Straining Their Brains: Why the Case Against Enhancement is Not Persuasive.

Your kid’s schoolwork not up to par? Looking for Mr. or Ms. Right? Any other problems caused by a mind’s eye seemingly not quite on the ball? Answers might lie in a brain-enhancing pill. Some argue this is merely better living through chemistry and in line with humanity’s self-improving actions throughout history, but others suggest that quick-fix medications could well distort the very things that make us human. Here a leading bioethicist squares off with a member of the President’s Council on Bioethics on the controversy about pursuing better brains with a little help from biotechnology

Comparison of the Value of Nursing Work Environments in Hospitals Across Different Levels of Patient Risk

Importance The literature suggests that hospitals with better nursing work environments provide better quality of care. Less is known about value (cost vs quality). Objectives To test whether hospitals with better nursing work environments displayed better value than those with worse nursing environments and to determine patient risk groups associated with the greatest value. Design, Setting, and Participants A retrospective matched-cohort design, comparing the outcomes and cost of patients at focal hospitals recognized nationally as having good nurse working environments and nurse-to-bed ratios of 1 or greater with patients at control group hospitals without such recognition and with nurse-to-bed ratios less than 1. This study included 25 752 elderly Medicare general surgery patients treated at focal hospitals and 62 882 patients treated at control hospitals during 2004-2006 in Illinois, New York, and Texas. The study was conducted between January 1, 2004, and November 30, 2006; this analysis was conducted from April to August 2015. Exposures Focal vs control hospitals (better vs worse nursing environment). Main Outcomes and Measures Thirty-day mortality and costs reflecting resource utilization. Results This study was conducted at 35 focal hospitals (mean nurse-to-bed ratio, 1.51) and 293 control hospitals (mean nurse-to-bed ratio, 0.69). Focal hospitals were larger and more teaching and technology intensive than control hospitals. Thirty-day mortality in focal hospitals was 4.8% vs 5.8% in control hospitals (P \u3c .001), while the cost per patient was similar: the focal-control was −$163 (95$542 to $215; P = .40), suggesting better value in the focal group. For the focal vs control hospitals, the greatest mortality benefit (17.3$941 per patient ($53 701 vs$52 760; P = .25). The greatest difference in value between focal and control hospitals appeared in patients in the second-highest risk quintile, with mortality of 4.2% vs 5.8% (P \u3c .001), with a nonsignificant cost difference of −$862 ($33 513 vs $34 375; P = .12). Conclusions and Relevance Hospitals with better nursing environments and above-average staffing levels were associated with better value (lower mortality with similar costs) compared with hospitals without nursing environment recognition and with below-average staffing, especially for higher-risk patients. These results do not suggest that improving any specific hospital’s nursing environment will necessarily improve its value, but they do show that patients undergoing general surgery at hospitals with better nursing environments generally receive care of higher value

The transparent failure of norms to keep up standards of belief

We argue that the most plausible characterisation of the norm of truth—it is permissible to believe that p if and only if p is true—is unable to explain Transparency in doxastic deliberation, a task for which it is claimed to be equipped. In addition, the failure of the norm to do this work undermines the most plausible account of how the norm guides belief formation at all. Those attracted to normativism about belief for its perceived explanatory credentials had better look elsewhere

