Zero to Three

With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. Because of China's massive population (1.37 billion), previous national incidence and mortality estimates have been limited to small samples of the population using data from the 1990s or based on a specific year. With high-quality data from an additional number of population-based registries now available through the National Central Cancer Registry of China, the authors analyzed data from 72 local, population-based cancer registries (2009-2011), representing 6.5% of the population, to estimate the number of new cases and cancer deaths for 2015. Data from 22 registries were used for trend analyses (2000-2011). The results indicated that an estimated 4292,000 new cancer cases and 2814,000 cancer deaths would occur in China in 2015, with lung cancer being the most common incident cancer and the leading cause of cancer death. Stomach, esophageal, and liver cancers were also commonly diagnosed and were identified as leading causes of cancer death. Residents of rural areas had significantly higher age-standardized (Segi population) incidence and mortality rates for all cancers combined than urban residents (213.6 per 100,000 vs 191.5 per 100,000 for incidence; 149.0 per 100,000 vs 109.5 per 100,000 for mortality, respectively). For all cancers combined, the incidence rates were stable during 2000 through 2011 for males (+0.2% per year; P = .1), whereas they increased significantly (+2.2% per year; P < .05) among females. In contrast, the mortality rates since 2006 have decreased significantly for both males (-1.4% per year; P < .05) and females (-1.1% per year; P < .05). Many of the estimated cancer cases and deaths can be prevented through reducing the prevalence of risk factors, while increasing the effectiveness of clinical care delivery, particularly for those living in rural areas and in disadvantaged populations.

OBJECTIVES: (1) To review the effects of parvovirus B19 on the pregnant woman and fetus, and (2) to discuss the management of women who are exposed to, who are at risk of developing, or who develop parvovirus B19 infection in pregnancy. OUTCOMES: Maternal outcomes of parvovirus B19 including erythema infectiosum, arthropathy, anemia, and myocarditis. Fetal outcomes including spontaneous abortion, congenital anomalies, hydrops fetalis, stillbirth, and long-term effects. EVIDENCE: MEDLINE search from 1966 to January 2002 for articles relating to parvovirus B19 infection, using key words "parvovirus" and "pregnancy," and guidelines of professional organizations including the American College of Obstetricians and Gynecologists. VALUES: The evidence obtained was reviewed and evaluated by both the Maternal Fetal Medicine and Infectious Diseases Committees of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and recommendations were made according to guidelines developed by the Canadian Task Force on the Periodic Health Examination. RECOMMENDATIONS: 1. Pregnant women exposed to, or who develop symptoms of, parvovirus B19 infection should be assessed to determine if they are susceptible to infection (nonimmune) or if they have a current infection, by determining their parvovirus B19 IgG and IgM status. (II-2A) 2. If parvovirus B19 IgG is present and IgM is negative, the woman is immune and can be reassured that she will not develop infection and that the virus will not adversely affect her pregnancy. (II-2A) 3. If both parvovirus B19 IgG and IgM are negative (and the incubation period has passed), the woman is not immune and has not developed the infection. Although she may wish to minimize further exposure, leave from the workplace is controversial and is not routinely recommended. Further studies are needed in this area. (III-B) 4. If a recent parvovirus B19 infection has been diagnosed in the woman, then referral to an obstetrician or a maternal-fetal medicine specialist should be considered (III-B). The woman should be counselled regarding risks of fetal transmission, fetal loss, and hydrops. Serial ultrasounds should be performed up to 8 to 12 weeks after infection to detect the development of hydrops (III-B). If hydrops develops, referral to a maternal-fetal medicine specialist should be made and consideration should be given to fetal blood sampling and intravascular transfusion (II-2B). VALIDATION: These guidelines have been reviewed and approved by the Maternal Fetal Medicine and Infectious Diseases Committees of the SOGC, and the Council of the SOGC.

