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Sex-related differences in diagnosis and treatment of hypertrophic obstructive cardiomyopathy (HOCM) are still unclear. Therefore, we analyzed baseline characteristics of symptomatic patients with indication for alcohol septal ablation (PTSMA) with respect to gender.Between 05/2000 and 06/2017 indication for PTSMA was seen in 1014 patients (420 (41.4%) women and 594 (58.6%) men). Women were older (61.4 ± 15.0 vs. 51.8 ± 13.6 years; p 0.00001) and suffered more often from dyspnea NYHA III/IV (81.4% vs. 67.7%; p 0.001), whereas angina pectoris and syncopes were comparable. Echocardiographic gradients were comparable in women (66.4 ± 39.1 mmHg at rest and 106.5 ± 46.6 mmHg at Valsalva) and men (62.7 ± 38.8 mmHg at rest and 103.7 ± 42.7 mmHg at Valsalva). Women had smaller absolute diameter of the left atrium (LA) (44.4 ± 6.9 vs. 47.2 ± 6.5 mm; p 0.0001), septal thickness (IVS) (20.5 ± 4.1 vs. 21.4 ± 4.5 mm; p 0.01), and left ventricular posterior wall thickness (LVPW) (12.7 ± 2.8 vs. 13.6 ± 2.9 mm; p 0.0001). But, indexed for BSA the relationship reversed in LA (25.2 ± 4.3 mm/mWomen with HOCM and indication for PTSMA are older and more symptomatic with advanced disease progression. Reconsideration of disease definition and awareness maybe necessary in order to avoid delayed diagnosis and treatment of HOCM in women.

Background Type 2 myocardial infarction (T2MI) is commonly encountered in clinical practice, yet little is known about this challenging condition. Outpatient cardiac rehabilitation (CR) is an integral component in the care of patients with MI. However, specific recommendations for CR, information on the feasibility of participation, and outcome measures for patients with T2MI are lacking. Clinical considerations The frequency of T2MI is markedly variable and depends on the studied population, disease definition, adjudication process, cardiac troponin assays, and cutoff values used to make the diagnosis of T2MI. Clinically, it is difficult to distinguish T2MI from type 1 MI or myocardial injury. Type 2 myocardial infarction occurs due to myocardial oxygen supply-demand mismatch without acute atherothrombotic plaque disruption and is associated with adverse short- and long-term prognoses. Currently, there are substantial gaps in knowledge regarding T2MI and there are no clear guidelines for the optimal management of these patients. Summary In this article, we present important current concepts surrounding T2MI including the definition, pathophysiology, epidemiology, diagnosis, prognosis, and management. We also discuss referral patterns to CR and participation rates and provide our experience with a case series of 17 patients. Very few patients with T2MI are referred to and participate in CR. Our small case series indicated that patients with T2MI respond favorably to CR and that exercise training following standard guidelines appears safe and is well tolerated.

Rationale: Aspergillus infection in patients with suspected ventilator-associated pneumonia remains uncharacterized because of the absence of a disease definition and limited access to sensitive di...

Pustulosis palmaris et plantaris, or palmoplantar pustulosis (PPP), is a chronic pustular dermatitis involving the palms and soles and is characterized by vesicles, pustules, erythema, lichenification, and abnormal desquamation. It is one of the most common skin diseases in Japan but its pathomechanism is unclear and the disease remains poorly defined. Consequently, adequate treatment for PPP is lacking. As a localized type of pustular psoriasis, PPP has long been treated with the conventional therapies used for plaque-type psoriasis, especially in Western countries. However, PPP may be a distinct entity, with a much lower prevalence in Western countries than in Japan. Furthermore, while treatment has yielded insights into the underlying pathology in plaque-type psoriasis, the pathogenesis of PPP has yet to be elucidated. In 2018, Gulselkumab, a monoclonal antibody against interleukin (IL)-23, was certified for use in Japan and is the first biologic effective in PPP both in Japanese and other patients. In this review, we summarize the current understanding of PPP, including the revised definition and possible pathomechanism. The information presented herein provides a more complete picture of PPP and may facilitate the development of improved treatment options.

