Demographic and clinical associations to employment status in older-age bipolar disorder: Analysis from the GAGE-BD database project.

OBJECTIVE: The current literature on employment in older adults with bipolar disorder (OABD) is limited. Using the Global Aging and Geriatric Experiments in Bipolar Disorder Database (GAGE-BD), we examined the relationship of occupational status in OABD to other demographic and clinical characteristics. METHODS: Seven hundred and thirty-eight participants from 11 international samples with data on educational level and occupational status were included. Employment status was dichotomized as employed versus unemployed. Generalized linear mixed models with random intercepts for the study cohort were used to examine the relationship between baseline characteristics and employment. Predictors in the models included baseline demographics, education, psychiatric symptom severity, psychiatric comorbidity, somatic comorbidity, and prior psychiatric hospitalizations. RESULTS: In the sample, 23.6% (n = 174) were employed, while 76.4% were unemployed (n = 564). In multivariable logistic regression models, less education, older age, a history of both anxiety and substance/alcohol use disorders, more prior psychiatric hospitalizations, and higher levels of BD depression severity were associated with greater odds of unemployment. In the subsample of individuals less than 65 years of age, findings were similar. No significant association between manic symptoms, gender, age of onset, or employment status was observed. CONCLUSION: Results suggest an association between educational level, age, psychiatric severity and comorbidity in relation to employment in OABD. Implications include the need for management of psychiatric symptoms and comorbidity across the lifespan, as well as improving educational access for people with BD and skills training or other support for those with work-life breaks to re-enter employment and optimize the overall outcome.

Managing the Long-Term Effects of Psychological Abuse on (Im)migrant Domestic Workers.

While researchers have highlighted the emotional distress of migrant domestic workers who experience abuse by employers, less is known about long-term effects of the psychological abuse that they experience. Drawing from a broader ethnographic study of Filipino and Indonesian migration to Chile, we analyze three Filipina domestic workers' migration narratives to examine how they narrate and manage the long-term effects of psychological abuse in the domestic workplace that they experienced more than ten years earlier. Building on insights from medical anthropology and using narrative analysis, we contribute to discussions on migrants' mental health and psychosocial wellbeing by showing how these migrants seek to make meaningful sense of their previous experiences to deal with the enduring effects. We show that they construct alternative narratives that foreground their experiences as linked to structural factors and suggest that their psychosocial wellbeing is linked to their ability to subvert or derive meaning from earlier experiences of structural violence.

Research priorities for children with neurological impairment and medical complexity in high-income countries.

AIM: To identify the highest-priority clinical research areas related to children with neurological impairment and medical complexity among clinicians and caregivers. METHOD: A modified, three-stage Delphi study using online surveys and guided by a steering committee was completed. In round 1, clinicians and family caregivers suggested clinical topics and related questions that require research to support this subgroup of children. After refinement of the suggestions by the steering committee, participants contributed to 1 (family caregivers) or 2 (clinicians) subsequent rounds to develop a prioritized list. RESULTS: A diverse international expert panel consisting of 49 clinicians and 12 family caregivers provided 601 responses. Responses were distilled into 26 clinical topics comprising 126 related questions. The top clinical topics prioritized for research were irritability and pain, child mental health, disorders of tone, polypharmacy, sleep, aspiration, behavior, dysautonomia, and feeding intolerance. The clinician expert panel also prioritized 10 specific research questions. INTERPRETATION: Study findings support a research agenda for children with neurological impairment and medical complexity focused on addressing clinical questions, prioritized by an international group of clinicians and caregivers.

Postoperative delirium and its relationship with biomarkers for dementia: a meta-analysis.