CLT, Cadaveric liver transplantation; LDLT, live donor liver transplantation; PEI, Percutanoeus ethanol injection; RF, radiofrequency; TACE, Transarterial chemoembolization; PS, Performance Status. These recommendations provide a data-supported approach to the diagnosis, staging and treatment of patients diagnosed with hepatocellular carcinoma (HCC). They are based on the following: (a) formal review and analysis of the recently-published world literature on the topic (Medline search through early 2005); (b) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines.1 (c) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the AGA Policy Statement on Guidelines2; (d) the experience of the authors in the specified topic. We have also reviewed the guidelines prepared at the time of the Monothematic Conference of the European Association for the Study of the Liver (EASL)3 and the practice of authors experienced in the field. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a category to be assigned and reported with each recommendation (Table 1). These recommendations are fully endorsed by the American Association for the Study of Liver Diseases. Over the last 5 to 8 years evidence has been accumulating in different countries that the incidence of hepatocellular carcinoma (HCC) is rising.4-9 Traditionally, the care of patients with HCC has been undertaken by hepatobiliary surgeons, interventional radiologists, and oncologists. Hepatologists in North America are not trained to perform the procedures required to treat HCC, such as alcohol injection, radiofrequency ablation, or hepatic artery catheterization, although hepatologists in Japan and elsewhere may perform many of these procedures. As a result, the role of the hepatologist traditionally has been limited to making the diagnosis and providing care of the underlying liver disease. However, more recently, the role of the hepatologist has changed. First, in many centers the development of multidisciplinary clinics has emphasized the role of the hepatologist in assessing the patient's liver disease status, and carefully managing the liver disease before and during treatment. The hepatologist has also become more actively involved in deciding what form of therapy is most appropriate and whether the patient's liver function would allow that form of therapy to be given. In addition, arising out of caring for patients with end stage liver disease, hepatologists also institute surveillance for HCC and manage the investigation of abnormal results. Finally, hepatologists are involved in the decision whether or not to offer liver transplantation to patients with HCC. There have been many reviews of various aspects of the care of patients with HCC, but only one clinical practice guideline has been published in the Western literature. The European Association for Study of the Liver (EASL) sponsored a single topic conference on HCC in 2000. The proceedings of this conference were published in 2001.3 This document largely reflected practices in Europe, and possibly North America, whereas practices in Japan are somewhat different. Definitions of the terms used in this section are given in Table 2. Surveillance for HCC involves more than simply applying a screening test or tests. Surveillance should be offered in the setting of a program or a process in which screening tests and recall procedures have been standardized and in which quality control procedures are in place. The process of surveillance also involves deciding what level of risk of HCC is high enough to trigger surveillance, what screening tests to apply and how frequently (surveillance interval), and how abnormal results should be dealt with (diagnosis and/or recall). Surveillance for HCC has become widely applied despite, until recently, the absence of evidence of benefit. There is a single randomized controlled trial of surveillance versus no surveillance that has shown a survival benefit to a strategy of 6-monthly surveillance with alphafetoprotein (AFP) and ultrasound.10 This study, which was performed in China, recruited 18,816 patients who had markers of current or prior hepatitis B infection. Adherence to surveillance was suboptimal (less than 60%) but in the subjects in the surveillance arm the HCC related mortality was reduced by 37%. These results probably represent the minimum benefit that can be expected from surveillance, because of poor compliance. In contrast, an earlier study, also conducted in China failed to show benefit, largely because patients who were diagnosed with HCC did not undergo appropriate treatment.11 Ideally, these results should be validated in other geographical areas and therefore, additional randomized controlled trials (RCT) assessing the benefits of surveillance are still considered necessary. Such trials would be difficult to undertake, but are essential to unequivocally determine the benefit of surveillance in reducing HCC mortality. The objective of HCC surveillance must be to decrease mortality from the disease. Fewer people should die from HCC, or if this is not possible, surveillance should at a minimum provide a meaningful improvement in survival duration. Other endpoints, such as stage migration (detecting earlier disease) and 5-year mortality rates are not appropriate surrogate endpoints. This has clearly been shown by analysis of the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI), which demonstrated that these endpoints did not correlate with a reduction in disease-specific mortality.12 There are several sources of bias to be considered in assessing reports of surveillance studies, such as lead-time bias and length bias. Only a RCT can eliminate these biases completely. Several studies have shown that surveillance does detect earlier disease (stage migration).13-16 However, as discussed above, this does not correlate well with reduction in disease-specific mortality. Uncontrolled studies, all subject to lead-time bias, have suggested that survival is improved after surveillance.13, 16 Surveillance for HCC is widely practiced and can generally be recommended for certain at-risk groups. HCC detected after the onset of symptoms has a dismal prognosis (0%-10% 5-year survival).17 In contrast, small HCCs can be cured with an appreciable frequency.17-21 Five-year disease-free survival exceeding 50% has been reported for both resection and liver transplantation.17, 22-30 Patients surviving free of disease for this duration must be considered cured. For these patients it is highly likely that surveillance did indeed decrease mortality. Since major advances in our ability to treat HCC are less likely to come from treating late stage disease it is therefore important to find early stage disease. The decision to enter a patient into a surveillance program is determined by the level of risk for HCC. This, in turn, is related to the incidence of HCC, and it is incidence that most people use to assess risk. However, there are no experimental data to indicate what level of risk or what incidence of HCC should trigger surveillance. Instead, decision analysis has been used to provide some guidelines as to the incidence of HCC at which surveillance may become effective. An intervention is considered effective if it provides an increase in longevity of about 100 days, i.e., about 3 months.31 Although the levels were set years ago, and may not be appropriate today, interventions that can be achieved at a cost of less than about $50,000/year of life gained are considered cost-effective.32 There are now several published decision analysis/cost-efficacy models for HCC surveillance. The models differ in the nature of the theoretical population being analyzed, and in the intervention being applied. Nonetheless, these models have several results in common. They all find that surveillance is cost-effective, although in some cases only marginally so, and most find that the efficacy of surveillance is highly dependent on the incidence of HCC. For example, Sarasin et al.33 studied a theoretical cohort of patients with Child–Pugh A cirrhosis and found that if the incidence of HCC was 1.5%/year surveillance resulted in an increase in longevity of about 3 months. However, if the incidence of HCC was 6% the increase in survival was about 9 months. This study did not include transplantation as a treatment option. Arguedas et al.,34 using