UiT The Arctic University of Norway

IMPORTANCE: Cancer is the second leading cause of death worldwide. Current estimates on the burden of cancer are needed for cancer control planning. OBJECTIVE: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 32 cancers in 195 countries and territories from 1990 to 2015. EVIDENCE REVIEW: Cancer mortality was estimated using vital registration system data, cancer registry incidence data (transformed to mortality estimates using separately estimated mortality to incidence [MI] ratios), and verbal autopsy data. Cancer incidence was calculated by dividing mortality estimates through the modeled MI ratios. To calculate cancer prevalence, MI ratios were used to model survival. To calculate YLDs, prevalence estimates were multiplied by disability weights. The YLLs were estimated by multiplying age-specific cancer deaths by the reference life expectancy. DALYs were estimated as the sum of YLDs and YLLs. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. Countries were categorized by SDI quintiles to summarize results. FINDINGS: In 2015, there were 17.5 million cancer cases worldwide and 8.7 million deaths. Between 2005 and 2015, cancer cases increased by 33%, with population aging contributing 16%, population growth 13%, and changes in age-specific rates contributing 4%. For men, the most common cancer globally was prostate cancer (1.6 million cases). Tracheal, bronchus, and lung cancer was the leading cause of cancer deaths and DALYs in men (1.2 million deaths and 25.9 million DALYs). For women, the most common cancer was breast cancer (2.4 million cases). Breast cancer was also the leading cause of cancer deaths and DALYs for women (523 000 deaths and 15.1 million DALYs). Overall, cancer caused 208.3 million DALYs worldwide in 2015 for both sexes combined. Between 2005 and 2015, age-standardized incidence rates for all cancers combined increased in 174 of 195 countries or territories. Age-standardized death rates (ASDRs) for all cancers combined decreased within that timeframe in 140 of 195 countries or territories. Countries with an increase in the ASDR due to all cancers were largely located on the African continent. Of all cancers, deaths between 2005 and 2015 decreased significantly for Hodgkin lymphoma (-6.1% [95% uncertainty interval (UI), -10.6% to -1.3%]). The number of deaths also decreased for esophageal cancer, stomach cancer, and chronic myeloid leukemia, although these results were not statistically significant. CONCLUSION AND RELEVANCE: As part of the epidemiological transition, cancer incidence is expected to increase in the future, further straining limited health care resources. Appropriate allocation of resources for cancer prevention, early diagnosis, and curative and palliative care requires detailed knowledge of the local burden of cancer. The GBD 2015 study results demonstrate that progress is possible in the war against cancer. However, the major findings also highlight an unmet need for cancer prevention efforts, including tobacco control, vaccination, and the promotion of physical activity and a healthy diet.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is thatthere is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the completeprocess including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increasedautophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in manycases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as forreviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multipleassays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagyrelated protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Protein degradation by basal constitutive autophagy is important to avoid accumulation of polyubiquitinated protein aggregates and development of neurodegenerative diseases. The polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy. It is found in cellular inclusion bodies together with polyubiquitinated proteins and in cytosolic protein aggregates that accumulate in various chronic, toxic, and degenerative diseases. Here we show for and proteins and and protein and The is by of of and we of of and that and bodies degraded in inclusion bodies degraded by autophagy. The and we is in degradation of that proteins in cytosolic bodies for bodies and that is for and degradation of bodies by autophagy. Protein degradation by basal constitutive autophagy is important to avoid accumulation of polyubiquitinated protein aggregates and development of neurodegenerative diseases. The polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy. It is found in cellular inclusion bodies together with polyubiquitinated proteins and in cytosolic protein aggregates that accumulate in various chronic, toxic, and degenerative diseases. Here we show for and proteins and and protein and The is by of of and we of of and that and bodies degraded in inclusion bodies degraded by autophagy. The and we is in degradation of that proteins in cytosolic bodies for bodies and that is for and degradation of bodies by autophagy. for protein and The is for degradation of and proteins with The and proteins by and by autophagy. of autophagy in of and autophagy is of of with and is to degradation for degradation of of proteins and protein for of and The is is by to cytosolic of to of that is with The is of autophagy and and and The of in autophagy is of autophagy cellular to avoid accumulation of proteins in neurodegenerative in of accumulation of protein aggregates in and show of with of that of autophagy by accumulation of protein aggregates that is basal constitutive autophagy that is in to avoid accumulation of protein aggregates to bodies in to various and to in for polyubiquitinated proteins to degradation inclusion bodies proteins of proteins to of and is of that aggregates that by of aggregates is found in inclusion bodies polyubiquitinated protein neurodegenerative is in protein bodies in in and aggregates in protein of of found in bodies of and bodies in and in aggregates The protein is to and It and we that to proteins and and to and to in found to for we to show that is