OBJECTIVES: This study seeks to identify Alzheimer's and related dementias (ADRD) biomarkers associated with postoperative delirium (POD) via meta-analysis. DESIGN: A comprehensive search was conducted. Studies met the following inclusion criteria: >18 years of age, identified POD with standardized assessment, and biomarker measured in the AT(N)-X (A = amyloid, T = tau, (N)=neurodegeneration, X-Other) framework. Exclusion criteria: focus on prediction of delirium, delirium superimposed on dementia, other neurologic or psychiatric disorders, or terminal delirium. Reviewers extracted and synthesized data for the meta-analysis. SETTING: Meta-analysis. PARTICIPANTS: Patients with POD. MEASUREMENTS: Primary outcome: association between POD and ATN-X biomarkers. Secondary outcomes involved sample heterogeneity. RESULTS: 28 studies were included in this meta-analysis. Studies focused on inflammatory and neuronal injury biomarkers; there were an insufficient number of studies for amyloid and tau biomarker analysis. Two inflammatory biomarkers (IL-6, and CRP) showed a significant relationship with POD (IL-6 n = 10, standardized mean difference (SMD): 0.53, 95% CI: 0.36-0.70; CRP n = 14, SMD: 0.53, 95% CI: 0.33-0.74). Two neuronal injury biomarkers (blood-based S100B and NfL) were positively associated with POD (S100B n = 5, SMD: 0.40, 95% CI: 0.11-0.69; NFL n = 2, SMD: 0.93, 95% CI: 0.28-1.57). Of note, many analyses were impacted by significant study heterogeneity. CONCLUSIONS: This meta-analysis identified an association between certain inflammatory and neuronal injury biomarkers and POD. Future studies will need to corroborate these relationships and include amyloid and tau biomarkers in order to better understand the relationship between POD and ADRD.

Depression in multiple sclerosis across the adult lifespan.

OBJECTIVES: The objective of this study is to examine the burden of depressive symptoms across the adult age span in people with multiple sclerosis (MS) and test if the relationship between depressive symptoms and MS characteristics vary across age groups. METHODS: In analyses of the MS Partners Advancing Technology and Health Solutions (MS PATHS) network of adults with MS, we compared the prevalence of depression in MS PATHS with non-MS controls across age and evaluated for effect modification by age in the association between depressive symptoms and clinical and neuroperformance measures via multivariable-adjusted regression models. RESULTS: In total, 13,821 individuals with MS were included. The prevalence of depression was higher in MS versus non-MS controls, but was similar between men/women across age. The association between depression and processing speed (PST; p for interaction = 0.009) or walking speed (p for interaction = 0.04) varied by age. For example, younger depressed individuals had 0.45 standard deviation (SD) (95% confidence interval (CI) = -0.62, -0.29) worse PST Z-scores versus non-depressed younger participants, whereas older depressed individuals had 0.20 SD (95% CI = -0.32, -0.08) worse PST Z-scores versus non-depressed older participants. CONCLUSION: Depressive symptoms and age should be considered when interpreting measures of walking speed and cognitive function; these findings may have implications for analyses of neuroperformance change.

Association of Depressive Symptoms With Postoperative Delirium and CSF Biomarkers for Alzheimer's Disease Among Hip Fracture Patients.

OBJECTIVES: While there is growing evidence of an association between depressive symptoms and postoperative delirium, the underlying pathophysiological mechanisms remain unknown. The goal of this study was to explore the association between depression and postoperative delirium in hip fracture patients, and to examine Alzheimer's disease (AD) pathology as a potential underlying mechanism linking depressive symptoms and delirium. METHODS: Patients 65 years old or older (N = 199) who were undergoing hip fracture repair and enrolled in the study "A Strategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients" completed the 15-item Geriatric Depression Scale (GDS-15) preoperatively. Cerebrospinal fluid (CSF) was obtained during spinal anesthesia and assayed for amyloid-beta (Aß) 40, 42, total tau (t-tau), and phosphorylated tau (p-tau)181. RESULTS: For every one point increase in GDS-15, there was a 13% increase in odds of postoperative delirium, adjusted for baseline cognition (MMSE), age, sex, race, education and CSF AD biomarkers (OR = 1.13, 95%CI = 1.02-1.25). Both CSF Aß42/t-tau (ß = -1.52, 95%CI = -2.1 to -0.05) and Aß42/p-tau181 (ß = -0.29, 95%CI = -0.48 to -0.09) were inversely associated with higher GDS-15 scores, where lower ratios indicate greater AD pathology. In an analysis to identify the strongest predictors of delirium out of 18 variables, GDS-15 had the highest classification accuracy for postoperative delirium and was a stronger predictor of delirium than both cognition and AD biomarkers. CONCLUSIONS: In older adults undergoing hip fracture repair, depressive symptoms were associated with underlying AD pathology and postoperative delirium. Mild baseline depressive symptoms were the strongest predictor of postoperative delirium, and may represent a dementia prodrome.