a similar analysis which did include liver transplantation in a population of hepatitis C patients with cirrhosis and normal liver function, found that surveillance with either CT scanning alone or CT scanning plus ultrasound became cost-effective when the incidence of HCC was more than 1.4%. However, this study has to be interpreted cautiously, because the performance characteristics of CT scanning were derived from diagnostic studies, not surveillance studies (see Surveillance Tests). Lin et al.35 found that surveillance with AFP and ultrasound was cost-effective regardless of HCC incidence. Thus, for patients with cirrhosis of varying etiologies, surveillance should be offered when the risk of HCC is 1.5%/year or greater. Table 3 describes the groups of patients in which these limits are exceeded. These groups of patients are also discussed in more detail below. The above cost-efficacy analyses, which were restricted to cirrhotic populations, cannot be applied to hepatitis B carriers without cirrhosis. These patients, particularly in Asia and Africa, are also at risk for HCC. A cost-efficacy analysis of surveillance of hepatitis B carriers using ultrasound and AFP levels suggested that surveillance became cost-effective once the incidence of HCC exceeded 0.2%/year (Collier J and Sherman M, unpublished observations). The subgroups of hepatitis B carriers in which the incidence of HCC exceeds 0.2%/year are given in Table 3. These groups are discussed in more detail below. Beasley et al., in a prospective controlled study showed that the annual incidence of HCC in hepatitis B carriers was 0.5%.36-38 The annual incidence increased with age, so that at age 70 the incidence was 1%. The incidence in patients with known cirrhosis was 2.5%/year. The relative risk of HCC was about 100, i.e., hepatitis B carriers were 100 times more likely to develop HCC than the uninfected. Sakuma et al.39 found the incidence of HCC in male Japanese railway workers was 0.4%/year. Both these populations were male and Asian, with the hepatitis B infection likely acquired at birth or in early childhood. Uncontrolled prospective cohort studies in North America, where the epidemiology of hepatitis B is different, i.e., hepatitis is acquired later in life, have indicated that the incidence of HCC in HBV carriers varies widely.40-42 Villeneuve et al.40 found no tumors in a cohort infected with HBV and followed for 16 years. McMahon et al.41 reported an incidence of HCC of 0.26%/year in a study of HBV-infected individuals in Alaska. Sherman et al.42 described an incidence of 0.46%/year in their cohort. In Europe HCC in hepatitis B carriers occurs mainly in patients with established cirrhosis.43, 44 Non- Asian chronic carriers who are anti-HBe-positive with long-term inactive viral replication and who do not have cirrhosis seem to have little risk of developing HCC.45-48 Whether surveillance is worthwhile in this population is not clear. This is not true for Asian hepatitis B carriers without cirrhosis, who remain at risk for HCC regardless of replication status.45, 49-51 Similarly, the risk of HCC persists in long-term HBV carriers from Asia who lose HBsAg, and these patients should continue to undergo surveillance.52 In Caucasian hepatitis B carriers who lose surface antigen the risk of HCC seems to decline dramatically.53, 54 The annual incidence of HCC in male hepatitis B carriers from South East Asia only starts to exceed 0.2% at about age 4038 irrespective of presence of cirrhosis or disease activity. In contrast, in Caucasians the risk is related to inflammatory activity and the presence of cirrhosis. Therefore Asian men should undergo surveillance from age 40 onwards. HCC will occur in younger patients, but the efficacy of providing surveillance to all carriers younger than age 40 is likely to be low. The incidence of HCC in women is lower than in men, although age-specific incidence rates are hard to come by. Nonetheless, it seems appropriate to start surveillance at about age 50 in Asian women. All hepatitis B carriers with cirrhosis, regardless of age should be screened for HCC. In the presence of a history of a first degree relative with HCC surveillance should start at a younger age than 40,55 although what that age should be is hard to define. Africans with hepatitis B seem to get HCC at a younger age.56, 57 Expert opinion suggests that surveillance in these populations should also start at a younger age. Whether this is true in Blacks born elsewhere is uncertain. In Caucasian hepatitis B carriers with no cirrhosis and with inactive hepatitis, as determined by a long term normal ALT and low HBV DNA concentration44, 46, 47, 58 the incidence of HCC is probably too low to make surveillance worthwhile. However, there are additional risk factors that have to be taken into account, including older age, persistence of viral replication and co-infection with hepatitis C or HIV, or the presence of other liver diseases. Nevertheless, even in the absence of cirrhosis, adult Caucasian patients with active disease are likely at risk for HCC, and should be screened. The risk of HCC in patients with chronic hepatitis C is highest and has been best studied in patients who have established cirrhosis,59-62 in whom the incidence of HCC is between 2%-8% per year. It should be noted that these data come from clinic-based studies. There is a single prospective population-based study of the risk of HCC in patients with hepatitis C.63 In this study of 12,008 men being anti-HCV-positive conferred a 20-fold increased risk of HCC compared to anti-HCV-negative subjects. The presence or absence of cirrhosis was not evaluated. Hepatitis C infected individuals who do not have cirrhosis have a much lower risk of developing HCC.64 However, the transition from bridging fibrosis to cirrhosis cannot be determined clinically so that the clinician cannot easily determine when these patients start to develop a significant increase in risk of HCC. For this reason the EASL conference3 suggested that surveillance may be offered to patients with hepatitis C and cirrhosis or with bridging fibrosis or transition to cirrhosis. The cost-efficacy of this recommendation has not been evaluated. Based on current knowledge, all patients with hepatitis C and cirrhosis should undergo surveillance. Whether patients with bridging fibrosis should also undergo surveillance remains controversial. There have been several attempts to develop non-invasive markers to predict the stage of fibrosis65-67 and if properly validated, these could be used to determine when to initiate surveillance. Similarly, several other markers may predict a significant risk of HCC. One such marker may be the platelet count. It has been suggested that the incidence of HCC in hepatitis C cirrhosis only increases substantially once the platelet count is less than 100×109/L,62, 68, 69 regardless of liver function. This needs to be validated. Others have attempted to develop predictive indices based on panels of commonly performed serological tests such as alpha 2-macroglobulin, apolipoprotein A1, haptoglobin, bilirubin and gamma-glutamyl-transpeptidase and the AST/ALT ratio.67, 70 However, these indices have still to be validated before entering general use and cannot be recommended at present. Patients who are co-infected with HIV and either hepatitis B or hepatitis C may have more rapidly progressive liver disease71 and when they reach cirrhosis they are also at increased risk of HCC.72 The MORTAVIC study indicated that HCC was responsible for 25% of all liver deaths in the post-HAART era.73, 74 The criteria for entering co-infected patients into programs for HCC screening are the same as for mono-infected patients, i.e., criteria based on the stage and grade of liver disease as described above. The incidence of HCC in cirrhosis caused by diseases other than viral hepatitis is, with some exceptions, not accurately known. Most of the studies of the incidence of HCC in alcoholic cirrhosis date from before the identification of the hepatitis C virus. Given that hepatitis C is relatively frequent in alcoholics75-77 most of the reported HCC incidence rates in earlier studies must be over-estimates. That alcoholic cirrhosis is a risk factor for HCC is clear. In one study alcoholic liver disease accounted for 32% of all HCCs.78 In an Austrian cohort with HCC alcoholic