Hjalte Holm Andersen

Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016

The last 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs may reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems.Summary Background Monitoring levels and trends in premature mortality is crucial to understanding how societies can address prominent sources of early death. The Global Burden of Disease 2016 Study (GBD 2016) provides a comprehensive assessment of cause-specific mortality for 264 causes in 195 locations from 1980 to 2016. This assessment includes evaluation of the expected epidemiological transition with changes in development and where local patterns deviate from these trends. Methods We estimated cause-specific deaths and years of life lost (YLLs) by age, sex, geography, and year. YLLs were calculated from the sum of each death multiplied by the standard life expectancy at each age. We used the GBD cause of death database composed of: vital registration (VR) data corrected for under-registration and garbage coding; national and subnational verbal autopsy (VA) studies corrected for garbage coding; and other sources including surveys and surveillance systems for specific causes such as maternal mortality. To facilitate assessment of quality, we reported on the fraction of deaths assigned to GBD Level 1 or Level 2 causes that cannot be underlying causes of death (major garbage codes) by location and year. Based on completeness, garbage coding, cause list detail, and time periods covered, we provided an overall data quality rating for each location with scores ranging from 0 stars (worst) to 5 stars (best). We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to generate estimates for each location, year, age, and sex. We assessed observed and expected levels and trends of cause-specific deaths in relation to the Socio-demographic Index (SDI), a summary indicator derived from measures of average income per capita, educational attainment, and total fertility, with locations grouped into quintiles by SDI. Relative to GBD 2015, we expanded the GBD cause hierarchy by 18 causes of death for GBD 2016. Findings The quality of available data varied by location. Data quality in 25 countries rated in the highest category (5 stars), while 48, 30, 21, and 44 countries were rated at each of the succeeding data quality levels. Vital registration or verbal autopsy data were not available in 27 countries, resulting in the assignment of a zero value for data quality. Deaths from non-communicable diseases (NCDs) represented 72·3% (95% uncertainty interval [UI] 71·2–73·2) of deaths in 2016 with 19·3% (18·5–20·4) of deaths in that year occurring from communicable, maternal, neonatal, and nutritional (CMNN) diseases and a further 8·43% (8·00–8·67) from injuries. Although age-standardised rates of death from NCDs decreased globally between 2006 and 2016, total numbers of these deaths increased; both numbers and age-standardised rates of death from CMNN causes decreased in the decade 2006–16—age-standardised rates of deaths from injuries decreased but total numbers varied little. In 2016, the three leading global causes of death in children under-5 were lower respiratory infections, neonatal preterm birth complications, and neonatal encephalopathy due to birth asphyxia and trauma, combined resulting in 1·80 million deaths (95% UI 1·59 million to 1·89 million). Between 1990 and 2016, a profound shift toward deaths at older ages occurred with a 178% (95% UI 176–181) increase in deaths in ages 90–94 years and a 210% (208–212) increase in deaths older than age 95 years. The ten leading causes by rates of age-standardised YLL significantly decreased from 2006 to 2016 (median annualised rate of change was a decrease of 2·89%); the median annualised rate of change for all other causes was lower (a decrease of 1·59%) during the same interval. Globally, the five leading causes of total YLLs in 2016 were cardiovascular diseases; diarrhoea, lower respiratory infections, and other common infectious diseases; neoplasms; neonatal disorders; and HIV/AIDS and tuberculosis. At a finer level of disaggregation within cause groupings, the ten leading causes of total YLLs in 2016 were ischaemic heart disease, cerebrovascular disease, lower respiratory infections, diarrhoeal diseases, road injuries, malaria, neonatal preterm birth complications, HIV/AIDS, chronic obstructive pulmonary disease, and neonatal encephalopathy due to birth asphyxia and trauma. Ischaemic heart disease was the leading cause of total YLLs in 113 countries for men and 97 countries for women. Comparisons of observed levels of YLLs by countries, relative to the level of YLLs expected on the basis of SDI alone, highlighted distinct regional patterns including the greater than expected level of YLLs from malaria and from HIV/AIDS across sub-Saharan Africa; diabetes mellitus, especially in Oceania; interpersonal violence, notably within Latin America and the Caribbean; and cardiomyopathy and myocarditis, particularly in eastern and central Europe. The level of YLLs from ischaemic heart disease was less than expected in 117 of 195 locations. Other leading causes of YLLs for which YLLs were notably lower than expected included neonatal preterm birth complications in many locations in both south Asia and southeast Asia, and cerebrovascular disease in western Europe. Interpretation The past 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs might reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems. Funding Bill & Melinda Gates Foundation.

Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration

Abstract Neurodegenerative disorders are characterized by the presence of inflammation in areas with neuronal cell death and a regional increase in iron that exceeds what occurs during normal aging. The inflammatory process accompanying the neuronal degeneration involves glial cells of the central nervous system (CNS) and monocytes of the circulation that migrate into the CNS while transforming into phagocytic macrophages. This review outlines the possible mechanisms responsible for deposition of iron in neurodegenerative disorders with a main emphasis on how iron-containing monocytes may migrate into the CNS, transform into macrophages, and die out subsequently to their phagocytosis of damaged and dying neuronal cells. The dying macrophages may in turn release their iron, which enters the pool of labile iron to catalytically promote formation of free-radical-mediated stress and oxidative damage to adjacent cells, including neurons. Healthy neurons may also chronically acquire iron from the extracellular space as another principle mechanism for oxidative stress-mediated damage. Pharmacological handling of monocyte migration into the CNS combined with chelators that neutralize the effects of extracellular iron occurring due to the release from dying macrophages as well as intraneuronal chelation may denote good possibilities for reducing the deleterious consequences of iron deposition in the CNS.

Human surrogate models of histaminergic and non-histaminergic itch.

Within the last decade understanding of the mechanistic basis of itch has improved significantly, resulting in the development of several human surrogate models of itch and related dysesthetic states. Well-characterized somatosensory models are useful in basic studies in healthy volunteers, in clinical studies for diagnostic and segmentation purposes, and in pharmacological studies to evaluate the antipruritic efficacy of existing and novel compounds. This review outlines recently introduced histamine-independent human models of itch, their mechanisms, their ability to induce clinically relevant phenomena, such as alloknesis, and the results obtained through their use. The article also introduces recent advances in the understanding of itch and provides an overview of the methods to assess experimentally-induced itch and associated manifestations. Major improvements are warranted in the treatment of chronic pruritus, and reliable human surrogate models are a valuable tool in achieving them, both for basic researchers and for clinicians.

Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers

Activation of TRPM8 and TRPA1 receptors generates cold and cold pain sensations, respectively, and is presumably important in clinical pain manifestations, such as cold hyperalgesia. This study investigated the interaction between TRPM8 and TRPA1 receptors through stimulation of glabrous human skin (volar forearm) by topical administration of 40% L‐menthol and 10% trans‐cinnamaldehyde (CA), individually and in combination.

MicroRNA Expression Signatures Determine Prognosis and Survival in Glioblastoma Multiforme—a Systematic Overview

Despite advances in our knowledge about glioblastoma multiforme (GBM) pathology, clinical challenges still lie ahead with respect to treatment in GBM due to high prevalence, poor prognosis, and frequent tumor relapse. The implication of microRNAs (miRNAs) in GBM is a rapidly expanding field of research with the aim to develop more targeted molecular therapies. This review aims to present a comprehensive overview of all the available literature, evaluating miRNA signatures as a function of prognosis and survival in GBM. The results are presented with a focus on studies derived from clinical data in databases and independent tissue cohorts where smaller samples sizes were investigated. Here, miRNA associated to longer survival (protective) and miRNA with shorter survival (risk-associated) have been identified and their signatures based on different prognostic attributes are described. Finally, miRNAs associated with disease progression or survival in several studies are identified and functionally described. These miRNAs may be valuable for future determination of patient prognosis and could possibly serve as targets for miRNA-based therapies, which hold a great potential in the treatment of this severe malignant disease.

A review of topical high‐concentration L‐menthol as a translational model of cold allodynia and hyperalgesia

Cold allodynia and cold hyperalgesia are both elusive features of neuropathic pain, particularly in patients with various polyneuropathies. Numerous studies have suggested that topical application of L‐menthol causes temporary cold hypersensitivity and thus acts as a proxy for associated symptoms. This review summarizes studies on L‐menthol‐induced nociception, cold allodynia and cold hyperalgesia in vitro, in animals and in humans.

