Age‐related macular degeneration (AMD) is a degenerative disease of the macula, often leading to progressive vision loss. The rate of disease progression can vary among individuals and has been associated with multiple risk factors. In this review, we provide an overview of the current literature investigating phenotypic, demographic, environmental, genetic, and molecular risk factors, and propose the most consistently identified risk factors for disease progression in AMD based on these studies. Finally, we describe the potential use of these risk factors for personalised healthcare.CFH, rs116503776 in C2/CFB/SKIV2L, rs3750846 in ARMS2/HTRA1 and rs2230199 in C3. However, it seems likely that other AMD variants also contribute to disease progression but to a lesser extent. Rare variants have probably a large effect on disease progression in highly affected families. Furthermore, current prediction models do not include molecular risk factors, while these factors can be measured accurately in the blood. Possible promising molecular risk factors are High‐Density Lipoprotein Cholesterol (HDL‐C), Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), zeaxanthin and lutein.While phenotypic risk factors such as drusen and pigment abnormalities become more important to predict disease progression during the course of the disease, demographic, environmental, genetic and molecular risk factors are more valuable at earlier disease stages. Demographic and environmental risk factors such as age and smoking are consistently reported to be related to disease progression, while other factors such as sex, body mass index (BMI) and education are less often associated. Of all known AMD variants, variants that are most consistently reported with disease progression are rs10922109 and rs570618 in Phenotypic, demographic, environmental, genetic and molecular risk factors can be combined in prediction models to predict disease progression, but the selection of the proper risk factors for personalised risk prediction will differ among individuals and is dependent on their current disease stage. Future prediction models should include a wider set of genetic variants to determine the genetic risk more accurately, and rare variants should be taken into account in highly affected families. In addition, adding molecular factors in prediction models may lead to preventive strategies and personalised advice. Age‐related macular degeneration (AMD) is a degenerative disease of the macula, often leading to progressive vision loss. AMD is the most prevalent retinal disease in the Western world with approximately 1–3% of the total population suffering from an advanced stage of the disease.The aim of this review is to provide an overview of the current literature investigating phenotypic, demographic, environmental, genetic, and molecular risk factors for disease progression in age‐related macular degeneration. In addition, we describe the most promising risk factors that could improve current prediction models for personalised healthcare.A comprehensive review of literature was performed through a PubMed search in July 2019. We used the following keywords and their synonyms in various combinations: age‐related macular degeneration, prospective cohort study, follow‐up, progression, risk factors and prediction. When a specific risk factor was identified, the specific risk factor was also used as a keyword in a second PubMed search to identify additional publications with prospective data on the specific risk factor. Articles cited in the reference list of articles obtained through this search were also reviewed whenever relevant. After article selection, all specific risk factors were grouped based on their corresponding risk category and results were discussed accordingly. A complete overview of the studies and references is provided in Tables Disease progression in AMD has been defined using various approaches. Although deteriorating vision seems a logical outcome measure for defining AMD progression in natural history studies or clinical trials, it is often unrealistic to use visual acuity as an endpoint since vision loss may take years to develop. For this reason, studies on AMD have used anatomical endpoints to measure disease progression over a relatively short time span.GA, also referred to as dry AMD, is characterised by the loss of photoreceptors, retinal pigment epithelium (RPE) and choriocapillaris, causing a gradual loss of vision over time.When GA has already developed, the growth rate of GA may be used as a quantifiable measure for disease progression.CNV, also referred to as wet AMD or neovascular AMD (nAMD) is characterised by the formation of new fragile vessels that originate from the choriocapillaris. These new vessels grow into the retina with subsequent leakage and/or hemorrhage, which can result in serous RPE detachment accompanied by a rapid loss of vision and eventually provoking a vision‐threatening scar in the macula.Central GA and nAMD are strongly associated with the loss of vision, but both advanced stages can take years to develop. Therefore, conversion to GA or nAMD is not always the best outcome measure for disease progression in natural history studies or clinical trials. In addition, advanced stage AMD may be too late in the disease process to demonstrate the effectiveness of newly developed treatments, which may be more effective when administered earlier in the disease process.Drusen are deposits of extracellular debris between the retinal pigment epithelium (RPE) and Bruch's membrane (BM). Drusen may be a manifestation of the normal ageing process or can represent an early sign of AMD, depending on the number, size, shape, distribution, and morphology of the drusen.Figure Small drusen are classified as discrete yellow‐white deposits (≤63 µm in diameter) with clear defined margins and are located between the RPE and BM Figure .14 IndivFigureMedium drusen (>63 µm and ≤125 µm in diameter) and large drusen (>125 µm in diameter) are large focal yellow‐white deposits with unclearly defined margins and are located between the BM and RPE, most often in the central macula  are dot‐like subretinal deposits between the RPE and photoreceptor layer which most frequently first appear in the upper part of the retina and then extend towards the macula over time, forming interlacing networks.FigureCFH gene.Cuticular drusen are multiple small drusen that may cluster between the BM and RPE layer, often first visible in the peripheral retina and later in the macula.FigurePigmentary changes in the macula are a feature of early AMD. Pigmentary changes appear on CFP either as hypopigmentation, which is seen as depigmented areas of the RPE not meeting criteria for GA, or as hyperpigmentation, which are deposits of pigment from the RPE within the retina Figure. The invFigureHyperreflective foci (HRF) on OCT are lesions of equal or higher reflectivity than the RPE band, located in the neuroretina, often above drusen, and are associated with the hyperpigmentation on CFP Figure.48 StudiFigurePigment epithelial detachment (PED) is characterised by the separation of the RPE from the BM. PEDs can be classified into fibrovascular, serous and drusenoid types. Fibrovascular PEDs and serous PEDs are both associated with nAMD and are caused by the accumulation of fluid between the BM and RPE. On OCT, fibrovascular PEDs are RPE detachments which have a flattened or notched border and are frequently associated with a hidden CNV . Serous PEDs appear as a large dome‐shaped detachment of the RPE and are thought to develop by an increased hydrostatic pressure from an underlying CNV.−1, independent of the lesion size.Several studies have attempted to identify features of the GA lesions that are predictive for faster GA enlargement. Natural history studies show that the GA enlargement is dependent on the baseline GA area, showing an exponential increase in GA area over time. −1 or 0.9–1.97 mm2 year−1) as compared to eyes with unifocal lesions (0.19–0.26 mm year−1 or 0.3–1.05 mm2 year−1).−1 or 2.05 mm2 year−1) when compared to foveal lesions (0.22–0.27 mm year−1 or 1.28 mm2 year−1).Multiple studies have reported increased rates of GA growth in eyes with multifocal lesions (0.32–0.42 mm year−1) when compared to GA lesions with an irregular shape .The shape of the GA lesion is also an indicator of disease progression. One study showed that the Geographic Atrophy Circularity Index (GACI), a measurement of the circularity of the GA lesion based on the GA area and its perimeter, is associated with the progression rate of GA. GA lesions with a circular shape (GACI > 0.75) have a slower growth rate  and focal FAF patterns (0.53–0.81 mm2 year−1), while progression rates of GA are higher in eyes with banded (1.69–1.81 mm2 year−1) and diffuse FAF patterns (1.74–1.77 mm2 year−1). These results have been replicated in multiple studies.The perilesional FAF pattern surrounding the GA lesions has been shown to correlate with the growth rates of GA. These FAF patterns can be subdivided into multiple categories, based on the position of the hyperfluorescence. Figure. ProgresSeveral studies found evidence for the importance of the choroid in the pathogenesis of AMD established that the choroid vascular structures deplete in eyes with early AMD, GA and nAMD.OCT angiography (OCTA) can detect blood flow by analysing changes in tissue reflectivity between rapidly acquired images, visualising the blood flow of the retina and the choroidal vasculature. Although OCTA is still developing as an imaging modality, it has already demonstrated some potential features for predicting GA growth. Flow impairment in the choriocapillaris surrounding the atrophic lesions was associated with the increased GA growth rate over 1.3 years of follow‐up in one study.FigureUsing ICGA or OCTA, it is also possible to visualise a CNV in nAMD before exudation occurs Figure. When thFigure a).Incomplete RPE and outer retinal atrophy (iRORA) is a feature preceding the development of complete RPE and outer retina atrophy (cRORA).Figure b). They develop in response to injury as Müller cells move between the functional and dead photoreceptors. ORTs can both be found in areas of fibrosis after the development of exudative nAMD, or at the border of GA. In nAMD, eyes with ORTs often have a larger decline in visual acuity over time than those without ORTs.Outer retinal tubulations (ORTs) can be identified on OCT as circular hyperreflective band structures in the outer nuclear layer Figure b. They There are many modifiable and non‐modifiable risk factors that have been linked to increased risk of the progression of AMD. As the name already suggests, age is the most important demographic risk factor for AMD.While AMD is common in males and females, some studies suggest that female sex is associated with a higher progression rate to early AMD OR 2.2),.2,2, 102Another hypothesis for sex‐associated differences in AMD progression may be caused by the number of X‐linked genes which may affect cellular functions in the onset and progression of AMD.