Avoiding Irrational NeuroLaw Exuberance: A Plea for Neuromodesty

In a 2002 editorial published in The Economist, the following warning was given: Genetics may yet threaten privacy, kill autonomy, make society homogeneous and gut the concept of human nature. But neuroscience could do all of these things first. The genome was fully sequenced in 2001, and there has not been one resulting major advance in therapeutic medicine since. Thus, even in its most natural applied domain-medicine-genetics has not had the far-reaching consequences that were envisioned. The same has been true for various other sciences that were predicted to revolutionize the law, including behavioral psychology, sociology, psychodynamic psychology, and others. This will also be true of neuroscience, which is simply the newest science on the block. Neuroscience is not going to do the terrible things The Economist fears, at least not for the foreseeable future. Neuroscience has many things to say but not nearly as much as people would hope, especially in relation to law. At most, in the near to intermediate term, neuroscience may make modest contributions to legal policy and case adjudication. Nonetheless, there has been irrational exuberance about the potential contribution of neuroscience, an issue I have addressed previously and referred to as Brain Overclaim Syndrome. I first consider the law\u27s motivation and the motivation of some advocates to turn to science to solve the very hard normative problems that law addresses. Part III discusses the law\u27s psychology and its concepts of the person and responsibility. The next Part considers the general relation of neuroscience to law, which I characterize as the issue of translation. Part V canvasses various distractions that have bedeviled clear thinking about the relation of scientific, causal accounts of behavior to responsibility. The following Part examines the limits of neurolaw and Part VII considers why neurolaw does not pose a genuinely radical challenge to the law\u27s concepts of the person and responsibility. Part VIII makes a case for cautious optimism about the contribution neuroscience may make to law in the near and intermediate term. A brief conclusion follows..

Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks

DNA interstrand crosslinks (ICLs) are among the most cytotoxic types of DNA damage, thus ICL-inducing agents such as psoralen, are clinically useful chemotherapeutics. Psoralen-modified triplex-forming oligonucleotides (TFOs) have been used to target ICLs to specific genomic sites to increase the selectivity of these agents. However, how TFO-directed psoralen ICLs (Tdp-ICLs) are recognized and processed in human cells is unclear. Previously, we reported that two essential nucleotide excision repair (NER) protein complexes, XPA–RPA and XPC–RAD23B, recognized ICLs in vitro, and that cells deficient in the DNA mismatch repair (MMR) complex MutSβ were sensitive to psoralen ICLs. To further investigate the role of MutSβ in ICL repair and the potential interaction between proteins from the MMR and NER pathways on these lesions, we performed electrophoretic mobility-shift assays and chromatin immunoprecipitation analysis of MutSβ and NER proteins with Tdp-ICLs. We found that MutSβ bound to Tdp-ICLs with high affinity and specificity in vitro and in vivo, and that MutSβ interacted with XPA–RPA or XPC–RAD23B in recognizing Tdp-ICLs. These data suggest that proteins from the MMR and NER pathways interact in the recognition of ICLs, and provide a mechanistic link by which proteins from multiple repair pathways contribute to ICL repair

An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/ Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8 + T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. Significance: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade

British signals intelligence and the 1916 Easter Rising in Ireland

Historians for decades have placed Room 40, the First World War British naval signals intelligence organization, at the centre of narratives about the British anticipation of and response to the Easter Rising in Ireland in 1916. A series of crucial decrypts of telegrams between the German embassy in Washington and Berlin, it has been believed, provided significant advance intelligence about the Rising before it took place. This article upends previous accounts by demonstrating that Room 40 possessed far less advance knowledge about the Rising than has been believed, with most of the supposedly key decrypts not being generated until months after the Rising had taken place

A Systematic Approach to Multiple Breath Nitrogen Washout Test Quality

Background: Accurate estimates of multiple breath washout (MBW) outcomes require correct operation of the device, appropriate distraction of the subject to ensure they breathe in a manner representative of their relaxed tidal breathing pattern, and appropriate interpretation of the acquired data. Based on available recommendations for an acceptable MBW test, we aimed to develop a protocol to systematically evaluate MBW measurements based on these criteria. Methods: 50MBWtest occasions were systematically reviewed for technical elements and whether the breathing pattern was representative of relaxed tidal breathing by an experienced MBW operator. The impact of qualitative and quantitative criteria on inter-observer agreement was assessed across eight MBW operators (n = 20 test occasions, compared using a Kappa statistic). Results: Using qualitative criteria, 46/168 trials were rejected: 16.6%were technically unacceptable and 10.7% were excluded due to inappropriate breathing pattern. Reviewer agreement was good using qualitative criteria and further improved with quantitative criteria from (κ = 0.53– 0.83%) to (κ 0.73–0.97%), but at the cost of exclusion of further test occasions in this retrospective data analysis. Conclusions: The application of the systematic review improved inter-observer agreement but did not affect reported MBW outcomes

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure