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Gestational weight gain (GWG) outside recommended parameters can lead to pregnancy or birth complications. Avoidance coping may influence GWG. We examined the association of avoidance coping with GWG among a sample of 112 pregnant Black women in the Midwest. Participants completed avoidance coping questionnaires at three time points throughout pregnancy. Data were abstracted from medical records for BMI and GWG. Overall, 23.2% gained inadequate weight, 30.4% adequate weight, and 46.4% excess weight. Multinomial logistic regression models indicated associations between avoidance coping and GWG adjusted for covariates. Participants with higher avoidance coping scores at 22–29 weeks’ gestation were more likely to experience excess weight gain (odds ratio [ OR] = 1.19, 95% CI [1.02, 1.37]). Participants with higher avoidance coping scores at 30–36 weeks’ gestation were less likely to experience excess weight gain, ( OR = 0.82, 95% CI [0.72, 0.93]). The impact of higher avoidance coping on excess weight gain depends on the time period in pregnancy.

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.Significance:Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.

Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or whole RNA sequencing. Supplementary figure 2: Phylogeny and WGD events in CRUKP1047. Supplementary figure 3: Ploidy and SCNA burden. Supplementary figure 4: Overview of each case. Supplementary figure 5: MEDICC2 copy number sample trees. Supplementary figure 6: MEDICC tree of all exome samples demonstrating that samples cluster together by patient, and not by melanoma subtype. Supplementary figure 7: SCNA frequency of cutaneous (a), acral (b) and melanoma of unknown primary (MUP, c). Supplementary figure 8: Correlation between liver copy number distance to other sites and time of emergence after stage IV diagnosis. Supplementary figure 9: Examination of tumour heterogeneity of alterations to antigen-presentation machinery genes, with site and patient annotation. Supplementary figure 10: Boxplots indicating the proportion of losses in the cohort for each segment. Supplementary figure 11: Balance of expression between nonsynonymous mutations that were not predicted to be neoantigens and clonal predicted neoantigens. Supplementary figure 12: Barplot of TIL infiltration score frequencies, determined by pathologist assessment of histology, across all samples. Supplementary figure 13: Number of samples per patient that are classified as either none-low in terms of TILs or moderate-heavy. Supplementary figure 14: Histogram of purity for samples with RNA-seq data. Supplementary figure 15: TME deconvolution. Supplementary figure 16: The effect of metastatic site on transcriptional profiles. Supplementary figure 17: Association of PHF3 copy number with expression. Supplementary figure 18: Overview of gene fusions identified in RNA-seq data. Supplementary figure 19: Comparison of ploidy estimates from panel sequencing data, exome data and FISH. Supplementary figure 20: Comparison of ploidy estimates in panel, exome, FISH and single cell data. Supplementary figure 21: FACs sort plot for CRUKP2567 diaphragmatic metastasis. Supplementary figure 22: Ploidy and wGII values from single cell sequencing of FACS-sorted tumour cells. Supplementary figure 23: Copy number profiles on chromosome 5 for bulk samples from primary and DI_2_R2, a diaphragmatic metastasis. Supplementary figure 24: Histogram of purity of samples for which RNA-seq was performed faceted by patient. Supplementary figure 25: Histogram of purity of samples for which RNA-seq was performed faceted by tissue site.

S. Table 1: List of PEACE Consortium members. S. Table 2: Sample database used for the study for Panel, Exome and RNASeq samples. S. Table 3: Overview of lines of treatment given to each patient. S. Table 4: Lesions and patients included in the lesion-level response to ICI analysis. S. Table 5: Hallmark genesets significantly upregulated in normal tissue vs tumor tissue. Table shows p-values for tissue type, purity; T value for tissue type, purity; q-value for tissue type, purity (FDR corrected). S. Table 6: Hallmark genesets significantly upregulated in tumor tissue vs normal tissue. Table shows p-values for tissue type, purity; T value for tissue type, purity; q-value for tissue type, purity (FDR corrected). S. Table 7: Genes included in the target panel. S. Table 8: Tree topology comparisons between manually constructed trees and pairtree-constructed trees.

