Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug.

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.

Association between parental resource depletion and parent use of specific food parenting practices: An ecological momentary assessment study.

The resource depletion model proposes that self-control is a limited resource that may become depleted after repeated use. This study aimed to improve our understanding of the correlates of resource depletion in parents, examine the association between resource depletion and use of coercive food parenting practices, and explore the relationship between resource depletion and stress. Children aged 5-9 and their parents (n = 631 dyads) were recruited from primary care clinics in a large metropolitan area in the United States in 2016-2019. Ecological momentary assessment was carried out over seven days with parents. Frequency tabulations and descriptive statistics were calculated to examine the overall, between-participant, and within-participant frequency of resource depletion, stress, and coercive food parenting practices. Resource depletion was higher among mothers (as compared to fathers) and native born participants (as compared to immigrants). Resource depletion was found to decrease significantly with each increase in household income level and perceived co-parenting support was negatively associated with resource depletion. Greater resource depletion earlier in the day was positively associated with coercive food parenting practices (e.g., food restriction, pressure-to-eat) at dinner the same night. Further, prior day resource depletion was associated with greater pressure-to-eat the next day. Parents with lower chronic stress were found to engage in pressuring when experiencing higher depletion. Clinicians and public health professionals should be aware of the role the resource depletion can play in parent's use of specific food parenting practices and seek to provide parents with the support they need to manage the cognitive load they are experiencing.

Preparation of high-efficiency HILIC capillary columns utilizing slurry packing at 2100 bar.

Complex mixture analysis requires high-efficiency chromatography columns. Although reversed phase liquid chromatography (RPLC) is the dominant approach for such mixtures, hydrophilic interaction liquid chromatography (HILIC) is an important complement to RPLC by enabling the separation of polar compounds. Chromatography theory predicts that small particles and long columns will yield high efficiency; however, little work has been done to prepare HILIC columns longer than 25 cm packed with sub-2 µm particles. In this work, we tested the slurry packing of 75 cm long HILIC columns with 1.7 µm bridged-ethyl-hybrid amide HILIC particles at 2,100 bar (30,000 PSI). Acetonitrile, methanol, acetone, and water were tested as slurry solvents, with acetonitrile providing the best columns. Slurry concentrations of 50-200 mg/mL were assessed, and while 50-150 mg/mL provided comparable results, the 150 mg/mL columns provided the shortest packing times (9 min). Columns prepared using 150 mg/mL slurries in acetonitrile yielded a reduced minimum plate height (hmin) of 3.3 and an efficiency of 120,000 theoretical plates for acenaphthene, an unretained solute. Para-toluenesulfonic acid produced the lowest hmin of 1.9 and the highest efficiency of 210,000 theoretical plates. These results identify conditions for producing high-efficiency HILIC columns with potential applications to complex mixture analysis.

Hypothalamic CRF neurons facilitate brain reward function.

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.

Transcriptional and epigenetic regulation of microglia in substance use disorders.

Microglia are widely known for their role in immune surveillance and for their ability to refine neurocircuitry during development, but a growing body of evidence suggests that microglia may also play a complementary role to neurons in regulating the behavioral aspects of substance use disorders. While many of these efforts have focused on changes in microglial gene expression associated with drug-taking, epigenetic regulation of these changes has yet to be fully understood. This review provides recent evidence supporting the role of microglia in various aspects of substance use disorder, with particular focus on changes to the microglial transcriptome and the potential epigenetic mechanisms driving these changes. Further, this review discusses the latest technical advances in low-input chromatin profiling and highlights the current challenges for studying these novel molecular mechanisms in microglia.

Comparative digestive morphology and physiology of five species of Peromyscus under controlled environment and diet.

Digestive morphology and physiology differ across animal species, with many comparative studies uncovering relationships between animal ecology or diet, and the morphology and physiology of the gastrointestinal tract. However, many of these studies compare wild-caught animals feeding on uncontrolled diets and compare broadly related taxa. Thus, few studies have disentangled the phenotypic consequences of genetics from those potentially caused by the environment, especially across closely related species that occupy similar ecological niches. Here, we examined differences in digestive morphology and physiology of five closely related species of Peromyscus mice that were captive bred under identical environmental conditions and identical diets for multiple generations. Using phylogenetic generalized least squares (PGLS) of species means to control for body size, we identified a phylogenetic signal in the mass of the foregut and length of the small intestine across species. As proportions of total gut mass, we identified phylogenetic signals in relative foregut and small intestine masses, indicating that the sizes of these structures are more similar among closely related species. Finally, we detected differences in activities of the protease aminopeptidase-N enzyme across species. Overall, we demonstrate fine-scale differences in digestive morphology and physiology among closely related species. Our results suggest that Peromyscus could provide a system for future studies to explore the interplay between natural history, morphology, and physiology (e.g. ecomorphology and ecophysiology), and to investigate the genetic architecture that underlies gut anatomy.

