A Helping Hand Out of the River: Refugee Perspectives for Provider Engagement.

Purpose: A growing number of refugee groups are seeking care within the U.S. health care system for medical, psychological, and social needs. Research is limited in understanding refugee-specific conceptualizations of helping relationships and provider characteristics that improve interactions in health systems. This study aimed to identify provider characteristics that facilitate engagement and helpfulness in a refugee-specific population from refugee participant voices to inform future practices of health care clinics. Methods: Semi-structured interviews with refugee participants were conducted to assess 1) experiences moving on from difficult experiences, 2) engagement with the health system, and 3) provider characteristics that facilitated engagement and healing. Qualitative data were analyzed using a grounded theory approach. Results: An emergent theory was revealed on refugee-defined provider characteristics that facilitated healing and engagement in the health system. Providers who support an individual's story to be told, show awareness of barriers to accessing resources and prioritization of addressing barriers, maintain cultural humility, and demonstrate compassion, empathy, warmth, and openness toward patient engagement were the primary characteristics that facilitated engagement and healing. Conclusions: Utilization of engagement strategies by providers at the onset of treatment is critical to providing culturally sensitive health care. Nonspecific but essential provider characteristics are thought to improve relational dynamics, trust-building, and overall engagement in the U.S. health care system from the perspective of refugee participants.

The impact of the COVID-19 pandemic on socially marginalised women: Material and mental health outcomes.

There is little knowledge about how the COVID-19 pandemic has impacted people who are socially marginalised, including individuals who face barriers when attempting to access services such as social safety nets, the labour market, or housing. There is even less understanding about women living under these circumstances. The aims of this study are therefore to examine the material and mental impacts of COVID-19 among socially marginalised women (compared with socially marginalised men) as well as influencing factors. The study is based on survey data (N = 304) involving people who are clients of social care organisations in thirteen European countries. The sample includes clients: a) living in their homes, b) in facilities, and c) on the street and in temporary accommodations. Results indicate that although material impacts were not significantly different for female and male respondents, socially marginalised women have experienced more severe mental impacts of the COVID-19 pandemic than socially marginalised men. Female respondents have been significantly more worried about COVID-19 infection than men, and they report significantly more PTSD-symptoms related to the pandemic. Quantitative results indicate that these differences are related to the fact that the female respondents worry more about health risks (e.g. falling ill). Female respondents also seem to be harder hit mentally by the material impacts of COVID-19. Among the free text survey answers regarding the biggest problem for the respondents after the outbreak of the pandemic, the most prevalent reply (among both men and women) was related to material impacts of the pandemic (39% of the respondents), particularly the loss of work (65%). While women reported deterioration of social relations more often, men mentioned lacking access to services more frequently.

Socio-economic outcomes of COVID-19 on the marginalised: Who have taken the hardest hit?

This article aims to examine the socioeconomic outcomes of COVID-19 for socially marginalised people who are clients of social care organisations (e.g. people experiencing homelessness), and the factors influencing these outcomes. We tested the role of individual and socio-structural variables in determining socioeconomic outcomes based on a cross-sectional survey with 273 participants from eight European countries and 32 interviews and five workshops with managers and staff of social care organisations in ten European countries. 39% of the respondents agreed that the pandemic has had a negative effect on their income and access to shelter and food. The most common negative socio-economic outcome of the pandemic was loss of work (65% of respondents). According to multivariate regression analysis, variables such as being of a young age, being an immigrant/asylum seeker or residing in the country without documentation, living in your own home, and having (in)formal paid work as the main source of income are related to negative socio-economic outcomes following the COVID-19 pandemic. Factors such as individual psychological resilience and receiving social benefits as the main source of income tend to "protect" respondents from negative impacts. Qualitative results indicate that care organisations have been an important source of economic and psycho-social support, particularly significant in times of a huge surge in demand for services during the long-term crises of pandemic.

A novel de novo variant in CASK causes a severe neurodevelopmental disorder that masks the phenotype of a novel de novo variant in EEF2.