for degradation of inclusion bodies that inclusion bodies and that is for and to and polyubiquitinated proteins and and and The and and and and and and in in in for and by in in and The and with The for and in with and with and with by and The and to and in of with of with of to and to by The protein in and and and proteins in proteins proteins and with in proteins proteins in with of with of proteins in of with for and with of with proteins in of with of in of for with of with and to with with and proteins with proteins to and by with with of proteins to with of in of for with of with of and to and The with by with in and in with and and for to with with with with and and and with for and in and with of and to and with by protein in we in with to that and with is is of It is is for of we and proteins by with and with and The protein in protein protein of we and The and by protein in protein we proteins and by and protein of and protein in is and we with proteins found to and in to of of to found to and avoid of of of and of we of of of of we of of that in in of and to with to to of by with of in of to of and of is for with for to and of and of of by and of by in and in of of of proteins in The show of and with of of by and of to and of The of of to of of and of and of by and in of by to for with of in The is and to in and of in and of we to we in to and in to in and to is by is by of and is that is of is with that of to found that of of and and and of of and of The of with and that of with in to with with of in to and and is of of found in of proteins to to we and in and to of by with in with and with we we and and with in in of by to and proteins found to to is in in of is for to and proteins with with of and of proteins cellular of and to by with proteins with and in to proteins of and with with in and in and with and of and proteins to bodies in with and and and for of proteins to bodies show that is to in to and that proteins to bodies in of we for to of with in bodies It to and in in aggregates that polyubiquitinated proteins and is of that is with of to to by with to The of of to and of and of is that to with to inclusion bodies to to and we protein to The of is protein with we to with of and that and of that in is to of proteins in to to inclusion bodies and and in we to in of and in of and of in that of of and of proteins of is of that of and degradation of with accumulate with found in with to that of in of that is in in found in and The to of to by The in and and of inclusion bodies and with of to with with and with of degraded we in of in of and in of with and to is and that and to protein of proteins with with for of of The of bodies in for that with to and we for with with and and is for and is in we found and of in of with with with to inclusion in inclusion and with with and of is with for of and in with and that we in and in The to by to in is and in inclusion bodies and in in to and in of autophagy in of of is of of in is autophagy to is of of and of in of to in to of that with with and of bodies is autophagy. with and in for to to and autophagy to by is is of inclusion bodies that degraded by autophagy. It is to bodies and of that with proteins and for in we to bodies of with we that bodies degraded by autophagy. in is of by of of in of is of is in for inclusion bodies by with to of in of and in various and and The of in with of by and that bodies degraded by of bodies with and with with with to to for of for of of inclusion bodies is of various is to of and and of cytosolic bodies and polyubiquitinated proteins with in by and in of The of protein by with of with of of we found that bodies and in of and inclusion bodies and for and of bodies is with with to of and and with and of protein bodies with of The of protein bodies is by of to for of bodies for that for with in of to in that of in of in proteins to in bodies that degraded by autophagy. and in in of of proteins to with for and with and of of with cellular of that with to proteins and and for of of with and to proteins that proteins in together with and of accumulation of in with we in of proteins in of that in degradation of polyubiquitinated proteins with to with of we in and for of in of proteins with protein with in of is with by of of of for of and of of in of and of and of in of we in of in of for is in to of is for of with in together with and of inclusion bodies in inclusion by of in and of in with and of of with that is for of of is for degradation of of to and with The of to of with and to and with to inclusion with and and of is important for of to and with of and and with of and of of for of to is important for degradation of in together with we of that in with protein of of to with with that bodies by in of that of is we that to that that of of is for degradation of and we show that to and and and is protein in The and is by in and and of and and and and to that and is for degradation of bodies polyubiquitinated by autophagy. polyubiquitinated proteins and to protein bodies that degraded by to of proteins and is to with and to and and of in of and of we by with for autophagy is to of The of to with with to to is to to protein and and in and we to and and of and that of is in and The for and is to and bodies that The is to proteins and The to and degradation of by is degraded by we and found of autophagy and of to is important to in that by of inclusion bodies is proteins we that bodies and proteins degraded by autophagy. in and in protein bodies by autophagy. bodies to to we accumulation of in in that is that bodies degraded by basal constitutive autophagy to by that in autophagy with of we show that in of inclusion bodies and to with The found for inclusion with proteins show that to and of and is to bodies with of It important to proteins that and to show that and inclusion bodies and that of bodies by of The bodies in p62/SQSTM1 of of and of to to of of by of of in to and with It important to in protein degradation by autophagy is to show is protein of Protein and in to of important to autophagy of and in It to show neurodegenerative of