¹⁶⁶Ho-microspheres have recently been approved for clinical use for hepatic radioembolization in the European Union. The aim of this study was to investigate the absorbed dose–response relationship and its association with overall survival for ¹⁶⁶Ho radioembolization in patients with liver metastases. Methods: Patients treated in the HEPAR I and II studies who underwent an ¹⁸F-FDG PET/CT scan at baseline, a posttreatment ¹⁶⁶Ho SPECT/CT scan, and another ¹⁸F-FDG PET/CT scan at the 3-mo follow-up were included for analysis. The posttreatment ¹⁶⁶Ho-microsphere activity distributions were estimated with quantitative SPECT/CT reconstructions using a quantitative Monte Carlo–based method. The response of each tumor was based on the change in total lesion glycolysis (TLG) between baseline and follow-up and was placed into 1 of 4 categories, according to the PERCIST criteria, ranging from complete response to progressive disease. Patient-level response was grouped according to the average change in TLG per patient. The absorbed dose–response relationship was assessed using a linear mixed model to account for correlation of tumors within patients. Median overall survival was compared between patients with and without a metabolic liver response, using a log-rank test. Results: Thirty-six patients with a total of 98 tumors were included. The relation between tumor-absorbed dose and both tumor-level and patient-level response was explored. At a tumor level, a significant difference in geometric mean absorbed dose was found between complete response (232 Gy; 95% confidence interval [CI], 178–303 Gy; n = 32) and stable disease (147 Gy; 95% CI, 113–191 Gy; n = 28) (P = 0.01) and between complete response and progressive disease (117 Gy; 95% CI, 87–159 Gy; n = 21) (P = 0.0008). This constitutes a robust absorbed dose–response relationship. At a patient level, a significant difference was found between patients with complete or partial response (210 Gy; 95% CI, 161–274 Gy; n = 13) and patients with progressive disease (116 Gy; 95% CI, 81–165 Gy; n = 9) (P = 0.01). Patients were subsequently grouped according to their average change in TLG. Patients with an objective response (complete or partial) exhibited a significantly higher overall survival than nonresponding patients (stable or progressive disease) (median, 19 mo vs. 7.5 mo; log-rank, P = 0.01). Conclusion: These results confirm a significant absorbed dose–response relationship in ¹⁶⁶Ho radioembolization. Treatment response is associated with a higher overall survival.

M2 macrophages play an important role in tissue repair and regeneration. They have also been found to modulate β-cell replication in mouse models of pancreatic injury and disease. We previously reported that β-cell replication is strongly increased in a subgroup of human organ donors characterized by prolonged duration of stay in an intensive care unit (ICU) and increased number of leukocytes in the pancreatic tissue. In the present study we investigated the relationship between duration of stay in the ICU, M2 macrophages, vascularization, and pancreatic cell replication. Pancreatic organs from 50 donors without diabetes with different durations of stay in the ICU were analyzed by immunostaining and digital image analysis. The number of CD68⁺CD206⁺ M2 macrophages increased three- to sixfold from ≥6 days’ duration of stay in the ICU onwards. This was accompanied by a threefold increased vascular density and a four- to ninefold increase in pancreatic cells positive for the replication marker Ki67. A strong correlation was observed between the number of M2 macrophages and β-cell replication. These results show that a prolonged duration of stay in the ICU is associated with an increased M2 macrophage number, increased vascular density, and an overall increase in replication of all pancreatic cell types. Our data show evidence of marked levels of tissue repair in the human donor pancreas.

The action mechanisms revealed by the biochemical and structural analyses of replicative and translesion synthesis (TLS) DNA polymerases (Pols) are retained in their cellular roles. In this regard, DNA polymerase θ differs from other Pols in that whereas purified Polθ misincorporates an A opposite 1,N6-ethenodeoxyadenosine (ϵdA) using an abasic-like mode, Polθ performs predominantly error-free TLS in human cells. To test the hypothesis that Polθ adopts a different mechanism for replicating through ϵdA in human cells than in the purified Pol, here we analyze the effects of mutations in the two highly conserved tyrosine residues, Tyr-2387 and Tyr-2391, in the Polθ active site. Our findings that these residues are indispensable for TLS by the purified Pol but are not required in human cells, as well as other findings, provide strong evidence that the Polθ active site is reconfigured in human cells to stabilize ϵdA in the syn conformation for Hoogsteen base pairing with the correct nucleotide. The evidence that a DNA polymerase can configure its active site entirely differently in human cells than in the purified Pol establishes a new paradigm for DNA polymerase function.

