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Understanding how humans code for and respond to environmental uncertainty/regularity is a question shared by current computational and neurobiological approaches to human cognition. To date, studies investigating neurobiological systems that track input uncertainty have examined responses to uni-sensory streams. It is not known, however, whether there exist brain systems that combine information about the regularity of input streams presented to different senses. We report an fMRI study that aimed to identify brain systems that relate statistical information across sensory modalities. We constructed temporally extended auditory and visual streams, each of which could be random or highly regular, and presented them concurrently. We found strong signatures of “regularity matching” in visual cortex bilaterally; responses were higher when the level of regularity in the auditory and visual streams mismatched than when it matched, [(AudHigh/VisLow and AudLow/VisHigh) >(AudLow/VisLow and AudHigh/VisHigh)]. In addition, several frontal and parietal regions tracked regularity of the auditory or visual stream independently of the other stream's regularity. An individual-differences analysis suggested that signatures of single-modality-focused regularity tracking in these fronto-parietal regions are inversely related to signatures of regularity-matching in visual cortex. Our findings suggest that i) visual cortex is a junction for integration of temporally-extended auditory and visual inputs and that ii) multisensory regularity-matching depends on balanced processing of both input modalities. We discuss the implications of these findings for neurobiological models of uncertainty and for understanding computations that underlie multisensory interactions in occipital cortex.

NMR spectroscopy provides a powerful approach for the characterisation of chemical exchange and molecular interactions by analysis of series of experiments acquired over the course of a titration measurement. The appearance of NMR resonances undergoing chemical exchange depends on the frequency difference relative to the rate of exchange, and in the case of one-dimensional experiments chemical exchange regimes are well established and well known. However, two-dimensional experiments present additional complexity, as at least one additional frequency difference must be considered. Here we provide a systematic classification of chemical exchange regimes in two-dimensional NMR spectra. We highlight important differences between exchange in HSQC and HMQC experiments, that on a practical level result in more severe exchange broadening in HMQC spectra, but show that complementary alternatives to the HMQC are available in the form of HZQC and HDQC experiments. We present the longitudinal relaxation optimised SOFAST-H(Z/D)QC experiment for the simultaneous acquisition of sensitivity-enhanced HZQC and HDQC spectra, and the longitudinal and transverse relaxation optimised BEST-ZQ-TROSY for analysis of large molecular weight systems. We describe the application of these experiments to the characterisation of the interaction between the Hsp90 N-terminal domain and a small molecule ligand, and show that the independent analysis of HSQC, HMQC, HZQC and HDQC experiments provides improved confidence in the fitted dissociation constant and dissociation rate. Joint analysis of such data may provide improved sensitivity to detect and analyse more complex multi-state interaction mechanisms such as induced fit or conformational selection. Electronic supplementary material The online version of this article (10.1007/s10858-019-00297-7) contains supplementary material, which is available to authorized users.

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.

We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.

Aim: The objective was to investigate factors influencing patients’ willingness to pay (WTP) and physician’s views on the cost of therapy for two contrasted chronic diseases, chronic heart failure and psoriasis. Methods: A cross-sectional survey was conducted in ten developing countries, using a stated WTP contingent valuation method. Multivariate analyses were performed by linear regression. Results: Independent factors influencing patient WTP were income (+0.04 $PPP [purchasing power parity] in WTP per $PPP in monthly income; p Conclusion: Disease-specific factors may affect WTP for treatment that should be accounted for to support effective public health programs in developing countries.

Population growth and urbanization are associated with economic development. Structural transformation entails workers leaving less productive agriculture and moving to more productive industries, often in urban centers. Population growth slows with development, leading to greater dependence on capital and technology rather than on labor. This was Asia’s successful pathway. Sub-Saharan Africa (SSA) is also transforming, but far less than other regions are and with its own distinctive features. Though Africa is urbanizing, rapid population growth means that rural populations are still expanding. While African workers also are leaving agriculture, they do so at a slower pace than workers in Asia and are finding work in less productive services rather than in manufacturing. Such “urbanization without industrialization” raises concerns about Africa’s ability to create enough jobs for its urban workforce and underscores the need for continued focus on rural Africa. This chapter reviews the linkages between urbanization, agriculture and rural poverty in SSA, where most of the world’s poor will soon reside. It suggests that much of the economic growth and structural change that Africa enjoyed over the past two decades, attributable to a shift out of agriculture, was in fact an expansion of downstream components of the agriculture food system. Like agriculture, many downstream activities have strong linkages to poverty reduction. Governments concerned about jobs and poverty will need to raise productivity, not only in agriculture, but also throughout the entire food system. Since many downstream processing and trading activities are in towns and cities, promoting future poverty reduction will require greater alignment between agricultural and urban policies. Demographic change and rural-urban linkages will continue to be powerful drivers of global poverty reduction, but ensuring inclusive transformation will require broader development perspectives and policy coordination.