neurodegenerative proteins in important for protein and The is for degradation of and proteins with The and proteins by and by autophagy. of autophagy in of and autophagy is of of with and is to degradation for degradation of of proteins and protein for of and The is is by to cytosolic of to of that is with The is of autophagy and and and The of in autophagy is of autophagy cellular to avoid accumulation of proteins in neurodegenerative in of accumulation of protein aggregates in and show of with of that of autophagy by accumulation of protein aggregates that is basal constitutive autophagy that is in to avoid accumulation of protein aggregates to bodies in to various and to in for polyubiquitinated proteins to degradation inclusion bodies proteins of proteins to of and is of that aggregates that by of aggregates The is found in inclusion bodies polyubiquitinated protein neurodegenerative is in protein bodies in in and aggregates in protein of of found in bodies of and bodies in and in aggregates The protein is to and It and Here we that to proteins and and to and to in found to for we to show that is for degradation of inclusion bodies that inclusion bodies and that is for and to and polyubiquitinated proteins and and and The and and and and and and in in in for and by in in and The and with The for and in with and with and with by and The and to and in of with of with of to and to by The protein in and and and proteins in proteins proteins and with in proteins proteins in with of with of proteins in of with for and with of with proteins in of with of in of for with of with and to with with and proteins with proteins to and by with with of proteins to with of in of for with of with of and to and The with by with in and in with and and for to with with with with and and and with for and in and with of and to and with by protein in we in with and to and polyubiquitinated proteins and and and The and and and and and and in in in for and by and The and with The for and in with and with and with by and The and to and in of with of with of to and to by The protein in and and and proteins in proteins proteins and with in proteins proteins in with of with of proteins in of with for and with of with proteins in of with of in of for with of with and to with with and proteins with proteins to and by with with of proteins to with of in of for with of with of and to and The with by with in and in with and and for to with with with with and and and with for and in and with of and to and with by protein in we in with to that and with is is of It is is for of we and proteins by with and with and The protein in protein protein of we and The and by protein in protein we proteins and by and protein of and protein in is and we with proteins found to and in to of of to found to and avoid of of of and of we of of of of we of of that in in of and to with to to of by with of in of to of and of of by and of to and of The of of to of of and of and of by and in of by to for with of in The is and to in and of in and of we to we in to and in to in and to is by is by of and is that is of is with that of to found that of of and and and of of and of The of with and that of with in to with with of in to and and is of of found in of proteins to to we and in and to of by with in with and with we we and and with in in of by to and proteins found to to is in in of is for to and proteins with with of and of proteins cellular of and to by with proteins with and in to proteins of and with with in and in and with and of and proteins to bodies in with and and and for of proteins to bodies show that is to in to and that proteins to bodies in of we for to of with in bodies It to and in in aggregates that polyubiquitinated proteins and is of that is with of to to by with to The of of to and of and of is that to with to inclusion bodies to to and we protein to The of is protein with we to with of and that and of that in is to of proteins in to to inclusion bodies and and in we to in of and in of and of in that of of and of proteins of is of that of and degradation of with accumulate with found in with to that of in of that is in in found in and The to of to by The in and and of inclusion bodies and with of to with with and with of degraded we in of in of and in of with and to is and that and to protein of proteins with with for of of The of bodies in for that with to and we for with with and and is for and is in we found and of in of with with with to inclusion in inclusion and with with and of is with for of and in with and that we in and in The to by to in is and in inclusion bodies and in in to and in of autophagy in of of is of of in is autophagy to is of of and of in of to in to of that with with and of bodies is autophagy. with and in for to to and autophagy to by is is of inclusion bodies that degraded by autophagy. It is to bodies and of that with proteins and for in we to bodies of with we that bodies degraded by autophagy. in is of by of of in of is of is in for inclusion bodies by with to of in of and in various and and The of in with of by and that bodies degraded by of bodies with and with with with to to for of for of of inclusion bodies is of various is to of and and of cytosolic bodies and polyubiquitinated proteins with in by and in of The of protein by with of with of of we found that bodies and in of and inclusion bodies and for and of bodies is with with to of and and with and of protein bodies with of The of protein bodies is by of to for of bodies for that for with in of to in that of in of in proteins to in bodies that degraded by autophagy. and in in of of proteins to with for and with and of of with cellular of that with to proteins and and for of of with and to proteins that proteins in together with and of accumulation of in with we in of proteins in of that in degradation of polyubiquitinated proteins with to with of we in and for of in of proteins with protein with in of is with by of of of for of and of of in of and of and of in of we in of in of for is in to of is for of with in together with and of inclusion bodies in inclusion by of in and of in with and