Sequential neuronal processing of number values, abstract decision, and action in the primate prefrontal cortex.

Decision-making requires processing of sensory information, comparing the gathered evidence to make a judgment, and performing the action to communicate it. How neuronal representations transform during this cascade of representations remains a matter of debate. Here, we studied the succession of neuronal representations in the primate prefrontal cortex (PFC). We trained monkeys to judge whether a pair of sequentially presented displays had the same number of items. We used a combination of single neuron and population-level analyses and discovered a sequential transformation of represented information with trial progression. While numerical values were initially represented with high precision and in conjunction with detailed information such as order, the decision was encoded in a low-dimensional subspace of neural activity. This decision encoding was invariant to both retrospective numerical values and prospective motor plans, representing only the binary judgment of "same number" versus "different number," thus facilitating the generalization of decisions to novel number pairs. We conclude that this transformation of neuronal codes within the prefrontal cortex supports cognitive flexibility and generalizability of decisions to new conditions.

Dopamine receptor activation regulates reward expectancy signals during cognitive control in primate prefrontal neurons.

Dopamine neurons respond to reward-predicting cues but also modulate information processing in the prefrontal cortex essential for cognitive control. Whether dopamine controls reward expectation signals in prefrontal cortex that motivate cognitive control is unknown. We trained two male macaques on a working memory task while varying the reward size earned for successful task completion. We recorded neurons in lateral prefrontal cortex while simultaneously stimulating dopamine D1 receptor (D1R) or D2 receptor (D2R) families using micro-iontophoresis. We show that many neurons predict reward size throughout the trial. D1R stimulation showed mixed effects following reward cues but decreased reward expectancy coding during the memory delay. By contrast, D2R stimulation increased reward expectancy coding in multiple task periods, including cueing and memory periods. Stimulation of either dopamine receptors increased the neurons' selective responses to reward size upon reward delivery. The differential modulation of reward expectancy by dopamine receptors suggests that dopamine regulates reward expectancy necessary for successful cognitive control.

Clonal hematopoiesis and cardiovascular disease: deciphering interconnections.

Cardiovascular and oncological diseases represent the global major causes of death. For both, a novel and far-reaching risk factor has been identified: clonal hematopoiesis (CH). CH is defined as clonal expansion of peripheral blood cells on the basis of somatic mutations, without overt hematological malignancy. The most commonly affected genes are TET2, DNMT3A, ASXL1 and JAK2. By the age of 70, at least 20-50% of all individuals carry a CH clone, conveying a striking clinical impact by increasing all-cause mortality by 40%. This is due predominantly to a nearly two-fold increase of cardiovascular risk, but also to an elevated risk of malignant transformation. Individuals with CH show not only increased risk for, but also worse outcomes after arteriosclerotic events, such as stroke or myocardial infarction, decompensated heart failure and cardiogenic shock. Elevated cytokine levels, dysfunctional macrophage activity and activation of the inflammasome suggest that a vicious cycle of chronic inflammation and clonal expansion represents the major functional link. Despite the apparently high impact of this entity, awareness, functional understanding and especially clinical implications still require further research. This review provides an overview of the current knowledge of CH and its relation to cardiovascular and hematological diseases. It focuses on the basic functional mechanisms in the interplay between atherosclerosis, inflammation and CH, identifies issues for further research and considers potential clinical implications.

How Azanucleosides Affect Myeloid Cell Fate.

The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms of action; decitabine interferes primarily with the methylation of DNA and azacytidine with that of RNA. Here, we examine the role of DNA methylation in the lineage commitment of stem cells during normal hematopoiesis and consider how mutations in epigenetic regulators such as DNMT3A and TET2 can lead to clonal expansion and subsequent neoplastic progression. We also consider why the efficacy of azanucleoside treatment is not limited to neoplasias carrying mutations in epigenetic regulators. Finally, we summarise recent data describing a role for azacytidine-sensitive RNA methylation in lineage commitment and in the cellular response to stress. By summarising and interpreting evidence for azanucleoside involvement in a range of cellular processes, our review is intended to illustrate the need to consider multiple modes of action in the design and stratification of future combination therapies.

Case Report: Personalized Therapeutical Approaches with Lenalidomide in Del(5q): A Case Series.