We explored the associations among perceived stress, depressive symptoms, loneliness, and social support during the COVID-19 pandemic; and differences in perceived stress, depressive symptoms, and social support prior to the pandemic and during the pandemic among pregnant Black women. A sample of 33 pregnant Black women who participated in the Biosocial Impact on Black Births (BIBB) and were still pregnant in May–June 2020 were invited to complete an online survey about their experiences during the pandemic. Fifteen women responded very much or somewhat to experiencing stress and anxiety because of the COVID-19 pandemic. Eight women had CES-D scores ≥23, which have been correlated with depression diagnosis. Women who reported higher levels of loneliness during the COVID-19 pandemic also reported higher levels of perceived stress and depressive symptoms and lower levels of social support during the pandemic. Women who reported lower levels of social support during the pandemic also reported higher levels of perceived stress and depressive symptoms during the pandemic. There were no changes in perceived stress, depressive symptoms, or social support prior to the pandemic and during the pandemic. Clinicians should assess for signs of loneliness and depressive symptoms for pregnant women and offer recommendations for therapy and support groups.

Participation by people of color in research studies is important for generalizability and to mitigate health disparities. Barriers to recruitment are well documented, but less well known is how to succeed. This paper describes successful strategies for recruitment and retention of pregnant Black women for a multisite study of preterm birth. Recruiters provided input on strategies. Participant level strategies include: commitment to being respectful, friendly, and reliable; addressing concerns regarding confidentiality; acknowledging competing priorities; and when possible, matching recruiters by gender and race. Clinical level strategies include: the formation of a good working relationship with the clinical staff; prioritizing clinical care above research activities; and obtaining access to the electronic medical record systems. Protocol level strategies include: a wide enrollment window; coordinating biospecimen collection with the clinical laboratory tests; collecting survey data on an electronic tablet; text messaging; and providing compensation for the time needed to complete study activities.

Background: In the US, approximately 10 million people with diabetes require insulin; the vast majority using MDI therapy. Diabetes is associated with sustained daily burdens due to complex, demanding, and often confusing self-care directives, which may be more pronounced with MDI. Bigfoot Unity is a unique, interconnected smart pen cap diabetes management system designed to address an unmet medical need to support MDI therapy, incorporating CGM data (Abbott FreeStyle Libre 2) , real-time alerts and clinician-directed dose recommendations. Methods: The Bigfoot Unity System received FDA clearance in May 2021. We report a retrospective analysis on an initial cohort (N=49 at 11 clinics) with insulin-requiring diabetes managing MDI with Bigfoot Unity for 90 days. Deidentified data were evaluated to analyze glycemic metrics during use, and HbA1c obtained from medical records prior to use. Results: Within the cohort, mean age was 60 years and 40 (82%) had T2D. The mean HbA1c prior to Bigfoot Unity use was 8.5±2.0% (N=43) . Mean GMI was 7.5±0.9% after 3 months use. Discussion: These data show that for people using MDI with suboptimal glycemic control, using the Bigfoot Unity System has the potential for rapid and durable improvement in glycemic control. Considering the mean age of the cohort, results demonstrate close adherence to established glycemic targets including a short time spent in the hypoglycemia range. Further studies are planned to investigate this hypothesis. Disclosure B. Baliga: Speaker’s Bureau; Abbott Diabetes, Amarin Corporation, AstraZeneca, Bigfoot Biomedical, Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intuity Medical, Inc., Merck & Co., Inc., Novo Nordisk, Stock/Shareholder; Amarin Corporation, Insulet Corporation, Merck & Co., Inc., Moderna, Inc., Senseonics. J. Tillman: Employee; Bigfoot Biomedical, Inc. B. P. Olson: Employee; Bigfoot Biomedical, Inc. S. Vaughan: Employee; Bigfoot Biomedical, Inc. F. Sheikh: Employee; Bigfoot Biomedical, Inc. J. K. Malone: Consultant; Eli Lilly and Company, Insulet Corporation, Thermalin Inc., Employee; Bigfoot Biomedical, Inc. Funding Bigfoot Biomedical

Pratt et al. (2020) tackle a seeming lack of consensus about the ethical goals of community engagement (CE) in global health research. Their paper “identifies an additional or complementary role fo...