liver disease was the risk factor in 35% of subjects.79 In the United States the approximate hospitalization rate for HCC related to alcoholic cirrhosis is 8-9/100,000/year compared to about 7/100,000/year for hepatitis C.80 This study did not determine the incidence of HCC in alcoholic liver disease, but it does confirm that alcoholic cirrhosis is a significant risk factor for HCC, probably sufficient to warrant surveillance for HCC. With the recognition of steatohepatitis as a cause of cirrhosis, has come the suspicion that this too is a risk factor for HCC. No study to date has followed a sufficiently large group of such patients for long enough to describe an incidence rate for HCC. In one cohort study of patients with HCC81 diabetes was found in 20% as the only risk factor for HCC. Whether or not these patients were cirrhotic was not noted. Non-alcoholic fatty liver disease (NAFLD) has been described in cohorts of patients with HCC.82, 83 Since the incidence of HCC in cirrhosis due to NAFLD is unknown it is not possible to assess whether surveillance might be effective or cost-efficient. No recommendations can be made whether this group should be screened for HCC or not. This does not preclude the possibility that surveillance is beneficial in this group, and future data may change this recommendation. Patients with genetic hemochromatosis (GH) who have established cirrhosis have an increased risk of HCC.84-86 The relative risk of HCC is about 20. The standardized incidence ratio for HCC in cirrhotic GH is 92.9 (95% confidence interval [CI] 25-237.9). The incidence of HCC in cirrhosis due to GH is sufficiently high (about 3%-4%/year) that these patients should be included in surveillance programs. The incidence of HCC in stage 4 primary biliary cirrhosis is about the same as in cirrhosis due to hepatitis C.87 For cirrhosis due to alpha 1-antitrypsin (AAT) or hepatitis there are data from cohort studies to accurately assess HCC incidence. There is as no evidence that treatment of chronic hepatitis B the incidence of HCC. in Europe suggested that therapy for chronic hepatitis B improved survival and reduced the incidence of A study from also indicated that i.e., the development of was with a reduced incidence of However, in these studies the rate was and the were relatively In contrast, a but controlled study from that included a cohort followed for found that the incidence of HCC was not in the A single RCT suggests that treatment of chronic hepatitis B carriers with cirrhosis does the incidence of but whether the risk reduction is sufficient that surveillance is not clear. a patient is a for surveillance before the of it seems to continue to offer surveillance even after or of inflammatory activity. There are a of studies the of treatment of chronic hepatitis C on the incidence of HCC. A single RCT in Japan suggested that the incidence of HCC was reduced in both and to These results could not be in a RCT from The results of these other studies were in a which that the benefit is mainly in who were i.e., had a and even the was A of studies in Japan compared the incidence of HCC in patients with that in These have suggested that there is a reduced incidence of HCC in However, no data that treating or hepatitis C the risk for HCC. it seems that patients with hepatitis C and cirrhosis who have achieved viral on therapy at for continue to undergo surveillance. that patients with or chronic hepatitis B or C may show of fibrosis sufficient to suggest of cirrhosis. The risk of HCC in these patients probably does not decrease with the improvement in There are many about the of HCC in these patients, but one factor seems to be that of and are necessary. The required to initiate the probably occur many years before the disease and so the of HCC remains even if fibrosis fibrosis is not a reason to surveillance. There are a of factors with an increased risk of HCC that are in patients at risk for developing HCC. These include an AFP presence of small and large on to and increased for antigen or of the Although such patients are at more risk of developing HCC they will likely be in surveillance programs because of other risk factors such as cirrhosis or chronic hepatitis The increased does not a change in surveillance Patients at high risk for developing HCC should be into surveillance programs The at-risk groups are in There are several for screening patients on the liver Patients should be screened for HCC to small tumors that might and to patients who develop that exceeds the guidelines for In addition, in the United the current criteria the development of HCC provides liver Thus, it would seem to be in a patient's to have a small HCC diagnosed on the liver One cost-efficacy analysis has suggested that the increase in longevity the cohort of patients is because although there may be an increase in longevity in who develop HCC, it is by the of longevity in other patients on the are so that the patient with HCC can have In contrast, identification of HCC that exceeds and of such patients, is beneficial to other patients on the analysis suggested that there were benefits to treating patients with HCC on the with either resection or The benefit in on the length of the The the the the benefit of In the United States patients to be for liver transplantation with an AFP without of HCC, even in the absence of a on It is important to that AFP is being used for diagnosis, not surveillance. Nonetheless, the performance characteristics of even as a diagnostic test are particularly in the absence of a on (see 2. Patients on the should be screened for HCC because in the the development of HCC increased for and because to for HCC that patients may develop HCC and criteria without the being that is used to determine the presence or absence of a disease must be validated using a of that determine how well the test in the disease no test is The are the and which are For single test and the underlying disease, as the diagnostic of test is related to the of the underlying disease in the population being This is by the and predictive i.e., the rates at which or results are An of the of a test can also be free of the of disease incidence by using the This is a of the and the performance characteristics of a test the of the test results the for diagnosis can be from the a of the of the test results. An important additional is that the history of liver is not the same as for clinical In rates of may be different than rates in clinically may not to clinically in all it cannot be that all found on surveillance will develop into Similarly, the performance characteristics of a test used to disease as a screening are not the same as when the test is used for Therefore one cannot the performance characteristics of a test used in diagnosis CT and the and to the surveillance tests into serological and the serological tests the performance characteristics of AFP have been best analysis of AFP used as a diagnostic test suggests that a of about provides the between and However, at this level the is only i.e., AFP surveillance would of HCC if a of is used as the trigger for This is for general a is used a of HCCs will be the AFP is the to reducing the that more HCCs would be but at the cost of a progressive increase in the This analysis was performed in a control study where the of HCC was set at this the predictive of an AFP of was However, if the HCC rates were more in most liver i.e., about the predictive of an AFP of is only and even at a of the is only In cohorts surveillance the incidence of HCC may be even lower than on the criteria for into surveillance. For example, in hepatitis B carriers infected at birth the incidence of HCC is less than 1%. AFP is an screening AFP still has a role in the diagnosis of HCC, in cirrhotic patients with a in the liver an AFP than has a high predictive for a AFP has been clearly shown to be a risk factor for Thus, the AFP can be used to patients at but to have limited as a screening serological test used to HCC is the also known as by Most reports on the use of have the use of this test in a diagnostic than for surveillance. Although there are reports of use in a surveillance these do not provide sufficient for use of this There are also reports that is a marker for by this would also suggest that is not a screening A screening test should be to early