−1 in smokers compared to 0.27 mm year−1 in non‐smokers).Smoking is the most consistently reported modifiable risk factor for AMD and is associated with a 2–4 fold increased risk for any form of AMD,Having a higher body mass index (BMI) is found to be associated with increased probabilities of developing AMD in half of the studies,Studies have shown that pro‐inflammatory factors, such as complement components and cytokines are elevated in obese individuals. These proinflammatory factors regulate inflammation and could disturb the functions of the RPE, which contributes to the development of AMD. In addition, adipose tissue is a storage site of protective carotenoids (see section on carotenoids) and as the bodyweight increases, more carotenoids would be absorbed into adipocytes and as a consequence less of these carotenoids would be available in the macula.Diet is found to have a potential role in preventing and/or delaying the progression of AMD. High adherence to the Mediterranean diet reduces the risk of developing late AMD, which has been confirmed in two prospective cohorts,In addition, other prospective studies investigating nutrition have found that the consumption of a high‐glycemic‐index diet (diet with carbohydrates that have a large and fast effect on blood glucose levels) is a risk factor for the development and progression of AMD.Furthermore, individual components of the diet, such as the number of specific vegetables and fruits are also thought to be protective for disease progression since they are rich in antioxidants, including vitamins and carotenoids (see section on anti‐oxidative factors). Yet, individual diet components are not often found to be associated with disease progression in prospective studies.Regular exercise is thought to increase antioxidant enzyme activity and therefore physical activity may influence the progression of AMD. A few studies support the positive impact of physical activity on the progression of AMD, and physical activity is associated with lower odds of both early and late AMD.Education levels seem to be inversely related with the development of AMD in some longitudinal population studies, in which having an education level of high school or higher is associated with a lower risk for early AMD OR 0.86)86, 91, 9Sunlight exposure is thought to result in more oxidative stress in the retina, causing the development of AMD. However, the quantification of the total amount of sunlight exposure is difficult to determine and therefore not often found to be associated with disease progression.Multi‐ethnic studies show difference prevalence rates of any form of AMD between ethnic groups .Several large epidemiological studies have found an increased association between the development of cataract, cataract surgery and late AMD (both GA and nAMD),The possible involvement of hypertension in AMD has been well covered in literature,−1 1.73 m−2, OR 1.3).CFH gene, requires additional investigation.The association between chronic kidney disease has been reported in some studies, but evidence have been conflicting.−1, HR 1.04)Longitudinal population studies show that thyroid disease causing hyperthyroidism has been implicated as a risk factor for developing late AMDDiabetes is a major concern in ophthalmic care. Whether it also contributes to the development of AMD remains unclear. Several studies present positive correlations between diabetes and the development of AMD,APOE) gene. Interestingly, while the APOE Ԑ2 and Ԑ4 isoforms, encoded by two APOE alleles, are associated with a decreased and increased risk for AD respectively, opposite directions are reported for AMD (see section on lipid metabolism genes).Studies have found several clinical and pathologic similarities between AD and AMD. First of all, ageing is a major risk factor for both multifactorial degenerative disorders.Parkinson’s disease is a progressive neurodegenerative disorder that results in the loss of dopaminergic neurons in the substantia nigra and causes motor abnormalities including bradykinesia, resting tremor and imbalance. A recent epidemiologic study showed that patients with PD treated with levodopa less often developed AMD (OR 0.78) and at a later age (mean age of onset 79 years) compared to untreated patients (mean age of onset 71 years).TableGenetic factors are known to play an important role in the development of AMD and genetic studies have contributed significantly to our knowledge on AMD pathology. To date, more than half of the genomic heritability can be explained by both common and rare genetic variants in 34 genetic loci, which are mostly involved in the complement system, extracellular matrix remodeling, and lipid metabolism.CFH) gene which had a strong effect on the risk of AMD. This variant is in perfect LD (R2 = 1.0) with the rs570618 variant in the original discovery GWAS of 2016. Multiple prospective studies have confirmed that the minor allele of this variant is a risk allele for the incidence of early AMD (HR 1.2–2.3),CFH gene is the rs10922109 variant, of which the minor allele is confirmed to be a protective allele for the progression to late stage AMD (HR 0.43).CFH gene have not yet been confirmed to be also associated with a more rapid GA enlargement in two prospective studies.In 2005, several research groups identified a common variant rs1061170) in the complement factor H CFI is a risk allele for AMD, but has only been confirmed to be associated with disease progression to GA (HR 1.19)C3 is a risk allele for AMD and confirmed to be a risk factor for the incidence of early AMD (HR 1.22),C3 was a protective factor for GA growth , which was later confirmed in another cohort.Variants in other complement loci, including Age‐related maculopathy susceptibility 2 and high‐temperature requirement A serine peptidase 1 (ARMS2/HTRA1) genes has also a strong effect on the risk of AMD and was also identified in the first genetic AMD studies. This common variant is in perfect LD (R2 = 1.0) with the rs3750846 variant in the original discovery GWAS of 2016. Several prospective studies have confirmed that the minor allele of this variant is a risk factor for the incidence of early AMD (OR 1.36), −1, respectively).ARMS2 gene may encode a protein which has a function in the mitochondrial outer membrane of the retina, while other reports suggest that it encodes an extracellular protein.HTRA1 gene encodes a heat shock serine protease and regulates TGF‐β signalling, which is involved in regulating extracellular matrix deposition and angiogenesis.ARMS2/HTRA1 genes and how either or both genes are related to the pathophysiology of AMD is still not fully understood.The common rs10490924 variant near the ABCA1 and minor allele of the rs5817082 variant in CETP are both confirmed to be protective alleles for the incidence of early AMD . LIPC gene, the minor allele of the rs2043085 variant, is a protective allele for the progression towards late AMD (HR 0.83).Genes encoding proteins of the lipid metabolism are also involved in the pathogenesis of AMD, and are probably involved in the formation of drusen.APOE gene, which is known to be polymorphic. Variants in the APOE gene at amino acid positions 112 (rs429358) and 158 (rs7412) determine three major isoforms: the Ԑ2 isoform , the most common Ԑ3 isoform  and the Ԑ4 isoform .Another gene involved in lipid metabolism is the APOE Ԑ4 isoform is associated with an increased risk of Alzheimer’s disease and the APOE Ԑ2 isoform is associated with a decreased risk of Alzheimer’s disease. Interestingly these two isoforms have an opposite effect in AMD: the APOE Ԑ4 isoform is associated with a decreased risk of AMD, and there is a trend for the APOE Ԑ2 isoform to be associated with an increased risk of developing AMD. APOE isoforms and other AMD‐associated variants in the APOE gene have not yet been investigated with AMD disease progression in prospective cohort studies.Studies show that the RAD541B and rs72802342 in CTRB2/CTRB1.MMP9 was associated with progression to nAMD (HR 0.66) but not with GA.TNR and the rs28368872 variant near ATF7IP2 are associated with disease progression to nAMD but not GA.Other variants that were identified in the original discovery GWAS