of of with that is for of of is for degradation of of to and with The of to of with and to and with to inclusion with and and of is important for of to and with of and and with of and of of for of to is important for degradation of in together with we of that in with protein of of to with with that bodies by in of that of is we that to that that of of is for degradation of and p62/SQSTM1 to that and with is is of It is is for of we and proteins by with and with and The protein in protein protein of we and The and by protein in protein we proteins and by and protein of and protein in is and we with proteins found to and in to of of to found to and avoid of of of and of we of of of of we of of that in in of and to with to to of by with of in of to of and The is and to in and of in and of we to we in to and in to in and to is by is by of and is that is of is with that of to found that of of and and and of of and of The of with and that of with in to with with of in to and and is of of found in of proteins to to we and in and to of by with in with and with we we and and with in in of by to and proteins found to to is in in of is for to and proteins of and proteins to bodies in with and and and for of proteins to bodies show that is to in to and that proteins to bodies in of we for to of with in bodies It to and in in aggregates that polyubiquitinated proteins and is of that is with of to to by with to The of of to and of and of is that to with to inclusion bodies to to and we protein to The of is protein with we to with of and that and of that in is to of proteins in to to inclusion bodies and and in we to in of and in of and of in that of of and of proteins of is of that of and degradation of with accumulate with found in with to that of in of that is in in found in and The to of to by The in and and of inclusion bodies and with of to with with and with of degraded we in of in of and in of with and to is and that and that with to and we for with with and and is for and is in we found and of in of with with with that we in and in The to by to in is and in inclusion bodies and in in to and in of autophagy in of of is of of in is autophagy to is of of and of in of to in to of that with with and by is is of inclusion bodies that degraded by autophagy. It is to bodies and of that with proteins and for in we to bodies of with we that bodies degraded by autophagy. in is of by of of in of is of is in for inclusion bodies by with to of in of and in various and and The of in with of by and that bodies degraded by autophagy. for of of inclusion bodies is of various is to of and and of cytosolic bodies and polyubiquitinated proteins with in by and in of The of protein by with of with of of we found that bodies and in of and for of of with and to proteins that proteins in together with and of accumulation of in with we in of proteins in of that in degradation of polyubiquitinated proteins with to with of we in and for of in of proteins with protein with in of is with by of of The of for of and of of in of and of and of in of we in of in of for is in to of is for of with in together with and of inclusion bodies in inclusion by of in and of in with and of of with that is for of is important for degradation of in together with we of that in with protein of of to with with that bodies by in of that of is we that to that that of of is for degradation of and we show that to and and and is protein in The and is by in and and of and and and and to that and is for degradation of bodies polyubiquitinated by autophagy. polyubiquitinated proteins and to protein bodies that degraded by to of proteins and is to with and to and and of in of and of we by with for autophagy is to of The of to with with to to is to to protein and and in and we to and and of and that of is in and The for and is to and bodies that The is to proteins and The to and degradation of by is degraded by we and found of autophagy and of to is important to in that by of inclusion bodies is proteins we that bodies and proteins degraded by autophagy. in and in protein bodies by autophagy. bodies to to we accumulation of in in that is that bodies degraded by basal constitutive autophagy to by that in autophagy with of we show that in of inclusion bodies and to with The found for inclusion with proteins show that to and of and is to bodies with of It important to proteins that and to show that and inclusion bodies and that of bodies by of The bodies in p62/SQSTM1 of of and of to to of of by of of in to and with It important to in protein degradation by autophagy is to show is protein of Protein and in to of important to autophagy of and in It to show neurodegenerative of neurodegenerative proteins in important we show that to and and and is protein in The and is by in and and of and and and and to that and is for degradation of bodies polyubiquitinated by autophagy. polyubiquitinated proteins and to protein bodies that degraded by autophagy. to of proteins and is to with and to and and of in of and of we by with for autophagy is to of The of to with with to to is to to protein and and in and we to and and of and that of is in and The for and is to and bodies that The is to proteins and The to and degradation of by is degraded by we and found of autophagy and of to is important to in that by of inclusion bodies is proteins we that bodies and proteins degraded by autophagy. in and in protein bodies by autophagy. bodies to to we accumulation of in in that is that bodies degraded by basal constitutive autophagy to by that in autophagy with of we show that in of inclusion bodies and to with The found for inclusion with proteins show that to and of and is to bodies with of It important to proteins that and to show that and inclusion bodies and that of bodies by of The bodies in p62/SQSTM1 of of and of to to of of by of of in to and with It important to in protein degradation by autophagy is to show is protein of Protein and in to of important to autophagy of and in It to show neurodegenerative of neurodegenerative proteins in important to for of to for of and for for with to for of and for of with with