In recent years, the impact of Plant Protection Products (PPPs) on insect pollinator decline has stimulated significant amounts of research, as well as political and public interest. PPP residues have been found in various bee-related matrices, resulting in governmental bodies worldwide releasing guidance documents on methods for the assessment of the overall risk of PPPs to different bee species. An essential part of these risk assessments are PPP residues found in pollen and nectar, as they represent a key route of exposure. However, PPP residue values in these matrices exhibit large variations and are not available for many PPPs and crop species combinations, which results in inaccurate estimations and uncertainties in risk evaluation. Additionally, residue studies on pollen and nectar are expensive and practically challenging. An extrapolation between different cropping scenarios and PPPs is not yet justified, as the behaviour of PPPs in pollen and nectar is poorly understood. Therefore, this review aims to contribute to a better knowledge and understanding of the fate of PPP residues in pollen and nectar and to outline knowledge gaps and future research needs. The literature suggests that four primary factors, the crop type, the application method, the physicochemical properties of a compound and the environmental conditions have the greatest influence on PPP residues in pollen and nectar. However, these factors consist of many sub-factors and initial effects may be disguised by different sampling methodologies, impeding their exact characterisation. Moreover, knowledge about these factors is ambiguous and restricted to a few compounds and plant species. We propose that future research should concentrate on identifying relationships and common features amongst various PPP applications and crops, as well as an overall quantification of the described parameters; in order to enable a reliable estimation of PPP residues in pollen, nectar and other bee matrices.

Pain is a universal, multidimensional experience with sensory, emotional, cognitive, and social components, which is fundamental to our environmental learning when functioning typically. Understanding pain processing in psychiatric conditions could provide unique insight into the underlying pathophysiology or psychiatric disease, especially given the psychobiological overlap with pain processing pathways. Studying pain in psychiatric conditions is likely to provide important insights, yet, there is a limited understanding beyond the work in depression and anxiety. This is a missed opportunity to describe psychiatric conditions in terms of neurobiological alterations. To examine the research into the pain experiences of these groups and the extent to which a-typicality is present, a systematic review was conducted. An electronic search strategy was developed and conducted in several databases. The current systematic review included 46 studies covering five Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) disorders: autism, attention-deficit hyperactivity disorder (ADHD), schizophrenia, personality disorder, and eating disorders, confirming tentative evidence of altered pain and touch processing. Specifically, hyposensitivity is reported in schizophrenia, personality disorder and eating disorder, hypersensitivity in ADHD, and mixed results for autism. Review of the research highlights a degree of methodological inconsistency in the utilization of comprehensive protocols, the lack of which fails to allow us to understand whether a-typicality is systemic or modality specific.

Neonicotinoid insecticides have been used in a wide range of crops through seed treatment, soil and foliar applications and a large database exists on both their lethal and sub-lethal effects on honey bees under controlled laboratory conditions. However, colony-level studies on the effects of neonicotinoids in field studies are limited, primarily due to their complexity and the resources required. This paper reports the combined results of two large-scale colony-feeding studies, each with 6 weeks of continuous dosing of 12 colonies per treatment (24 control) to 12.5, 25, 37.5, 50 or 100 ng thiamethoxam/g sucrose solution. Exposure continued beyond dosing with residues present in stored nectar and bee-bread. The studies were conducted in an area with limited alternative forage and colonies were required to forage for pollen and additional nectar The studies provide colony-level endpoints: significant effects (reductions in bees, brood) were observed after exposure to the two highest dose rates, colony loss occurred at the highest dose rate, but colonies were able to recover (2–3 brood cycles after the end of dosing) after dosing with 50 ng thiamethoxam/g sucrose. No significant colony-level effects were observed at lower dose rates. The data reported here support the conclusions of previous colony-level crop-based field studies with thiamethoxam, in which residues in pollen and nectar were an order of magnitude below the colony-level NOEC of 37.5 ng thiamethoxam/g sucrose. The feeding study data are also compared to the outcomes of regulatory Tier 1 risk assessments conducted using guidance provided by the USA, Canada, Brazil and the EU regulatory authorities. We propose an adaptation of the European chronic adult bee risk assessment that takes into account the full dataset generated in laboratory studies while still providing an order of magnitude of safety compared with the colony feeding study NOEC.