Myelodysplastic Syndrome (MDS) with del(5q) represents a unique WHO entity, which is often treated with lenalidomide according to standard clinical practice. Guidelines concerning treatment duration have thus far not been implemented, but rather comprise an indefinite therapy until loss of response. This review presents three red blood cell (RBC) transfusion-dependent MDS with del(5q) cases, starting with one rare case with an unbalanced translocation t(2;5), involving the breakpoint of del(5q) and loss of the 5q15-5q31 region. To the best of our knowledge, no comparable case has been described before with a response to lenalidomide. Strikingly, treatment-induced and maintained cytogenetic complete remission (cCR) in this patient. Furthermore, we report two cases of classical del(5q), in which lenalidomide was interrupted after a short period of lenalidomide therapy at the time cCR was achieved. Despite drug holiday cCR was maintained for seven and nine years, respectively. Then del(5q) re-emerged in the absence of novel molecular aberrations and re-treatment with lenalidomide could again achieve cCR in both cases. Together, this series presents three cases of personalized therapy of MDS with del(5q).

Receptor-mediated endocytosis 8 (RME-8)/DNAJC13 is a novel positive modulator of autophagy and stabilizes cellular protein homeostasis.

The cellular protein homeostasis (proteostasis) network responds effectively to insults. In a functional screen in C. elegans, we recently identified the gene receptor-mediated endocytosis 8 (rme-8; human ortholog: DNAJC13) as a component of the proteostasis network. Accumulation of aggregation-prone proteins, such as amyloid-ß 42 (Aß), α-synuclein, or mutant Cu/Zn-superoxide dismutase (SOD1), were aggravated upon the knockdown of rme-8/DNAJC13 in C. elegans and in human cell lines, respectively. DNAJC13 is involved in endosomal protein trafficking and associated with the retromer and the WASH complex. As both complexes have been linked to autophagy, we investigated the role of DNAJC13 in this degradative pathway. In knockdown and overexpression experiments, DNAJC13 acts as a positive modulator of autophagy. In contrast, the overexpression of the Parkinson's disease-associated mutant DNAJC13(N855S) did not enhance autophagy. Reduced DNAJC13 levels affected ATG9A localization at and its transport from the recycling endosome. As a consequence, ATG9A co-localization at LC3B-positive puncta under steady-state and autophagy-induced conditions is impaired. These data demonstrate a novel function of RME-8/DNAJC13 in cellular homeostasis by modulating ATG9A trafficking and autophagy.

Post-artemisinin delayed hemolysis after oral therapy for P. falciparum infection.

A documented side-effect of artemisinin therapy is post-artemisinin delayed hemolysis (PADH), primarily occurring after parenteral treatment for severe P. falciparum infections. PADH has been infrequently reported after oral therapy and is rarely severe enough to require hospitalization and blood transfusions. A 24 year old man was diagnosed with P. falciparum, prompting initiation of oral artemether-lumefantrine (AL). Further work-up demonstrated that he met WHO criteria for severe malaria infection on the basis of high parasitemia and his regimen was switched to intravenous quinidine and oral doxycycline. He was transitioned back to AL after 4 days and was discharged on hospital day six. Five days later, he was readmitted for hemolytic anemia. His peripheral blood was absent of malaria parasites and he was diagnosed with PADH, ultimately requiring multiple blood transfusions. Severe hemolytic anemia requiring blood transfusions after oral artemisinin therapy is rare and may be associated with higher parasite loads. This case demonstrates the importance of close reassessment and consideration of PADH in patients treated with oral therapies, particularly in the setting of severe malarial infections.

Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial.

INTRODUCTION: Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma. METHODS: ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure. CONCLUSIONS: ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.

The use of Electronic Health Records to Support Population Health: A Systematic Review of the Literature.

Electronic health records (EHRs) have emerged among health information technology as "meaningful use" to improve the quality and efficiency of healthcare, and health disparities in population health. In other instances, they have also shown lack of interoperability, functionality and many medical errors. With proper implementation and training, are electronic health records a viable source in managing population health? The primary objective of this systematic review is to assess the relationship of electronic health records' use on population health through the identification and analysis of facilitators and barriers to its adoption for this purpose. Authors searched Cumulative Index of Nursing and Allied Health Literature (CINAHL) and MEDLINE (PubMed), 10/02/2012-10/02/2017, core clinical/academic journals, MEDLINE full text, English only, human species and evaluated the articles that were germane to our research objective. Each article was analyzed by multiple reviewers. Group members recognized common facilitators and barriers associated with EHRs effect on population health. A final list of articles was selected by the group after three consensus meetings (n = 55). Among a total of 26 factors identified, 63% (147/232) of those were facilitators and 37% (85/232) barriers. About 70% of the facilitators consisted of productivity/efficiency in EHRs occurring 33 times, increased quality and data management each occurring 19 times, surveillance occurring 17 times, and preventative care occurring 15 times. About 70% of the barriers consisted of missing data occurring 24 times, no standards (interoperability) occurring 13 times, productivity loss occurring 12 times, and technology too complex occurring 10 times. The analysis identified more facilitators than barriers to the use of the EHR to support public health. Wider adoption of the EHR and more comprehensive standards for interoperability will only enhance the ability for the EHR to support this important area of surveillance and disease prevention. This review identifies more facilitators than barriers to using the EHR to support public health, which implies a certain level of usability and acceptance to use the EHR in this manner. The public-health industry should combine their efforts with the interoperability projects to make the EHR both fully adopted and fully interoperable. This will greatly increase the availability, accuracy, and comprehensiveness of data across the country, which will enhance benchmarking and disease surveillance/prevention capabilities.