Health professionals' perception of the New Zealand National Child Protection Alert System: An online survey.

AIM: To describe the multi-disciplinary child protection teams which administer the National Child Protection Alert System in District Health Boards in New Zealand and the understanding and perceptions of that system held by team members. METHODS: This is a mixed-method observational study. In December 2016 and January 2017, all child protection alert system multi-disciplinary team members were invited to participate in an online survey. Quantitative data were expressed with simple descriptive statistics. Qualitative findings were analysed using thematic analysis. RESULTS: Ninety-one (56.9%) of 160 team members nationwide completed the survey. All 20 District Health Boards and multiple disciplines were represented. Most respondents agreed that they received good information to make decisions (74/90, 82.2%), that it was usually easy to reach consensus (82/91, 90.1%), that the system helped to keep children safe (72/91, 79.1%) and that it did not stigmatise families (49/91, 53.9%). Qualitative analysis identified considerable variation in understanding of the system and a need for more training to support more consistent implementation of the system. CONCLUSIONS: Overall, health professionals responsible for the child protection alert system regard it positively but express a need for more training for team members and front-line staff to maximise the system's potential and minimise any risk of stigmatisation.

Comparison of DNA fragmentation levels in spermatozoa with different sex chromosome complements.

RESEARCH QUESTION: Do spermatozoa with different sex chromosome complements (X and Y; aneuploidy and monosomy) exhibit different degrees of DNA damage? DESIGN: A prospective, observational study to measure the DNA fragmentation level and sex chromosome complement simultaneously using combined sperm chromosome dispersion (SCD) and fluorescence in-situ hybridization tests. Two methods were used to evaluate SCD images: a traditional semi-quantitative method to categorize halo size and a newly developed quantitative method based on the Matlab image analysis programme to more precisely measure the halo area and calculate the halo size index (HSI). RESULTS: The HSI (which was inversely proportional to DNA fragmentation level) of Y chromosome-bearing spermatozoa was significantly (P < 0.05) lower than that of X chromosome-bearing spermatozoa in both normozoospermic and pathozoospermic groups. The HSI of sex chromosome-aneuploid spermatozoa was also significantly (P < 0.05) lower than that of monosomic spermatozoa. CONCLUSIONS: Our results indicated that Y chromosome-bearing spermatozoa are more susceptible to DNA damage than X chromosome-bearing spermatozoa, and the segregation errors during the meiotic division of spermatogenesis (resulting in aneuploidy) constitute an important contributory cause of DNA damage.

Depressive symptoms in relation to clinical symptom onset of mild cognitive impairment.

ABSTRACTObjective:There is increasing evidence of an association between depressive symptoms and mild cognitive impairment (MCI) in cross-sectional studies, but the longitudinal association between depressive symptoms and risk of MCI onset is less clear. The authors investigated whether baseline symptom severity of depression was predictive of time to onset of symptoms of MCI. METHOD: These analyses included 300 participants from the BIOCARD study, a cohort of individuals who were cognitively normal at baseline (mean age = 57.4 years) and followed for up to 20 years (mean follow-up = 2.5 years). Depression symptom severity was measured using the Hamilton Depression Scale (HAM-D). The authors assessed the association between dichotomous and continuous HAM-D and time to onset of MCI within 7 years versus after 7 years from baseline (reflecting the mean time from baseline to onset of clinical symptoms in the cohort) using Cox regression models adjusted for gender, age, and education. RESULTS: At baseline, subjects had a mean HAM-D score of 2.2 (SD = 2.8). Higher baseline HAM-D scores were associated with an increased risk of progression from normal cognition to clinical symptom onset ≤ 7 years from baseline (p = 0.043), but not with progression > 7 years from baseline (p = 0.194). These findings remained significant after adjustment for baseline cognition. CONCLUSIONS: These results suggest that low levels of depressive symptoms may be predictive of clinical symptom onset within approximately 7 years among cognitively normal individuals and may be useful in identifying persons at risk for MCI due to Alzheimer's disease.

Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients.

The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z-score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool.

The changing pattern of uterine contractions before and after fresh embryo transfer and its relation to clinical outcome.

