The Predicted Long-Term Benefits of Ensuring Timely Treatment and Medication Adherence in Early Schizophrenia.

The impact of initiatives aimed at reducing time in untreated psychosis during early-stage schizophrenia will be unknown for many years. Thus, we simulate the effect of earlier treatment entry and better antipsychotic drug adherence on schizophrenia-related hospitalizations, receipt of disability benefits, competitive employment, and independent/family living over a ten-year horizon. We predict that earlier treatment entry reduces hospitalizations by 12.6-14.4% and benefit receipt by 7.0-8.5%, while increasing independent/family living by 41.5-46% and employment by 42-58%. We predict larger gains if a pro-adherence intervention is also used. Our findings suggest substantial benefits of timely and consistent early schizophrenia care.

Fossilized melanosomes and the colour of Cretaceous dinosaurs and birds.

Spectacular fossils from the Early Cretaceous Jehol Group of northeastern China have greatly expanded our knowledge of the diversity and palaeobiology of dinosaurs and early birds, and contributed to our understanding of the origin of birds, of flight, and of feathers. Pennaceous (vaned) feathers and integumentary filaments are preserved in birds and non-avian theropod dinosaurs, but little is known of their microstructure. Here we report that melanosomes (colour-bearing organelles) are not only preserved in the pennaceous feathers of early birds, but also in an identical manner in integumentary filaments of non-avian dinosaurs, thus refuting recent claims that the filaments are partially decayed dermal collagen fibres. Examples of both eumelanosomes and phaeomelanosomes have been identified, and they are often preserved in life position within the structure of partially degraded feathers and filaments. Furthermore, the data here provide empirical evidence for reconstructing the colours and colour patterning of these extinct birds and theropod dinosaurs: for example, the dark-coloured stripes on the tail of the theropod dinosaur Sinosauropteryx can reasonably be inferred to have exhibited chestnut to reddish-brown tones.

Ordovician faunas of Burgess Shale type.

The renowned soft-bodied faunas of the Cambrian period, which include the Burgess Shale, disappear from the fossil record in the late Middle Cambrian, after which the Palaeozoic fauna dominates. The disappearance of faunas of Burgess Shale type curtails the stratigraphic record of a number of iconic Cambrian taxa. One possible explanation for this loss is a major extinction, but more probably it reflects the absence of preservation of similar soft-bodied faunas in later periods. Here we report the discovery of numerous diverse soft-bodied assemblages in the Lower and Upper Fezouata Formations (Lower Ordovician) of Morocco, which include a range of remarkable stem-group morphologies normally considered characteristic of the Cambrian. It is clear that biotas of Burgess Shale type persisted after the Cambrian and are preserved where suitable facies occur. The Fezouata biota provides a link between the Burgess Shale communities and the early stages of the Great Ordovician Biodiversification Event.

Fossilized biophotonic nanostructures reveal the original colors of 47-million-year-old moths.

Structural colors are generated by scattering of light by variations in tissue nanostructure. They are widespread among animals and have been studied most extensively in butterflies and moths (Lepidoptera), which exhibit the widest diversity of photonic nanostructures, resultant colors, and visual effects of any extant organism. The evolution of structural coloration in lepidopterans, however, is poorly understood. Existing hypotheses based on phylogenetic and/or structural data are controversial and do not incorporate data from fossils. Here we report the first example of structurally colored scales in fossil lepidopterans; specimens are from the 47-million-year-old Messel oil shale (Germany). The preserved colors are generated by a multilayer reflector comprised of a stack of perforated laminae in the scale lumen; differently colored scales differ in their ultrastructure. The original colors were altered during fossilization but are reconstructed based upon preserved ultrastructural detail. The dorsal surface of the forewings was a yellow-green color that probably served as a dual-purpose defensive signal, i.e. aposematic during feeding and cryptic at rest. This visual signal was enhanced by suppression of iridescence (change in hue with viewing angle) achieved via two separate optical mechanisms: extensive perforation, and concave distortion, of the multilayer reflector. The fossils provide the first evidence, to our knowledge, for the function of structural color in fossils and demonstrate the feasibility of reconstructing color in non-metallic lepidopteran fossils. Plastic scale developmental processes and complex optical mechanisms for interspecific signaling had clearly evolved in lepidopterans by the mid-Eocene.

Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus.