Plasma cell leukemia (PCL) is clinically and genetically distinct from multiple myeloma (MM), despite controversies regarding the disease definition. To determine the distinct features of PCL, the genetic property of primary PCL (pPCL) was compared with that of secondary PCL (sPCL) and MM. In patients with pPCL, Eighty-nine non-synonymous mutations were observed in 68 genes. The most frequently mutated genes were

Articulating a satisfactory definition of a disease is surprisingly difficult. Despite the alarming individual, societal and economic burden of chronic obstructive pulmonary disease (COPD), diagnosis is still largely based on a physiologically dominated disease conception, with spirometrically determined airflow limitation as a cardinal feature of the disease. The diagnostic inaccuracy and insensitivity of this physiological disease definition is reviewed considering scientific developments of imaging of the respiratory system in particular. Disease must be approached as a fluid concept in response to new scientific and medical discoveries, but labelling as well as mislabelling someone as diseased, will have enormous individual, social and financial implications. Nosology of COPD urgently needs to dynamically integrate more sensitive diagnostic procedures to detect the breadth of abnormalities early in the disease process. Integration of broader information for the identification of abnormalities in the respiratory system is a cornerstone for research models of underlying pathomechanisms to create a breakthrough in research.

Haff disease is an unexplained rhabdomyolysis syndrome occurring within 24 h of consumption of certain types of cooked fish or crustaceans. The current epidemiological status of crayfish-transmitted Haff disease in China was investigated by analyzing retrospective data linked with cases of the rhabdomyolysis syndrome recorded during the period 2016–2017. This information was acquired from the National Foodborne Disease Surveillance and Reporting System. These data were filtered, based on the disease definition and a markedly elevated serum creatine phosphokinase level, that is, fivefold or greater increase than normal levels. Data analysis indicated that crayfish-transmitted Haff disease was mainly concentrated in the middle and lower reaches of the Yangtze River Valley, and the current epidemiological curve was notable seasonal. Most patients were aged 20–49 years and the proportion of female patients was higher than male patients. Based on this initial study, it will be necessary to follow up the trace-back investigation of crayfish poisoning reports; further analyze the correlation between the aquatic environment of the associated crayfish together with establishing virulence factors of crayfish-transmitted Haff disease; and explore whether certain individuals have receptor pathways to trigger rhabdomyolysis syndrome.

This review focuses on the management of elderly patients with chronic myeloid leukemia and chronic myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and primary myelofibrosis. Median age in these neoplasms is within the 6th decades of age. All new therapies can be done at any age without absolute contraindication. However, the selection of the precise therapy for the single patient is mandatory. For these reasons, an accurate definition of diagnosis and prognostication is necessary. Precision in disease definition and prognostication is definitively helpful for personalizing therapeutic approach.

Summary Robust phenotyping of patients from electronic health records (EHRs) at scale is a challenge in clinical informatics. Here, we introduce Phe2vec, an automated framework for disease phenotyping from EHRs based on unsupervised learning and assess its effectiveness against standard rule-based algorithms from Phenotype KnowledgeBase (PheKB). Phe2vec is based on pre-computing embeddings of medical concepts and patients' clinical history. Disease phenotypes are then derived from a seed concept and its neighbors in the embedding space. Patients are linked to a disease if their embedded representation is close to the disease phenotype. Comparing Phe2vec and PheKB cohorts head-to-head using chart review, Phe2vec performed on par or better in nine out of ten diseases. Differently from other approaches, it can scale to any condition and was validated against widely adopted expert-based standards. Phe2vec aims to optimize clinical informatics research by augmenting current frameworks to characterize patients by condition and derive reliable disease cohorts., Highlights • Automated framework for disease phenotyping from electronic health records • Unsupervised learning to identify cohorts for any disease of interest • Comparable or superior performance with that of widely adopted expert-based standards, The bigger picture Electronic health record (EHR)-based research is central to fulfill the vision of personalized medicine. However, due to EHRs being structured for billing purposes, reliably identifying patients with a phenotype of interest in a clinical data warehouse is difficult. Phe2vec uses unsupervised learning to derive medical concept embeddings and build phenotype definitions to identify patient cohorts. Pre-training embeddings leads to a flexible solution which is applicable to any disease by simply defining a seed concept. This method showed performance comparable or superior to that of other widely adopted EHR phenotyping approaches. Phe2vec aims to contribute to the next generation of clinical systems that use machine learning to effectively support clinicians in their activities. These systems capable of scaling to a large number of diseases, patients, and health data promise to offer a more holistic way to examine disease complexity and to improve clinical practice and medical research., De Freitas et al. present Phe2vec, an automated framework for disease phenotyping based on unsupervised learning. Phe2vec derives embeddings of medical concepts from electronic health records and uses them to define phenotypes and measure the association between diseases and patients. The authors demonstrate the method's effectiveness via comparison with both rule-based algorithms and standard automated methods. Phe2vec can be used to identify patient cohorts by simply specifying a seed concept associated to any disease of interest.