Price deregulation in Australia's National Electricity Market has led to increased competition and greater price dispersion in retail electricity markets. However, recent increases in electricity prices and concerns around disengaged customers have led policy makers to impose a ‘default offer’ to cap retail electricity prices. In this article, we develop a model that demonstrates the mechanism through which a price cap leads to the withdrawal of the lowest priced offers from the market, in effect reducing the benefits available to customers that ‘shop around’. We calculate a measure of actual price dispersion showing that a compression of offers since the price cap was imposed has reduced the returns from search by 2.3 per cent, or $37 per year on average. We argue that the important issue of vulnerable, disengaged customers on high priced offers is best addressed through non-price regulation policy options, such as an auction for the right to serve customers that are both vulnerable and disengaged.

Sleep has been shown to subtly disrupt the spatial organization of functional connectivity networks in the brain, but in a way that largely preserves the connectivity within sensory cortices. Here we evaluated the hypothesis that sleep does impact sensory cortices, but through alteration of activity dynamics. We therefore examined the impact of sleep on hemodynamics using a method for quantifying non-random, high frequency signatures of the blood-oxygen-level dependent (BOLD) signal (amplitude variance asymmetry; AVA). We found that sleep was associated with the elimination of these dynamics in a manner that is restricted to auditory, motor and visual cortices. This elimination was concurrent with increased variance of activity in these regions. Functional connectivity between regions showing AVA during wakefulness maintained a relatively consistent hierarchical structure during wakefulness and N1 and N2 sleep, despite a gradual reduction of connectivity strength as sleep progressed. Thus, sleep is related to elimination of high frequency non-random activity signatures in sensory cortices that are robust during wakefulness. The elimination of these AVA signatures conjointly with preservation of the structure of functional connectivity patterns may be linked to the need to suppress sensory inputs during sleep while still maintaining the capacity to react quickly to complex multimodal inputs., Highlights • We examined time-domain dynamics of BOLD activity during sleep. • We used a method previously showing unique dynamics in sensory cortices during wakefulness. • We find elimination of wakefulness dynamics during N2 and N3 sleep, but not N1.

The objective of this study was to measure and examine 3-axis acceleration data from 6 locations within commercial transport trailers shipping market pigs. Over winter months (December through February) of 2018 to 2019 and 2019 to 2020, 16 pot-belly and 14 straight-deck trailer loads of market pigs were measured from 2 producers located in Kansas and North Carolina, respectively. Six accelerometers were placed in protective cases and affixed to the underside of the floor in the approximate center of the front compartment, middle of the trailer, and back compartment of the top and bottom decks. Data were post-processed to calculate power spectral density (PSD) functions and corresponding root mean square (RMS) accelerations. The PSDs lend insight into the vibrational frequency content of the trailers, while the RMS values indicate the severity of the vibration over the duration of each trip. With the exception of the lower aft portion of the trailer where levels are significantly higher, RMS values were consistent across trips and largely similar between sensor location and axis. Accelerations ranged between 0.06 and 0.18 g and varied in time, indicating data were non-stationarity. The PSD results reveal a largely broadband frequency response of the loaded trailers between 0 and 50 Hz, especially for sensors on the lower deck. Preliminary analysis of the data indicates the severity of vibrations experienced by pigs during transport would be considered uncomfortable by humans.

A 33-year-old female, 32 weeks and 1 day gestation, with known placenta accreta who presented to the emergency department with 2 h of severe abdominal pain, nausea and vomiting. She became hypotensive and underwent emergency cesarean section. Emergency general surgery was consulted for placement of a resuscitative endovascular balloon for aortic occlusion (REBOA). After successful delivery, the balloon was inflated in zone 3 and systolic blood pressure rose from 70 to 170 mmHg. The patient underwent hysterectomy for ongoing hemorrhage. The patient was taken to the surgical intensive care unit. The patient was noted to have pulses following removal of the sheath. Arterial brachial indices and arterial duplex was performed 48 h after sheath removal. The patient was found to have complete occlusion of the right external iliac artery. Vascular surgery was consulted and cut-down performed with thrombus removal via fogarty catheter. The patient was discharged 2 days later without further complication.

A 30-year-old male presented to an outside facility with acute pancreatitis and triglycerides of 1594. He was transferred to our facility after becoming febrile, hypoxic and in acute renal failure with triglycerides of 4243. CT scan performed showed wall-off pancreatic necrosis. He underwent continuous renal replacement therapy and his acute renal failure resolved. He was treated with broad spectrum antibiotics and discharged. He developed a fever to 101 a week later and was found to have a large infected pancreatic pseudocyst. This was managed with an IR placed drain. This was continued for 6 weeks. He came to the emergency department several weeks later with shortness of breath and 3+ edema to bilateral lower extremities and lower abdomen. TTE performed showed an EF of 15%. He was diuresed 25 L during that stay. His heart failure was medically managed. We present this case of dilated cardiomyopathy secondary to acute pancreatitis.

