structures in nature have great potential for the development of ultrasensitive biosensors. Here, motivated by the unique structures and extraordinary functionalities of ordered structures in nature, a biosensor based on butterfly wings is presented. In this study, a flexible Morpho menelaus (M. menelaus) based wearable sensor is integrated with a microfluidic system and electronic networks to facilitate the diagnosis of neurodegenerative disease (ND). In the microfluidic section, the structural characteristics of the M. menelaus wings up layer are combined with SiO2 nanoparticles to form a heterostructure. The fluorescent enhancement property of the heterostructure is used to increase the fluorescent intensity for multiplex detection of two proteins: IgG and AD7c-NTP. For the electronic section, conductive ink is blade-coated on the under layer of wings for measuring resistance change rate to obtain the frequency of static tremors of ND patients. The disposable M. menelaus based flexible microfluidic and electronic sensor enables biochemical-physiological hybrid monitoring of ND. The sensor is also amenable to a variety of applications, such as comprehensive personal healthcare and human-machine interaction.

Lung cancer remains one of the greatest medical challenges with nearly 1.5 million new cases worldwide each year and a growing tobacco epidemic in the developing world. This review summarizes briefly the current status in growing areas of clinical research. The value of screening for early disease is not yet established and trials to see if mortality can be improved as a result are in progress. Better and more accurate staging will both streamline investigation and prove cost-effective once ultrasound-guided biopsy and aspiration of mediastinal nodes become universally accepted. This, allied to the new staging classification, will improve selection of cases for surgery, intensive multimodality therapy and for adjuvant treatment postoperatively. Much still needs to be done to refine staging as within a particular stage group, the outcome shows great variation. More information is needed on the genetic make-up in some groups of tumours and not just their size; that is, more biological data on tumour growth patterns are likely to be at least as discriminating. The place of the stem cell theory of tumorigenesis is also explored in this paper. Finally, targeted therapy for advanced non-small-cell lung cancer is highlighted as a development with early promise, but still much clarification is required, before it can be considered as a universal approach in late disease.

Multiple endocrine neoplasia type 1 (MEN 1) is a complex multi-system disease manifesting a diverse range of primary and secondary metabolic and neoplastic disorders. It is possible to improve patient prognosis by early disease detection and treatment. Regular biochemical and radiological screening for parathyroid, gastro-enteropancreatic, pituitary, intrathorasic and adrenal lesions forms the basis of surveillance. The likelihood of adverse sequelea such as renal and bone disease resulting from hyperparathyroidism, severe peptic ulceration and gastric carcinoidosis secondary to hypergastrinaemia can be ameliorated by early detection and management.

Bladder cancer is a common cause for cancer admission to hospital in the UK and survival rates have not improved over the past two decades. The author highlights the importance of early disease detection and describes the symptoms and diagnosis, and the treatments for each risk category. Copyright © 2009 Wiley Interface Ltd

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. Traditionally, attention has focused on the motor symptomatology of PD, but it is now appreciated that the nonmotor symptoms affecting neuropsychiatric, sleep, autonomic, and sensory domains occur in up to 88% of PD patients and can be an important source of disability. Nonmotor manifestations of PD play a significant role in the impairment of disease-related quality of life. The cause of nonmotor manifestations of PD is multifactorial, but to a large extent, these manifestations are related to the nature of the neurodegenerative process and the widespread nondopaminergic neuropathological changes associated with the disease. Recognition of nonmotor disability is essential not only for ascertaining the functional status of patients but also for better appreciating the nature of the neurodegenerative process in PD. In addition, a number of nonmotor manifestations can precede the onset of motor symptoms in PD and can be used as screening tools allowing for early disease identification and for trials of possible disease-modifying interventions. This article reviews depression, sleep, and autonomic dysfunction in PD. Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. Traditionally, motor symptomatology of PD has received the most attention, but the nonmotor symptoms affecting neuropsychiatric, sleep, autonomic, and sensory domains occur in up to 88% of PD patients. 1 Nonmotor manifestations of PD play a significant role in the impairment of disease-related quality of life (QOL). Based on a survey of 1,000 PD patients, classic motor disability was responsible for merely 17% of variance in the impairment of QOL, whereas depression was the major contributor to the worsening of QOL. 2 The spectrum of nonmotor manifestations of PD is broad as, detailed in Table 1. This article focuses on depression, sleep, and autonomic dysfunction in PD. Other sections of this supplement review dementia, impulse control disorders, and olfactory dysfunction in PD. Depression in Parkinson’s Disease Epidemiology The reported prevalence rates of depression in PD range from 4 to 76%. 3,4 The wide variation is attributed to inconsistency in study methodologies, including differences in sampling procedures, choice of diag