Standard survival data measure the time span from some time origin until the occurrence of one type of event. If several types of events occur, a model describing progression to each of these competing risks is needed. Multi-state models generalize competing risks models by also describing transitions to intermediate events. Methods to analyze such models have been developed over the last two decades. Fortunately, most of the analyzes can be performed within the standard statistical packages, but may require some extra effort with respect to data preparation and programming. This tutorial aims to review statistical methods for the analysis of competing risks and multi-state models. Although some conceptual issues are covered, the emphasis is on practical issues like data preparation, estimation of the effect of covariates, and estimation of cumulative incidence functions and state and transition probabilities. Examples of analysis with standard software are shown.

Human skin is a remarkable organ. It consists of an integrated, stretchable network of sensors that relay information about tactile and thermal stimuli to the brain, allowing us to maneuver within our environment safely and effectively. Interest in large-area networks of electronic devices inspired by human skin is motivated by the promise of creating autonomous intelligent robots and biomimetic prosthetics, among other applications. The development of electronic networks comprised of flexible, stretchable, and robust devices that are compatible with large-area implementation and integrated with multiple functionalities is a testament to the progress in developing an electronic skin (e-skin) akin to human skin. E-skins are already capable of providing augmented performance over their organic counterpart, both in superior spatial resolution and thermal sensitivity. They could be further improved through the incorporation of additional functionalities (e.g., chemical and biological sensing) and desired properties (e.g., biodegradability and self-powering). Continued rapid progress in this area is promising for the development of a fully integrated e-skin in the near future.