BackgroundReadmissions after a traumatic brain injury (TBI) have significant impact on long-term patient outcomes through interruption of rehabilitation. This study examined readmissions in a rural population, hypothesizing that readmitted patients after TBI will be older and have more comorbidities than those not readmitted.MethodsDischarge data on all patients 15 years and older who were admitted to an Arkansas-based hospital for TBI were obtained from the Arkansas Hospital Discharge Data System from 2010 to 2014. This data set includes diagnoses (principal discharge diagnosis, up to 3 external cause of injury codes, 18 diagnosis codes using the International Classification of Disease, 9th Edition, Clinical Modifications), age, gender, and inpatient costs. Hospital Cost and Utilization Project Clinical Classification and Chronic Condition Indicator were used to identify chronic disease and body systems affected in principal diagnosis.ResultsOf the 3114 cases of significant head trauma, more than two-thirds were attributed to fall injuries, with motor vehicle crashes accounting for 20% of the remainder. The mean length of stay was 6.5 days. 691 of these patients were admitted to an Arkansas hospital in the following year, totaling 1368 readmissions. Of the readmissions, 16.4% of patients were admitted for altered mental status, 12.9% with shortness of breath (SOB), and 9.4% with chest pain. Mental disorders (psychosis, dementia, and depression) and organic nervous symptoms (Alzheimer’s disease, encephalopathy, and epilepsy) were the primary source of readmissions. More than one-third of the patients were admitted in the following year for chronic diseases such as heart failure (8.6%), psychosis (5.2%), and cerebral artery occlusion (4.1%).DiscussionThis study showed that there is a significant rate of readmissions in the year after a diagnosis of TBI. Complications with existing chronic diseases are among the most reported reasons for admission in this time period, demonstrating the effect severe head trauma has on long-term treatment.Level of evidenceLevel IV, Retrospective epidemiological study.

We explore a combinatorial framework which efficiently quantifies the asymmetries between minima and maxima in local fluctuations of time series. We first showcase its performance by applying it to a battery of synthetic cases. We find rigorous results on some canonical dynamical models (stochastic processes with and without correlations, chaotic processes) complemented by extensive numerical simulations for a range of processes which indicate that the methodology correctly distinguishes different complex dynamics and outperforms state of the art metrics in several cases. Subsequently, we apply this methodology to real-world problems emerging across several disciplines including cases in neurobiology, finance and climate science. We conclude that differences between the statistics of local maxima and local minima in time series are highly informative of the complex underlying dynamics and a graph-theoretic extraction procedure allows to use these features for statistical learning purposes. Fil: Hasson, Uri. University of Chicago; Estados Unidos. University of Trento; Italia Fil: Iacovacci, Jacopo. The Francis Crick Institute; Reino Unido. Imperial College London; Reino Unido Fil: Davis, Ben. University of Trento; Italia Fil: Flanagan, Ryan. Queen Mary University of London; Reino Unido Fil: Tagliazucchi, Enzo Rodolfo. Netherlands Institute for Neuroscience; Países Bajos Fil: Laufs, Helmut. Goethe Universitat Frankfurt; Alemania. University Hospital Kiel; Alemania Fil: Lacasa, Lucas. Queen Mary University of London; Reino Unido

There is limited data pertaining to the triage and transportation of patients with penetrating trauma in rural states. Large urban trauma centers have found rapid transport to be beneficial even when done by nonemergency medical staff. However, there is limited application to a rural state with only a single level 1 trauma center.This a retrospective observational study of 854 trauma patients transported by helicopter emergency services between 2009 and 2015 to the state's only level 1 trauma center.After excluding patients with other injuries or lack of data, 854 patients underwent final analysis. Compared with penetrating trauma, blunt trauma had a significantly different chance of survival (92.0% versus 81.2%, P = 0.002) and a significantly different injury severity score (17 ± 12 versus 12 ± 9, P = 0.002). After controlling for blunt injuries, age, gender, injury severity score, tachycardia, tachypnea, hypotension, glasgow coma scale, and dispatch to hospital arrival time in multivariate analysis, blunt trauma had higher odds of survival than penetrating trauma (OR, 5.97; 95% CI, 2.52-14.12; P = 0.001 = 1). Gender, tachycardia, tachypnea, and dispatch to arrival time did not impact a patient's likelihood of survival.Penetrating trauma has a higher mortality when compared with blunt trauma in Helicopter Emergency Services transported patients in a rural state. Perhaps a new algorithm in the management of penetrating trauma would include hemorrhage control at a locoregional hospital before definitive care. Further study is required to understand the exact variables that lead to a higher mortality in penetrating trauma in a rural state.