of 2016, and confirmed to be associated with disease progression in AMD include rs61985136 in C3, C9, CFH, and CFI.Several studies support a role for rare variants in the pathogenesis of AMD.Angiogenic factors, including vascular endothelial growth factor (VEGF), pigment epithelium derived factor (PEDF) and transforming growth factor beta (TGF‐β) have been extensively investigated in case‐control studies.Increased oxidative stress is thought to be one of the underlying factors in the occurrence of AMD.Oxidative stress reflects an imbalance between the manifestation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage components of cells, and the biological ability to detoxify these reactive intermediates to maintain oxidant homeostasis.Malondialdehyde (MDA) is a reactive carbonyl compound that originates from the oxidation of PUFAs. Case‐control studies have consistently observed increased systemic levels of MDA in AMD patients compared to controls.Another product of oxidative stress is the oxidation of low‐density lipoproteins (LDL) forming oxidized LDL (ox‐LDL). LDL are lipoproteins (see section Lipoproteins) that are an easy target for oxidation by free radicals. While some cross‐sectional studies show increased levels of systemic ox‐LDL in AMD patients,Several case‐control studies show a relation between AMD and toxic trace elements, such as cadmium, lead, and mercury.Antioxidants, including vitamins, carotenoids and essential trace elements such as zinc, both enhance the clearance and prevent the formation of ROS and RNS, reducing the damage in retinal cells caused by oxidative stress.Vitamin C protects against oxidative stress‐induced cellular damage by scavenging ROS and mediating reactivation of vitamin E. The idea that vitamin C may be protective was primarily based on a series of animal studies, which showed an association between vitamin C and a reduction of light‐induced damage in rat retinas.Vitamin E is a lipophilic antioxidant in the plasma membrane of RPE cells and photoreceptors, and prevents lipid peroxidation. Prospective cohorts investigating the relationship between dietary intake of vitamin E and the risk of AMD are inconsistent. Two longitudinal population studies show a reduced risk of developing AMD when consuming a higher dietary intake of vitamin E,Vitamin A is a cofactor in photoreceptors to form rhodopsin, which is a protein involved in the visual phototransduction. Dietary intake of vitamin A has not been associated with the onset of AMD in four longitudinal population studies.B vitamins, such as vitamin B9 (folate) and B12  are essential cofactors to convert homocysteine into methionine. Homocysteine is an amino acid that is susceptible to oxidation and thought to induce vascular endothelial dysfunction in nAMD.Vitamin D can be produced in the dermis upon sunlight exposure or obtained through diet. There has been only one longitudinal population study regarding the role of vitamin D in AMD. This study found a decreased risk of developing nAMD when consuming a diet rich in vitamin D.Carotenoids are organic pigments that are synthesised in plants and can be subdivided into carotenes and xanthophylls. Because humans are unable to synthesise carotenoids, they must be obtained through dietary consumption. The proposed protective mechanism of carotenoids for AMD is their ability to have an antioxidative effect through the absorptions of free electrons from ROS. Six carotenoids are commonly found in the human diet: α‐carotene, β‐carotene, β‐cryptoxanthin, lycopene, lutein and zeaxanthin.α‐carotene and β‐carotene are both vitamin A precursors and have antioxidative properties. Both carotenes can be found in dark leafy vegetables such as spinach and kale, and yellow/orange vegetables such as carrots and bell peppers.β‐carotene was added in the first supplement formula of the Age‐Related Eye Disease Study 1 (AREDS1) study  to investigate its properties to alter disease progression to central GA or neovascular AMD.After five years follow‐up, 20% of patients with supplementation progressed to late stage AMD, while 28% of the patients with placebo progressed to late stage AMD. This risk reduction was only found in patients with at least intermediate stage AMD.Other clinical trials with high‐dose β‐carotene supplementation reported an increased risk of lung cancer in smokers, which raised concerns regarding the prescription of the supplements according to the formula of the AREDS1 study in AMD patients, since a large proportion of the AMD population are smokers.Longitudinal population studies reported conflicting results between dietary α‐carotene and β‐carotene levels and AMD onset and disease progression. Higher levels of α‐carotene and β‐carotene were associated with decreased risk of early and late AMD in some studies,β‐cryptoxanthin is also a vitamin A precursor, closely related to β‐carotene and commonly found in the rinds of oranges, but also inside papaya and apples. Only one longitudinal population study found a protective effect of adhering to a β‐cryptoxanthin diet for developing late AMD,Lycopene is a red carotenoid found in tomatoes and bell peppers and has an antioxidative effect but no vitamin A activity. While some case‐control studies show lycopene levels are lower in patients with AMD compared to controls,Lutein and zeaxanthin are two carotenoids that are found in the macular pigment located in the ganglion cells, cone axons and Müller cells of the macula. Both carotenoids have antioxidative properties and a protective effect by absorbing hazardous blue and ultraviolet light before it can reach the photoreceptors.The main aim of the AREDS2 study was to improve the supplement formula of the AREDS1 study by exploring the additional effect of lutein, zeaxanthin, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to the formula, and to evaluate the effect of eliminating β‐carotene and lowering zinc doses.There was no difference in progression to late AMD in patients who used the AREDS supplements with lutein and zeaxanthin, compared with patients who only used the AREDS supplements. A subgroup analysis, however, did reveal a significant reduction in progression to late stage AMD in patients using the AREDS supplements with lutein and zeaxanthin and no β‐carotene, compared with patients using the AREDS supplements with β‐carotene (HR 0.82).Several studies have shown a link between supplementation of lutein and zeaxanthin and higher systemic levels.Longitudinal population studies are also not conclusive whether dietary lutein and zeaxanthin levels decrease disease progression. Half of these studies confirmed the protective effect of consuming higher dietary levels of lutein and zeaxanthin for the incidence of early AMD and progression to late AMD.Zinc is an essential trace element and plays a key role in many cellular processes such as DNA synthesis, RNA transcription, cell division, and prevention of cell apoptosis. In addition, zinc is essential for the development and maintenance of the immune system, including complement activation.The AREDS1 trial showed that patients using zinc supplements (80 mg zinc oxide) have a lower progression rate to late AMD after six years when compared to controls (HR 0.71).Many longitudinal population studies show a protective effect of high dietary zinc intake for early and late AMD.The complement system is a key component of innate immunity. It protects the host from invading microorganisms  by providing inflammatory signals and eliminating pathogens and infected cells, but it also contributes to the homeostasis of the host by the clearance of apoptotic cells and cellular debris.As mentioned in the section on complement genes, AMD is associated with many variants in genes encoding components and regulators of the complement system. Although the complement system acts locally in AMD, its components can also be measured systemically. Many case‐control studies have found differences in expression levels of systemic complement regulators and components between AMD patients and controls.Cytokines are a broad category of small proteins that are important in cell signalling and can be subdivided into interleukins, tumor necrosis factor, chemokines, and interferons. There are currently only a few studies that have investigated the predictive value of systemic interleukin and tumor necrosis factor levels for disease progression in AMD, possibly because previous case‐control studies did not find differences in systemic chemokine and interferon levels between AMD patients and controls.Interleukins are a group of cytokines that are expressed by leukocytes and influence the function of the immune system. Interleukin 6 (IL‐6) is a cytokine produced by macrophages and T‐cells. Three prospective studies reported that systemic IL‐6 levels are positively correlated with the development of early AMD,Tumor necrosis factor–α (TNF‐α) is a cytokine involved in cell activation, differentiation, and apoptosis and its receptor, TNF‐αR2, is expressed on the choroidal vascular cells, RPE, and on Müller cells in the retina. One longitudinal population study found a positive relation between TNF‐αR2 levels and early AMD development.C‐reactive protein (CRP) is a protein of hepatic origin that increases following IL‐6 secretion. CRP activates the complement system through promoting phagocytosis by macrophages. Evidence of studies using CRP values to predict disease progression in AMD are inconclusive. Five prospective studies found no relation between systemic CRP levels and AMD progression.Intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) regulate inflammation by attracting white blood cells and controlling their migration into the blood vessel wall. Complement‐mediated activation of choroidal endothelial secretion of ICAM and VCAM has been hypothesised to play a role in the pathogenesis of AMD. Two longitudinal population studies showed no association between systemic ICAM levels and disease progression to early AMD and late AMD., genetic variants in complement genes are related to AMD, thus the immune system is linked to the pathogenesis of AMD. The increase of several immune components also causes cellular proliferation of immune cells increasing the white blood cell (WBC) count. A relatively large number of studies have investigated the WBC count and the progression of AMD but did not detect any association.As discussed in the section on complement genesBoth case‐control studies and prospective studies show associations between several lipid factors and AMD.