Background: Cerebellar atrophy is a neuroradiological definition that categorizes conditions heterogeneous for clinical findings, disease course, and genetic defect. Most of the papers proposing a diagnostic workup for pediatric ataxias are based on neuroradiology or on the literature and experimental knowledge, with a poor participation of clinics in the process of disease definition. Our study aims to offer a different perspective on the way we approach cerebellar atrophy in developmental age, building a clinical-based diagnostic workup to guide molecular diagnosis. Methods: we recruited 52 patients with pediatric-onset cerebellar atrophy and definite disease categorization. Children underwent brain MRI, neurophysiological exams, metabolic investigations, and muscle biopsy with respiratory chain complex study. Single-gene sequencing, next-generation sequencing NGS panels, whole-exome sequencing (WES), and disease-specific techniques have been used to reach genetic confirmation. Results: Brain MRI is the main method of diagnosis, followed by tests on muscle biopsy and peripheral nervous system study. Other exams (e.g., metabolic investigations or evoked potentials) may be useful to narrow the list of diagnostic possibilities. Conclusions: We propose a diagnostic approach to cerebellar atrophy in children based on clinical findings, and support the evidence that a precise phenotypic definition may lead to the formulation of a definite diagnosis or otherwise guide the back phenotyping process derived from large molecular data.

The clinical and phenotypic complexity of GERD requires a detailed, multimodality diagnostic evaluation prior to decision-making for pharmacological, endoscopic, or surgical therapies. An individualized selection has to be based on symptoms, clinical presentation, proper disease definition, therapeutic objectives, and available local endoscopic and surgical expertise. As these novel endoscopic and laparoscopic technologies evolve and mature and long-term data becomes available, decision-making will remain in flux but best done at multidisciplinary esophageal centers of excellence.

Automated milk feeders (AMF) are computerized systems that provide producers with a tool that can be used to more efficiently raise dairy calves and allow for easier implementation of a high plane of nutrition during the milk feeding phase. Automated milk feeders also have the ability to track individualized behavioral data, such as milk consumption, drinking speed, and the number of rewarded and unrewarded visits to the feeder, that could potentially be used to predict disease development. The objective of this scoping review was to characterize the body of literature investigating the use of AMF data to predict morbidity and mortality in dairy calves during the preweaning stage. This review lists the parameters that have been examined for associations with disease in calves and identify discrepancies found in the literature. Five databases and relevant conference proceedings were searched. Eligible studies focused on the use of behavioral parameters measured by AMF to predict morbidity or mortality in preweaned dairy calves. Two reviewers independently screened titles and abstracts from 6,675 records identified during the literature search. After title and abstract screening, 382 studies were included and then assessed at the full-text level. Of these, 56 studies fed calves using an AMF and provided some measure of morbidity or mortality. Thirteen examined AMF parameters for associations with morbidity or mortality. The studies were completed in North America (n = 6), Europe (n = 6), and New Zealand (n = 1). The studies varied in sample size, ranging from 30 to 1,052 calves with a median of 100 calves. All 13 studies included enteric disease as an outcome and 11 studies evaluated respiratory disease. Of the studies measuring enteric disease, 8 provided disease definitions (n = 8/13, 61.2%); however, for respiratory disease, only 5 provided a disease definition (n = 5/11, 45.5%). Disease definitions and thresholds varied greatly between studies, with 10 using some form of health scoring. When evaluating feeding metrics as indicators of disease, all 13 studies investigated milk consumption and 6 and 7 studies investigated drinking speed and number of rewarded and unrewarded visits, respectively. Overall, this scoping review identified that daily milk consumption, drinking speed, and rewarded and unrewarded visits may provide insight into early disease detection in preweaned dairy calves. However, the disparity in reporting of study designs and results between included studies made comparisons challenging. In addition, to aid with the interpretation of studies, standardized disease outcomes should be used to improve the utility of this primary research.