Background Artemisinin-based combination therapy (ACT) is recommended as the first-line anti-malarial treatment strategy in sub-Saharan African countries. WHO policy recommends parasitological confirmation by microscopy or rapid diagnostic test (RDT) in all cases of suspected malaria prior to treatment. Gaps remain in understanding the factors that influence patient treatment-seeking behaviour and anti-malarial drug purchase decisions in the private sector. The objective of this study was to identify patient treatment-seeking behaviour in Ghana, Kenya, Nigeria, Tanzania, and Uganda. Methods Face-to-face patient interviews were conducted at a total of 208 randomly selected retail outlets in five countries. At each outlet, exit interviews were conducted with five patients who indicated they had come seeking anti-malarial treatment. The questionnaire was anonymous and standardized in the five countries and collected data on different factors, including socio-demographic characteristics, history of illness, diagnostic practices (i.e. microscopy or RDT), prescription practices and treatment purchase. The price paid for the treatment was also collected from the outlet vendor. Results A total of 994 patients were included from the five countries. Location of malaria diagnosis was significantly different in the five countries. A total of 484 blood diagnostic tests were performed, (72.3% with microscopy and 27.7% with RDT). ACTs were purchased by 72.5% of patients who had undergone blood testing and 86.5% of patients without a blood test, regardless of whether the test result was positive or negative (p

The physical and psychological health benefits of exercise are well established, yet patients undergoing dialysis commonly live sedentary lives, contributing to comorbidities with other health problems. Motivational interviewing was used to promote exercise during dialysis; the levels of patient exercise correlated positively with the fidelity of the intervention delivery and levels of change talk, and correlated negatively with the levels of sustain talk. Patients were also motivated by seeing other patients engage in intradialytic exercise, and this was an effective method to increase the number of patients engaging in exercise. Patients welcomed the opportunity to try out the exercise; they were motivated by improvements to their health as well as reductions in their boredom and restlessness during a dialysis session. Sustainability proved to be a key issue and efforts should be made to improve staff engagement in promoting an exercise culture that helps continued exercise uptake.

Complex systems are described according to two central dimensions: (a) the randomness of their output, quantified via entropy; and (b) their complexity, which reflects the organization of a system's generators. Whereas some approaches hold that complexity can be reduced to uncertainty or entropy, an axiom of complexity science is that signals with very high or very low entropy are generated by relatively non-complex systems, while complex systems typically generate outputs with entropy peaking between these two extremes. In understanding their environment, individuals would benefit from coding for both input entropy and complexity; entropy indexes uncertainty and can inform probabilistic coding strategies, whereas complexity reflects a concise and abstract representation of the underlying environmental configuration, which can serve independent purposes, e.g., as a template for generalization and rapid comparisons between environments. Using functional neuroimaging, we demonstrate that, in response to passively processed auditory inputs, functional integration patterns in the human brain track both the entropy and complexity of the auditory signal. Connectivity between several brain regions scaled monotonically with input entropy, suggesting sensitivity to uncertainty, whereas connectivity between other regions tracked entropy in a convex manner consistent with sensitivity to input complexity. These findings suggest that the human brain simultaneously tracks the uncertainty of sensory data and effectively models their environmental generators., Highlights • Complexity science holds that highly ordered and random signals have low complexity. • We examine whether effective connectivity tracks both stimulus entropy and complexity. • Connectivity tracked entropy both linearly and via an inverse U-shaped profile. • Both profiles were identified for hippocampal and anterior cingulate networks.

Current models of brain function assign a central role to predictive processes calibrated to the structure of the environment. Although several neuroimaging studies have examined how the human brain encodes the uncertainty of incoming stimuli, most have relied exclusively on experimental manipulations of uncertainty in which stimuli were presented in a single sensory modality, and further assumed that neural responses vary monotonically with uncertainty. This has left a gap in theoretical development with respect to two core issues: i) are there cross-modal brain systems that encode input uncertainty in way that generalizes across sensory modalities, and ii) are there brain systems that track input uncertainty in a non-monotonic fashion? Here we directly addressed the issues of cross-modal and non-monotonic processing by quantifying neural sensitivity to uncertainty in auditory, visual and audiovisual inputs using multivariate pattern analysis. We found signatures of cross-modal encoding in frontoparietal, orbitofrontal, and association cortices using a searchlight cross-classification analysis where classifiers trained to discriminate levels of uncertainty in one modality were tested in another modality. Additionally, we found widespread systems encoding uncertainty non-monotonically using classifiers trained to discriminate intermediate levels of uncertainty from both the highest and lowest uncertainty levels. These findings comprise the first comprehensive report of cross-modal and non-monotonic neural sensitivity to statistical regularities in the environment, and suggest that conventional paradigms testing for monotonic responses to uncertainty in a single sensory modality may have limited generalizability.