We report a 9-year-old Spanish boy with severe psychomotor developmental delay, short stature, microcephaly and abnormalities of the brain morphology, including cerebellar atrophy. Whole-exome sequencing (WES) uncovered two novel de novo variants, a hemizygous variant in CASK (Calcium/Calmodulin Dependent Serine Protein Kinase) and a heterozygous variant in EEF2 (Eukaryotic Translation Elongation Factor 2). CASK gene encodes the peripheral plasma membrane protein CASK that is a scaffold protein located at the synapses in the brain. The c.2506-6 A > G CASK variant induced two alternative splicing events that account for the 80% of the total transcripts, which are likely to be degraded by NMD. Pathogenic variants in CASK have been associated with severe neurological disorders such as mental retardation with or without nystagmus also called FG syndrome 4 (FGS4), and intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH). Heterozygous variants in EEF2, which encodes the elongation factor 2 (eEF2), have been associated to Spinocerebellar ataxia 26 (SCA26) and more recently to a childhood-onset neurodevelopmental disorder with benign external hydrocephalus. The yeast model system used to investigate the functional consequences of the c.34 A > G EEF2 variant supported its pathogenicity by demonstrating it affects translational fidelity. In conclusion, the phenotype associated with the CASK variant is more severe and masks the milder phenotype of EEF2 variant.

Deep mutational analysis of elongation factor eEF2 residues implicated in human disease to identify functionally important contacts with the ribosome.

An emerging body of research is revealing mutations in elongation factor eEF2 that are implicated in both inherited and de novo neurodevelopmental disorders. Previous structural analysis has revealed that most pathogenic amino acid substitutions map to the three main points of contact between eEF2 and critical large subunit rRNA elements of the ribosome, specifically to contacts with Helix 69, Helix 95, also known as the sarcin-ricin loop, and Helix 43 of the GTPase-associated center. In order to further investigate these eEF2-ribosome interactions, we identified a series of yeast eEF2 amino acid residues based on their proximity to these functionally important rRNA elements. Based on this analysis, we constructed mutant strains to sample the full range of amino acid sidechain biochemical properties, including acidic, basic, nonpolar, and deletion (alanine) residues. These were characterized with regard to their effects on cell growth, sensitivity to ribosome-targeting antibiotics, and translational fidelity. We also biophysically characterized one mutant from each of the three main points of contact with the ribosome using CD. Collectively, our findings from these studies identified functionally critical contacts between eEF2 and the ribosome. The library of eEF2 mutants generated in this study may serve as an important resource for biophysical studies of eEF2/ribosome interactions going forward.

Self-imposed social isolation among clients of social care organisations in the COVID-19 pandemic.

Although self-imposed social isolation is an important way of reducing the risk of COVID-19 infection, previous research indicates that this behaviour varies substantially between different groups and individuals. Socially marginalized people are generally less involved in protective health behaviours, but there are few studies of their COVID-19 protective behaviours. The aims of the paper are therefore to: 1) compare self-imposed social isolation to avoid COVID-19 among socially marginalized groups, and to 2) examine factors influencing this, focusing especially on the role of social capital, risk awareness and sources of information about COVID-19. The study is based on survey data (N = 173) from people who are clients of social care organisations in Estonia, Norway, Hungary and Portugal. The sample involves clients living: a) in their homes, b) in facilities, and c) on the street or under temporary arrangements. Results indicate that the level of social isolation among the marginalized groups is comparable to that of the general population in previous studies. As hypothesized, we find that respondents living on the street or under temporary arrangements engage in less self-imposed social isolation than e.g. the respondents living in their homes. We also find lower levels of risk awareness, social capital and trust in authorities' information about COVID-19 among people living on the street or under temporary arrangements. Only linking social capital and trust in authorities' information was significantly related to respondents' social isolation, and not worry for COVID-19 infection. Thus, it seems that respondents largely self-isolated because of "duty" and not worry for infection.

Resilience in care organisations: challenges in maintaining support for vulnerable people in Europe during the Covid-19 pandemic.