−1 cholesterol, OR 0.94), while they are a risk factor for the development of GA  over five years follow‐up.Cholesterol is an organic molecule biosynthesised by cells or ingested with the diet, and is an essential structural component of cell membranes, involved in several cell signalling processes, and a precursor for the biosynthesis of steroid hormones, bile acid, and vitamin D. The vast majority of studies did not find any relationship between systemic cholesterol levels and progression to early AMD, GA or nAMD.Triglycerides are molecules consisting of glycerol bound to three fatty acids of variable length. Triglycerides are the main constituents of body fat and are also present in the blood to enable the transference of adipose fat and blood glucose. Most studies do not find a relation between systemic triglyceride levels and disease progression in AMD.Lipoproteins are biochemical proteins whose primary purpose is to transport hydrophobic lipids, such as cholesterol and triglycerides, through the circulation. Lipoproteins can be classified into five different lipoproteins, as based on their density and size: chylomicrons; very‐low‐density lipoprotein (VLDL); intermediate‐density lipoprotein (IDL); low‐density lipoprotein (LDL); and high‐density lipoprotein (HDL). Both LDL and HDL transport cholesterol between the liver and periphery and have been extensively studied for their association with the development of AMD and disease progression.LDL‐cholesterol (LDL‐C) is the main carrier of cholesterol in the circulation. Five large longitudinal population studies have investigated the association between systemic LDL‐C levels and disease progression in AMD over different lengths of follow‐up ranging from two to 18 years. Nonetheless, none of these studies found an association with the development of early and late AMD.Longitudinal population studies evaluating systemic HDL‐C levels in AMD show mixed results. The majority of the studies report that patients with increased levels of HDL‐C have an increased risk of developing early and late AMD,Apolipoproteins (apo) are structural proteins that bind triglycerides and cholesterol to form lipoproteins. During the development of AMD, it has been suggested that RPE cells secret Apo into the Bruch’s membrane, forming a lipid barrier that retards the transportation of oxygen, nutrition, and waste products, which stimulates drusen formation. There are two longitudinal studies investigating systemic apolipoproteins and the progression of AMD.Fatty acids consist of a carboxyl group with a hydrocarbon chain, which is either saturated or unsaturated. Fatty acids have different functions, including storage as triglycerides to be used as an energy substrate, the formation of cholesterol esters, and usage as structural components for cell membranes. Fatty acids are characterised by their number of carbon and double bonds. Saturated fatty acids (SFAs) have no double bond, monounsaturated fatty acids (MUFAs) have one double bond, and polyunsaturated fatty acids (PUFAs) have two or more double bonds. The latter can be subdivided into omega‐3 fatty acids and omega‐6 fatty acids, depending on the location of the first double bond. Studies suggest that metabolites derived from omega‐3, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are anti‐inflammatory and antiangiogenic, whereas those derived from omega‐6 are pro‐inflammatory and pro‐angiogenic.All longitudinal population studies which investigated dietary intake of SFAs, including palmitic acid and stearic acids, found no relation with the development of early AMD or progression to late stage AMD.There are currently no longitudinal prospective studies that investigated systemic plasma or serum SFA levels with AMD progression.Dietary intake of MUFAs, including oleic acids (OAs) and palmitoleic acids (PAs), have been extensively investigated for the development and progression of AMD. However, none of the longitudinal population studies found an association of dietary MUFA levels with the development of early AMD or progression to late stage AMD,Several dietary omega‐3 fatty acid levels have been investigated in AMD, including a‐linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega‐3 fatty acids are in high quantities found in fatty fish, which is a diet component that has been confirmed to reduce the risk of AMD development in multiple studies (see section Diet).Whether increased dietary intake or higher systemic levels of ALA are associated AMD progression is not clear. Three longitudinal population studies showed no association between a higher dietary intake of ALA and AMD progression,Several longitudinal studies have investigated dietary intake and systemic levels of EPA and DHA in AMD. Half of these studies found a decreased risk of developing early or late AMD in patients consuming higher amounts of EPA,The Age‐Related Eye Disease Study 2 (AREDS2), a double‐blind trial in AMD patients, found no decreased risk of AMD progression after five years follow‐up in patients using EPA and DHA supplementation in addition to the original supplement formulation of the AREDS1 study  when compared to patients using the original supplement formulation of the AREDS1 study only.Furthermore, the nutritional AMD Treatment 2 (NAT‐2) study, a double‐blind trial which investigated the effect of EPA and DHA supplementation in patients with early AMD in the study eye and neovascular AMD in the fellow eye, did also not find a decreased risk of nAMD development in the fellow‐eye after three years follow‐up.Two kinds of omega‐6 fatty acids have been studied for disease progression in AMD: linoleic acid (LA) and arachidonic acid (AA). The majority of longitudinal studies found no association between dietary intake or systemic levels of LA or AA and AMD development.CFH and rs860846 in ARMS2/HTRA1.For the development of personalised prediction models, accurate and easy quantification of risk factors is important. As discussed in the previous sections, numerous phenotypic, demographic, environmental, genetic and molecular risk factors have been described to be associated with disease progression in AMD. These risk factors can be combined in prediction models to predict disease progression, but the selection of the proper risk factors for personalised risk prediction will differ among individuals and may be dependent on their current disease stage. While phenotypic risk factors are more important to predict disease progression during the course of the disease, demographic, environmental, genetic and molecular risk factors may be more valuable at earlier disease stages. The prediction models developed to date include similar risk factors: phenotypic disease classification based on drusen and pigment abnormalities identified on CFP; demographic factors such as age and sex; environmental risk factors such as smoking and BMI; and a subset of AMD variants, including rs570618 in TableDespite a relatively high discriminative performance of the current prediction models for late stage AMD, they could be further improved by including other promising risk factors. Phenotypic risk factors in the current prediction models are all identified on CFP, while it is recommended to use a multimodal imaging approach to identify phenotypic risk factors.Secondly, the current prediction models only use a restricted set of genetic variants. For future development of prediction models and personalised prediction, using a wider set of AMD‐associated variants as discovered in the most recent GWASThirdly, current prediction models do not include molecular risk factors, while these factors can be measured quantitatively.The author(s) have no proprietary or commercial interest in any materials discussed in this article.Table S1. Overview of the association between phenotypic factors and the prediction to late AMD in prospective cohort studiesTable S2. Overview of the association between demographic and environmental factors and the prediction to early and late AMD in prospective cohort studiesTable S3. Overview of the top hits in the 34 AMD associated loci, as identified in the case‐control GWAS  from the International AMD Genomics Consortium, and their association with disease progression as described in the GWAS of the AREDS study , and several prospective cohort studiesTable S4. Overview of the association between anti‐oxidative factors and the prediction of early and late AMD in prospective cohort studiesTable S5. Overview of the association between immune factors and the prediction of early and late AMD in prospective cohort studiesTable S6. Overview of the association between lipid factors and the prediction of early and late AMD in prospective cohort studiesClick here for additional data file.