BACKGROUND: Hand knob infarction is a well-known stroke entity. Based on very limited data, embolic stroke mechanism has been considered the most frequent cause; however, prognosis is considered good. We wanted to shed more light on this phenomenon by assessing a cohort of patients referred to a general hospital stroke unit. METHODS: Every subject admitted to our stroke unit with an acute isolated hand paresis in the period from 2007 to 2012 was identified prospectively. Patients who had suffered from a stroke in the hand motor cortex or an adjacent area explaining the acute loss of hand function were included in the study. The Trial of Org 10172 in Acute Stroke Treatment criteria were used to classify subtypes of stroke according to etiology. The patients were followed up during autumn 2012. RESULTS: Seventeen subjects were admitted, but in 2 of them symptoms were transitory and magnetic resonance imaging was negative. Two patients were excluded due to persisting sensory deficits. The remaining 13 (11 males and 2 females) patients with an average age of 62.9 (± 13.4) years were included, representing 1.5% of all ischemic strokes diagnosed at the stroke unit in the given period. All patients were right-handed, and the dominant hand was affected only in 4 (31%). The average Medical Research Council's scale score was 3.1 (± 1.4) on admission, and classified as bad. On follow-up, which occurred on average 29.8 (± 19.8) months after the stroke, the score was 4.6 (± 0.4) and was classified as fair to good. No patient experienced a new stroke. The outcome was good to excellent in 10 patients (77%). Two patients died (15%), 1 of probable cardiac arrest and 1 of unknown cause. One patient did not participate in the follow-up. The majority of patients had evidence of both small artery (77%) and large artery (85%) disease. On average, there were 1.6 (± 0.4) new ischemic lesions per patient. Six patients had a solitary lesion (46%). In 5 of them, small artery occlusion was considered the probable stroke mechanism. In 4 cases, the stroke was of undetermined etiology. Three patients had atrial fibrillation, and in 2 of them cardioembolism was the probable stroke mechanism. Two patients with definite large artery atherosclerosis underwent carotid endarterectomy, and 1 of them had comorbid atrial fibrillation. CONCLUSION: Strokes causing isolated hand paresis seem to have a heterogeneous etiology. Prognosis regarding hand function is good, but long-term outcome depends on stroke etiology and secondary prophylaxis.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

