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While donor-conceived children have similar mental health outcomes compared to spontaneously conceived children, there is an inconsistency between studies investigating mental health outcomes of donor-conceived people in adulthood. This study is an online health survey that was completed by 272 donor sperm-conceived adults and 877 spontaneously conceived adults from around the world. Donor sperm-conceived adults had increased diagnoses of attention deficit disorder (P = 0.004), and autism (P = 0.044) in comparison to those conceived spontaneously. Donor sperm-conceived adults self-reported increased incidences of seeing a mental health professional (P < 0.001), identity formation problems (P < 0.001), learning difficulties (P < 0.001), panic attacks (P = 0.038), recurrent nightmares (sperm P = 0.038), and alcohol/drug dependency (P = 0.037). DASS-21 analysis revealed that donor sperm-conceived adults were also more stressed than those conceived spontaneously (P = 0.013). Both donor sperm and spontaneously conceived cohorts were matched for sex, age, height, alcohol consumption, smoking, exercise, own fertility, and maternal smoking. The increase in adverse mental health outcomes is consistent with some studies of donor-conceived adult mental health outcomes. These results are also consistent with the Developmental Origins of Health and Disease (DOHaD) phenomenon that has linked adverse perinatal outcomes, which have been observed in donor-conceived neonates, to increased risk of chronic disease, including mental health. Further work is required to reconcile our observations in adults to contrary observations reported in donor-conceived children.
ABSTRACT IMPACT: Melanoma leptomeningeal disease (LMD) is a devastating subtype of central nervous system (CNS) metastatic disease that is associated with limited treatment options and an extremely poor prognosis, thus requiring the development of preclinical models of LMD for therapeutic development. OBJECTIVES/GOALS:
1. Develop an immunocompetent murine model of melanoma LMD with tumors bearing genetic mutations commonly found in patients, specifically BRAF(V600E)/PTEN-/-
2. Assess the safety of intrathecal (IT) immunotherapy, specifically anti-PD1 antibody (aPD1)
3. Evaluate the therapeutic efficacy of IT aPD1 checkpoint blockade in murine melanoma LMD METHODS/STUDY POPULATION: To develop BRAF(V600E)/PTEN-/- LMD models, we acquired BP, D4M, and D4M-UV2 (irradiated) murine melanoma cell lines and luciferase-tagged them. 1.5x10^4 cells were suspended in 10 uL serum-free media and injected into the cisterna magna of female C57BL/6 mice. Brain and spinal cord were harvested for histologic assessment once mice were moribund. To assess safety of IT aPD1, we injected IT control IgG or IT aPD1 (13 ug, 26 ug, 39 ug) and monitored weights or harvested at days 7 or 14 for IHC staining of inflammation markers. To evaluate therapeutic efficacy of IT aPD1, BP cells were directly injected as above. After 3 days, mice underwent imaging to confirm tumor uptake and randomization to receive 13 ug IT control IgG or aPD1 once + 200 ug systemic (Sys) control IgG or aPD1 (days 0, 3, and 5), and then monitored for survival. RESULTS/ANTICIPATED RESULTS: For LMD development, all mice survived cisternal injection of BP, D4M, and D4M-UV2 cells and median survival was 17, 19, and 30 days, respectively. Presence of leptomeningeal deposits was confirmed for all tumor-bearing mice by IHC for MART1. For safety of IT aPD1, all mice survived the procedure and no mice displayed morbidity or >10% weight loss over 14 days of observation. IHC assessment of brain and spinal cord samples from mice treated with 13 ug aPD1 revealed focal ischemia related to injection site and no other signs of neurological damage or inflammation. IT aPD1 treatment of mice with BP leptomeningeal tumors demonstrated no significant survival advantage, although both IT aPD1 +/- Sys aPD1 had mice live up to days 29 and 26, respectively, compared to both IT control IgG +/- Sys aPD1, for which all mice died by day 22. DISCUSSION/SIGNIFICANCE OF FINDINGS: We demonstrate that cisternal injection of murine BRAF(V600E)/PTEN-/- melanoma cell lines yield LMD with reproducible survival and that treatment with IT aPD1 in this model is feasible and safe. Together these findings establish a new model to facilitate the development of more effective immunotherapy strategies for melanoma patients with LMD.