Background The growing burden of dengue in many countries worldwide and the difficulty of preventing outbreaks have increased the urgency to identify alternative public health management strategies and effective approaches to control and prevent dengue outbreaks. The objectives of this study were to understand the impact of dengue outbreak on different stakeholders in Brazil, to explore their perceptions of approaches used by governmental authorities to control and prevent dengue outbreaks and to define the challenges and implications of preventing future outbreaks. Methods In 2015, a qualitative study was conducted in two urban states in Brazil: São Paulo, which was experiencing an outbreak in 2015, and Rio de Janeiro, which experienced outbreaks in 2011 and 2012. Face-to-face interviews using a semi-structured questionnaire were conducted with nine different categories of stakeholders: health workers (physicians, nurses), hospital administrators, municipal government representatives, community members and leaders, school administrators, business leaders and vector control managers. Interviews were focused on the following areas: impact of the dengue outbreak, perceptions of control measures implemented by governmental authorities during outbreaks and challenges in preventing future dengue outbreaks. Results A total of 40 stakeholders were included in the study. Health workers and community members reported longer waiting times at hospitals due to the increased number of patients receiving care for dengue-related symptoms. Health workers and hospital administrators reported that there were no major interruptions in access to care. Overall financial impact of dengue outbreaks on households was greatest for low-income families. Despite prevention and control campaigns implemented between outbreak periods, various stakeholders reported that dengue prevention and control efforts performed by municipal authorities remained insufficient, suggesting that efforts should be reinforced and better coordinated by governmental authorities, particularly during outbreak periods. Conclusion The study shows that a dengue outbreak has a multisectorial impact in the medical, societal, economic and political sectors. The study provides useful insights and knowledge in different stakeholder populations that could guide local authorities and government officials in planning, designing and initiating public health programs. Research focused on a better understanding of how communities and political authorities respond to dengue outbreaks is a necessary component for designing and implementing plans to decrease the incidence and impact of dengue outbreaks in Brazil., Author summary Since the beginning of the 21st century, dengue fever has been a significant vector-borne arboviral disease; actually more than 3.9 billion people are at risk of infection in 128 countries. Dengue has become an increasing public health concern in Latin America, especially in Brazil, which has the highest incidence rate of dengue. Researches are needed to gain in-depth understanding of stakeholder and community reactions to outbreak and to explore the societal impact of dengue outbreaks. In 2015, a qualitative study was conducted in two urban states in Brazil, which experienced recent outbreaks. Longer waiting times at hospitals due to the increased number of patients receiving care for dengue-related symptoms were reported, but without interruptions in access to care. Various stakeholders reported that dengue prevention and control efforts performed by municipal authorities remained insufficient. The consequences of a dengue outbreak reach far beyond the patients, undermining medical, social, economic and political sectors. Research focused on a better understanding of how communities and political authorities respond to dengue outbreaks is a necessity for designing and implementing plans to control dengue outbreaks.

Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.

Purpose: The purpose of this study was to evaluate patient satisfaction and clinical outcomes among subjects with mandibular overdentures supported by one or two immediately placed dental implants 5 years after loading. Materials and Methods: Thirty-six subjects (16 men and 20 women) received one or two dental implants in the anterior mandible, and all implants were loaded the day of surgery. Subjects were scheduled for follow-up 3-, 6-, and 12 months after implant placement and thereafter annually for 4 more years. Patient satisfaction scores were measured with the Oral Health Impact Profile-EDENT (OHIPEDENT) questionnaire. Results: Seventeen subjects (7 male and 10 female) with a mean age of 59.4 years (range, 44 to 74 years) were available for the 5-year follow-up examination. Nine subjects with 10 failing implants were excluded during the first year and nine subjects were lost to follow-up. No implants failed between the 12- and 60-month follow-up examinations, and the need for denture maintenance was low. Mean peri-implant bone change was 0.92 mm, and the Spearman test failed to show correlation between the insertion torque value and implant stability quotient. Patient satisfaction scores increased significantly when compared with baseline values and continued to be high for both groups, with no significant differences. Conclusion: Ten implants in nine subjects failed early, but no failures were observed after the 12-month examination. No significant differences were found between subjects in the two groups with respect to implant survival rates and peri-implant bone loss, and patient satisfaction scores continued to be high. Although patient satisfaction and implant success were high during the 12- to 60-month period, the results should be interpreted with caution because of the high number of failing implants and patients lost to followup. More research is needed to study outcomes of treatment with immediately loaded mandibular implant overdentures.

Since its inception in the late 1990s, fragment-based lead discovery (FBLD) has developed into a robust and generic approach for drug discovery. Two clinically approved drugs have been developed using the FBLD approach, and at least 30 FBLD-derived compounds are in various stages of clinical development. Based on the principle of the identification of small (and hence typically low affinity) ligands which make well-defined interactions with the receptor, and the evolution of these initial fragment hits into larger, more potent ligands that maintain these key interactions, FBLD has proven to be a reliable technique which is applicable to wide range of targets. In this chapter, we will discuss the philosophy and rationale underpinning the FBLD approach, theoretical and practical considerations of fragment library design, fragment screening and characterization, and the evolution of initial low molecular weight fragment hits into larger, potent molecules suitable for lead optimization and preclinical development. We will also discuss informative case histories, showing the challenges, pitfalls, and successful approaches, which have been applied to a number of therapeutically relevant targets.