Individuals living with spinal cord injury or disease (SCI/D) are at increased risk for sleep-disordered breathing (SDB), with a prevalence that is three- to fourfold higher than the general population. The main features of SDB, including intermittent hypoxemia and sleep fragmentation, have been linked to adverse cardiovascular outcomes including nocturnal hypertension in patients with SCI/D. The relationship between SDB and SCI/D may be multifactorial in nature given that level and completeness of injury can affect central control of respiration and upper airway collapsibility differently, promoting central and/or obstructive types of SDB. Despite the strong association between SDB and SCI/D, access to diagnosis and management remains limited. This review explores the role of SCI/D in the pathogenesis of SDB, poor sleep quality, the barriers in diagnosing and managing SDB in SCI/D, and the alternative approaches and future directions in the treatment of SDB, such as novel pharmacologic and nonpharmacologic treatments.

Studies in humans and animal models with spinal cord injury (SCI) have demonstrated that medications targeting serotonin receptors may decrease the susceptibility to central sleep-disordered breathing (SDB). We hypothesized that mirtazapine would decrease the propensity to develop hypocapnic central sleep apnea (CSA) during sleep. We performed a single-blind pilot study on a total of 10 men with SDB (7 with chronic SCI and 3 noninjured) aged 52.0 ± 11.2 yr. Participants were randomly assigned to either mirtazapine (15 mg at bedtime) or a placebo for at least 1 wk, followed by a 7-day washout period before crossing over to the other intervention. Split-night studies included polysomnography and induction of hypocapnic CSA using a noninvasive ventilation (NIV) protocol. The primary outcome was CO(2) reserve, defined as the difference between eupneic and end of NIV end-tidal CO(2) (PET(CO(2))) preceding induced hypocapneic CSA. Secondary outcomes included controller gain (CG), other ventilatory parameters, and SDB severity. CG was defined as the ratio of change in minute ventilation (V̇e) between control and hypopnea to the change in CO(2) during sleep. CO(2) reserve was significantly widened on mirtazapine than placebo (−3.8 ± 1.2 vs. −2.0 ± 1.5 mmHg; P = 0.015). CG was significantly decreased on mirtazapine compared with placebo [2.2 ± 0.7 vs. 3.5 ± 1.9 L/(mmHg × min); P = 0.023]. There were no significant differences for other ventilatory parameters assessed or SDB severity between mirtazapine and placebo trials. These findings suggest that the administration of mirtazapine can decrease the susceptibility to central apnea by reducing chemosensitivity and increasing CO(2) reserve; however, considering the lack of changes in apnea-hypopnea index (AHI), further research is required to understand the significance of this finding. NEW & NOTEWORTHY To our knowledge, this research study is novel as it is the first study in humans assessing the effect of mirtazapine on CO(2) reserve and chemosensitivity in individuals with severe sleep-disordered breathing. This is also the first study to determine the potential therapeutic effects of mirtazapine on sleep parameters in individuals with a spinal cord injury.