What is faith? Is it just a matter of propositions, claims, such as “God is love”? Or is it more a matter of commitment, perhaps not fully articulated, of having a background awareness of God and his love? And what is the position of faith for the Christian? Is faith alone enough, or does one need to supplement it with reasoned argument and possibly appeal to outside evidence? The New Atheists argue that Christianity fails because it rests on faith, and, today, we see that reason and evidence, most notably science and its confirmed theories, negate faith claims. Faith therefore is seen as delusional, a function of the fact that people are scared of death and the apparent meaninglessness of their lives. Ruse and Davies raise and argue these questions, coming to very different conclusions.
The authors run through the major arguments for the existence of God: Anselm’s ontological argument (and also Descartes’s version), arguing that the very notion of God a priori proves hs existence; Aquinas’s cosmological (or causal) argument, that God is needed to stop an infinite regression of causes from the present to the past; and the teleological argument or the argument from design, that the design-like natural objects of this world demand a designer. Then they raise the standard objections: Gaunilo’s criticism that the ontological argument proves the existence of perfect islands, which is ridiculous, and Kant’s objection that you cannot infer matters of fact by a priori reasoning; Dawkins’s criticism that the cosmological argument raises the unanswered question of what causes God; and Hume’s criticism of the design argument, and Darwin’s subsequent demonstration that natural selection can explain final causes naturalistically, and so there is no need to invoke a Designer God.
Why do we disagree? Ultimately, it comes down to faith. The Christianity Ruse is rejecting is the Christianity of Kierkegaard. Faith demands a leap into the absurd. Reason and evidence backing up the faith commitment would render it inauthentic. Believe without seeing the scars! Hence, for Ruse, given that he thinks this the only authentic Christianity, all attempts to make sense of Christianity are pointless. You are trying to square the circle. Davies is a committed Christian, a Roman Catholic philosopher, and theologian. For him, faith and reason do not clash; they are complementary. Hence, for Davies it is legitimate – demanded – that he bring reason to bear on his faith beliefs, for instance, concerning the Trinity and the Incarnation. In the end, although there is sympathy for the beliefs of the other and much respect, Michael Ruse and Brian Davies are on different tracks, and they do not run in parallel.
The tensions between our two authors start to rise. Ruse dismisses natural theology and proofs for the existence of God. Faith or nothing, and that means nothing because faith does not work. Davies responds by pointing out that there is biblical evidence for natural theology, and turns to Aquinas for guidance. The saint agrees that faith trumps reason and is enough alone for Christian belief, but argues also that reason, natural theology, has its place. It can supplement and back up the commitments through faith. There is therefore no conflict between reason and faith. Both have their role. In any case, argues Davies, scientists make faith commitments, having to start somewhere without prior proof, so in the end science is in the same business as religion. Ruse responds that the commitments of science and the commitments of religion are entirely different. The Christian cannot end the case by using this line of argument.
This chapter deals with arguments against the existence of God, at least a God as is supposed by Christianity – Creator, omnipotent and omniscient, all-loving especially toward his special creation, humankind. Ruse thinks that the arguments are effective. Above all, he cannot reconcile the Christian God with the problem of evil. He sees that human free will, including the power to do great evil, can in some sensed be reconciled with the Creator. He sees also that natural evil can likewise be reconciled with the Creator. He just cannot see that the Creator, knowing it was going to happen, let it happen. The suffering of small children cannot ever be reconciled with the end, no matter how good. Davies, taking a position much influenced by the great theologians, especially Aquinas, thinks that people like Ruse have an altogether mistaken understanding of God and his nature. The Bible is far from portraying God as the friendly chap in the sky, as supposed by Ruse. And theology backs up this realization by showing that, properly understood, we can speak of God as all-powerful and all-loving.