Pratik Choudhary
Jun 1, 2015; 38:1016-1029
Type 1 Diabetes at a Crossroads

Caroline S. Fox
Sep 1, 2015; 38:1777-1803
Scientific Statement

Frank Qian
Feb 1, 2020; 43:265-271
Perspectives in Care

The National Academies of Sciences, Engineering, and Medicine announced March 5 that it does not find that the National Toxicology Program adequately supported its conclusion that fluoride is “presumed” to be a cognitive neurodevelopmental hazard to humans.

The Supreme Court on Friday granted a Justice Department request to temporarily block release of secret grand jury material from special counsel Robert Mueller's probe to Congress.

With displacement at a record high, governments around the world are looking for ways to jumpstart, expand, or maximize the impact of their refugee resettlement programs. Yet the evidence base regarding the effectiveness of such programs is particularly thin. This report maps the monitoring and evaluation gaps that exist and identifies areas where further research could help inform policymakers' actions.

Marking the release of an MPI Europe report commissioned as part of the EU-FRANK project, this webinar examines critical gaps in the research and evaluation of refugee resettlement programs and recommendations for improving evidence gathering and knowledge sharing between resettlement countries. 

European countries have ramped up their investments in helping refugees find work and integrate into society. Yet little hard evidence exists of what programs and policies work best. This report proposes a new framework for thinking smartly about integration programming, using cost-benefit analysis to look beyond short-term, economic outcomes to also measure indirect benefits through a social-value concept.

As the top destination in Europe for asylum seekers in recent years, Germany has rolled out a number of integration policy changes. Based on an early look at how newcomers’ integration is progressing, the report finds the policies have had ambiguous implications. The report also provides insights into the demographic and socioeconomic characteristics of the asylum seeker and refugee population.

RJ Wenthold
Mar 15, 1996; 16:1982-1989
Articles

It has been proposed that people can generate probabilistic predictions at multiple levels of representation during language comprehension. We used magnetoencephalography (MEG) and electroencephalography (EEG), in combination with representational similarity analysis, to seek neural evidence for the prediction of animacy features. In two studies, MEG and EEG activity was measured as human participants (both sexes) read three-sentence scenarios. Verbs in the final sentences constrained for either animate or inanimate semantic features of upcoming nouns, and the broader discourse context constrained for either a specific noun or for multiple nouns belonging to the same animacy category. We quantified the similarity between spatial patterns of brain activity following the verbs until just before the presentation of the nouns. The MEG and EEG datasets revealed converging evidence that the similarity between spatial patterns of neural activity following animate-constraining verbs was greater than following inanimate-constraining verbs. This effect could not be explained by lexical-semantic processing of the verbs themselves. We therefore suggest that it reflected the inherent difference in the semantic similarity structure of the predicted animate and inanimate nouns. Moreover, the effect was present regardless of whether a specific word could be predicted, providing strong evidence for the prediction of coarse-grained semantic features that goes beyond the prediction of individual words.

SIGNIFICANCE STATEMENT Language inputs unfold very quickly during real-time communication. By predicting ahead, we can give our brains a "head start," so that language comprehension is faster and more efficient. Although most contexts do not constrain strongly for a specific word, they do allow us to predict some upcoming information. For example, following the context of "they cautioned the...," we can predict that the next word will be animate rather than inanimate (we can caution a person, but not an object). Here, we used EEG and MEG techniques to show that the brain is able to use these contextual constraints to predict the animacy of upcoming words during sentence comprehension, and that these predictions are associated with specific spatial patterns of neural activity.