How local health departments work towards health equity.

BACKGROUND: Health inequities are exacerbated when health promotion programs and resources do not reach selected populations. Local health departments (LHDs)1 have the potential to address health equity via engaging priority populations in their work. However, we do not have an understanding of what local agencies are doing on this front. METHODS: In the summer of 2016, we collaborated with informants from thirteen LHDs across North Carolina. Via semi-structured interviews, the research team asked informants about their LHD's understanding of health equity and engaging priority populations in program planning, implementation, and evaluation. FINDINGS: All informants discussed that a key function of their LHD was to improve the health of all residents. LHDs with a more comprehensive understanding of health equity engaged members of priority populations in their organizations' efforts to a greater extent than LHDs with a more limited understanding. Additionally, while all LHDs identified similar barriers to engaging priority populations, LHDs that identified facilitators more comprehensively engaged members of the priority population in program planning, implementation, and evaluation. CONCLUSIONS: LHDs are ideally situated between the research and practice worlds to address health equity locally. To promote this work, we should ensure LHDs hold an understanding of health equity, have the means to realize facilitators of health equity work, and recognize the complex context in which health equity work exists.

Mapping of homoeologous chromosome exchanges influencing quantitative trait variation in Brassica napus.

Genomic rearrangements arising during polyploidization are an important source of genetic and phenotypic variation in the recent allopolyploid crop Brassica napus. Exchanges among homoeologous chromosomes, due to interhomoeologue pairing, and deletions without compensating homoeologous duplications are observed in both natural B. napus and synthetic B. napus. Rearrangements of large or small chromosome segments induce gene copy number variation (CNV) and can potentially cause phenotypic changes. Unfortunately, complex genome restructuring is difficult to deal with in linkage mapping studies. Here, we demonstrate how high-density genetic mapping with codominant, physically anchored SNP markers can detect segmental homoeologous exchanges (HE) as well as deletions and accurately link these to QTL. We validated rearrangements detected in genetic mapping data by whole-genome resequencing of parental lines along with cytogenetic analysis using fluorescence in situ hybridization with bacterial artificial chromosome probes (BAC-FISH) coupled with PCR using primers specific to the rearranged region. Using a well-known QTL region influencing seed quality traits as an example, we confirmed that HE underlies the trait variation in a DH population involving a synthetic B. napus trait donor, and succeeded in narrowing the QTL to a small defined interval that enables delineation of key candidate genes.

A user guide to the Brassica 60K Illumina Infinium™ SNP genotyping array.

The Brassica napus 60K Illumina Infinium™ SNP array has had huge international uptake in the rapeseed community due to the revolutionary speed of acquisition and ease of analysis of this high-throughput genotyping data, particularly when coupled with the newly available reference genome sequence. However, further utilization of this valuable resource can be optimized by better understanding the promises and pitfalls of SNP arrays. We outline how best to analyze Brassica SNP marker array data for diverse applications, including linkage and association mapping, genetic diversity and genomic introgression studies. We present data on which SNPs are locus-specific in winter, semi-winter and spring B. napus germplasm pools, rather than amplifying both an A-genome and a C-genome locus or multiple loci. Common issues that arise when analyzing array data will be discussed, particularly those unique to SNP markers and how to deal with these for practical applications in Brassica breeding applications.

Shared Use of Physical Activity Facilities Among North Carolina Faith Communities, 2013.

INTRODUCTION: Shared use of recreational facilities is a promising strategy for increasing access to places for physical activity. Little is known about shared use in faith-based settings. This study examined shared use practices and barriers in faith communities in North Carolina. METHODS: Faith communities in North Carolina (n = 234) completed an online survey (October-December 2013) designed to provide information about the extent and nature of shared use of recreational facilities. We used binary logistic regression to examine differences between congregations that shared use and those that did not share use. RESULTS: Most of the faith communities (82.9%) that completed the survey indicated that they share their facilities with outside individuals and organizations. Formal agreements were more common when faith communities shared indoor spaces such as gymnasiums and classroom meeting spaces than when they shared outdoor spaces such as playgrounds or athletic fields. Faith communities in the wealthiest counties were more likely to share their spaces than were faith communities in poorer counties. Faith communities in counties with the best health rankings were more likely to share facilities than faith communities in counties that had lower health rankings. The most frequently cited reasons faith communities did not share their facilities were that they did not know how to initiate the process of sharing their facilities or that no outside groups had ever asked. CONCLUSION: Most faith communities shared their facilities for physical activity. Research is needed on the relationship between shared use and physical activity levels, including the effect of formalizing shared-use policies.