Pyruvate dehydrogenase kinase (PDK) is a pivotal enzyme in cellular energy metabolism that has previously been implicated in cancer through both RNAi based studies and clinical correlations with poor prognosis in several cancer types. Here, we report the discovery of a novel and selective ATP competitive pan-isoform inhibitor of PDK, VER-246608. Consistent with a PDK mediated MOA, VER-246608 increased pyruvate dehydrogenase complex (PDC) activity, oxygen consumption and attenuated glycolytic activity. However, these effects were only observed under D-glucose-depleted conditions and required almost complete ablation of PDC E1α subunit phosphorylation. VER-246608 was weakly anti-proliferative to cancer cells in standard culture media; however, depletion of either serum or combined D-glucose/L-glutamine resulted in enhanced cellular potency. Furthermore, this condition-selective cytostatic effect correlated with reduced intracellular pyruvate levels and an attenuated compensatory response involving deamination of L-alanine. In addition, VER-246608 was found to potentiate the activity of doxorubicin. In contrast, the lipoamide site inhibitor, Nov3r, demonstrated sub-maximal inhibition of PDK activity and no evidence of cellular activity. These studies suggest that PDK inhibition may be effective under the nutrient-depleted conditions found in the tumour microenvironment and that combination treatments should be explored to reveal the full potential of this therapeutic strategy.

Neuroimaging studies have shown that task demands affect connectivity patterns in the human brain not only during task performance but also during subsequent rest periods. Our goal was to determine whether ongoing connectivity patterns during rest contain information about both the current rest state, as well as the recently terminated task. Our experimental design consisted of two types of active tasks that were followed by two types of low-demand rest states. Using this design, we examined whether hippocampal functional connectivity during wakeful rest reflects both features of a recently terminated task and those of the current resting-state condition. We identified four types of networks: (i) one whose connectivity with the hippocampus was determined only by features of a recently terminated task, (ii) one whose connectivity was determined only by features of the current resting-state, (iii) one whose connectivity reflected aspects of both the recently terminated task and ongoing resting-state features, and (iv) one whose connectivity with the hippocampus was strong, but not affected by any external factor. The left and right hippocampi played distinct roles in these networks. These findings suggest that ongoing hippocampal connectivity networks mediate information integration across multiple temporal scales, with hippocampal laterality moderating these connectivity patterns. Hum Brain Mapp 36:519–537, 2015. © 2014 Wiley Periodicals, Inc.

We examined the potential for patterns in invertebrate prey distribution to act as a key driver of fish distribution across a coastal wetland system. Seascape and metacommunity approaches recognise that faunal assemblages in coastal and freshwater systems are structured by responses to multi-scale connectivity and local environmental conditions. However, we cur- rently have a poor understanding of how different groups of aquatic organisms affect each other's distribution. Most fish in freshwater and coastal wetland systems feed predominantly on benthic invertebrates and zooplankton. To investigate the extent to which these invertebrate taxa exert control over fish distribution, we sampled fish, benthic invertebrate and zooplankton assemblages across 13 inter-connected pools on a salt-marsh in North Queensland, Australia. We found strong and inter-annually consistent spatial concordances among the 3 faunal components, characterised by higher densities of benthic invertebrates and zooplankton in pools at lower elevations on the salt-marsh — reflected by high densities of planktivorous and benthivorous fish, and lower densi- ties of benthic invertebrates and zooplankton in pools at higher elevations — reflected by domi- nance of fish species trophically de-coupled from these taxa (detritivores, insectivores, and herbi- vores). Further supporting the idea of trophic linkages, the 2 most invertebrate-rich pools also harboured the greatest densities of benthivorous and zooplanktivorous fish, which in turn attracted the wetland piscivores Lates calcarifer and Megalops cyprinoides. This is indicative of bottom-up forcing acting across 3 trophic levels, a process that is likely facilitated by the frequent tidal connections among pools, which allows for regular redistribution of fish. Prey availability should be considered as a key component of the spatial ecology processes that shape fish assem- blages across coastal and freshwater wetland systems.