The human brain is often considered to be the most cognitively capable among mammalian brains and to be much larger than expected for a mammal of our body size. Although the number of neurons is generally assumed to be a determinant of computational power, and despite the widespread quotes that the human brain contains 100 billion neurons and ten times more glial cells, the absolute number of neurons and glial cells in the human brain remains unknown. Here we determine these numbers by using the isotropic fractionator and compare them with the expected values for a human-sized primate. We find that the adult male human brain contains on average 86.1 +/- 8.1 billion NeuN-positive cells ("neurons") and 84.6 +/- 9.8 billion NeuN-negative ("nonneuronal") cells. With only 19% of all neurons located in the cerebral cortex, greater cortical size (representing 82% of total brain mass) in humans compared with other primates does not reflect an increased relative number of cortical neurons. The ratios between glial cells and neurons in the human brain structures are similar to those found in other primates, and their numbers of cells match those expected for a primate of human proportions. These findings challenge the common view that humans stand out from other primates in their brain composition and indicate that, with regard to numbers of neuronal and nonneuronal cells, the human brain is an isometrically scaled-up primate brain.

Answer questions and earn CME/CNE To update the melanoma staging system of the American Joint Committee on Cancer (AJCC) a large database was assembled comprising >46,000 patients from 10 centers worldwide with stages I, II, and III melanoma diagnosed since 1998. Based on analyses of this new database, the existing seventh edition AJCC stage IV database, and contemporary clinical trial data, the AJCC Melanoma Expert Panel introduced several important changes to the Tumor, Nodes, Metastasis (TNM) classification and stage grouping criteria. Key changes in the eighth edition AJCC Cancer Staging Manual include: 1) tumor thickness measurements to be recorded to the nearest 0.1 mm, not 0.01 mm; 2) definitions of T1a and T1b are revised (T1a, <0.8 mm without ulceration; T1b, 0.8-1.0 mm with or without ulceration or <0.8 mm with ulceration), with mitotic rate no longer a T category criterion; 3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB); 4) the N category descriptors "microscopic" and "macroscopic" for regional node metastasis are redefined as "clinically occult" and "clinically apparent"; 5) prognostic stage III groupings are based on N category criteria and T category criteria (ie, primary tumor thickness and ulceration) and increased from 3 to 4 subgroups (stages IIIA-IIID); 6) definitions of N subcategories are revised, with the presence of microsatellites, satellites, or in-transit metastases now categorized as N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes, if any; 7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and 8) a new M1d designation is added for central nervous system metastases. This evidence-based revision of the AJCC melanoma staging system will guide patient treatment, provide better prognostic estimates, and refine stratification of patients entering clinical trials. CA Cancer J Clin 2017;67:472-492. © 2017 American Cancer Society.