The ban imposed by the European Union on the use of neonicotinoids as sugar beet seed treatments was based on the exposure of bees to residues of neonicotinoids in pollen and nectar of succeeding crops. To address this concern, residues of thiamethoxam (TMX) and clothianidin (CTD) were analyzed in soil collected from fields planted in at least the previous year with thiamethoxam-treated sugar beet seed. This soil monitoring program was conducted at 94 sites across Germany in two separate years. In addition, a succeeding crop study assessed residues in soil, guttation fluid, pollen, and nectar sampled from untreated succeeding crops planted in the season after thiamethoxam seed-treated sugar beet at eight field sites across five countries. The overall mean residues observed in soil monitoring were 8.0 ± 0.5 µg TMX + CTD/kg in the season after the use of treated sugar beet seed. Residue values decreased with increasing time interval between the latest thiamethoxam or clothianidin application before sugar beet drilling and with lower application frequency. Residues were detected in guttation fluid (2.0-37.7 µg TMX/L); however, the risk to pollinators from this route of exposure is likely to be low, based on the reported levels of consumption. Residues of thiamethoxam and clothianidin in pollen and nectar sampled from the succeeding crops were detected at or below the limit of quantification (0.5-1 µg a.i./kg) in 86.7% of pollen and 98.6% of nectar samples and, unlike guttation fluid residues, were not correlated with measured soil residues. Residues in pollen and nectar are lower than reported sublethal adverse effect concentrations in studies with honeybee and bumble bee individuals and colonies fed only thiamethoxam-treated sucrose, and are lower than those reported to result in no effects in honeybees, bumble bees, and solitary bees foraging on seed-treated crops. Integr Environ Assess Manag 2021;00:1-13. © 2021 SYNGENTA. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Introduction: Black women experience significant maternal mortality (3.3 times higher) compared to White women, and experience higher adverse outcomes. In the United States, cardiovascular disease is the second leading cause of maternal mortality for Black women. Hypertensive disorders of pregnancy (HDOP) falls under the cardiovascular disease spectrum. Objective: To explore differences in women diagnosed with a HDOP compared to those that do not have HDOP. Methods: A total of 226 African American women from Metro-Detroit and Columbus, Ohio enrolled in a cross-sectional study who had recently gave birth. Women enrolled in a mixed methods study on social and biological stressors to preterm birth with a completed medical record abstraction were identified as having chronic hypertension or a hypertensive disorder of pregnancy (HDOP) prior to the current pregnancy. HDOP is defined as chronic hypertension, chronic hypertension with superimposed preeclampsia, gestational hypertension, preeclampsia or eclampsia. Perinatal complications and birth outcomes were explored. Sociodemographic was derived from completed prenatal questionnaires. Chi square was used for categorical variable and T-test was used for continuous variables. Significance is defined as p ≤ 0.05. Results: The mean age was 26.8±5.9 years. Approximately 70.4% (n=159) were from Detroit, MI and 29.6% were from Columbus, OH. The mean previous live births were 1.9±1.8 (range 0-8). The average number of prenatal visits with a physician were 9.2±2.9 (range 2-19) and the total number of any prenatal visits were 16.0±6.9 (range 1-44). Average baby gestational age is 37.9±2.2 weeks (range 15-26 weeks), and weight is 2998±703.4 grams. Approximately 60 women (26.5%) were identified with a hypertensive disorder of pregnancy. Compared to women not diagnosed with a HDOP, women with a HDOP had an older mean age (28.3±6.4 vs 26.3±5.6), p=0.023; had more prenatal visits (18.2±7.6 vs 15.6±6.5) p=0.007; had babies at a younger gestational age (37.2±2.1 vs 38.2±2.1), p=0.002. Conclusion: These findings will aid in determining factors associated with HDOP in our population, and aid in determining next steps to reduce historic mortality in this group.

Spinal cord injury (SCI) is a risk factor for central sleep apnea (CSA). Previous studies in animal models with SCI have demonstrated a promising recovery in respiratory and phrenic nerve activity post-injury induced by the systemic and local administration of serotonin receptor agonists such as Buspirone and Trazodone. Human trials must be performed to determine whether individuals with SCI respond similarly. We hypothesized that Buspirone and Trazodone would decrease the propensity to hypocapnic CSA during sleep. We studied eight males with chronic SCI and sleep-disordered breathing (SDB) [age: 48.8 ± 14.2 yr; apnea-hypopnea index (AHI): 44.9 ± 23.1] in a single-blind crossover design. For 13 days, participants were randomly assigned either Buspirone (7.5–15 mg twice daily), Trazodone (100 mg), or a placebo followed by a 14-day washout period before crossing over to the other interventions. Study nights included polysomnography and induction of CSA using a noninvasive ventilation protocol. We assessed indexes of SDB, CO(2) reserve, apneic threshold (AT), controller gain (CG), plant gain (PG), and ventilatory parameters. CO(2) reserve was significantly widened on Buspirone (−3.6 ± 0.9 mmHg) compared with both Trazodone (−2.5 ± 1.0 mmHg, P = 0.009) and placebo (−1.8 ± 1.5 mmHg, P < 0.001) but not on Trazodone vs. placebo (P = 0.061). CG was significantly decreased on Buspirone compared with placebo (1.8 ± 0.4 vs. 4.0 ± 2.0 L/(mmHg·min), P = 0.025) but not on Trazodone compared with placebo (2.5 ± 1.1 vs. 4.0 ± 2.0 L/(mmHg·min); P = 0.065). There were no significant differences for PG, AT, or any SDB indexes (AHI, obstructive apnea index, central apnea index, oxygen desaturation index). The administration of Buspirone decreased the susceptibility to induced hypocapnic central apnea by reducing chemosensitivity and increasing CO(2) reserve in chronic SCI patients. NEW & NOTEWORTHY This research study is novel as it is the first study in a humans that we are aware of that demonstrates the ability of Buspirone to increase CO(2) reserve and hence decrease susceptibility to hypocapnic central apnea in patients with spinal cord injury.