The two authors come apart here, not simply because Ruse is a nonbeliever and Davies a practicing Christian. Ruse was raised a Quaker and so, thinking theologically, he thinks in a Quaker context. More than anything he is accepting (or he would be if he were still a believer) of apophatic theology. One cannot say what God is but rather what He is not. How one works out the details of the Trinity are not that important. One is committed to the Trinity on faith, and for the rest – “now we see through a glass darkly.” For Davies, by contrast, theology is grounded in the thinking of the great theologians. He believes one can make progress on understanding the Trinity. Here is where the clash comes, not so much because Ruse is a nonbeliever, but because his theology tells him that all such attempts as those of Davies are bound to fail. 1 + 1 + 1 ≠ 1.
Morality is about right and wrong. There is the question of what we should do, substantive ethics, and the question of why we should do what we do, metaethics. There is little if any real difference between Ruse and Davies at the substantive level. At the metaethical level, Ruse takes a subjective view and Davies an objective view, but in important respects there is shared belief. Both ground morality in human nature. Right and wrong at the substantive level is a matter of who and what we are. Kindness to children is a good thing, because that is natural for humans. Hate of the disabled is wrong, because that is unnatural. But whereas Ruse grounds human nature in Darwinian evolutionary theory, and believes that there is no extra appeal to authority, and so is subjective, Davies grounds human nature in God’s loving creation, and hence in this sense is objective. An action is good is because God made us that way, and to do the right thing is to do the (God-created) natural thing.
There is global interest in the reconfiguration of community mental health services, including primary care, to improve clinical and cost effectiveness.
This study seeks to describe patterns of service use, continuity of care, health risks, physical healthcare monitoring and the balance between primary and secondary mental healthcare for people with severe mental illness in receipt of secondary mental healthcare in the UK.
We conducted an epidemiological medical records review in three UK sites. We identified 297 cases randomly selected from the three participating mental health services. Data were manually extracted from electronic patient medical records from both secondary and primary care, for a 2-year period (2012–2014). Continuous data were summarised by mean and s.d. or median and interquartile range (IQR). Categorical data were summarised as percentages.
The majority of care was from secondary care practitioners: of the 18 210 direct contacts recorded, 76% were from secondary care (median, 36.5; IQR, 14–68) and 24% were from primary care (median, 10; IQR, 5–20). There was evidence of poor longitudinal continuity: in primary care, 31% of people had poor longitudinal continuity (Modified Modified Continuity Index ≤0.5), and 43% had a single named care coordinator in secondary care services over the 2 years.
The study indicates scope for improvement in supporting mental health service delivery in primary care. Greater knowledge of how care is organised presents an opportunity to ensure some rebalancing of the care that all people with severe mental illness receive, when they need it. A future publication will examine differences between the three sites that participated in this study.
Is debate on issues related to faith and reason still possible when dialogue between believers and non-believers has collapsed? Taking God Seriously not only proves that it is possible, but also demonstrates that such dialogue produces fruitful results. Here, Brian Davies, a Dominican priest and leading scholar of Thomas Aquinas, and Michael Ruse, a philosopher of science and well-known non-believer, offer an extended discussion on the nature and plausibility of belief in God and Christianity. They explore key topics in the study of religion, notably the nature of faith, the place of reason in discussions about religion, proofs for the existence of God, the problem of evil, and the problem of multiple competing religious systems, as well as the core concepts of Christian belief including the Trinity and the justification of morality. Written in a jargon-free manner, avoiding the extremes of evangelical literalism and New Atheism prejudice, Taking God Seriously does not compromise integrity or shy from discussing important or difficult issues.
Haematopoietic stem cell transplantation is an important and effective treatment strategy for many malignancies, marrow failure syndromes, and immunodeficiencies in children, adolescents, and young adults. Despite advances in supportive care, patients undergoing transplant are at increased risk to develop cardiovascular co-morbidities.