The Covid-19 pandemic has challenged the resilience of care organisations (and those dependent on them), especially when services are stopped or restricted. This study focuses on the experiences of care organisations that offer services to individuals in highly precarious situations in 10 European countries. It is based on 32 qualitative interviews and three workshops with managers and staff. The four key types of organisations reviewed largely had the same adaptation patterns in all countries. The most drastic changes were experienced by day centres, which had to suspend or digitise services, whereas night shelters and soup kitchens had to reorganise broadly their work; residential facilities were minimally affected. Given the drastic surge in demand for services, reliance on an overburdened (volunteer) workforce, and a lack of crisis plans, the care organisations with long-term trust networks with clients and intra-organisational cooperation adapted easier. The outcomes were worse for new clients, migrants, psychologically vulnerable people, and those with limited communicative abilities.

De Novo variants in EEF2 cause a neurodevelopmental disorder with benign external hydrocephalus.

Eukaryotic translation elongation factor 2 (eEF2) is a key regulatory factor in gene expression that catalyzes the elongation stage of translation. A functionally impaired eEF2, due to a heterozygous missense variant in the EEF2 gene, was previously reported in one family with spinocerebellar ataxia-26 (SCA26), an autosomal dominant adult-onset pure cerebellar ataxia. Clinical exome sequencing identified de novo EEF2 variants in three unrelated children presenting with a neurodevelopmental disorder (NDD). Individuals shared a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly. Populational data and bioinformatic analysis underscored the pathogenicity of all de novo missense variants. The eEF2 yeast model strains demonstrated that patient-derived variants affect cellular growth, sensitivity to translation inhibitors and translational fidelity. Consequently, we propose that pathogenic variants in the EEF2 gene, so far exclusively associated with late-onset SCA26, can cause a broader spectrum of neurologic disorders, including childhood-onset NDDs and benign external hydrocephalus.

Two Ribosomes Are Better Than One... Sometimes.

In this issue of Molecular Cell, Meydan and Guydosh present an elegant and rigorous addition to the exciting investigation of the roles played by ribosome collisions in eukaryotic translation and cellular homeostasis.

Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS-CoV-2.

17 years after the SARS-CoV epidemic, the world is facing the COVID-19 pandemic. COVID-19 is caused by a coronavirus named SARS-CoV-2. Given the most optimistic projections estimating that it will take over a year to develop a vaccine, the best short-term strategy may lie in identifying virus-specific targets for small molecule interventions. All coronaviruses utilize a molecular mechanism called -1 PRF to control the relative expression of their proteins. Prior analyses of SARS-CoV revealed that it employs a structurally unique three-stemmed mRNA pseudoknot to stimulate high rates of -1 PRF, and that it also harbors a -1 PRF attenuation element. Altering -1 PRF activity negatively impacts virus replication, suggesting that this molecular mechanism may be therapeutically targeted. Here we present a comparative analysis of the original SARS-CoV and SARS-CoV-2 frameshift signals. Structural and functional analyses revealed that both elements promote similar rates of -1 PRF and that silent coding mutations in the slippery sites and in all three stems of the pseudoknot strongly ablated -1 PRF activity. The upstream attenuator hairpin activity has also been functionally retained. Small-angle x-ray scattering indicated that the pseudoknots in SARS-CoV and SARS-CoV-2 had the same conformation. Finally, a small molecule previously shown to bind the SARS-CoV pseudoknot and inhibit -1 PRF was similarly effective against -1 PRF in SARS-CoV-2, suggesting that such frameshift inhibitors may provide promising lead compounds to counter the current pandemic.

Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS coronavirus 2 (SARS-CoV-2).