We summarize an advanced, thoroughly documented, and quite general purpose discrete ordinate algorithm for time-independent transfer calculations in vertically inhomogeneous, nonisothermal, plane-parallel media. Atmospheric applications ranging from the UV to the radar region of the electromagnetic spectrum are possible. The physical processes included are thermal emission, scattering, absorption, and bidirectional reflection and emission at the lower boundary. The medium may be forced at the top boundary by parallel or diffuse radiation and by internal and boundary thermal sources as well. We provide a brief account of the theoretical basis as well as a discussion of the numerical implementation of the theory. The recent advances made by ourselves and our collaborators-advances in both formulation and numerical solution-are all incorporated in the algorithm. Prominent among these advances are the complete conquest of two illconditioning problems which afflicted all previous discrete ordinate implementations: (1) the computation of eigenvalues and eigenvectors and (2) the inversion of the matrix determining the constants of integration. Copies of the FORTRAN program on microcomputer diskettes are available for interested users.

Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytosol and nucleus or occur within autophagosomes and lysosomal structures. Inhibition of autophagy led to an increase in the size and number of p62 bodies and p62 protein levels. The autophagic marker light chain 3 (LC3) colocalized with p62 bodies and co-immunoprecipitated with p62, suggesting that these two proteins participate in the same complexes. The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation conditions. Strikingly, p62 and LC3 formed a shell surrounding aggregates of mutant huntingtin. Reduction of p62 protein levels or interference with p62 function significantly increased cell death that was induced by the expression of mutant huntingtin. We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery.

BACKGROUND: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). METHODS: We estimated the incidence of infections with 16 antibiotic resistance-bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011-12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. FINDINGS: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148-763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480-38 430) attributable deaths and 874 541 (768 837-989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. INTERPRETATION: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases. FUNDING: European Centre for Disease Prevention and Control.

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.

BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain. METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies. RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths. CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

INTRODUCTION: The SCARE Guidelines were published in 2016 to provide a structure for reporting surgical case reports. Since their publication, SCARE guidelines have been widely endorsed by authors, journal editors, and reviewers, and have helped to improve reporting transparency of case reports across a range of surgical specialties. In order to encourage further progress in reporting quality, the SCARE guidelines must themselves be kept up to date. We completed a Delphi consensus exercise to update the SCARE guidelines. METHODS: A Delphi consensus exercise was undertaken. All members of the previous Delphi group were invited to participate, in addition to researchers who have previously studied case reports, and editors from the International Journal of Surgery Case Reports. The expert group was sent an online questionnaire where they were asked to rate their agreement with proposed changes to each of the 24 items. RESULTS: 56 people agreed to participate and 45 (80%) invitees completed the survey which put forward modifications to the original guideline. The collated responses resulted in modifications. There was high agreement amongst the expert group. CONCLUSION: A modified and improved SCARE checklist is presented, after a Delphi consensus exercise was completed. The SCARE 2018 Statement: Updating Consensus Surgical CAse REport (SCARE) Guidelines.