Pacing-induced Cardiomyopathy.

We present a case of pacing-induced cardiomyopathy. The patient presented with clinical symptoms of dyspnea, leg swelling, and orthopnea several months after a dual-chambered pacemaker was placed for third-degree heart block. The echocardiogram demonstrated a depressed ejection fraction. Coronary angiography was performed, which showed widely patent vessels. Single- and dual-chambered pacemakers create ventricular dyssynchrony, which in turn can cause structural, molecular changes leading to cardiomyopathy. With early intervention of biventricular pacemaker replacement, these changes can be reversible; thus, a timely diagnosis and awareness is warranted.

The Experience With Smoke-Free Policies in Affordable Multiunit Housing in North Carolina: A Statewide Survey.

PURPOSE: Previous surveys of housing operators have identified concerns about enforcement, legal issues, and loss of market share as the main barriers to implementing smoke-free policies in multiunit housing. The purpose of this study was to examine enforcement practices as well as economic and legal outcomes in smoke-free affordable multiunit housing. DESIGN: Cross-sectional. SETTING: Affordable multiunit housing in North Carolina. SUBJECTS: Affordable multiunit housing properties (n = 1063, 57% response rate). MEASURES: Property representatives completed a written survey with questions regarding the existence of smoke-free policies, smoke-free policy implementation and enforcement practices, and smoking-related costs. ANALYSIS: Descriptive statistics, χ(2) goodness-of-fit test, and t-test. RESULTS: A total of 16.5% of properties had policies that prohibited smoking in all residential units. Half (49.8%) of smoke-free properties reported no violations to their policies in the past 12 months. Legal actions to enforce policies were rarely needed and were successful when they did occur. Compared to smoking-allowed properties, smoke-free properties did not experience a loss of market share in terms of occupancy rate (t = .09; p = .93) or residents moving away (χ(2) =. 5; p = .48). CONCLUSION: Housing operators' concerns about enforcement, legal issues, and loss of market share associated with smoke-free policies are largely unfounded among affordable housing properties in North Carolina. Public health professionals should use messaging strategies that refute these concerns to encourage more properties to adopt smoke-free policies.

Smoke-Free Multiunit Housing Policy: Caretakers' Perspectives on Economic and Personal Impacts.

OBJECTIVE: Multiunit housing (MUH) operators may be motivated to adopt smoke-free policies to achieve cost savings. MUH caretakers provide a unique perspective for understanding the implications of smoke-free policies because of their role in property maintenance. We examine MUH caretakers' perceptions regarding the economic and personal impact of smoke-free policies at their properties. METHODS: We conducted and analyzed qualitative interviews with 20 multiunit housing caretakers from two large property management companies in the southeastern United States that had implemented smoke-free policies. RESULTS: For non-smoking units, caretakers reported shortened turnover times, in addition to reduction in the need for turnover supplies and capital replacements. Caretakers reported an improvement in their work environments due to reduced workload and exposure to secondhand and thirdhand smoke after implementation of smoke-free policies. CONCLUSION: The potential for cost savings exists for MUH operators who enact smoke-free policies because of decreased labor, supplies, and capital costs. Smoke-free policies may also improve the work environment of caretakers and other frontline MUH employees. These are important findings for MUH companies seeking to lower their operation costs and improve their employees' working conditions, as well as for smoke-free advocates seeking to promote policy change.

Predictors of smoke-free policies in affordable multiunit housing, North Carolina, 2013.