Primary intraosseous osteolytic meningiomas are not common, and total surgical removal is the best treatment option if the location allows that; however, long‐term follow‐up is recommended since it may recur. Primary intraosseous osteolytic meningiomas are not common, and total surgical removal is the best treatment option if the location allows that; however, long‐term follow‐up is recommended since it may recur. A 45‐year‐old obese woman presented with headache only for six months, and skull lesion was diagnosed. Total surgical removal was done, and the histopathology result revealed meningioma. Primary intraosseous meningiomas are usually benign, and their growth correlates with their histological grade and can show malignant changes more than its intracranial equivalent. Total surgical resection is the treatment of choice with safe margins. A long‐term follow‐up period is recommended even if total resection is carried out.Meningiomas are the most frequent intracranial benign neoplasia; they arise from arachnoid granulations and represent approximately from 14% to 20% of intracranial tumors.In this article, we present a case of intraosseous osteolytic meningioma and describe the steps of management.2A 45‐year‐old obese woman with history of diabetes mellitus and hypertension presented with headache for six months of duration. Neurological examination was normal, and there was no scalp mass or deformity. Computed tomography scan (CT scan) revealed hypodense (osteolytic) lesion occupying the right temporoparietal region with destruction of inner and outer table, differential diagnosis was suspected and includes fibrous dysplasia, aneurysmal bone cyst, and primary intraosseous meningioma. She underwent magnetic resonance imaging (MRI) that revealed hypointense in T1 and hyperintense in T2 with homogenous contrast enhancement lesion in the right temporoparietal region with mild compression of the right ventricle, which most likely represent a meningioma. Surgical resection was planned; a large question mark skin incision was made, after periosteal dissection and reflection of temporalis muscle; en bloc resection of tumor with safe margins was done; dura was intact; we control the feeders of the tumor, which were mainly from middle meningeal artery branches, wound closed in layers; and cranioplasty was postponed for another time to shorten the operation time due to patient medical condition (Figure 3This neoplasm has no gender predilection, and it has two peaks of incidence in the second decade and between the fifth and seventh decades with a median age of 40‐49 years,4Primary intraosseous meningiomas are usually benign, and their growth correlates with their histological grade and can show malignant changes more than its intracranial equivalent. Total surgical resection is the treatment of choice with safe margins. If there is doubt about complete resection, the lesion should be followed with appropriate imaging studies. A long‐term follow‐up period is recommended even if total resection is carried out.The authors declare no conflict of interest; the manuscript is not published elsewhere.AD and SH: conceived and designed the study. GL: involved in overall supervision of the paper. All authors: read and approved the final manuscript.


Female sex workers (FSWs) experience overlapping burdens of HIV, sexually transmitted infections and unintended pregnancy. Pre‐exposure prophylaxis (PrEP) is highly efficacious for HIV prevention. It represents a promising strategy to reduce HIV acquisition risks among FSWs specifically given complex social and structural factors that challenge consistent condom use. However, the potential impact on unintended pregnancy has garnered little attention. We discuss the potential concerns and opportunities for PrEP to positively or negatively impact the sexual and reproductive health and rights (SRHR) of FSWs.FSWs have high unmet need for effective contraception and unintended pregnancy is common in low‐ and middle‐income countries. Unintended pregnancy can have enduring health and social effects for FSWs, including consequences of unsafe abortion and financial impacts affecting subsequent risk‐taking. It is possible that PrEP could negatively impact condom and other contraceptive use among FSWs due to condom substitution, normalization, external pressures or PrEP provision by single‐focus services. There are limited empirical data available to assess the impact of PrEP on pregnancy rates in real‐life settings. However, pregnancy rates are relatively high in PrEP trials and modelling suggests a potential two‐fold increase in condomless sex among FSWs on PrEP, which, given low use of non‐barrier contraceptive methods, would increase rates of unintended pregnancy. Opportunities for integrating family planning with PrEP and HIV services may circumvent these concerns and support improved SRHR. Synergies between PrEP and family planning could promote uptake and maintenance for both interventions. Integrating family planning into FSW‐focused community‐based HIV services is likely to be the most effective model for improving access to non‐barrier contraception among FSWs. However, barriers to integration, such as provider skills and training and funding mechanisms, need to be addressed.As PrEP is scaled up among FSWs, there is growing impetus to consider integrating family planning services with PrEP delivery in order to better meet the diverse SRHR needs of FSWs and to prevent unintended consequences. Programme monitoring combined with research can close data gaps and mobilize adequate resources to deliver comprehensive SRHR services respectful of all women’s rights. Although the potential benefits and acceptability of PrEP among FSWs have been previously established Depending on approaches to scale‐up, there is the possibility that PrEP programming could increase rates of unintended pregnancy among FSWs. Risk compensation, normalization of PrEP use and external pressures for condomless sex could impact on condom use, while PrEP provision within single‐focus services that insufficiently cater to family planning needs could impact use of other contraceptive methods. Drawing from our experience in working with national PrEP implementation programmes, the purpose of this commentary is to elaborate on the context in which PrEP is being implemented with FSWs and the potential concerns and opportunities for PrEP to impact unintended pregnancy and other aspects of SRHR.22.12.1.1PrEP offers personal control over HIV, and is therefore a prevention option of particular benefit to FSWs because it can help counter pervasive social and structural factors that limit FSWs’ capacity to consistently use condoms to prevent HIV, including gender norms, criminalization, intersecting stigmas and sexual and physical violence 2.1.2Preventing pregnancy may be the greater motivator for FSWs to use condoms compared to HIV prevention 2.1.3The potential for individuals on PrEP to reduce their use of condoms due to negation of HIV risk is a commonly voiced concern 2.1.4Most concerns raised around the potential implications of condomless sex focus on STIs – perhaps given the predominance of PrEP studies involving MSM in the literature. Although less frequently considered, mistimed or unwanted pregnancies are a potential adverse outcome of PrEP use that may have enduring social and health consequences. Among FSWs, unintended pregnancy is commonplace and is often followed by unsafe abortion In addition to the immediate health risks of unintended pregnancy due to unsafe abortion and high maternal mortality in areas most affected by HIV 2.1.5Evidence of the impact of PrEP on pregnancy rates among all women is scant. The FEM‐PrEP randomized controlled trial (RCT) did not show a significant impact of PrEP compared to placebo on unintended pregnancy among women 2.1.6Choice of contraceptive is important, and in FEM‐PrEP, the pregnancy rate was much higher among those using oral contraceptive pills  compared to injectables (incidence rate 1.6 per 100 person years) or long‐acting or permanent methods (none reported) 2.2There are opportunities to meet the HIV prevention needs of many FSWs while minimizing additional unintended pregnancy risk through the integration of PrEP and family planning services. Such service integration would also enhance opportunities for STI prevention and treatment and could promote more efficacious approaches such as LARCs and multipurpose prevention technologies for combined HIV prevention and contraception.2.2.1PrEP and family planning services for FSWs are likely to be complementary. PrEP adherence and maintenance among FSWs with sustained high‐risk behaviours remains a major challenge, with studies consistently demonstrating low PrEP continuation among FSWs even at one month 2.2.2Current programmes providing PrEP to FSWs are predominantly implemented through FSW‐focused services, which include drop‐in centres and clinics led by community‐based organizations Alternative models for the integration of family planning and HIV services have focused on antenatal or family planning services Family planning entails not only provision of contraception, but also non‐judgemental and non‐coercive discussions around method options, fertility desires and safer conception counselling. Based on learnings from SRHR, regardless of integration model, providing multiple contraceptive options 2.2.3There are several barriers to realizing integrated PrEP and family planning services. Common reliance on donor‐driven funding schemes favour vertical, disease‐specific programming, thus limiting the availability of sufficient funding for adequate family planning and STI services within HIV programmes STI management is already commonly integrated in HIV programmes for FSW 2.2.4Combined delivery of PrEP and hormonal contraception could be a convenient and efficient means of simultaneously preventing HIV and unintended pregnancy. Multipurpose prevention technologies for modern contraception and HIV are in early development stages, including intravaginal ring and gel preparations. A dual‐purpose intravaginal ring delivering dapivirine and levonorgestrel has undergone Phase I trials through the MTN‐030/IPM‐041 study in the US and demonstrated high tolerance and safety 3Given the significant social and health impacts of unintended pregnancy for FSWs, there is impetus to consider family planning as an integral component of PrEP programming. Surprisingly, the potential for unintended pregnancy in the provision of PrEP use has garnered limited attention to date despite well‐documented concerns around condom migration and STI risk. Bi‐directional integration of PrEP and family planning could have a broad positive impact on FSWs across low‐ and middle‐income countries. In view of the complex social and structural influences on condom use, settings with low use of non‐barrier methods pose a major concern in terms of unintended pregnancy risk and should be prioritized for integrated delivery of PrEP and family planning. As PrEP is scaled up among FSWs, it remains important to measure the unintended consequences of PrEP as well as its benefits. Systematic collection and reporting of implementation data pertaining to PrEP, family planning and related outcomes will support the optimization of integration strategies to meet the multifaceted needs of FSWs. Furthermore, dedicated research is needed to test the hypotheses that integrating contraception with PrEP delivery improves PrEP continuation and decreases unintended pregnancy and to compare models of PrEP and family planning integration. These data can be used by researchers and programmatic implementers alike to mobilize adequate resources to deliver comprehensive SRH services respectful of all women’s SRH needs and reproductive rights.The authors have no competing interest to declare.MH proposed the initial concept. ALB took the lead role in writing the manuscript, reviewing the literature and developing the initial framework. FHA, SS, SL, MS, SB and MH provided valuable feedback into the content and structure of the manuscript. All authors provided intellectual input on the contents and perspective of the commentary.