A new derivation of the GLYCAM06 force field, which removes its previous specificity for carbohydrates, and its dependency on the AMBER force field and parameters, is presented. All pertinent force field terms have been explicitly specified and so no default or generic parameters are employed. The new GLYCAM is no longer limited to any particular class of biomolecules, but is extendible to all molecular classes in the spirit of a small-molecule force field. The torsion terms in the present work were all derived from quantum mechanical data from a collection of minimal molecular fragments and related small molecules. For carbohydrates, there is now a single parameter set applicable to both alpha- and beta-anomers and to all monosaccharide ring sizes and conformations. We demonstrate that deriving dihedral parameters by fitting to QM data for internal rotational energy curves for representative small molecules generally leads to correct rotamer populations in molecular dynamics simulations, and that this approach removes the need for phase corrections in the dihedral terms. However, we note that there are cases where this approach is inadequate. Reported here are the basic components of the new force field as well as an illustration of its extension to carbohydrates. In addition to reproducing the gas-phase properties of an array of small test molecules, condensed-phase simulations employing GLYCAM06 are shown to reproduce rotamer populations for key small molecules and representative biopolymer building blocks in explicit water, as well as crystalline lattice properties, such as unit cell dimensions, and vibrational frequencies.

In medicine, nanotechnology has sparked a rapidly growing interest as it promises to solve a number of issues associated with conventional therapeutic agents, including their poor water solubility (at least, for most anticancer drugs), lack of targeting capability, nonspecific distribution, systemic toxicity, and low therapeutic index. Over the past several decades, remarkable progress has been made in the development and application of engineered nanoparticles to treat cancer more effectively. For example, therapeutic agents have been integrated with nanoparticles engineered with optimal sizes, shapes, and surface properties to increase their solubility, prolong their circulation half-life, improve their biodistribution, and reduce their immunogenicity. Nanoparticles and their payloads have also been favorably delivered into tumors by taking advantage of the pathophysiological conditions, such as the enhanced permeability and retention effect, and the spatial variations in the pH value. Additionally, targeting ligands (e.g., small organic molecules, peptides, antibodies, and nucleic acids) have been added to the surface of nanoparticles to specifically target cancerous cells through selective binding to the receptors overexpressed on their surface. Furthermore, it has been demonstrated that multiple types of therapeutic drugs and/or diagnostic agents (e.g., contrast agents) could be delivered through the same carrier to enable combination therapy with a potential to overcome multidrug resistance, and real-time readout on the treatment efficacy. It is anticipated that precisely engineered nanoparticles will emerge as the next-generation platform for cancer therapy and many other biomedical applications.

Abstract Plasmonics is a research area merging the fields of optics and nanoelectronics by confining light with relatively large free‐space wavelength to the nanometer scale ‐ thereby enabling a family of novel devices. Current plasmonic devices at telecommunication and optical frequencies face significant challenges due to losses encountered in the constituent plasmonic materials. These large losses seriously limit the practicality of these metals for many novel applications. This paper provides an overview of alternative plasmonic materials along with motivation for each material choice and important aspects of fabrication. A comparative study of various materials including metals, metal alloys and heavily doped semiconductors is presented. The performance of each material is evaluated based on quality factors defined for each class of plasmonic devices. Most importantly, this paper outlines an approach for realizing optimal plasmonic material properties for specific frequencies and applications, thereby providing a reference for those searching for better plasmonic materials.

Full-length cDNAs are essential for functional analysis of plant genes in the post-sequencing era of the Arabidopsis genome. Recently, cDNA microarray analysis has been developed for quantitative analysis of global and simultaneous analysis of expression profiles. We have prepared a full-length cDNA microarray containing approximately 7000 independent, full-length cDNA groups to analyse the expression profiles of genes under drought, cold (low temperature) and high-salinity stress conditions over time. The transcripts of 53, 277 and 194 genes increased after cold, drought and high-salinity treatments, respectively, more than fivefold compared with the control genes. We also identified many highly drought-, cold- or high-salinity- stress-inducible genes. However, we observed strong relationships in the expression of these stress-responsive genes based on Venn diagram analysis, and found 22 stress-inducible genes that responded to all three stresses. Several gene groups showing different expression profiles were identified by analysis of their expression patterns during stress-responsive gene induction. The cold-inducible genes were classified into at least two gene groups from their expression profiles. DREB1A was included in a group whose expression peaked at 2 h after cold treatment. Among the drought, cold or high-salinity stress-inducible genes identified, we found 40 transcription factor genes (corresponding to approximately 11% of all stress-inducible genes identified), suggesting that various transcriptional regulatory mechanisms function in the drought, cold or high-salinity stress signal transduction pathways.

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.

Homogeneous and dense arrays of ZnO nanowires were synthesized on silicon wafers (and many other substrates) using a mild solution process at 90 °C. Uniform ZnO nanocrystals were deposited to act as seeds for subsequent hydrothermal nanowire growth, which yielded single-crystalline ZnO nanowires grown along the [0001] direction and oriented perpendicular to the wafer surface (see picture; scale bar=1μm). The photoluminescence and lasing behavior of the arrays has been studied as a function of annealing treatment conditions.