Faunal complexity is an impediment to understanding the function of fragmented coastal wetlands. Conceiving faunal communities as part of a larger network of communities (or a metacommunity) helps to resolve this complexity by enabling simultaneous consideration of local environmental influences and 'regional' dispersal-driven processes. We assessed the role of local vs. regional factors on the fish assemblage structure of a wetland system comprising 20 tidal pools. In equivalent freshwater metacommunities, regional factors often override local influences, result- ing in patterns of nestedness among patches as species and individuals are progressively filtered out along gradients of isolation. While the tidal pool assemblage was primarily structured by regional processes, patterns deviated from freshwater systems, as 2 faunal groups exhibited con- trasting responses to tidal connectivity. A subset of typical estuary channel fauna was restricted to better connected pools at lower elevations, which connect to the estuary channel or other pools on most neap high tides. Frequent connections among these pools subsequently enabled sorting of species relative to preferred environmental condition (including depth and substrate). Contradict- ing models of nestedness, a distinct faunal group including salt marsh residents and juvenile marine-spawned taxa occurred in greater abundances in more isolated, higher elevation pools, which connect to the estuary channel or other pools only on larger spring high tides. These higher elevation pools represent a functionally unique seascape component, and colonisation by marine- spawned taxa seems to reflect an innate drive to ascend upstream gradients to access them. This illustrates how seemingly similar patches within coastal wetlands may perform considerably dif- ferent nursery functions because of their position in the landscape. Together, metacommunity and seascape frameworks offer complementary perspectives in understanding the role of spatial eco - logy in structuring coastal ecosystem function and productivity.

Objective: Communication in the hospital setting is an easy target for quality improvement. Capturing this change via communication between providers during hand-offs is necessary to reduce delays and errors. While this process has been more widely characterized in medical specialties, we designed this study to address the knowledge gap in surgical specialties.Methods: Our institution’s division of Acute Care Surgery (ACS) implemented Morning Report (MR) in October of 2015. At MR, all admissions and service transfers were discussed from Trauma, Emergency General Surgery (EGS), and Surgical Critical Care services from the previous 24 hours. This study compared patients who underwent a surgical procedure during their hospital stay before and after protocol implementation.Results: 974 patients were included in this study. The average patient was 50.3 years of age, 65.4% were white, and 51.7% were male. The average length of stay (LOS) was 8.3 days with 1.75 days to procedure. The post-MR cohort LOS was 2.7 shorter and had 0.85 fewer days to procedure. In an adjusted regression analysis, days to procedure and LOS decreased by 33% (p < .01) and 17% (p < .01) respectively.Conclusions: Implementation of MR led to a decrease in the overall LOS and days to procedure for operative patients. Our results advocate for the standard use of structured hand-offs in surgical units.

Condyle fractures are a common injury, but only a few of these injuries require immediate or late reconstruction. The complications that most frequently necessitate condylar reconstruction include proximal segment degeneration, malunion, and ankylosis. Costochondral grafts and total joint prostheses, both stock and custom, remain the most common methods of reconstruction. Reconstruction plates with condylar extensions should only be used temporarily as an unacceptable number cause serious complications. Distraction osteogenesis may have an occasional role in reconstructing the posttraumatic condyle.

Boldness is a personality trait that defines how individuals respond to risky situations and has clear fitness consequences. Since the adaptive value of boldness is context dependent, the benefit of a distinct personality is less clear when the environment is unpredictable. An ability to modulate behaviour can be beneficial, although as behavioural plasticity itself may be costly this depends on the levels of environmental stability. Both boldness and its plasticity are linked with physiological stress coping mechanisms, whereby animals with reduced glucocorticoid responses to stress are bolder and less flexible in behaviour. We investigated the behavioural changes made by bold and shy rainbow trout, and the magnitude of those changes, in response to predation risk and exposure to two environmental challenges. Behavioural and physiological responses under biotic (either no, predictable or unpredictable predation risk) and abiotic (temperature increase or hypoxia) factors were measured. Boldness was determined using a standard novel object paradigm. In general, after exposure to the treatments, fish exhibited less extreme bold or shy behaviour; the greatest change was observed in fish exposed to hypoxia, or those exposed to high risk particularly in shy fish held at a lower temperature. Higher risk also resulted in increased stress, suggesting that extreme bold or shy behaviour might have been maladaptive under a potential predator threat. These results represent novel evidence that boldness is flexible depending upon particular environmental challenges, with important implications for populations facing environmental extremes caused by anthropogenic activity and climate change.

In the past 15 years, fragment-based lead discovery (FBLD) has been adopted widely throughout academia and industry. The approach entails discovering very small molecular fragments and growing, merging, or linking them to produce drug leads. Because the affinities of the initial fragments are often low, detection methods are pushed to their limits, leading to a variety of artifacts, false positives, and false negatives that too often go unrecognized. This Digest discusses some of these problems and offers suggestions to avoid them. Although the primary focus is on FBLD, many of the lessons also apply to more established approaches such as high-throughput screening.