Bladder cancer (BC) patients with advanced disease have poor outcomes. The use of patient‐reported outcomes (PROs) could lead to improvements in symptom management and hence quality of life (QoL). The aim of this study is to report correlations between selected PROs and QoL and thus to present symptoms that influence QoL. Identification of these symptoms during treatment can lead to earlier symptom management and thus secure improvements in QoL.BC patients in chemo‐ or immunotherapy for locally advanced or metastatic disease reported weekly PROs for the duration of their treatment. The PROs included EORTC QLQ‐C30 and QLQ‐BLM30 and 45 selected PRO‐CTCAE items. Spearman's correlation analysis was performed for all PRO‐CTCAE items and QLQ‐C30 global QoL and subdomains.rs = −0.603, P < .0001), concentration  and cognitive function , discouraged (F) and emotional function , fatigue (S) and role function  and sad (F) and emotional function . The weakest correlations were found for the PRO‐CTCAE items urinary frequency, incontinence and urge, all with variations in the direction and significance of the correlations.In this study, 78 BC patients reported 724 questionnaires. Spearman's analysis showed significant correlations between almost all PRO‐CTCAE items and the expected domain of QoL. The PRO‐CTCAE items with the strongest correlations with QoL were anxiety  and emotional function (This study delivers information on which PROs may influence QoL for patients in clinical trials or daily clinic. Psychological issues have a strong impact on QoL and should be dealt with during treatment to secure the best possible QoL for BC patients. For bladder cancer patients, psychological items have a strong impact on the quality of life while urinary items have a weak impact on the quality of life. Toxicity reporting from clinical trials and supportive care in daily practice may be incomplete and not reflective of the full picture of symptomatology for bladder cancer patients. In perspective, we are interested in directing the supportive care in the right direction for this patient group thereby securing focus on timely symptom management and the impact of such on QoL and clinical outcomes. At the same time, we hope that this information on pivotal symptomatic items for the bladder cancer population could be helpful when designing clinical trials regarding which items are relevant to this population to reflect the total toxicity burden during treatment and its effect on QoL.22.1Bladder cancer (stages T2‐)Initiating treatment with chemotherapy  or immunotherapy (pembrolizumab) as the standard neoadjuvant or metastatic treatment.Able to read Danish.No serious cognitive impairment as evaluated by the treating team of physician and/or nurse.Data for this study were obtained from two prospective clinical studies (study 1 and 2) in patients with locally advanced or metastatic bladder cancer receiving chemo‐ or immunotherapy at two university hospitals (H1 and H2), Copenhagen, Denmark. The purposes of these two studies were to collect PROs longitudinally, report clinical outcomes (study 1&2) and evaluate electronic PRO completion (study 2), data on these issues will be reported elsewhere. Study 1 was conducted at H1 with both paper and electronic completion of questionnaires whereas study 2 was conducted at H1 and H2 with only electronic capture of PROs. Criteria for inclusion in both studies were as follows:2.2In both studies, the patients completed the same questionnaires weekly by paper or electronically through the Ambuflex software system in a web‐browser.For patients completing questionnaires by Web they were prompted to do so weekly by receiving a notification in e‐Boks, a national communication system between authorities, companies, and citizens ensuring delivery of official communication regardless of geographical home address ensuring secure data delivery.The specific scores from the EORTC and HADS questionnaires are hence the aim of this study reported elsewhere.2.3The PRO‐CTCAE Item library consists of 78 symptom items explored by 128 questions as many symptoms are explored by attributes on frequency (F), severity (S), interference with daily activities (I) and/or presence (P).2.4s, in either direction from 0) of 0‐0.19 were regarded as very weak, 0.2‐0.39 as weak, 0.40‐0.59 as moderate, 0.6‐0.79 as strong and 0.8‐1 as very strong correlation. A PRO‐CTCAE symptom was included in the above rs categories if one or more correlation coefficient between a PRO‐CTCAE item and the expected domain was found within the given intervals. Descriptive analysis was used to describe the symptom burden from PRO‐CTCAE scores. Linear regression analysis was performed to estimate the relation between summarized PRO‐CTCAE scores and QoL and its subdomains.To test the association between two instruments as a way of testing for construct validity when developing new measurement tools correlation analyses were performed. These analyses verify that the tool in question can distinguish between groups of patients with differences in the symptom under study. The analyses can also identify shifts in symptom severity within the same patient when using a well‐known tool as the anchor, in this case, the EORTC QLQ‐C30. Scatter plots were used to check for monotonicity, as a determination of strength and direction of the correlation in question, between the given PRO‐CTCAE item and calculated global QoL score, including all subdomains: physical function, role function, emotional function, cognitive function, and social function. The spearman's test was then performed to test for correlations between the PRO‐CTCAE item and QoL and its subdomains. Correlation analyses were performed for the total population and for the locally advanced and metastatic population separately. Absolute values of rho  did not fulfill inclusion criteria due to either poor performance status inhibiting treatment initiation , enrollment into a clinical trial , initiating radiotherapy instead of chemo‐/immunotherapy , synchronic metastatic cancer of another site  or lack of access to electronic communication with authorities through e‐Boks™ . A further three patients (2%) were missed at treatment initiation and three (2%) declined treatment altogether. Participation was declined by 10/122 patients (8%) leaving 79 patients who completed written informed consent, one of whom did not initiate questionnaire completion due to a cerebral stroke on the day of completing informed consent. The clinical data of the participating patients are listed in Table A total of 711 questionnaires were completed by the participating 78 patients. The median number of completed questionnaires was 9 (range 0‐20). The overall completion rate was 76%. Twenty patients completed questionnaires on paper and 58 by web‐browser in Ambuflex. Analysis of missing data revealed an overall completion of 93% and missing data in 7% of the 724 questionnaires, all with 158 items equaling 8007 missing item responses out of a total of 114.392 item responses. After imputing zeros in the PRO‐CTCAE items following a zero in the frequency item, the missing data analysis showed 6% missing data. The transformation of values 5 and 6 to ‘missing’ for the item ‘decreased libido’ was not included as missing data in this analysis as they were completed by the patients.rs = −0.603, P < .0001), concentration (S), and cognitive function , discouraged (F) and emotional function , fatigue (S) and role function , memory (S) and cognitive function , and sad (F) and emotional function , all with the expected direction of correlation with QoL, see Table rs > 0.8). The PRO‐CTCAE items concerning abdominal pain, dizziness, memory, muscle pain, nausea, pain, and shortness of breath all reached moderate correlations of Spearman's rho 0.4‐0.59. The items with the lowest rank‐order correlations with the expected QoL domain were the PRO‐CTCAE items concerning pain and swelling at the injection site (P) , urinary frequency (F) , urinary incontinence (F) , and urinary urgency (F) , all with very weak correlations, nonsignificant and with converging directions of the correlations. For the corresponding interference with daily activities items (I) of the urinary items, the correlations were very weak or weak but significant within the expected domain of QoL. No significant differences were found between the patients with locally advanced disease vs. metastatic disease although patients with locally advanced disease generally experienced higher correlations between a larger amount of symptoms (more symptoms with weak rs) and QoL than the metastatic population (more symptoms with very weak rs).When analyzing the relationship between all single