The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17ß-estradiol (E(2)) is dependent on mTOR signaling in the dorsal hippocampus, and whether E(2)-induced mTOR signaling is dependent on dorsal hippocampal phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) activation. We first demonstrated that the enhancement of object recognition induced by E(2) was blocked by dorsal hippocampal inhibition of ERK, PI3K, or mTOR activation. We then showed that an increase in dorsal hippocampal ERK phosphorylation 5 min after intracerebroventricular (ICV) E(2) infusion was also blocked by dorsal hippocampal infusion of the three cell signaling inhibitors. Next, we found that ICV infusion of E(2) increased phosphorylation of the downstream mTOR targets S6K (Thr-421) and 4E-BP1 in the dorsal hippocampus 5 min after infusion, and that this phosphorylation was blocked by dorsal hippocampal infusion of inhibitors of ERK, PI3K, and mTOR. Collectively, these data demonstrate for the first time that activation of the dorsal hippocampal mTOR signaling pathway is necessary for E(2) to enhance object recognition memory consolidation and that E(2)-induced mTOR activation is dependent on upstream activation of ERK and PI3K signaling.

Experimental maturation of feathers: implications for reconstructions of fossil feather colour.

Fossil feathers often preserve evidence of melanosomes-micrometre-scale melanin-bearing organelles that have been used to infer original colours and patterns of the plumage of dinosaurs. Such reconstructions acknowledge that evidence from other colour-producing mechanisms is presently elusive and assume that melanosome geometry is not altered during fossilization. Here, we provide the first test of this assumption, using high pressure-high temperature autoclave experiments on modern feathers to simulate the effects of burial on feather colour. Our experiments show that melanosomes are retained despite loss of visual evidence of colour and complete degradation of other colour-producing structures (e.g. quasi-ordered arrays in barbs and the keratin cortex in barbules). Significantly, however, melanosome geometry and spatial distribution are altered by the effects of pressure and temperature. These results demonstrate that reconstructions of original plumage coloration in fossils where preserved features of melanosomes are affected by diagenesis should be treated with caution. Reconstructions of fossil feather colour require assessment of the extent of preservation of various colour-producing mechanisms, and, critically, the extent of alteration of melanosome geometry.

The original colours of fossil beetles.

Structural colours, the most intense, reflective and pure colours in nature, are generated when light is scattered by complex nanostructures. Metallic structural colours are widespread among modern insects and can be preserved in their fossil counterparts, but it is unclear whether the colours have been altered during fossilization, and whether the absence of colours is always real. To resolve these issues, we investigated fossil beetles from five Cenozoic biotas. Metallic colours in these specimens are generated by an epicuticular multi-layer reflector; the fidelity of its preservation correlates with that of other key cuticular ultrastructures. Where these other ultrastructures are well preserved in non-metallic fossil specimens, we can infer that the original cuticle lacked a multi-layer reflector; its absence in the fossil is not a preservational artefact. Reconstructions of the original colours of the fossils based on the structure of the multi-layer reflector show that the preserved colours are offset systematically to longer wavelengths; this probably reflects alteration of the refractive index of the epicuticle during fossilization. These findings will allow the former presence, and original hue, of metallic structural colours to be identified in diverse fossil insects, thus providing critical evidence of the evolution of structural colour in this group.

The progesterone-induced enhancement of object recognition memory consolidation involves activation of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) pathways in the dorsal hippocampus.

Although much recent work has elucidated the biochemical mechanisms underlying the modulation of memory by 17ß-estradiol, little is known about the signaling events through which progesterone (P) regulates memory. We recently demonstrated that immediate post-training infusion of P into the dorsal hippocampus enhances object recognition memory consolidation in young ovariectomized female mice (Orr et al., 2009). The goal of the present study was to identify the biochemical alterations that might underlie this mnemonic enhancement. We hypothesized that the P-induced enhancement of object recognition would be dependent on activation of the ERK and mTOR pathways. In young ovariectomized mice, we found that bilateral dorsal hippocampal infusion of P significantly increased levels of phospho-p42 ERK and the mTOR substrate S6K in the dorsal hippocampus 5 min after infusion. Phospho-p42 ERK levels were downregulated 15 min after infusion and returned to baseline 30 min after infusion, suggesting a biphasic effect of P on ERK activation. Dorsal hippocampal ERK and mTOR activation were necessary for P to facilitate memory consolidation, as suggested by the fact that inhibitors of both pathways infused into the dorsal hippocampus immediately after training blocked the P-induced enhancement of object recognition. Collectively, these data provide the first demonstration that the ability of P to enhance memory consolidation depends on the rapid activation of cell signaling and protein synthesis pathways in the dorsal hippocampus.

Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation.