Approximately 17 years after the severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic, the world is currently facing the COVID-19 pandemic caused by SARS corona virus 2 (SARS-CoV-2). According to the most optimistic projections, it will take more than a year to develop a vaccine, so the best short-term strategy may lie in identifying virus-specific targets for small molecule-based interventions. All coronaviruses utilize a molecular mechanism called programmed -1 ribosomal frameshift (-1 PRF) to control the relative expression of their proteins. Previous analyses of SARS-CoV have revealed that it employs a structurally unique three-stemmed mRNA pseudoknot that stimulates high -1 PRF rates and that it also harbors a -1 PRF attenuation element. Altering -1 PRF activity impairs virus replication, suggesting that this activity may be therapeutically targeted. Here, we comparatively analyzed the SARS-CoV and SARS-CoV-2 frameshift signals. Structural and functional analyses revealed that both elements promote similar -1 PRF rates and that silent coding mutations in the slippery sites and in all three stems of the pseudoknot strongly ablate -1 PRF activity. We noted that the upstream attenuator hairpin activity is also functionally retained in both viruses, despite differences in the primary sequence in this region. Small-angle X-ray scattering analyses indicated that the pseudoknots in SARS-CoV and SARS-CoV-2 have the same conformation. Finally, a small molecule previously shown to bind the SARS-CoV pseudoknot and inhibit -1 PRF was similarly effective against -1 PRF in SARS-CoV-2, suggesting that such frameshift inhibitors may be promising lead compounds to combat the current COVID-19 pandemic.

Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism.

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.

Altered neural correlates of episodic memory in adolescents with severe obesity.

Negative effects of obesity on memory and associated medial temporal circuitry have been noted in animal models, but the status in humans, particularly children, is not well established. Our study is the first to examine neural correlates of successful memory encoding of visual scenes and their associated context in adolescents with severe obesity (age 14-18 years, 43% male). Despite similar subsequent memory as adolescents without obesity (BMI for age and sex <95th percentile), those with severe obesity (BMI for age and sex 120% above the 95th percentile) showed reduced hippocampal, parahippocampal, frontal, and parietal engagement during encoding of remembered visual scenes and greater lateral temporal engagement during encoding of their associated context. Standardized testing revealed a trend level group difference in memory performance, with a larger magnitude of obesity-related difference in recollection-related memory that was mediated by individual differences in lateral temporal activation during contextual encoding. The observed widespread functional alterations are concerning in light of the importance of mnemonic processing for academic achievement and feeding behavior and underscore the need for prevention and intervention initiatives for pediatric obesity.

Cognitive Performance as Predictor and Outcome of Adolescent Bariatric Surgery: A Nonrandomized Pilot Study.

Objectives: Evidence in adults suggests that improvements in cognitive performance may follow weight loss resulting from bariatric surgery, and baseline cognitive performance may be associated with weight loss following surgery. This has not been evaluated in adolescents. Method: Participants were 38 adolescents of age 14-21 years composed of three groups: (1) 12 adolescents with severe obesity who received vertical sleeve gastrectomy during the study (VSG); (2) 14 adolescents with severe obesity who were wait-listed for VSG (WL); and (3) 12 healthy weight controls (HC). Participants completed testing of visual memory, verbal memory, and executive functioning at baseline (T1), which occurred presurgery for the VSG group, and approximately 4 months after baseline (T2). Body mass index (BMI) was assessed at T1, T2, and additionally at 6 months following VSG for the adolescents who received surgery. Results: Although there was evidence of greater improvement for the VSG as compared with WL and HC groups in visual and verbal memory, group differences did not reach significance and effect sizes were small (η2 < 0.01). There was a significant positive association between indices of baseline executive functioning and excess BMI loss at 6 months postsurgery. Conclusions: This small pilot study showed no significant differences by group in cognitive performance post-VSG. There was a significant association of baseline cognitive performance with weight loss outcomes. Given the very preliminary nature of these results in a small sample, future research should examine these relationships in a larger sample and evaluate mechanisms of these associations (e.g., insulin resistance, sleep, physical activity).

Perceived Social Support for Exercise and Weight Loss in Adolescents Undergoing Sleeve Gastrectomy.