PRO‐CTCAE items and QLQ‐C30 quality of life including subdomains (see Table P < .0001 for all analyses, see Table Figure 4This study identifies imperative symptoms for bladder cancer patients during chemo‐ or immunotherapy most likely to influence QoL. Interestingly the symptoms with the highest correlations are predominantly of a psychological nature whereas urinary symptoms known to be frequent for this population and over time anticipated to influence QoL the most, do not show positive or significant correlations with QoL. We find that our data may inform caregivers to focus on supportive care in these areas during treatment in order to best assist bladder cancer patients to achieve a better QoL. Likewise, this study may inform future investigators of imperative symptoms to report from a clinical trial for a comprehensive collection of the full symptom burden of enrolled patients for more transparent toxicity reporting in clinical trials.Our findings of the correlations between the PRO‐CTCAE and the EORTC QLQ‐C30 are similar to that of Dueck et al in the validation process of the PRO‐CTCAE instrument in 2015.The symptoms with moderate or strong correlations are all general symptoms likely to reflect symptomology of a broad group of cancer patients and not specific to bladder cancer patients or to the stage of disease. With the added attention toward active management of PROs during treatment, this finding speaks for a general, nondisease specific, model of PROs during treatment if the aim is to reflect QoL. This approach has also been shown to be beneficial for patients in previous trials testing the impact of PROs.We found significant associations between summarized PRO‐CTCAE scores and QoL, including subdomains, in our linear regression model. When performing the same analysis without the inclusion of the psychological items found to have strong correlations from Table The strengths of this study include the prospective collection of data in a broad cohort of bladder cancer patients receiving active oncological treatment. This study is, to the best of our knowledge, the first to perform these analyses in a population of patients receiving chemo‐ or immunotherapy for advanced disease. We believe that the data are representative and that the results are applicable for a wide spectrum of bladder cancer patients. Also, with the disease‐specific PRO‐CTCAE item selection performed prior to our analysis and described in detail in a separate publication we believe that we in this study capture PROs relevant for the bladder cancer patients without adding substantial burden of questionnaire completion for the patients while reporting.Some limitations do however need to be addressed. First, although correlation analysis from 724 questionnaires have been presented, only 78 patients report in this study thereby including a single patient's reports over time multiple times in the analysis. Patients responding to treatment and thus reporting for a longer period will therefore weigh more in this analysis potentially skewing the data and underestimating symptom burden in Figure With the increasing focus on PROs as part of clinical trials investigators should be aware of the pitfalls of item selection when planning trials and especially of the items imperative for the population at question. Bladder cancer patients with advanced disease have a poor prognosis, partly due to a burden of comorbidity troubling treatment adherence.5The Danish National Data Protection Agency approved the conduction of studies included in this manuscript. The studies described in the manuscript were carried out prospectively during treatment for all patients completing written informed consent. In Denmark, the Danish Health Authority waivers the need for ethical approval for scientific studies assembling questionnaire data only. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institution and the national research committee, the Danish Health Authority, and also with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Supplementary MaterialClick here for additional data file.


ABCC8 and KCNJ11. These genes encode the subunits of the β‐cell ATP‐sensitive potassium channel, a key component of the glucose‐stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in  ABCC8 and KCNJ11. These genes encode the subunits of the β‐cell ATP‐sensitive potassium channel, a key component of the glucose‐stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in  In 2006, 124 disease‐causing mutations were reported, which increased to 265 pathogenic variants 3 years later , do not have the sustained neonatal hypoglycemia observed in humans with homozygous null mutations. Instead the blood glucose levels normalize in the mouse within a few days of birth with glucose intolerance developing in later life  has a monogenic cause  recapitulated the biphasic phenotype with the mice having increased insulin secretion in early life and reduced insulin secretion later on. This was shown to be resulting from a reduction in insulin content rather than a reduction of islet number and/or size. Heterozygosity for the mutation did, however, not result in a phenotype in the mouse, further highlighting differences between the mouse models and human disease , have been dominantly acting. The majority (~60%) of dominant mutations arise “de novo,” so there is often no family history of diabetes; however, germline mosaicism has been observed in some families  features are frequently reported in individuals with KATP channel NDM have characterized the neurological features in more detail. Additional features reported include autism and attention deficit hyperactivity disorder (ADHD), anxiety and sleep disorders, dyspraxia, and learning difficulties, resulting in impaired attention, memory, visuospatial abilities, and executive function . In addition, starting sulphonylurea therapy as early as possible after a genetic diagnosis is crucial as the largest improvements appear to occur in younger patients  is located 4.5Kb from ABCC8 on chromosome 11p15.1 and has a single exon encoding for the 390‐amino acid Kir6.2 protein (GenBank NM_000525.3). ABCC8 consists of 39 exons that encode for the 1,582 amino acids of SUR1 . This gene has an alternatively spliced recognition site at the 5′ end of exon 17, which results in two different transcripts differing in length by a single amino acid (GenBank AH003589.2). This alternative splicing has led to discrepancies in the literature for nomenclature of variants present in 17–39, which differ by a single amino acid depending on the isoform used . For the purpose of this review, we have described ABCC8 variants according to the longer isoform (NM_001287174.1).4.1ABCC8 and 205 KCNJ11 pathogenic or likely pathogenic variants have been identified in individuals with CHI or NDM  were not re‐assessed.A total of 748 ABCC8 p.(Phe1388del) and c.3992‐9G>A mutations present in >90% of cases from the Ashkenazi Jewish population  in ABCC8, predispose to type 2 diabetes  in an individual with CHI provides strong evidence for pathogenicity, finding a missense variant is insufficient to assign disease causality and, as such, additional support is required to achieve a “pathogenic” classification according to the guidelines set out by the American College of Medical Genetics (Richards et al., Given the highly polymorphic nature of Large variant databases such as GnomAD and LOVD are powerful tools that aid in variant interpretation and allow for reclassification of variants (Fokkema et al., 5ATP channel NDM, for patients with CHI, pharmacological management of the condition is not always successful. Current efforts are, therefore, focusing on the development of new pharmacological treatments for this condition (Banerjee, De Leon, & Dunne, Although sulphonylureas provide a safe and effective treatment for the majority of individuals with KKCNJ11 activating mutation in cell‐free fetal DNA (De Franco et al., Progress is also being made in terms of genetic screening, with a recent report describing the use of noninvasive prenatal testing of a paternally inherited 6ATP channel mutations has firmly established the critical role of the channel in insulin secretion. The highly polymorphic nature of the two genes along with the occurrence of both gain‐of‐function and loss‐of‐function mutations as well as multiple different modes of inheritance can make variant interpretation extremely challenging. Rapid testing is absolutely crucial for all patients with CHI or NDM because finding a mutation has a huge impact on the clinical management of these conditions.The discovery of both inactivating and activating KSupporting informationClick here for additional data file.