We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17beta-estradiol (E(2)) to enhance novel object recognition in young ovariectomized mice (Fernandez et al., 2008). Here, we asked whether E(2) has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, and whether these effects depend on ERK and phosphatidylinositol 3-kinase (PI3K)/Akt activation. We first demonstrated that intracerebroventricular or intrahippocampal E(2) infusion immediately after object recognition training enhanced memory consolidation in middle-aged, but not aged, females. The E(2)-induced enhancement in middle-aged females was blocked by intrahippocampal inhibition of ERK or PI3K activation. Intrahippocampal or intracerebroventricular E(2) infusion in middle-aged females increased phosphorylation of p42 ERK in the dorsal hippocampus 15 min, but not 5 min, after infusion, an effect that was blocked by intrahippocampal inhibition of ERK or PI3K activation. Dorsal hippocampal PI3K and Akt phosphorylation was increased 5 min after intrahippocampal or intracerebroventricular E(2) infusion in middle-aged, but not aged, females. Intracerebroventricular E(2) infusion also increased PI3K phosphorylation after 15 min, and this effect was blocked by intrahippocampal PI3K, but not ERK, inhibition. These data demonstrate for the first time that activation of dorsal hippocampal PI3K/Akt and ERK signaling pathways is necessary for E(2) to enhance object recognition memory in middle-aged females. They also reveal that similar dorsal hippocampal signaling pathways mediate E(2)-induced object recognition memory enhancement in young and middle-aged females and that the inability of E(2) to activate these pathways may underlie its failure to enhance object recognition in aged females.

Organic preservation of fossil musculature with ultracellular detail.

The very labile (decay-prone), non-biomineralized, tissues of organisms are rarely fossilized. Occurrences thereof are invaluable supplements to a body fossil record dominated by biomineralized tissues, which alone are extremely unrepresentative of diversity in modern and ancient ecosystems. Fossil examples of extremely labile tissues (e.g. muscle) that exhibit a high degree of morphological fidelity are almost invariably replicated by inorganic compounds such as calcium phosphate. There is no consensus as to whether such tissues can be preserved with similar morphological fidelity as organic remains, except when enclosed inside amber. Here, we report fossilized musculature from an approximately 18 Myr old salamander from lacustrine sediments of Ribesalbes, Spain. The muscle is preserved organically, in three dimensions, and with the highest fidelity of morphological preservation yet documented from the fossil record. Preserved ultrastructural details include myofilaments, endomysium, layering within the sarcolemma, and endomysial circulatory vessels infilled with blood. Slight differences between the fossil tissues and their counterparts in extant amphibians reflect limited degradation during fossilization. Our results provide unequivocal evidence that high-fidelity organic preservation of extremely labile tissues is not only feasible, but likely to be common. This is supported by the discovery of similarly preserved tissues in the Eocene Grube Messel biota.

Taphonomic experiments resolve controls on the preservation of melanosomes and keratinous tissues in feathers.

Fossils are a key source of data on the evolution of feather structure and function through deep time, but their ability to resolve macroevolutionary questions is compromised by an incomplete understanding of their taphonomy. Critically, the relative preservation potential of two key feather components, melanosomes and keratinous tissue, is not fully resolved. Recent studies suggesting that melanosomes are preferentially preserved conflict with observations that melanosomes preserve in fossil feathers as external moulds in an organic matrix. To date, there is no model to explain the latter mode of melanosome preservation. We addressed these issues by degrading feathers in systematic taphonomic experiments incorporating decay, maturation and oxidation in isolation and combination. Our results reveal that the production of mouldic melanosomes requires interactions with an oxidant and is most likely to occur prior to substantial maturation. This constrains the taphonomic conditions under which melanosomes are likely to be fossilized. Critically, our experiments also confirm that keratinous feather structures have a higher preservation potential than melanosomes under a range of diagenetic conditions, supporting hitherto controversial hypotheses that fossil feathers can retain degraded keratinous structures.

Effects of Health Care Payment Models on Physician Practice in the United States: Follow-Up Study.

This study, sponsored by the American Medical Association (AMA), describes how alternative payment models (APMs) affect physicians, physicians' practices, and hospital systems in the United States and also provides updated data to the original 2014 study. Payment models discussed are core payment (fee for service, capitation, episode-based and bundled), supplementary payment (shared savings, pay for performance, retainer-based), and combined payment (medical homes and accountable care organizations). The effects of changes since 2014 in the Affordable Care Act (ACA) and of new alternative payment models (APMs), such as the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) Quality Payment Program (QPP), are also examined. This project uses the same qualitative multiple-case study method as the 2014 study, relying primarily on semistructured interviews with physician practice leaders, physicians, and other observers. Findings describe the challenges posed by APMs, strategies adopted to deal with APMs, the effects of rapidly changing and increasingly complex payment models, and how risk aversion influences physician practices' decisions to engage in new payment models. Project findings are intended to help guide efforts by the AMA and other stakeholders to improve current and future APMs and help physician practices succeed in them.