The aim of our research was to obtain expert consensus for updated definition and classification of dry eye disease using formal methodology. The nominal group technique (NGT) involved a steering committee of four ophthalmologists began with collection of ideas followed by group discussion. The ideas were collated, refined, and voted upon. The main characteristics considered, each with different degrees of severity in types I, II, and III, were the ability or not of the ocular surface to re-equilibrate itself, frequency of symptoms, presence of inflammation, epithelial alterations, and possible alterations in the quality of vision. This was followed by three rounds of a “mini-Delphi” involving an expert panel of 13 ophthalmologists, with the last round including all 17 ophthalmologists. Consensus in the final round of voting (⩾75% of votes) was reached on the definition of dry eye disease and on criteria for its classification in three forms. Type I is a transient and reversible form with subclinical inflammation, possible epithelial alterations, and occasional alterations in vision. Type II is a recurrent form characterized by a reduced ability to re-equilibrate the ocular surface, frequent symptoms and alterations in vision with clinically-evident inflammation, and clear evidence of epithelial alterations. Type III is a chronic form with inability to re-equilibrate the ocular surface and accompanied by clinically-evident and chronic inflammation, persistent epithelial alterations, and frequent alterations in quality of vision. The vast majority of patients with dry eye disease can be easily classified into one of these three forms. Dry eye disease definition was updated accordingly.

Essential tremor (ET) is a neurological movement disorder characterised by bilateral limb kinetic/postural tremor, with or without tremor in other body parts including head, voice and lower limbs. Since no causative genes for ET have been identified, it is likely that the disorder occurs as a result of complex genetic factors interacting with various cellular and environmental factors that can result in abnormal function of circuitry involving the cerebello–thalamo–cortical pathway. Genetic analyses have uncovered at least 14 loci and 11 genes that are related to ET, as well as various risk or protective genetic factors. Limitations in ET genetic analyses include inconsistent disease definition, small sample size, varied ethnic backgrounds and many other factors that may contribute to paucity of relevant genetic data in ET. Genetic analyses, coupled with functional and animal studies, have led to better insights into possible pathogenic mechanisms underlying ET. These genetic studies may guide the future development of genetic testing and counselling, and specific, pathogenesis-targeted, therapeutic strategies.

BACKGROUND Acute respiratory infections (ARIs) are among the most frequent childhood diseases in Western countries. Assessment of ARI episodes for research purposes is usually based on parent-administered retrospective questionnaires or prospective symptom diaries. The aim of our analysis was to compare the effect of ARI definitions on the corresponding disease burden in a prospective cohort study using symptom diaries. METHODS A literature search was performed to identify definitions of ARI used in research studies. The definitions were applied to a symptom diary dataset from a cohort study of 1-3-year-old children conducted in the winter season 2013/2014. We compared the total number of ARI episodes, the total number of days with ARI and the median and mean duration of ARI episodes resulting from the use of the different definitions. RESULTS Six ARI definitions were identified in the literature. Depending on ARI definition, the total number of ARI episodes and the total number of days with ARI in our dataset varied by a factor of 1.69 and 1.53, respectively, between the lowest and the highest. The median duration of the episodes ranged from 7 to 10 days. DISCUSSION Different definitions led to considerable differences in the number and duration of ARI episodes, making direct comparisons of studies with different methods questionable. We propose the use of a standardized ARI definition in upcoming cohort studies working with diary data. This process could be conducted using a Delphi survey with experts in this study field.