The coronavirus pandemic of 2020 has highlighted both similarities and vast inequalities between nations. Periods of preparation, lockdown and recovery from COVID‐19, staggered across regions, have refocused national priorities on strengthening health system capacity, scaling up acute care, future‐proofing economies and adapting education for remote delivery.Disruption to formal education is not unusual in countries experiencing multiple continuing crises. Regions affected by both geoclimatic vulnerability and chronic political unrest regularly experience interruptions to health care and education provision. Between 2016 and 2017, the schools and colleges of Kashmir, northern India, were closed for 60% of all working days. The region is currently nearing a full year under lockdown.High‐quality medical education remains essential to health care delivery, especially during pandemics and periods of geopolitical and sociopolitical unrestHigh‐quality medical education remains essential to health care delivery, especially during pandemics and periods of geopolitical and sociopolitical unrest. COVID‐19 has increased the global recognition of health care workers, highlighting the need for uninterrupted clinical education. With nations forced to recruit medical and nursing students to deliver frontline care, rapidly expand bed capacity and share ventilators, the coronavirus pandemic has exposed the scarcity of health care resources globally. Low‐ and middle‐income countries (LMICs) are especially vulnerable and most in need of continued remote education and training.Lancet commission emphasised the benefits to global mental health of digital technologies, for the training and supervision of health workers, as well as for the provision of care in the most remote and underserved regions.In the long term, frequent disruption to health care education can impact clinical standards and encourage a ‘brain drain’ of skilled professionals to high‐income regions. Innovative pedagogical approaches are required to fill gaps in medical education, especially during global health emergencies such as COVID‐19. E‐learning has been recognised by the World Health Organization (WHO) as an important means of addressing health workers’ educational needs, especially in LMICs.Innovative pedagogical approaches are required to fill gaps in medical education, especially during global health emergencies such as COVID‐19Peer learning can enhance medical education when senior faculty members must prioritise clinical care. A peer‐to‐peer e‐learning partnership (‘Aqoon’) between medical students from Somaliland and the UK demonstrated reciprocal knowledge and cross‐cultural benefits.Box 1We piloted a global mental health e‐learning partnership between volunteer medical students in Kashmir and the UK in 2015. Kashmir was gradually rebuilding after severe flooding in 2014 and a major earthquake in 2005. We guided five pairs of student volunteers to meet online for 10 fortnightly, hour‐long, peer‐led tutorials covering topics from the WHO mental health gap action programme (mhGAP) intervention guide. We used fortnightly e‐mails to remind partners to read specified mhGAP chapters covering core psychiatric presentations before discussing their understanding and clinical experience online, in pairs.We used pre‐ and post‐course questionnaires to evaluate the programme and elicit student reflections Box . KashmirBox 2KashmirOnline discussions with my UK peer helped me to gain a deeper understanding of cross‐cultural mental health scenarios. I reflected on the ways that conflict and cultural beliefs can impact mental health. This experience made me appreciate the protective value of Kashmir's family systems, and cultural and religious beliefs, as well as the scope to improve the delivery of mental health care services. My experience with this project influenced me to pursue psychiatry training in Kashmir.UKDiscussing different [WHO mental health gap action programme] mhGAP topics with my partner in Kashmir helped to consolidate my knowledge of symptoms, diagnosis and management strategies for common psychiatric conditions. Perhaps more importantly, we discussed the position of mental health within our respective health care systems. I found this aspect of the partnership particularly instructive. The experience has helped me to appreciate our mental health service infrastructure, despite its limitations.Frequent internet and communication blackouts in conflict regions may be the biggest impediment to their feasibility. Internet access in Kashmir remains restricted to low‐speed 2G services, impacting the general population and health care professionals’ ability to keep up to date with clinical guidelines and research developments. Where connectivity, electricity and the availability of computers and smartphones are limited, more conventional alternatives may be required. Radio and television broadcasts lack the real‐time interaction, bi‐directional communication and instant feedback of a simulated classroom environment, however. User‐friendly interfaces, versatility and familiarity to learners make online approaches preferable in settings where the internet is reliable. Political commitment to ensure fast and continuous internet connectivity, at least for professionals working in essential services and delivering clinical education, is increasingly important.Digital literacy and the availability of affordable technologies impact the accessibility of online education. Three years after the flagship ‘digital India’ launch, India was one of the world's most rapidly digitising nations. In China, the Ministry of Education has directed major telecommunication service providers to boost internet connectivity and upgrade the bandwidth of online education service platforms in the wake of COVID‐19. Similarly, telecommunication companies in Croatia are providing free internet access to students of low socio‐economic status.Teaching methods must be flexible if they are to ensure the continuity of medical education during turbulent times. E‐learning models represent low‐cost innovations that can be customised to the clinical and pragmatic context. Peer learning has the potential to benefit learners in more‐ and less‐resourced settings alike, whilst the resurgence in volunteerism provoked by COVID‐19 could see skilled, knowledgeable professionals who are unable to deliver front‐line care instead giving their time and expertise for remote education. Such initiatives require the same rigor and quality standards as any face‐to‐face teaching.COVID‐19 could see skilled, knowledgeable professionals who are unable to deliver front‐line care instead giving their time and expertise for remote educationThe coronavirus pandemic presents challenges and opportunities. One is to develop the evidence base for e‐learning models using randomised methods in larger samples, to determine their scalability and suitability to current needs. Lessons learned in the aftermath of emergencies can benefit long‐term practice and preparedness to respond to future upheaval.


Digitized images of herbarium specimens are highly diverse with many potential sources of visual noise and bias. The systematic removal of noise and minimization of bias must be achieved in order to generate biological insights based on the plants rather than the digitization and mounting practices involved. Here, we develop a workflow and data set of high‐resolution image masks to segment plant tissues in herbarium specimen images and remove background pixels using deep learning.We generated 400 curated, high‐resolution masks of ferns using a combination of automatic and manual tools for image manipulation. We used those images to train a U‐Net‐style deep learning model for image segmentation, achieving a final Sørensen–Dice coefficient of 0.96. The resulting model can automatically, efficiently, and accurately segment massive data sets of digitized herbarium specimens, particularly for ferns.The application of deep learning in herbarium sciences requires transparent and systematic protocols for generating training data so that these labor‐intensive resources can be generalized to other deep learning applications. Segmentation ground‐truth masks are hard‐won data, and we share these data and the model openly in the hopes of furthering model training and transfer learning opportunities for broader herbarium applications. Efforts to digitize natural history collections have resulted in large, open data sets that, when linked with collection data, offer an unprecedented opportunity to evaluate transformative research questions that link objects through space and time. The tens of millions of openly available digitized herbarium specimens allow botanists to evaluate ecological and evolutionary questions on a global scale, integrating across centuries of botanical collecting and piecing together collections with spatially biased holdings to generate biome‐level comparisons of biological patterns  a priori, eliminating noisy and biased visual information from all other parts of the herbarium specimen image ahead of subsequent analyses. Deep learning models can be trained to label image pixels based on their content . Labeling image pixels in this way is referred to as masks, images of identical resolution that define the identity of each pixel in the original image as belonging to an a priori designated set of pixel identities or classes . These data  are used to train the deep learning model to generate accurate pixel classifications by comparing the model predictions for each pixel against the pixel class defined in the mask . A more detailed description of the learning process is beyond the scope of this work, but see Garcia‐Garcia et al.  of our original images paired with ground‐truthed masks prepared using the protocol above. This resulted in approximately 21 million pixels with associated class labels for training this model. The goal of such training is to expose the model to a wide diversity of pixel values and contexts paired with the associated pixel class identity (plant or background). All images and associated masks were resized to 256 × 256 pixels to maximize the downstream training efficiency. Our model therefore produces predicted image masks of 256 × 256 pixels regardless of the size of the image input , zooming (maximum zoom by a factor of 1.1), lighting adjustments (maximum adjustment by a factor of 0.2), and warping (maximum warping by a factor of 0.2). All transformations were applied with a probability of 0.75 except for horizontal flipping (probability = 0.5) using fastai.https://pytorch.org/docs/stable/torchvision/models.html).The model was constructed using the U‐Net architecture  to validate our model. The pixels of these images were never presented to the model during training and thus model performance on these images can be viewed as a measure of the model’s applicability to novel data. We trained our model for 22 epochs , following the one‐cycle learning rate policy . However, the workflow we present is general to herbarium images broadly and can be used by botanists specializing in other plant taxa to create their own set of masks with which to train similar deep learning models for segmentation. We hope that members of the botanical community with interests in specific taxa or tissues will create and share similar high‐resolution data sets and models.https://www.idigbio.org/portal). This new scale of herbarium science requires modern tools and novel approaches to wield such massive data. Although automated segmentation is a large part of the preprocessing needed before a data set of herbarium images can be used for downstream deep learning applications, there are other concerns when using digital images of herbarium specimens not addressed in our workflow. For example, in any large data set, it is common to find multiple specimens in which the plant material is contained solely as fragments in envelopes and is therefore not visible. Deep learning may yet offer solutions to these challenges; however, workflows, training data, and models designed for preprocessing herbarium images for massive‐scale (millions of images) analyses are still needed to make deep learning tools accessible to the broader botanical community. It is critical to recognize the “human in the loop” component of machine learning and its applications in the biodiversity sciences. The extent to which botanists and biologists are willing to become familiar with these advanced computational tools will likely predict the utility of machine learning in botanical sciences as well as the novelty of the insights such tools may reveal.There are ~18.9 million digitized herbarium images currently accessible through the Integrated Digitized Biocollections portal (iDigBio,