Contrast agents are widely used with magnetic resonance imaging (MRI) to increase the contrast between regions of interest and the background signal, thus providing better quality information. Such agents can work in one of two ways, either to specifically enhance the signal that is produced or to localize in a specific cell type of tissue. Commonly used image contrast agents are typically based on gadolinium complexes or super-paramagnetic iron oxide, the latter of which is used for imaging lymph nodes. When blood-brain barrier (BBB) breakdown is a feature of central nervous system (CNS) pathology, intravenously administered contrast agent enters into the CNS and alters contrast on MR scans. However, BBB breakdown reflects downstream or end-stage pathology. The initial recruitment of leukocytes to sites of disease such as multiple sclerosis (MS), ischemic lesions, or tumours takes place across an intact, but activated, brain endothelium. Molecular imaging affords the ability to obtain a "non-invasive biopsy" to reveal the presence of brain pathology in the absence of significant structural changes. We have developed smart contrast agents that target and reversibly adhere to sites of disease and have been used to reveal activated brain endothelium when images obtained by conventional MRI look normal. Indeed, our selectively targeted micro-particles of iron oxide have revealed the early presence of cerebral malaria pathology and ongoing MS-like plaques in clinically relevant models of disease.

Multivariate cross-classification is a powerful tool for decoding abstract or supramodal representations from distributed neural populations. However, this approach introduces several methodological challenges not encountered in typical multivariate pattern analysis and information-based brain mapping. In the current report, we review these challenges, recommend solutions, and evaluate alternative approaches where possible. We address these challenges with reference to an example fMRI data set where participants were presented with brief series of auditory and visual stimuli of varying predictability with the aim of decoding predictability across auditory and visual modalities. In analyzing this data set, we highlight four particular challenges: response normalization, cross-validation, direction of cross-validation, and permutation testing.

There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein-ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other 'thermodynamic' methods. We demonstrate the potential of the docking-undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%.

Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.

Aim The objective of the study was to evaluate and compare treatments with mandibular overdentures supported by one or two immediately placed implants 3 years after loading. Materials and Methods Thirty-six edentulous subjects were eligible for inclusion. Using a random sampling system, one or two implants were placed in the mandible. Separate ball attachments were connected to the implants, and the denture was relined and delivered the day of surgery with the retentive components incorporated in the denture base. At the follow-up examinations peri-implant bone levels, implant and denture stability/retention, and need for maintenance and adjustments were evaluated. Moreover, the OHIP-EDENT questionnaire was used to measure patient satisfaction. Results Nineteen subjects (10 men and 9 women) with a mean age of 56 years were available for the 3-year follow-up examination. The group with 1 implant (Group 1) consisted of 11 subjects (5 women and 6 men) while the remaining 8 (5 women and 3 men) belonged to Group2. Nine subjects had been excluded during the first year due to failing implants, 6 had moved, 1 had died, and 1 reported severe illness. No implant failures between the 12-and 36 month follow-up were observed. The mean peri-implant bone change was.86 mm and the Implant Stability Quotient showed only minor changes with no significant difference between the groups when compared with the 12-month follow-up. Patient satisfaction scores increased significantly when compared with the baseline values and continued to be high for both groups and need for denture maintenance was low. Conclusion No significant differences were found between subjects in the two groups with respect to implant survival and peri implant bone loss, and patient satisfaction scores continued to be high for both groups. Need for denture maintenance was low in both groups.

Menchero and Davis present a flexible and general framework for attributing portfolio risk to the same decision variables used to attribute portfolio return. For each return source, the authors decompose the risk contribution into a product of exposure, volatility, and correlation. Their method is a generalization of the marginal contribution to risk approach. In addition to providing a highly intuitive risk attribution, the authors’ approach also allows drilldown capability into the volatility and the correlation, thus providing even greater insight into the sources of portfolio risk.

Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-μM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential.

BackgroundModern acute care surgery (ACS) programs depend on consistent patient hand-offs to facilitate care, as most programs have transitioned to shift-based coverage. We sought to determine the impact of implementing a morning report (MR) model on patient outcomes in the trauma service of a tertiary care center.MethodsThe University of Arkansas for Medical Sciences (UAMS) Division of ACS implemented MR in October 2015, which consists of the trauma day team, the emergency general surgery day team, and a combined night float team. This study queried the UAMS Trauma Registry and the Arkansas Clinical Data Repository for all patients meeting the National Trauma Data Bank inclusion criteria from January 1, 2011 to April 30, 2018. Bivariate frequency statistics and generalized linear model were run using STATA V.14.2ResultsA total of 11 253 patients (pre-MR, n=6556; post-MR, n=4697) were analyzed in this study. The generalized linear model indicates that implementation of MR resulted in a significant decrease in length of stay (LOS) in trauma patients.DiscussionThis study describes an approach to improving patient outcomes in a trauma surgery service of a tertiary care center. The data show how an MR session can allow for patients to get out of the hospital faster; however, broader implications of these sessions have yet to be studied. Further work is needed to describe the decisions being made that allow for a decreased LOS, what dynamics exist between the attendings and the residents in these sessions, and if these sessions can show some of the same benefits in other surgical services.Level of evidenceLevel 4, Care Management.