INTRODUCTION: Smoke-free policies can effectively protect nonsmokers from secondhand smoke (SHS) exposure in multiunit housing. We surveyed all affordable multiunit housing properties in North Carolina to determine the statewide prevalence of smoke-free policies and to identify predictors of smoke-free policies. METHODS: Representatives of affordable housing properties in North Carolina completed a mailed or online survey during June through October 2013. The primary outcome measure was presence of a smoke-free policy, defined as prohibiting smoking in all residential units. We used χ(2) analysis and multivariate logistic regression to identify correlates of smoke-free policies. RESULTS: Of 1,865 eligible properties, responses were received for 1,063 (57%). A total of 16.5% of properties had policies that prohibited smoking in all residential units, while 69.6% prohibited smoking in indoor common areas. In multivariate analysis, an increase in the number of children per unit was associated with a decrease in the odds of having a smoke-free policy at most properties. Newer properties across all company sizes were more likely to have smoke-free policies. Accessing units from interior hallways predicted smoke-free policies among medium-sized companies. CONCLUSION: More smoke-free policies in affordable multiunit housing are needed to protect vulnerable populations, particularly children, from SHS exposure. Public health professionals should continue to educate housing operators about SHS and the benefits of smoke-free policies at all properties, including older ones and ones where units are accessed from outside rather than from an interior hallway.

Challenges in promoting joint use agreements: experiences from Community Transformation Grant awardees in North Carolina, Illinois, and Wisconsin, 2011-2014.

Community Transformation Grant awardees in North Carolina, Illinois, and Wisconsin promoted joint use agreements (formal agreements between 2 parties for the shared use of land or facilities) as a strategy to increase access to physical activity in their states. However, awardees experienced significant barriers to establishing joint use agreements, including 1) confusion about terminology and an aversion to complex legal contracts, 2) lack of applicability to single organizations with open use policies, and 3) questionable value in nonurban areas where open lands for physical activity are often available and where the need is instead for physical activity programs and infrastructure. Furthermore, promotion of formal agreements may unintentionally reduce access by raising concerns regarding legal risks and costs associated with existing shared use of land. Thus, joint use agreements have practical limitations that should be considered when selecting among strategies to promote physical activity participation.

Sequence and annotation of the apicoplast genome of the human pathogen Babesia microti.

The apicomplexan intraerythrocytic parasite Babesia microti is an emerging human pathogen and the primary cause of human babesiosis, a malaria-like illness endemic in the United States. The pathogen is transmitted to humans by the tick vector, Ixodes scapularis, and by transfusion of blood from asymptomatic B. microti-infected donors. Whereas the nuclear and mitochondrial genomes of this parasite have been sequenced, assembled and annotated, its apicoplast genome remained incomplete, mainly due to its low representation and high A+T content. Here we report the complete sequence and annotation of the apicoplast genome of the B. microti R1 isolate. The genome consists of a 28.7 kb circular molecule encoding primarily functions important for maintenance of the apicoplast DNA, transcription, translation and maturation of organellar proteins. Genome analysis and annotation revealed a unique gene structure and organization of the B. microti apicoplast genome and suggest that all metabolic and non-housekeeping functions in this organelle are nuclear-encoded. B. microti apicoplast functions are significantly different from those of the host, suggesting that they might be useful as targets for development of potent and safe therapies for the treatment of human babesiosis.

Temporal vocal features suggest different call-pattern generating mechanisms in mice and bats.

BACKGROUND: Mice produce ultrasonic vocalizations in various inter-individual encounters and with high call rates. However, it is so far virtually unknown how these vocal patterns are generated. On the one hand, these vocal patterns could be embedded into the normal respiratory cycle, as happens in bats and other mammals that produce similar call rates and frequencies. On the other, mice could possess distinct vocal pattern generating systems that are capable of modulating the respiratory cycle, which is what happens in non-human and human primates. In the present study, we investigated the temporal call patterns of two different mammalian species, bats and mice, in order to differentiate between these two possibilities for mouse vocalizations. Our primary focus was on comparing the mechanisms for the production of rapid, successive ultrasound calls of comparable frequency ranges in the two species. RESULTS: We analyzed the temporal call pattern characteristics of mice, and we compared these characteristics to those of ultrasonic echolocation calls produced by horseshoe bats. We measured the distributions of call durations, call intervals, and inter-call intervals in the two species. In the bat, and consistent with previous studies, we found that call duration was independent of corresponding call intervals, and that it was negatively correlated with the corresponding inter-call interval. This indicates that echolocation call production mechanisms in the bat are highly correlated with the respiratory cycle. In contrast, call intervals in the mouse were directly correlated with call duration. Importantly, call duration was not, or was only slightly, correlated with inter-call intervals, consistent with the idea that vocal production in the mouse is largely independent of the respiratory cycle. CONCLUSIONS: Our findings suggest that ultrasonic vocalizations in mice are produced by call-pattern generating mechanisms that seem to be similar to those that have been found in primates. This is in contrast to the production mechanisms of ultrasonic echolocation calls in horseshoe bats. These results are particularly interesting, especially since mouse vocalizations have recently attracted increased attention as potential indicators for the degree of progression of several disease patterns in mouse models for neurodegenerative and neurodevelopmental disorders of humans.