As an important cognitive bias, the framing effect shows that our decision preferences are sensitive to the verbal description (i.e., frame) of options. This study focuses on the neural underpinnings of the social framing effect, which is based on decision-making regarding other people. A novel paradigm was used in which participants made a trade-off between economic benefits and the feelings of others. This decision was described as either a "harm" to, or "not helping," other persons in two conditions (Harm frame vs Help frame). Both human males and females were recruited. Participants behaved more prosocially for Harm frame compared with Help frame, resulting in a significant social framing effect. Using functional magnetic resonance imaging, Experiment 1 showed that the social framing effect was associated with stronger activation in the temporoparietal junction (TPJ), especially its right part. The functional connectivity between the right TPJ (rTPJ) and medial prefrontal cortex predicted the social framing effect on the group level. In Experiment 2, we used transcranial direct current stimulation to modulate the activity of the rTPJ and found that the social framing effect became more prominent under anodal (excitatory) stimulation, while the nonsocial framing effect elicited by the economic gain/loss gambling frame remained unaffected. The rTPJ results might be associated with moral conflicts modulated by the social consequences of an action or different levels of mentalizing with others under different frame conditions, but alternative interpretations are also worth noting. These findings could help elucidate the psychological mechanisms of the social framing effect.

SIGNIFICANCE STATEMENT Previous studies have suggested that the framing effect is generated from an interaction between the amygdala and anterior cingulate cortex. This opinion, however, is based on findings from nonsocial framing tasks. Recent research has highlighted the importance of distinguishing between the social and nonsocial framing effects. The current study focuses on the social framing effect and finds out that the temporoparietal junction and its functional connectivity with the medial prefrontal cortex play a significant role. Additionally, modulating the activity of this region leads to changes in social (but not nonsocial) framing effect. Broadly speaking, these findings help understand the difference in neural mechanisms between social and nonsocial decision-making. Meanwhile, they might be illuminating to promote helping behavior in society.

The impact that created Pluto’s 'heart' may have rippled through its ocean and damaged its rear

Nearly 2,000 years ago, women who rode horseback and practiced archery may have roamed the steppes of Mongolia

The Catholic Church's actions during World War II have long been a matter of historical debate

We document that corporate pension contributions respond to tax-based incentives using the 2017 Tax Cut & Jobs Act (TCJA) as a natural experiment. The TCJA cut the U.S. federal corporate tax rate, temporarily increasing contribution incentives for sponsors of defined-benefit retirement plans. We exploit cross-sectional variation in ex-ante exposure to these incentives.

Bank of Italy Working Papers by Eleonora Porreca and Alfonso Rosolia

Central Bank of Chile Working Papers by Carlos Madeira

Central Bank of Chile Working Papers by Gee Hee Hong, Matthew Klepacz, Ernesto Pasten and Raphael Schoenle

CONTEXT:

Recommendations conflict regarding universal application of formal screening instruments in primary care (PC) and PC-like settings for autism spectrum disorder (ASD).

The nutritional and immunologic properties of human milk, along with clear evidence of dose-dependent optimal health outcomes for both mothers and infants, provide a compelling rationale to support exclusive breastfeeding. US women increasingly intend to breastfeed exclusively for 6 months. Because establishing lactation can be challenging, exclusivity is often compromised in hopes of preventing feeding-related neonatal complications, potentially affecting the continuation and duration of breastfeeding. Risk factors for impaired lactogenesis are identifiable and common. Clinicians must be able to recognize normative patterns of exclusive breastfeeding in the first week while proactively identifying potential challenges. In this review, we provide new evidence from the past 10 years on the following topics relevant to exclusive breastfeeding: milk production and transfer, neonatal weight and output assessment, management of glucose and bilirubin, immune development and the microbiome, supplementation, and health system factors. We focus on the early days of exclusive breastfeeding in healthy newborns ≥35 weeks’ gestation managed in the routine postpartum unit. With this evidence-based clinical review, we provide detailed guidance in identifying medical indications for early supplementation and can inform best practices for both birthing facilities and providers.

Just before Christmas, federal lawmakers sent President Donald Trump the Foundations for Evidenced-Based Policymaking Act of 2017, which aims to improve how federal data is used, shared, and protected.

William Leou, a 6th grade science teacher at the Brooklyn School for Collaborative Studies, uses an organizational worksheet to help students draw arguments from evidence.