In this prospective cohort study of 286 women undergoing fresh embryo transfer after IVF, uterine contraction frequency and direction were measured before (-5 min), 5 min after (+5 min) and 60 min after (+60 min) embryo transfer. Mean ± SD uterine contraction frequency at -5 min was 1.8 ± 1.1 contractions per min, increasing significantly (P < 0.05) to 2.0 ± 1.1 at +5 min, and returning back to baseline 1.8 ± 1.1 at +60 min. At -5 min, the proportion of women the with retrograde, antegrade, indeterminate direction and absent contractions were 33%, 44%, 17% and 6%; at +5 min, 40%, 42%, 13% and 5%, and at +60 min, 42%, 38%, 14% and 6%. No significant change was observed in the proportion of direction at these three time points. Logistic regression analysis showed live birth rate was significantly reduced in older women (P = 0.035) and in those with higher uterine contraction frequency at +5 min (P = 0.006). Frequency of uterine contraction immediately after embryo transfer (+5 min) seemed to be a significant predictor of IVF outcome and may help to identify women who could benefit from the use of muscle relaxant therapy to improve outcome.

Changes in dural sac caliber with standing MRI improve correlation with symptoms of lumbar spinal stenosis.

PURPOSE: Weight bearing does alter the dimension of lumbar spinal canal, but no study has analyzed its clinical correlation. This study aims to evaluate whether the changes in dural sac cross-sectional area (DSCA) and sagittal anteroposterior (AP) diameter on standing magnetic resonance imaging (MRI) correlate better with clinical symptoms of lumbar spinal stenosis. METHODS: Seventy consecutive patients with neurogenic claudication were prospectively recruited to undergo a 0.25-T MRI examination performed in supine and standing positions. Clinical symptoms including the walking distance, Visual Analogue Score of leg pain, Chinese Oswestry Disability Index, and short form-12 were assessed. DSCA and sagittal AP diameter at the most constricted spinal level on supine and standing positions were measured and correlated with each clinical symptom by Pearson correlation coefficients (r). RESULTS: DSCA and AP diameter on standing MRI and their % changes from supine to standing showed significant (r = 0.55, 0.53, -0.44, -0.43; p < 0.001) and better correlations than those on supine MRI (r = 0.39, 0.42; p < 0.001) with walking distance. Significant correlations were also found between dural sac calibers on standing MRI and leg pain scores (r = -0.20, r = -0.25; p < 0.05). Patients walking ≤500 m had a significantly smaller DSCA, narrower AP diameter and greater % change in dural sac calibers (p < 0.01) than those walking >500 m. A >30% reduction of DSCA and AP diameter was observed in patients with worse claudication distance (p < 0.05). CONCLUSION: DSCA and sagittal AP diameter on standing MRI correlate significantly and better than findings on supine MRI with claudication symptoms. Standing MRI demonstrates dynamic changes of dural sac and provides an additional value to supine MRI in correlating clinical symptoms of lumbar spinal stenosis.

Assessment of the embryo flash position and migration with 3D ultrasound within 60 min of embryo transfer.

STUDY QUESTION: Does the air bubble (embryo flash) position and migration as visualized with 3D ultrasound (US) within 60 min of embryo transfer correlate with clinical outcome following fresh ART transfer cycles? SUMMARY ANSWER: The location of the embryo flash and the direction of its movement at 60 min, but not at 1 or 5 min after transfer, are associated with clinical pregnancy. WHAT IS KNOWN ALREADY: Studies assessing the relation between the pregnancy rate and the position of the catheter tip and/or the position of the air bubbles following embryo transfer show conflicting results to date. STUDY DESIGN, SIZE AND DURATION: This was a prospective cohort study including 277 infertile women undergoing ART between July 2011 and August 2013. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Good prognosis patients undergoing fresh ART cycles within a single tertiary University unit were assessed by 3D US at 1, 5 and 60 min after embryo transfer. The distance of the embryo flash from the fundus was measured at these time points, along with the direction of the embryo flash movement within 60 min of transfer. MAIN RESULTS AND THE ROLE OF CHANCE: Within 60 min of embryo transfer, 76.4% (198/259) of the embryo flashes migrated towards the fundus, 12.4% (32/259) migrated towards the cervix and 11.2% (29/259) remained static. There was no significant association between the embryo position or movement and the pregnancy rate at 1 and 5 min. At 60 min, however, the pregnancy and implantation rates among subjects with embryo flashes located <15 mm from the fundus was significantly higher than those with embryo flashes located >15 mm from the fundus (46.5 and 32.8% versus 25.8 and 18.2%, respectively; P < 0.05). The pregnancy and implantation rates when the embryo flash was seen moving towards the cervix (25.0 and 15.0%) was significantly lower (P < 0.05 and P < 0.01, respectively) compared with those remaining static (55.2 and 37.7%) or moving towards the fundus (45.5 and 32.8%). LIMITATIONS AND REASONS FOR CAUTION: Although the air bubbles seen at the time of embryo transfer are thought to represent the position of the embryo, they are in fact a surrogate marker of the embryo itself, as this cannot be directly visualized by US. WIDER IMPLICATIONS OF THE FINDINGS: Following embryo transfer the majority, but not all, embryo flashes undergo significant migration towards the fundus. The location of the embryo flash and the direction of its movement at 60 min, but not at 1 or 5 min after transfer, is associated with clinical outcome. These findings may challenge the traditional notion that the exact position of the embryo flash immediately following embryo transfer is related to clinical outcome. STUDY FUNDING/COMPETING INTERESTS: The authors have no relevant funding or conflicts of interest to disclose.