This study was performed as a feasibility study of a rapid cardiac MRI protocol to substitute for echocardiography in the assessment of left ventricular size and function, pericardial effusion, and right ventricular hypertension.
A total of 13 patients were enrolled for the study (age 17.5 ± 7.7 years, 77% male, 77% white). Mean study time was 13.2 ± 5.6 minutes for MRI and 18.8 ± 5.7 minutes for echocardiogram (p = 0.064). Correlation between left ventricular ejection fraction by MRI and echocardiogram was good (ICC 0.76; 95% CI 0.47, 0.92). None of the patients had documented right ventricular hypertension. Patients were given a survey regarding their experiences, with the majority both perceiving that the echocardiogram took longer (7/13) and indicating they would prefer the MRI if given a choice (10/13).
A rapid cardiac MRI protocol was shown feasible to substitute for echocardiogram in the assessment of key factors prior to or in follow-up after haematopoietic stem cell transplantation.
Type 2 diabetes results mainly from weight gain in adult life and affects one in twelve people worldwide. In the Diabetes REmission Clinical Trial (DiRECT), the primary care-led Counterweight-Plus weight management program achieved remission of type 2 diabetes (for up to six years) for forty-six percent of patients after one year and thirty-six percent after two years. The objective of this study was to estimate the implementation costs of the program, as well as its two-year within-trial cost effectiveness and lifetime cost effectiveness.
Within-trial cost effectiveness included the Counterweight-Plus costs (including training, practitioner appointments, and low-energy diet), medications, and all routine healthcare contacts, combined with achieved remission rates. Lifetime cost per quality-adjusted life-year (QALY) was estimated according to projected durations of remissions, assuming continued relapse rates as seen in year two of DiRECT and the consequent life expectancy, quality of life and healthcare costs.
The two-year intervention cost was EUR 1,580 per participant, with over eighty percent of the costs incurred in year one. Compared with the control group, medication savings were EUR 259 (95% confidence interval [CI]: 166–352) for anti-diabetes drugs and EUR 29 (95% CI: 12–47) for anti-hypertensive medications. The intervention was modeled with a lifetime horizon to achieve a mean 0.06 (95% CI: 0.04–0.09) gain in QALYs for the DiRECT population and a mean total lifetime cost saving per participant of EUR 1,497 (95% CI: 755–2,331), with the intervention becoming cost-saving within six years.
The intensive weight loss and maintenance program reduced the cost of anti-diabetes drugs through improved metabolic control, achieved diabetes remission in over one-third of participants, and reduced total healthcare contacts and costs over two years. A substantial lifetime healthcare cost saving is anticipated from periods of diabetes remission and delaying complications. Healthcare resources could be shifted cost effectively to establish diabetes remission services, using the existing DiRECT intervention, even if remissions are only maintained for limited durations. However, more research investment is needed to further improve weight-loss maintenance and extend remissions.
Potential effectiveness of harvest weed seed control (HWSC) systems depends upon seed shatter of the target weed species at crop maturity, enabling its collection and processing at crop harvest. However, seed retention likely is influenced by agroecological and environmental factors. In 2016 and 2017, we assessed seed-shatter phenology in 13 economically important broadleaf weed species in soybean [Glycine max (L.) Merr.] from crop physiological maturity to 4 wk after physiological maturity at multiple sites spread across 14 states in the southern, northern, and mid-Atlantic United States. Greater proportions of seeds were retained by weeds in southern latitudes and shatter rate increased at northern latitudes. Amaranthus spp. seed shatter was low (0% to 2%), whereas shatter varied widely in common ragweed (Ambrosia artemisiifolia L.) (2% to 90%) over the weeks following soybean physiological maturity. Overall, the broadleaf species studied shattered less than 10% of their seeds by soybean harvest. Our results suggest that some of the broadleaf species with greater seed retention rates in the weeks following soybean physiological maturity may be good candidates for HWSC.