Disease modifying antirheumatic drugs (DMARDs) are drugs used in rheumatoid arthritis (RA) to control the disease and to limit joint damage and improve long-term outcome. The last decade evidence has accumulated that suggests that low dosages of glucocorticoids are indeed able to control the disease and limit the destruction. This role is especially present in early disease and in combination with other drugs. The evidence is carefully evaluated and discussed. The ultimate conclusion is that indeed glucocorticoids are DMARDs and are especially useful in early RA.

The question of whether to screen for dementia and Alzheimer’s disease (AD) has been discussed in many forums throughout the world. Generally, medical advisory groups and policy-making groups have recognized the importance of early diagnosis but have uniformly avoided making recommendations to screen at-risk populations. This presentation reflects the support for reconsidering the importance of screening individuals at risk or above a certain age. In this statement, the majority of the authors support the consideration of dementia risk factors in individuals at age 50, with routine yearly screening after 75. Other authors remain concerned that the benefits of treatments of early disease do not yet support a general screening recommendation. These statements are made to encourage progress toward the development of a consensus regarding the widespread institution of screening policy. Accordingly, members of the worldwide scientific community are invited to add their perspective by contributing short commentaries (1500 words) on this subject.

Cardiovascular abnormalities are frequently the cause, as well as the effect, of elevated blood pressure. As such, early cardiovascular disease (CVD) may be established before identifiable blood pressure thresholds are crossed. To identify individuals at risk for CVD at an earlier point in the disease process, as well as to avoid labeling persons as hypertensive who are at low risk for CVD, the Hypertension Writing Group proposes incorporating the presence or absence of cardiovascular risk factors, early disease markers, and target organ damage into the definition and classification scheme of hypertension. To describe both the complexity and progressive nature of hypertension, the following definition is proposed: "Hypertension is a progressive cardiovascular syndrome arising from complex and interrelated etiologies. Early markers of the syndrome are often present before blood pressure elevation is observed; therefore, hypertension cannot be classified solely by discrete blood pressure thresholds. Progression is strongly associated with functional and structural cardiac and vascular abnormalities that damage the heart, kidneys, brain, vasculature, and other organs and lead to premature morbidity and death." Classification of hypertension must involve assessing global cardiovascular risk to situate an individual's risk for CVD and events along a continuum. As knowledge of early CVD continues to evolve, the approach to classifying individuals along that continuum can be expected to evolve accordingly. The four categories currently used to classify hypertension are normal, prehypertension, and stages 1 and 2 hypertension. The population identified with prehypertension includes a subgroup with early CVD. We believe it would be preferable to classify all individuals as either normal or hypertensive, based on their cardiovascular evaluation, using the four categories of normal and stages 1, 2, and 3 hypertension.

Over the past 15 years or so, there have been revolutionary changes in the treatment strategies of rheumatoid arthritis (RA). The traditional pyramidal approach has largely been replaced by the aggressive use of disease-modifying antirheumatic drugs (DMARDs) in early disease. There has been continuing excitement with the introduction and use of the newer biological agents. While these novel agents have added to the armamentarium of RA treatment, rheumatologists are faced with the dilemma of drug cost and treatment effectiveness. In this article, the current concept of RA therapies and data regarding the newer biological response modifiers are discussed.