It is critical for psychiatry as a field to develop approaches to define the molecular, cellular, and circuit basis of its brain diseases, especially for serious mental illnesses, and then to use these definitions to generate biologically based disease categories, as well as to explore disease mechanisms and illness etiologies. Our current reliance on phenomenology is inadequate to support exploration of molecular treatment targets and disease formulations, and the leap directly from phenomenology to disease biology has been limiting because of broad heterogeneity within conventional diagnoses. The questions addressed in this review are formulated around how we can use brain biomarkers to achieve disease categories that are biologically based. We have grouped together a series of vignettes as examples of early approaches, all using the Bipolar and Schizophrenia Network on Intermediate Phenotypes (BSNIP) biomarker database and collaborators, starting off with describing the foundational statistical methods for these goals. We use primarily criterion-free statistics to identify pertinent groups of involved genes related to psychosis as well as symptoms, and finally, to create new biologically based disease cohorts within the psychopathological dimension of psychosis. Although we do not put these results forward as final formulations, they represent a novel effort to rely minimally on phenomenology as a diagnostic tool and to fully embrace brain characteristics of structure, as well as molecular and cellular characteristics and function, to support disease definition in psychosis.

Kraepelin expected that the neuropathological hallmark of schizophrenia would be identified when he proposed the concept of dementia praecox 120 years ago. Although a variety of neuropathological findings have been reported since then, a consensus regarding the pathology of schizophrenia has not been established. The discrepancies have mainly been ascribed to limitations in the disease definition of schizophrenia that accompanies etiological heterogeneity and to the incompleteness of the visualization methodology and technology for biochemical analyses. However, macroscopic structural changes in the schizophrenia brain, such as volumetric changes of brain regions, must entail structural changes to cells composing the brain. This paper overviews neuropathology of schizophrenia and also summarizes recent application of synchrotron radiation nanotomography (nano-CT) to schizophrenia brain tissues. Geometric parameters of neurites determined from the 3-D nano-CT images of brain tissues indicated that the curvature of neurites in schizophrenia cases is significantly higher than that of controls. The schizophrenia case with the highest curvature carried a frameshift mutation in the glyoxalase 1 gene and exhibited treatment resistance. Controversies in the neuropathology of schizophrenia are mainly due to the difficulty in reproducing histological findings reported for schizophrenia. Nano-CT visualization using synchrotron radiation and subsequent geometric analysis should shed light on this long-standing question about the neuropathology of schizophrenia.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) which varies in prevalence across the world, depending on disease definition, diagnostic methods, exposure type and intensity, geographical environments, agricultural and industrial practices, and host risk factors. This study aimed to deepen knowledge about HP's clinical characteristics, diagnosis and functional and imaging features in a cohort of HP patients from the North of Portugal. To achieve this goal, a retrospective assessment of the clinical and diagnostic data was carried out, and patients were classified and compared according to disease presentation (acute, sub-acute and chronic HP forms). Of the 209 HP patients included (mean age 58.3 ± 16.0 years), 52.6% were female and 73.7% presented a chronic form. Most patients had prior exposure to birds (76.6%). Dyspnoea and cough were the most frequently experienced symptoms, but no statistically significant differences were found between groups (p = 0.089, p = 0.418, respectively). Fever was most common in acute HP form (p < 0.001). The most common patterns found in Chest CT were ground glass (p = 0.002) in acute/subacute presentation, and reticulation (p < 0.001) in chronic form, while mosaic attenuation, although was also frequently observed, no statistically significant differences were found between groups (p = 0.512). The most common functional pattern was restrictive (38% of patients, 73.7% with chronic HP form). Bronchoalveolar lavage lymphocytes were higher in acute and subacute forms although not reaching statistical significance (p = 0.072), with lowest CD4/CD8 ratio (p = 0.001) in acute forms. Thus, given the significant disease heterogeneity, further studies with different populations and ambient exposures are needed to achieve a better stratification of the exposure risk, to provide proper implementation of avoidance methods and a precise diagnostic and therapeutic approach. Martins N. would like to thank the Portuguese Foundation for Science and Technology (FCT-Portugal) for the Strategic project ref. UID/BIM/04293/2013 and ?NORTE2020?Programa Operacional Regional do Norte? (NORTE-01-0145-FEDER-000012).