A new method, embedded-3D printing (e-3DP), is reported for fabricating strain sensors within highly conformal and extensible elastomeric matrices. e-3DP allows soft sensors to be created in nearly arbitrary planar and 3D motifs in a highly programmable and seamless manner. Several embodiments are demonstrated and sensor performance is characterized. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

OBJECTIVE: Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients. METHODS: In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4). RESULTS: Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups. CONCLUSION: In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

BACKGOUND: To figure out whether diabetes is a risk factor influencing the progression and prognosis of 2019 novel coronavirus disease (COVID-19). METHODS: A total of 174 consecutive patients confirmed with COVID-19 were studied. Demographic data, medical history, symptoms and signs, laboratory findings, chest computed tomography (CT) as well the treatment measures were collected and analysed. RESULTS: We found that COVID-19 patients without other comorbidities but with diabetes (n = 24) were at higher risk of severe pneumonia, release of tissue injury-related enzymes, excessive uncontrolled inflammation responses and hypercoagulable state associated with dysregulation of glucose metabolism. Furthermore, serum levels of inflammation-related biomarkers such as IL-6, C-reactive protein, serum ferritin and coagulation index, D-dimer, were significantly higher (P < .01) in diabetic patients compared with those without, suggesting that patients with diabetes are more susceptible to an inflammatory storm eventually leading to rapid deterioration of COVID-19. CONCLUSIONS: Our data support the notion that diabetes should be considered as a risk factor for a rapid progression and bad prognosis of COVID-19. More intensive attention should be paid to patients with diabetes, in case of rapid deterioration.

OBJECTIVE: We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS. METHODS: Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjögren's International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American–European Consensus Group (AECG) criteria, a model-based “gold standard”obtained from latent class analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development. RESULTS: Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 of the following 3: 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, or 3) presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples. Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications. CONCLUSION: These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks.

The effective use of ring strain has been applied to considerable advantage for the construction of complex systems. The focus here is directed towards cyclopropanes as building blocks for organic synthesis. Although thermodynamics should take the side of synthetic chemists, only a specific substitution pattern at the cyclopropane ring allows for particularly mild, efficient, and selective transformations. The required decrease in the activation barrier is achieved by the combined effects of vicinal electron-donating and electron-accepting moieties. This Review highlights the appropriate tools for successfully employing donor-acceptor cyclopropanes in ring-opening reactions, cycloadditions, and rearrangements.

The objective of this paper was to present estimates on the prevalence of musculoskeletal pain of five different anatomical areas and ten anatomical sites, and their consequences and risk groups in the general Dutch population. Cross-sectional data from a population-based study of a sex-age stratified sample of Dutch inhabitants of 25 years and older were used. With a postal questionnaire data was assessed on musculoskeletal pain, additional pain characteristics (location, duration, course), its consequences (utilization of health care, sick leave and limitation in daily life) and general socio-demographic characteristics. The top three of self-reported musculoskeletal pain (point prevalence (P(p)) with 95% confidence interval (CI)) was: (1). low back pain, P(p)=26.9% (95% CI 25.5-28.3); (2). shoulder pain, P(p)=20.9% (95% CI 19.6-22.2); and (3). neck pain, P(p)=20.6% (95% CI 19.3-21.9). In most cases the pain was described as continuous or recurrent and mild. In every three out of ten cases the complaints about pain were accompanied by limitations in daily living. Between 33 and 42% of those with complaints consulted their general practitioner about their pain. With the exception of persons who are work disabled, general sociodemographic characteristics cannot be used to identify high risk groups. Musculoskeletal pain is common in all subgroups of the population and has far-reaching consequences for health, work and the use of health care.

Identification of ectomycorrhizal (ECM) fungi is often achieved through comparisons of ribosomal DNA internal transcribed spacer (ITS) sequences with accessioned sequences deposited in public databases. A major problem encountered is that annotation of the sequences in these databases is not always complete or trustworthy. In order to overcome this deficiency, we report on UNITE, an open-access database. UNITE comprises well annotated fungal ITS sequences from well defined herbarium specimens that include full herbarium reference identification data, collector/source and ecological data. At present UNITE contains 758 ITS sequences from 455 species and 67 genera of ECM fungi. UNITE can be searched by taxon name, via sequence similarity using blastn, and via phylogenetic sequence identification using galaxie. Following implementation, galaxie performs a phylogenetic analysis of the query sequence after alignment either to pre-existing generic alignments, or to matches retrieved from a blast search on the UNITE data. It should be noted that the current version of UNITE is dedicated to the reliable identification of ECM fungi. The UNITE database is accessible through the URL http://unite.zbi.ee