A human surrogate model of itch utilizing the TRPA1 agonist trans-cinnamaldehyde

The thermoreceptive transient receptor potential ankyrin 1 (TRPA1) is important in the transmission of itch, and its agonist trans-cinnamaldehyde has occasionally been reported to be a pruritogen in humans. However, no studies have accurately quantified the capabilities of trans-cinnamaldehyde to induce itch and related dysesthetic sensations. The present study examined alterations in somatosensory and vasomotor parameters in response to topical trans-cinnamaldehyde 5% and vehicle (ethanol) in 24 healthy subjects. During the study the following parameters were recorded: itch area and intensity, hyperknesis, alloknesis, neurogenic flare, skin blood flow and temperature. Trans-cinnamaldehyde evoked moderate itch sensation, flare, hyperknesis and alloknesis (p < 0.001). Blood flow and skin temperature were elevated in the area of trans-cinnamaldehyde application (p < 0.001). Significant positive correlations were found between blood flow and skin temperature, itch area and blood flow, and itch area and skin temperature. Topical trans-cinnamaldehyde proved feasible as a human itch model with applicability in studying itch mechanisms or anti-pruritic drug profiling.

Non-histaminergic and mechanical itch sensitization in atopic dermatitis

Abstract Chronic or episodic severe itch is recurrent in atopic dermatitis (AD). Nonhistaminergic itch pathways are suggested to dominate in AD itch, contributing to an “itch-scratch-itch cycle” that prolongs and worsens itch, pain, and skin lesions. We hypothesized that nonhistaminergic neuronal sensitization contributes to itch in AD. Hence, we compared sensitivity with thermal, mechanical, and chemical pruritic stimuli in patients with AD and controls. The study comprised 25 patients with AD with chronic itch and 25 healthy controls. Questionnaires on itch characteristics were administered, and sensory tests were conducted intralesionally, extralesionally, and in homologous areas of controls. Thermal and mechanical quantitative sensory testing (QST) as well as histamine and cowhage provocations were performed. Subsequently, hyperknesis and vasomotor reactivity were assessed. Average itch and associated pain among patients with AD were 60.7 ± 4.3 and 39.7 ± 5.2 (VAS0-100), respectively. Patients experienced significantly higher itch from cowhage both intralesionally and extralesionally compared with controls, whereas histamine-evoked itch intensity was not significantly different between groups. No group differences were found for thermal quantitative sensory testings or pain evoked by itch provocations. Patients had decreased mechanical detection thresholds intralesionally and increased mechanical pain sensitivity intralesionally and extralesionally. Lastly, patients exhibited intralesional and extralesional hyperknesis before chemical itch provocations and augmented hyperknesis after itch provocations. Increased itch in response to cowhage (but not histamine) suggests nonhistaminergic pathway-specific itch sensitization in AD, whereas increased susceptibility to mechanically evoked itch and pain, particularly intralesionally suggests sensitization of mechanosensitive circuitry not normally associated with itch. Drugs targeting the nonhistaminergic (PAR2/TRPA1+) itch pathway and itch sensitization are promising for treating AD itch.

Considerable Variability in the Efficacy of 8% Capsaicin Topical Patches in the Treatment of Chronic Pruritus in 3 Patients with Notalgia Paresthetica

Notalgia paresthetica (NP) is a focal neuropathic itch condition manifesting in intense chronic or recurrent episodic itch in a hyperpigmented, macular, uni- or bilateral skin area located below and/or medially to the scapulae. Achieving satisfactory relieve in NP patients is challenging. In this case-series three female NP patients were treated with 8% capsaicin patches following a spatial quantification of their alloknetic area with a von Frey filament. The use of a von Frey filament in order to delimit the precise area of itch sensitization and thus patch application, proved clinically feasible. Although 8% topical capsaicin relieved itch in all three patients, the duration of the effectiveness varied greatly from only 3 days to >2 months. The treatment was well tolerated in the patients and there appear to be no significant hindrances to applying this treatment with NP as an indication, although it may only exhibit satisfactory effectiveness in certain patients. Placebo-controlled double-blinded trials are needed to confirm the effectiveness of the treatment and assess predictive parameters of the treatment outcome.

Preclinical and human surrogate models of itch

Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine‐resistant itch, are limited. Relevant preclinical and human surrogate models of non‐histaminergic itch are needed to accelerate the development of novel antipruritics and diagnostic tools. Advances in basic itch research have facilitated the development of diverse models of itch and associated dysaesthesiae. While experimental itch in humans is induced over a short period of time and usually assessed psychophysically, the study of itch reactions in animals allows for both short‐term and long‐term studies but relies heavily on behavioural assessments. This review provides a background and a presentation of the established models of itch currently applied in animals and humans with emphasis on translatability.