ObjectiveTo assess which mental health-related states of being are perceived as diseases by psychiatrists, non-psychiatric physicians, nurses, parliament members and laypeople.Design and settingA population-based, mailed survey in Finland.ParticipantsRespondents from a random sample of 3000 laypeople, 1500 physicians, 1500 nurses and all 200 members of the parliament (MPs) of Finland.Primary outcome measuresRespondents’ perspectives on 20 mental health-related states of being as diseases, measuring the extent of agreement with the claim: ‘[This state of being] is a disease’.ResultsOf the 6200 people approached, we received 3259 eligible responses (53%). Two conditions (schizophrenia and autism) were considered to be diseases by at least 75% and two states (grief and homosexuality) were considered not to be diseases by at least 75% in each group. A majority (at least 50% in each group) considered seven states as diseases (anorexia, attention deficit hyperactivity disorder, bulimia, depression, generalised anxiety disorder, panic disorder and personality disorder) and three not to be diseases (absence of sexual desire, premature ejaculation and transsexualism). In six states, there was a wide divergence of opinion (alcoholism, drug addiction, gambling addiction, insomnia, social anxiety disorder and work exhaustion). Psychiatrists were significantly more inclined to considering states of being as diseases relative to other groups, followed by non-psychiatric physicians, nurses, MPs and laypeople.ConclusionsRespondents agreed that some conditions, such as schizophrenia and autism, are diseases and other states, such as grief and homosexuality, are not; for others, there was considerable disagreement. Psychiatrists are more inclined to consider mental health-related states of being as diseases compared with other physicians, who, in turn, are more inclined than other constituencies. Understanding notions of disease may underlie important debates in public policy and practice in areas of mental health and behaviour, and have implications for resource allocation and stigma.

Congenital myopathies (CM) are a genetically heterogeneous group of neuromuscular disorders most commonly presenting with neonatal/childhood-onset hypotonia and muscle weakness, a relatively static or slowly progressive disease course, and originally classified into subcategories based on characteristic histopathologic findings in muscle biopsies. This enduring concept of disease definition and classification based on the clinicopathologic phenotype was pioneered in the premolecular era. Advances in molecular genetics have brought into focus the increased blurring of the original seemingly "watertight" categories through broadening of the clinical phenotypes in existing genes, and continuous identification of novel genetic backgrounds. This review summarizes the histopathologic landscape of the 4 "classical" subtypes of CM-nemaline myopathies, core myopathies, centronuclear myopathies, and congenital fiber type disproportion and some of the emerging and novel genetic diseases with a CM presentation.

Purpose of Review: We discuss current topics on the definition of plasma cell leukemia and the distinction between plasma cell leukemia and multiple myeloma. Moreover, we review the latest literature on how to treat plasma cell leukemia. Recent Findings: Plasma cell leukemia is clinically and genetically distinct from multiple myeloma. Plasma cell leukemia is defined by the observation in blood of more than 20% clonal plasma cells by differential count of the leucocytes or by counting more than 2 × 109 per liter circulating clonal plasma cells. However, patients with lower levels of circulating plasma cells have the same adverse prognosis, which challenges the disease definition. Survival has improved after implementation of high-dose chemotherapy with stem-cell support, bortezomib, and lenalidomide in the treatment; yet, the prognosis remains poor. The results of allo-transplants have been disappointing. Summary: The diagnostic criteria of PCL are currently discussed in the international myeloma community. Despite some improvement in survival, the prognosis remains adverse. New, more targeted treatment modalities, including immunotherapies, will hopefully improve the outcome in the near future.