Change in presurgical diagnostic imaging evaluation affects subsequent pediatric epilepsy surgery outcome.

OBJECTIVE: Since 2008, we have changed our presurgical diagnostic imaging evaluation for medically refractory focal epilepsy to include high-resolution epilepsy protocol on 3 T magnetic resonance imaging (MRI), and combined magnetoencephalography and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) in selected patients with normal or subtle changes on MRI or discordant diagnostic tests. The aim of this study was to evaluate the effectiveness of the change in imaging practice on epilepsy surgery outcome in a tertiary pediatric epilepsy surgery center. METHODS: The change in practice occurred in early 2008, and patients were classified based on old or new practice. The patient characteristics, surgical variables, and seizure-free surgical outcome were compared, and the trend in seizure-free outcome over time was assessed. RESULTS: There was a trend for increased abnormal MRI (92% vs. 86%, respectively, p = 0.062), and increased utilization of FDG-PET (34% vs. 3% respectively, p < 0.001) with new relative to old practice. There were no statistically significant differences in invasive monitoring, location, and type of surgery and histology between the two periods (all p > 0.05). During the old practice, there was no statistically significant change in yearly trend of seizure-free outcome (odds ratio [OR] 0.960, 95% confidence interval [CI] 0.875-1.053, p = 0.386). The change in practice in 2008 was associated with a significant improvement in seizure-free outcome (OR 1.535, 95% CI 1.100-2.142, p = 0.012). During the new practice, there was a significant positive trend in yearly seizure-free outcome (OR 1.219, 95% CI 1.053-1.411, p = 0.008), after adjusting for age at seizure onset, invasive monitoring, location and type of surgery, histology, MRI, magnetoencephalography, and FDG-PET. SIGNIFICANCE: We have found an improvement in seizure-free surgical outcome following the change in imaging practice. This study highlights the importance of optimizing and improving presurgical diagnostic imaging evaluation to improve surgical outcome.

Predictors of intellectual functioning after epilepsy surgery in childhood: The role of socioeconomic status.

OBJECTIVE: The objective of this study was to evaluate the association between socioeconomic status and intellectual functioning in children with medically refractory epilepsy, before and after resective epilepsy surgery. Family environment is a strong contributor to cognitive development in children and has been recently shown to play a significant role in intellectual outcome after surgery in children with epilepsy. METHODS: One hundred children who had undergone resective epilepsy surgery and completed preoperative and postoperative assessments of IQ as part of clinical care were included in the study. We evaluated the impact of epilepsy-related variables, income quintile, and residence location on IQ. RESULTS: Greater improvements in IQ after surgery were associated with an older age at surgery (ß=.235, p=.018). Higher IQ scores at follow-up were associated with an older age of seizure onset (ß=.371, p<.001), older age at surgery (ß=.356, p<.001), unilobar epileptogenic focus (ß=.394, p<.001), and mesial temporal sclerosis (ß=.338, p=.001) or tumor (ß=.457, p<.001) in comparison with malformation of cortical development; age at seizure onset did not remain as a significant predictor in multivariable regression analysis. Income quintile, residence location, seizure control, and antiepileptic medication use were not significant predictors. CONCLUSIONS: Epilepsy-related variables were the strongest predictors of IQ and postoperative change in IQ. We were unable to identify a significant association between IQ and socioeconomic status. Future research should evaluate the impact of multiple aspects of family environment.

Socioeconomic status influences time to surgery and surgical outcome in pediatric epilepsy surgery.

The aims of this study were to evaluate the influence of socioeconomic status (SES) on time-to-surgery (TTS) and surgical outcome in children with treatment-resistant epilepsy in a universal health care system. The cohort consisted of children who had undergone resective epilepsy surgery between 2001 and 2013 in Canada. The patients' postal codes were linked to Statistics Canada National Household Survey data to obtain dissemination area income, which was used to infer SES. Time-to-surgery was defined as the interval from date of epilepsy onset to date of surgery. Seizure outcome was classified using ILAE classification. The associations between SES and TTS, as well as SES and surgical outcome, were assessed. Two hundred eighty-four children who had epilepsy surgery were included. Patients in the lowest income quintile had a significantly higher TTS relative to the highest income quintile (ß=0.121, p=0.044). There were no significant associations between income quintiles and seizure-free surgical outcome (odds ratio (OR)=0.746-1.494, all p>0.05). However, patients in the lowest income quintile had a significantly lower odds of an improvement in seizure frequency relative to the highest income quintile (OR=0.262, p=0.046). The TTS was not uniform across SES in spite of the existence of a universal health care system. This finding highlights the need to address social and economic barriers for epilepsy surgery to improve access to this potentially curative treatment. Those with lower SES had lower likelihood of improvement in seizure control following epilepsy surgery and may require additional support including social and financial support to mitigate the discrepancies in seizure control following surgery between SES levels.

Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing.

We explored the detection of genome-wide hypomethylation in plasma using shotgun massively parallel bisulfite sequencing as a marker for cancer. Tumor-associated copy number aberrations (CNAs) could also be observed from the bisulfite DNA sequencing data. Hypomethylation and CNAs were detected in the plasma DNA of patients with hepatocellular carcinoma, breast cancer, lung cancer, nasopharyngeal cancer, smooth muscle sarcoma, and neuroendocrine tumor. For the detection of nonmetastatic cancer cases, plasma hypomethylation gave a sensitivity and specificity of 74% and 94%, respectively, when a mean of 93 million reads per case were obtained. Reducing the sequencing depth to 10 million reads per case was found to have no adverse effect on the sensitivity and specificity for cancer detection, giving respective figures of 68% and 94%. This characteristic thus indicates that analysis of plasma hypomethylation by this sequencing-based method may be a relatively cost-effective approach for cancer detection. We also demonstrated that plasma hypomethylation had utility for monitoring hepatocellular carcinoma patients following tumor resection and for detecting residual disease. Plasma hypomethylation can be combined with plasma CNA analysis for further enhancement of the detection sensitivity or specificity using different diagnostic algorithms. Using the detection of at least one type of aberration to define an abnormality, a sensitivity of 87% could be achieved with a specificity of 88%. These developments have thus expanded the applications of plasma DNA analysis for cancer detection and monitoring.

Dynamic expression of epidermal caspase 8 simulates a wound healing response.

Tissue homeostasis and regeneration are regulated by an intricate balance of seemingly competing processes-proliferation versus differentiation, and cell death versus survival. Here we demonstrate that the loss of epidermal caspase 8, an important mediator of apoptosis, recapitulates several phases of a wound healing response in the mouse. The epidermal hyperplasia in the caspase 8 null skin is the culmination of signals exchanged between epidermal keratinocytes, dermal fibroblasts and leukocytic cells. This reciprocal interaction is initiated by the paracrine signalling of interleukin 1alpha (IL1alpha), which activates both skin stem cell proliferation and cutaneous inflammation. The non-canonical secretion of IL1alpha is induced by a p38-MAPK-mediated upregulation of NALP3 (also known as NLRP3), leading to inflammasome assembly and caspase 1 activation. Notably, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocytes in the stratified epidermis by IL1alpha-dependent NFkappaB signalling. Altogether, our findings illustrate how the loss of caspase 8 can affect more than programmed cell death to alter the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.