OBJECTIVES: Bariatric surgery is an effective treatment for youth with severe obesity. However, outcomes are variable and there remains sparse understanding of predictors of weight loss following surgery. The current study examines the role of adolescent-reported pre-operative social support around exercise, binge eating, and exercise to predict excess body mass index (EBMI) loss from 3 to 12 months post-surgery. METHOD: Participants were 101 adolescents ages 12-21 (M age = 16.6, SD = 1.8). Pre-operative body mass index (BMI) ranged from 35 to 87 (M = 50.3, SD = 8.6). Structural equation modeling (SEM) was used to evaluate a model of the association of adolescent report of perceived social support for exercise with less binge eating (items from the Eating Disorder Diagnostic Scale) and more self-reported exercise (items from the Youth Risk Behavior Surveillance System). The model was used to predict EBMI loss at 3, 6, 9, and 12 months post-surgery. RESULTS: Social support significantly predicted exercise and demonstrated a trend for predicting binge eating, such that more social support was associated with more exercise and a trend for less binge eating. Binge eating was associated with less EBMI loss. However, there was no association of exercise with EBMI loss. CONCLUSIONS: Pre-operative binge eating should be a target for identification and treatment prior to sleeve gastrectomy in adolescents. Although not directly or indirectly associated with EBMI loss, perceived social support around exercise was associated with increased exercise, which may make it a consideration for a target for intervention as well.

Effect of Adolescent Bariatric Surgery on the Brain and Cognition: A Pilot Study.

OBJECTIVE: Neurocognitive deficits in pediatric obesity relate to poor developmental outcomes. We sought preliminary evidence for changes in brain and cognitive functioning relevant to obesogenic behavior following vertical sleeve gastrectomy (VSG) in adolescents relative to wait-listed (WL) and healthy controls (HC). METHODS: Thirty-six adolescents underwent fMRI twice 4 months apart, during executive, reward, and episodic memory encoding, in addition to behavioral testing for reward-related decision making. RESULTS: VSG adolescents lost weight, while WL gained weight and HC did not change between time points. Gains in executive and reward-related performance were larger in VSG than control groups. Group × Time interaction (P < 0.05 corrected) in left prefrontal cortex during N-back showed greater presurgical activation and postsurgical reduction comparable to HC levels but increased in WL between time points. Similarly, left striatal parametric response to reward value reduced after surgery to HC levels; WL did not change. Memory-related medial temporal activation did not change in any group. CONCLUSIONS: Results provide pilot evidence for functional brain changes induced by VSG in adolescents with severe obesity. Weight loss and gain were paralleled by reduced and increased prefrontal activation, respectively, suggesting neural plasticity related to metabolic change.

Obesity Prevention and Screening.

Obesity is widespread, associated with several physical and psychosocial comorbidities, and is difficult to treat. Prevention of obesity across the lifespan is critical to improving the health of individuals and society. Screening and prevention efforts in primary care are an important step in addressing the obesity epidemic. Each period of human development is associated with unique risks, challenges, and opportunities for prevention and intervention. Screening tools for overweight/obesity, although imperfect, are quick and easy to administer. Screening should be conducted at every primary care visit and tracked longitudinally. Screening tools and cutoffs for overweight and obesity vary by age group.

Human risky choice in a repeated-gambles procedure: an up-linkage replication of Lakshminarayanan, Chen and Santos (2011).

Lakshminarayanan et al. (J Exp Soc Psychol 47: 689-693, 2011) showed that when choice is between variable (risky) and fixed (safe) food amounts with the same expected values, capuchins prefer the safe alternative if choice is framed as a gain, but the risky alternative if it is framed as a loss. These results seem similar to those seen in human prospect-theory tests in choice between variable and fixed gains or losses. Based on this similarity, they interpreted their results as identifying a between-species commonality in cognitive function. In this report, we repeat their experiment with humans as subjects (an up-linkage replication). Whether choices were rewarded with candy or nickels, choice approximated indifference whether framed as gains or losses. Our data mirror those of others who found that when humans make risky choices within a repeated-trials procedure without verbal instruction about outcome likelihoods, preference biases seen in one-shot, language-guided, prospect-theory tests such as Tversky and Kahneman's (Science 211:453-458, 1981) reflection effect may not appear. The disparity between our findings and those of Lakshminarayanan et al. suggests their study does not evidence a cognitive process shared by humans and capuchins.