Although several randomized trials have examined the efficacy of serotonin receptor inhibitors in the treatment of repetitive behaviors, there still remains clinical uncertainty as to whether these agents are effective in treating such behaviors in children and adults with autism spectrum disorders.

The goal of this meta-analysis was to examine randomized trials of serotonin receptor inhibitors for treating repetitive behaviors in autism spectrum disorders. Although a small but significant effect of these agents was observed, this effect is likely due to the selective publication of trial results. (Read the full article)

Clinical trials have demonstrated that prophylactic human papillomavirus (HPV) vaccines are highly effective in preventing HPV infection, but the impact of vaccination on HPV prevalence rates in real-world, community settings is uncertain.

This study provides evidence of a substantial decrease in the prevalence of vaccine-type HPV among young women and evidence of herd protection in a community only 4 years after the quadrivalent HPV vaccine was licensed. (Read the full article)

Childhood obesity is a public health concern. Although determinants of childhood overweight have been identified and their effect sizes have been calculated, prevention as well as treatment have had limited success.

We have calculated the population-based relevance of determinants of childhood overweight by using attributable risks, which can be interpreted as maximum success rates of preventive measures. New concepts were applied to estimate the relative contribution of each risk factor. (Read the full article)

Acquired widespread pain syndromes of youth are prevalent, disabling, usually unexplained, and untreatable. Small-fiber polyneuropathy causes widespread pain and multisystem complaints in older adults. Some causes are treatable. Neurodiagnostic skin biopsy, autonomic function testing, and nerve biopsy permit objective diagnosis.

It identifies definite (in 59%) and probable (in 17%) small-fiber polyneuropathy among 41 young patients with otherwise-unexplained, childhood-onset widespread pain. It characterizes this new disease’s clinical features, diagnostic, and treatment options. Some cases appeared immune mediated and responded to immunomodulatory therapies. (Read the full article)

In the only previous cross-sectional study, the quality of pediatric guidelines was rated low on the AGREE-II (Appraisal of Guidelines for Research and Evaluation II) scale. The levels of evidence used in pediatric clinical practice guidelines have never been described.

American Academy of Pediatrics guidelines score low on the AGREE-II scale. Approximately one-quarter of recommendations are based on expert opinion or no reference. These findings support the adoption of standards for guideline development and research targeted toward unsupported recommendations. (Read the full article)

A survey of educators around the country found that many reported looking up interventions on their own, when they really wanted more formal training, a survey found.

On May 3, Pompeo said that the US has "enormous evidence" to show that the coronavirus began in the Wuhan Institute of Virology and Beijing has refused to give international scientists access to learn what happened.

House Intelligence Committee chair Adam Schiff has published all the transcripts of ‘Russiagate’ interviews he had kept secret, blaming President Donald Trump for the delay, but their content belied his conspiracy narrative.
Read Full Article at RT.com

Effects observed in male rats

US lawmakers and experts have shown their anxiety over the US immigration agency's growing demand for "irrelevant" or earlier furnished information to decide an H-1B application, causing a delay in work visa processing, popular among the high skilled …

Civil cases are usually built around two cornerstones: contemporaneous documents and witness statements. In 2019 the Business and Property Courts implemented a pilot with the aim of streamlining the process for the disclosure of contemporaneous docu...

Expert evidence in procurement claims – no general admission On 28 September 2012 the High Court rejected an application under...

Gainesville: The decision to shelve detailed advice from the nation’s top disease control experts for reopening communities during the coronavirus pandemic came from the highest levels of the White House, according to internal government emails obtained by The Associated Press. The files also show that after the AP reported Thursday that the guidance document had been buried, the Trump administration ordered key parts of it to be fast-tracked for approval. The trove of emails shows the nation’s top public health experts at the Centers for Disease Control and Prevention spending weeks working on guidance to help the country deal with a public health emergency, only to see their...

Court turns down alleged Caruana Galizia assassination mastermind's request to have compilation of evidence continue 

Financial constraints are a significant barrier for India's SMEs participating in global value chains.

Export performance and firm size have a positive impact on trade participation at the intensive margin for firms of all sizes.

A well-designed evaluation system can be effective in motivating bureaucrats to shift their efforts toward a more environmentally friendly growth path.