Gastroesophageal reflux disease (GERD) is a common condition seen worldwide. The prevalence in North America and Europe ranges from 8.8% to 30% and is lower in Asia, ranging anywhere from 3.5% to 8.5%. GERD also can cause esophageal strictures and Barrett esophagus, and has a significant impact on patients' quality of life. Additionally, GERD results in millions of office visits, missed days of work, and lost productivity. In this chapter we explore the epidemiology of GERD along with the full scope of the problem, including the effect it has on patients' quality of life and economic burden.

Osteochondritis dissecans (OCD) is a rare yet fascinating disease affecting young, active patients. It remains a ‘mysterious disease’ whose etiopathology, still unclear, is the subject of ongoing studies aiming improving the knowledge of this condition and, therefore, treatment options, too. Even though the first descriptions of intra-articular loose bodies date back to very ancient times, it is only relatively recently that, thanks to the contribution of some very eminent physicians, it became recognized as a specific orthopaedic condition. The aim of the present manuscript is to trace the main steps in the journey that led to the acknowledgement of OCD as an autonomous clinical entity, and to recall the prominent figures involved.

Background The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guidelines establish international recommendations for the definition and treatment of kidney disease. Our objective was to characterize the strength of evidence supporting the KDIGO guidelines, the class of recommendations made, and the relationship between these. Study Design We reviewed and abstracted the level of evidence and strength of recommendations in the currently available KDIGO guidelines. Setting & Population KDIGO clinical practice guidelines target care of patients with kidney disease to improve outcomes. Selection Criteria for Studies All KDIGO guidelines published on the KDIGO website as of November 2013 were included. Predictor Recommendations pertaining to disease, diagnosis, or treatment. Outcomes Levels of evidence and strength of recommendations. Results Of 853 recommendations in 9 guidelines, 5% were supported by level A quality evidence; 17%, level B; 31%, level C; 18%, level D; and 20%, ungraded evidence. The strength of recommendations was class 1 for 25%, class 2 for 54%, and ungraded for 20%. Only 3% of recommendations were class 1 in strength and supported by level A evidence. Of the recommendations, 2% concerned disease definition and classification; 29%, diagnosis; and 69%, treatment. Limitations Our study included only the KDIGO guidelines. We did not assess historical changes in nephrology guidelines recommendations. Conclusions KDIGO recommendations were based largely on weak evidence, reflecting expert opinion. Few recommendations were both strong and supported by high-level evidence.

Purpose of review:Leukodystrophies are genetic disorders primarily and predominantly affecting CNS white matter. They are associated with connotations such as “much unknown,” “progressive myelin loss,” and “nothing can be done.” Recent technological progress is reversing this picture.Recent findings:Next-generation sequencing has created the revolution of whole-exome/genome sequencing, allowing disease definition and gene identification for numerous ultra-rare disorders by focusing on very small groups and individual patients. Knowledge of many new “white matter proteins” is transforming our understanding of white matter physiology and pathophysiology. Regarding therapy, especially stem cell and gene therapy are evolving rapidly, aiming at personalized therapy for a specific patient with a specific disease. Multimodal approaches targeting multiple aspects of the disease hold the highest promise.Summary:Technological developments are revolutionizing the leukodystrophy field. Unknown becomes known and untreatable becomes treatable. New insight is that not all leukodystrophies are irreversible and that some improve spontaneously.

Although I reject neuronormativity -- an idea central to the Brain Disease Model of Addiction (BDMA) -- Henden and Gjelsvik argue that the disease definition might refer to normativity in nonneural domains. They profess that a cognitive dysfunction (e.g., impaired response inhibition), or a mismatch of evolutionary intentions, could also qualify as norm violations, thus legitimizing the disease label. The need for dividing lines is questioned as well. I rebut these criticisms in turn, but I must admit they are thought provoking.