The current paper reports three experimental studies that investigate how selectively emphasising different treatment approaches (biological, psychological or social) for mental health difficulties affects lay beliefs about those illnesses. Online experimental vignettes exposed participants to different treatment narratives for a clinical case of Major Depressive Disorder (Study 1; n=164), Generalized Anxiety Disorder (Study 2; n=173) and Schizophrenia (Study 3, n=170). Measures of causal attributions and illness perceptions assessed effects on beliefs about the causes and course of the illness. Emphasising psychological treatment of Major Depressive Disorder promoted more causal attributions to personal weakness, while endorsing biological treatment weakened confidence in individual control over the course of the illness. For Generalized Anxiety Disorder, stressing social treatment encouraged more causal attributions to personal weakness and lifestyle factors. Causal attributions for Schizophrenia did not shift according to treatment modality, but highlighting biological treatment made the symptoms appear more treatable, while emphasising psychological treatment made the illness seem more personally controllable. As lay understandings of the causes and course of mental illness have implications for help-seeking, treatment engagement and stigma, effects on illness beliefs may be an important consideration when endorsing a particular treatment approach in public discourse or clinical communication.

International audience; Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias isinherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mmbiopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB butlow clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.

The principles of the best interest of children and subsidiarity constitute the conceptual foundation of the Convention on Protection of Children and Co-Operation in Respect of Intercountry Adoption (HCIA). Subsidiarity in the HCIA dictates a priority for domestic adoption placements for children over intercountry adoption. This article argues against subsidiarity on two fronts. First, the analysis shows that the in-principle priority of domestic adoption cannot be justified on the basis of either heritage rights or state sovereignty. Second, the principle of subsidiarity in the HCIA is a procedural principle, one that stipulates the political/geographical location of the placement of children through a priority ordering. This does not comport with the principle of subsidiarity as it has been conceptualized in ethics and social philosophy, which gives normative structure to the process of decision-making by stipulating the proper level for decisional authority. Subsidiarity in this original sense holds that decisions regarding child welfare should be made at the lowest level possible, by those most affected by the decisions, unless doing so would not be the most suited to protecting and promoting the best interests of children. Appealing to subsidiarity in this theoretical version reveals at least two significant problems with HCIA placement policy and leads to the conclusion that subsidiarity in the HCIA must be formally revised as a structural principle of ethics that will not support the general priority of domestic adoption.

This working paper presents preliminary conclusions from research carried out in Benishangul Gumuz and Amhara National Regional States of Ethiopia in November 2018 and January 2019. It explores the programme of resettlement of Gumuz farmers and others living at low altitude along the Nile and Beles rivers, whose home areas are expected to be flooded on completion of the Grand Ethiopian Renaissance Dam (GERD) and filling of a new reservoir. We focus on problems associated with access to social services and to common resources, notably water; on land, housing, property and compensation; on livelihoods impacts and prospects; on changes in social and community articulation; and on issues of planning, budgeting and coordination of responsibility among stakeholders. These findings, which indicate strong continuities with the well documented problems of global dam-induced displacement, and resettlement in Ethiopia’s past, suggest the potential for improving policy and institutional decision making by enhancing learning from existing experiences, rooted in a nuanced understanding of local conditions. The findings are designed both to inform the period to 2022, the currently projected conclusion of the GERD construction phase, and to encourage longer-term commitment and planning, once the dam is built, that would maximise shared benefits, in terms of social and economic development, locally, among the resettled Gumuz, and nationally and regionally.