<h3>Importance</h3> Liver cancer is among the leading causes of cancer deaths globally. The most common causes for liver cancer include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and alcohol use. <h3>Objective</h3> To report results of the Global Burden of Disease (GBD) 2015 study on primary liver cancer incidence, mortality, and disability-adjusted life-years (DALYs) for 195 countries or territories from 1990 to 2015, and present global, regional, and national estimates on the burden of liver cancer attributable to HBV, HCV, alcohol, and an “other” group that encompasses residual causes. <h3>Design, Settings, and Participants</h3> Mortality was estimated using vital registration and cancer registry data in an ensemble modeling approach. Single-cause mortality estimates were adjusted for all-cause mortality. Incidence was derived from mortality estimates and the mortality-to-incidence ratio. Through a systematic literature review, data on the proportions of liver cancer due to HBV, HCV, alcohol, and other causes were identified. Years of life lost were calculated by multiplying each death by a standard life expectancy. Prevalence was estimated using mortality-to-incidence ratio as surrogate for survival. Total prevalence was divided into 4 sequelae that were multiplied by disability weights to derive years lived with disability (YLDs). DALYs were the sum of years of life lost and YLDs. <h3>Main Outcomes and Measures</h3> Liver cancer mortality, incidence, YLDs, years of life lost, DALYs by etiology, age, sex, country, and year. <h3>Results</h3> There were 854 000 incident cases of liver cancer and 810 000 deaths globally in 2015, contributing to 20 578 000 DALYs. Cases of incident liver cancer increased by 75% between 1990 and 2015, of which 47% can be explained by changing population age structures, 35% by population growth, and −8% to changing age-specific incidence rates. The male-to-female ratio for age-standardized liver cancer mortality was 2.8. Globally, HBV accounted for 265 000 liver cancer deaths (33%), alcohol for 245 000 (30%), HCV for 167 000 (21%), and other causes for 133 000 (16%) deaths, with substantial variation between countries in the underlying etiologies. <h3>Conclusions and Relevance</h3> Liver cancer is among the leading causes of cancer deaths in many countries. Causes of liver cancer differ widely among populations. Our results show that most cases of liver cancer can be prevented through vaccination, antiviral treatment, safe blood transfusion and injection practices, as well as interventions to reduce excessive alcohol use. In line with the Sustainable Development Goals, the identification and elimination of risk factors for liver cancer will be required to achieve a sustained reduction in liver cancer burden. The GBD study can be used to guide these prevention efforts.

We argue that habit is a psychological construct, rather than simply past behavioral frequency. In 4 studies, a 12‐item index of habit strength (the Self‐Report Habit Index, SRHI) was developed on the basis of features of habit; that is, a history of repetition, automaticity (lack of control and awareness, efficiency), and expressing identity. High internal and test‐retest reliabilities were found. The SRHI correlated strongly with past behavioral frequency and the response frequency measure of habit (Verplanken, Aarts, van Knippenberg, &amp; van Knippenberg, 1994). The index discriminated between behaviors varying in frequency, and also between daily vs. weekly habits. The SRHI may be useful as a dependent variable, or to determine or monitor habit strength without measuring behavioral frequency.

The European Prospective Investigation into Cancer and Nutrition (EPIC) is an ongoing multi-centre prospective cohort study designed to investigate the relationship between nutrition and cancer, with the potential for studying other diseases as well. The study currently includes 519 978 participants (366 521 women and 153 457 men, mostly aged 35-70 years) in 23 centres located in 10 European countries, to be followed for cancer incidence and cause-specific mortality for several decades. At enrollment, which took place between 1992 and 2000 at each of the different centres, information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire addressing usual diet. Anthropometric measurements were performed and blood samples taken, from which plasma, serum, red cells and buffy coat fractions were separated and aliquoted for long-term storage, mostly in liquid nitrogen. To calibrate dietary measurements, a standardised, computer-assisted 24-hour dietary recall was implemented at each centre on stratified random samples of the participants, for a total of 36 900 subjects. EPIC represents the largest single resource available today world-wide for prospective investigations on the aetiology of cancers (and other diseases) that can integrate questionnaire data on lifestyle and diet, biomarkers of diet and of endogenous metabolism (e.g. hormones and growth factors) and genetic polymorphisms. First results of case-control studies nested within the cohort are expected early in 2003. The present paper provides a description of the EPIC study, with the aim of simplifying reference to it in future papers reporting substantive or methodological studies carried out in the EPIC cohort.