Estradiol-induced enhancement of object memory consolidation involves hippocampal extracellular signal-regulated kinase activation and membrane-bound estrogen receptors.

The extracellular signal-regulated kinase (ERK) pathway is critical for various forms of learning and memory, and is activated by the potent estrogen 17beta-estradiol (E(2)). Here, we asked whether E(2) modulates memory via ERK activation and putative membrane-bound estrogen receptors (ERs). Using ovariectomized mice, we first demonstrate that intraperitoneal injection of 0.2 mg/kg E(2) significantly increases dorsal hippocampal levels of phosphorylated ERK protein 1 h after injection. Second, we show that E(2) administered intraperitoneally (0.2 mg/kg) or via intrahippocampal infusion (5.0 microg/side) immediately after training in an object recognition task significantly enhances memory retention, and that the beneficial effect of intraperitoneal E(2) is blocked by dorsal hippocampal inhibition of ERK activation. Third, using bovine serum albumin-conjugated 17beta-estradiol (BSA-E(2)), we demonstrate that E(2) binding at membrane-bound ERs can increase dorsal hippocampal ERK activation and enhance object memory consolidation in an ERK-dependent manner. Fourth, we show that this effect is independent of nuclear ERs, but is dependent on the dorsal hippocampus. By demonstrating that E(2) enhances memory consolidation via dorsal hippocampal ERK activation, this study is the first to identify a specific molecular pathway by which E(2) modulates memory and to demonstrate a novel role for membrane-bound ERs in mediating E(2)-induced improvements in hippocampal memory consolidation.

Simulated long-term outcomes of early use of long-acting injectable antipsychotics in early schizophrenia.

AIM: Duration of untreated psychosis in early schizophrenia impacts long-term outcomes. Because long-acting injectable (LAI) antipsychotic drugs improve adherence in early-stage patients, they could reduce additional time in uncontrolled psychosis (TUP) during the critical period of the illness. However, the long-term benefit of early LAI use over oral formulations has not been quantified. This study explores the potential magnitude of the benefit with a simulation approach. METHODS: A microsimulation models the effects of 11 treatment pathways reflecting alternative decisions on whether and when LAI agents are used during a "calibration phase" that starts at treatment entry and lasts until the end of the 3-year critical period. Treatment failure prolongs time in psychosis. Long-term outcomes are predicted over the ensuing 7-year period as a function of TUP. RESULTS: An "early LAI" pathway where LAI treatment follows the second oral treatment failure is compared to an oral-only pathway. Under these pathways, 69% and 46% of patients, respectively, are estimated to exit the calibration phase with adequate symptom control (total positive and negative syndrome scale score below 68). Relative to the oral-only pathway, the early LAI pathway is predicted to increase competitive employment by 39% (25% vs 18%) and independent or family living by 22% (71% vs 58%), and to decrease receipt of disability benefits by 36% (42% vs 66%) and hospital admissions per 1000 patient-years by 15% (249% vs 294%). CONCLUSIONS: While these simulation results need to be confirmed empirically, they suggest that earlier use of LAI antipsychotics can meaningfully improve patient outcomes.

Pterosaur integumentary structures with complex feather-like branching.

Pterosaurs were the first vertebrates to achieve true flapping flight, but in the absence of living representatives, many questions concerning their biology and lifestyle remain unresolved. Pycnofibres-the integumentary coverings of pterosaurs-are particularly enigmatic: although many reconstructions depict fur-like coverings composed of pycnofibres, their affinities and function are not fully understood. Here, we report the preservation in two anurognathid pterosaur specimens of morphologically diverse pycnofibres that show diagnostic features of feathers, including non-vaned grouped filaments and bilaterally branched filaments, hitherto considered unique to maniraptoran dinosaurs, and preserved melanosomes with diverse geometries. These findings could imply that feathers had deep evolutionary origins in ancestral archosaurs, or that these structures arose independently in pterosaurs. The presence of feather-like structures suggests that anurognathids, and potentially other pterosaurs, possessed a dense filamentous covering that probably functioned in thermoregulation, tactile sensing, signalling and aerodynamics.