Advances in molecular profiling have opened up the possibility to map the expression of genes in cells, tissues, and organs in the human body. Here, we combined single-cell transcriptomics analysis with spatial antibody-based protein profiling to create a high-resolution single-cell type map of human tissues. An open access atlas has been launched to allow researchers to explore the expression of human protein-coding genes in 192 individual cell type clusters. An expression specificity classification was performed to determine the number of genes elevated in each cell type, allowing comparisons with bulk transcriptomics data. The analysis highlights distinct expression clusters corresponding to cell types sharing similar functions, both within the same organs and between organs.

Circadian rhythms of behavior are driven by oscillators in the brain that are coupled to the environmental light cycle. Circadian rhythms of gene expression occur widely in peripheral organs. It is unclear how these multiple rhythms are coupled together to form a coherent system. To study such coupling, we investigated the effects of cycles of food availability (which exert powerful entraining effects on behavior) on the rhythms of gene expression in the liver, lung, and suprachiasmatic nucleus (SCN). We used a transgenic rat model whose tissues express luciferase in vitro. Although rhythmicity in the SCN remained phase-locked to the light-dark cycle, restricted feeding rapidly entrained the liver, shifting its rhythm by 10 hours within 2 days. Our results demonstrate that feeding cycles can entrain the liver independently of the SCN and the light cycle, and they suggest the need to reexamine the mammalian circadian hierarchy. They also raise the possibility that peripheral circadian oscillators like those in the liver may be coupled to the SCN primarily through rhythmic behavior, such as feeding.

Mounting evidence suggests that autophagy is a more selective process than originally anticipated. The discovery and characterization of autophagic adapters, like p62 and NBR1, has provided mechanistic insight into this process. p62 and NBR1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. A direct interaction between these autophagic adapters and the autophagosomal marker protein LC3, mediated by a so-called LIR (LC3-interacting region) motif, their inherent ability to polymerize or aggregate as well as their ability to specifically recognize substrates are required for efficient selective autophagy. These three required features of autophagic cargo receptors are evolutionarily conserved and also employed in the yeast cytoplasm-to-vacuole targeting (Cvt) pathway and in the degradation of P granules in C. elegans. Here, we review the mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria. The emerging picture of selective autophagy affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is also addressed.

ABSTRACT Aim Concerns over how global change will influence species distributions, in conjunction with increased emphasis on understanding niche dynamics in evolutionary and community contexts, highlight the growing need for robust methods to quantify niche differences between or within taxa. We propose a statistical framework to describe and compare environmental niches from occurrence and spatial environmental data. Location Europe, North America and South America. Methods The framework applies kernel smoothers to densities of species occurrence in gridded environmental space to calculate metrics of niche overlap and test hypotheses regarding niche conservatism. We use this framework and simulated species with pre‐defined distributions and amounts of niche overlap to evaluate several ordination and species distribution modelling techniques for quantifying niche overlap. We illustrate the approach with data on two well‐studied invasive species. Results We show that niche overlap can be accurately detected with the framework when variables driving the distributions are known. The method is robust to known and previously undocumented biases related to the dependence of species occurrences on the frequency of environmental conditions that occur across geographical space. The use of a kernel smoother makes the process of moving from geographical space to multivariate environmental space independent of both sampling effort and arbitrary choice of resolution in environmental space. However, the use of ordination and species distribution model techniques for selecting, combining and weighting variables on which niche overlap is calculated provide contrasting results. Main conclusions The framework meets the increasing need for robust methods to quantify niche differences. It is appropriate for studying niche differences between species, subspecies or intra‐specific lineages that differ in their geographical distributions. Alternatively, it can be used to measure the degree to which the environmental niche of a species or intra‐specific lineage has changed over time.

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.