Estradiol-induced enhancement of object memory consolidation involves NMDA receptors and protein kinase A in the dorsal hippocampus of female C57BL/6 mice.

This study examined the role of dorsal hippocampal NMDA receptors and PKA activation in 17 beta-estradiol (E2)-induced enhancement of object memory consolidation. Mice explored two identical objects during training, after which they immediately received intraperitoneal injections of 0.2 mg/kg E2, and bilateral dorsal hippocampal infusions of Vehicle, the NMDA receptor antagonist APV (2.5 microg/side), or the cAMP inhibitor Rp-cAMPS (18.0 microg/side). Retention was tested 48 hours later. The enhanced object memory and increased ERK phosphorylation observed with E2 alone was reduced by APV and Rp-cAMPS, suggesting that estrogenic enhancement of object memory involves NMDA receptors and PKA activation within the dorsal hippocampus.

Differential effects of acute progesterone administration on spatial and object memory in middle-aged and aged female C57BL/6 mice.

The present study examined the effects of acute progesterone administration on hippocampal-dependent memory consolidation in ovariectomized middle-aged (16 months old) and aged (22 months old) female mice. Spatial memory was tested in a 2-day Morris water-maze task and object memory was tested using an object recognition task with 24- and 48-h delays. Immediately after water-maze training, mice received i.p. injections of vehicle, or 5.0, 10.0, or 20.0 mg/kg of water-soluble progesterone. Twenty-four hours later, retention of the platform location was tested. No overnight forgetting of the platform location was observed in middle-aged vehicle-treated mice. Acute progesterone administration had no effect on spatial memory in middle-aged mice. However, aged vehicle-treated mice demonstrated impaired memory for the platform location on Day 2 relative to Day 1. Twenty mg/kg, but not 5 or 10 mg/kg, progesterone reversed these deficits, suggesting that 20 mg/kg progesterone can improve spatial memory in aged females. In the object recognition task, mice explored two identical objects and then immediately received vehicle or progesterone injections. In middle-aged mice, 10 and 20 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24-h, but all doses were ineffective after 48-h. In aged mice, 10 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24 h, whereas both 5 and 10 mg/kg progesterone enhanced memory after 48 h. Together, these results indicate that acute progesterone differentially enhances hippocampal-dependent memory in middle-aged and aged females.

Acetaminophen disrupts memory in object recognition and increases extracellular signal-regulated kinase phosphorylation in male mice.

Acetaminophen (also known as paracetamol) is a commonly used over-the-counter pain medication, but recent evidence suggests that a single exposure or prenatal exposure may have significant behavioral effects. This investigation aimed to determine whether acetaminophen could disrupt memory formation in an object-recognition task and to quantify potential changes in memory-related signaling cascades in the hippocampus of mice after acetaminophen administration. Using male mice, we examined the effect of a single subcutaneous injection of acetaminophen on the object-recognition task, a single-trial, hippocampus-dependent memory task. We also investigated potential changes in the activation of extracellular signal-regulated kinase (ERK) in the dorsal mouse hippocampus 1 hr after a subcutaneous injection of acetaminophen. We found that 50 mg/kg and 100 mg/kg interfered with performance in the object-recognition memory task, whereas 10 mg/kg did not. We also found that a single 50 mg/kg injection of acetaminophen significantly increased p42 ERK phosphorylation in the dorsal mouse hippocampus. Overall, these results suggest that a single dose of acetaminophen can have significant effects on memory and alters signaling kinases critical for memory consolidation. Further work is needed to determine the involved mechanisms. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Non-integumentary melanosomes can bias reconstructions of the colours of fossil vertebrates.

The soft tissues of many fossil vertebrates preserve evidence of melanosomes-micron-scale organelles that inform on integumentary coloration and communication strategies. In extant vertebrates, however, melanosomes also occur in internal tissues. Hence, fossil melanosomes may not derive solely from the integument and its appendages. Here, by analyzing extant and fossil frogs, we show that non-integumentary melanosomes have high fossilization potential, vastly outnumber those from the skin, and potentially dominate the melanosome films preserved in some fossil vertebrates. Our decay experiments show that non-integumentary melanosomes usually remain in situ provided that carcasses are undisturbed. Micron-scale study of fossils, however, demonstrates that non-integumentary melanosomes can redistribute through parts of the body if carcasses are disturbed by currents. Collectively, these data indicate that fossil melanosomes do not always relate to integumentary coloration. Integumentary and non-integumentary melanosomes can be discriminated using melanosome geometry and distribution. This is essential to accurate reconstructions of the integumentary colours of fossil vertebrates.