Sex differences in adult social, cognitive, and affective behavioral deficits following neonatal phlebotomy-induced anemia in mice.

INTRODUCTION: Anemia is common in prematurely born infants due to blood loss resulting from frequent phlebotomies and may contribute to their neurobehavioral deficits. Preclinical models of phlebotomy-induced anemia (PIA) have revealed metabolic and genomic changes in multiple brain structures of young mice, yet the impact of neonatal PIA on early-life and adult behavior has not been assessed. METHODS: The present study employed a range of behavioral measures in phlebotomized anemic neonatal mice to investigate short- and long-term neurodevelopmental effects. PIA from postnatal (P) days 3 to 14 caused sex-specific changes in social behavior, novelty preference, and anxiety at P17 that persisted into adulthood. RESULTS: Our preclinical model suggests that PIA may contribute to acute and long-term behavioral and affective deficits and warrants further substantiation of the observed behavioral phenomena in larger samples. CONCLUSIONS: We conclude that this model is a useful tool for beginning to better understand the lasting effect that early-life PIA might have on the developing brain. The differential impact of PIA on male and female subjects warrants further exploration for the development of appropriately targeted interventions.

Childhood maltreatment experiences are associated with altered diffusion in occipito-temporal white matter pathways.

BACKGROUND: Childhood maltreatment may contribute to brain alterations in posttraumatic stress disorder (PTSD). We previously found that PTSD was associated with white matter compromise, or lower fractional anisotropy (FA), in the left inferior longitudinal fasciculus (ILF). In this study, including non-PTSD controls, we examined whether ILF FA was associated with maltreatment exposures, including those that meet DSM-IV criterion A (physical abuse, sexual abuse) and those that typically do not (emotional abuse, emotional neglect, physical neglect). We hypothesized that lower FA would be associated with PTSD diagnosis and with both categories of maltreatment. METHODS: Ninety-three participants (51 female), ages 20-50, were enrolled, including 32 with lifetime DSM-IV PTSD, 27 trauma-exposed non-PTSD controls, and 34 healthy controls. Participants completed structured interviews, the Childhood Trauma Questionnaire (CTQ), and diffusion-weighted imaging (36 directions). Probabilistic tractography (using FreeSurfer's TRACULA) was used to assess diffusion metrics in the ILF. RESULTS: Contrary to our hypothesis, there was no significant effect of diagnostic group on FA. In contrast, higher CTQ scores were significantly associated with lower FA in the ILF bilaterally. This association of maltreatment with lower FA remained statistically significant after controlling for diagnostic group, and it was significant for both criterion-A-type and noncriterion-A-type maltreatment categories. CONCLUSIONS: This work contributes to a growing body of literature indicating that different forms of childhood maltreatment are associated with altered white matter microstructure in the ILF, an association pathway involved in integrating visual information from occipital regions with emotion processing functions of the anterior temporal lobe.

Electro-chromic structure with a high degree of dielectric tunability.

In conjunction with their electronically reconfigurable optical properties, inorganic, WO3/LiNbO3/NiO Electro-Chromic materials (EC) have recently been shown to exhibit a degree of electric field induced dielectric tunability at radio frequencies, to the level comparable with more mature bulk-tuneable technologies. However, the full extent of their dielectric tunability remains fully unexplored, due to a fundamental lack of understanding of its intricate tuning mechanisms. The unveiling of their tuning principles is paramount towards a comprehension of not only their optical and radio frequency dielectric tunability, but also for the creation of EC structures with substantial permittivity tuning ratios. Here, we report on an inorganic, WO3 and LiNbO3 - based EC structure with perturbed constituent layers. We developed and synthesised a new EC structure by inserting the chromic layers in the interior of the device and partitioning the electrolyte layer and assigning it to the device's peripheries. This new arrangement allows for an increase in the dielectric tunability of over three times compared to previously reported standard EC structures in the frequency range from 1-20 GHz.

FGF-23 Deficiency Impairs Hippocampal-Dependent Cognitive Function.

Fibroblast growth factor receptor (FGFR) and α-Klotho transduce FGF-23 signaling in renal tubules to maintain systemic phosphate/vitamin D homeostasis. Mice deficient for either the ligand, FGF-23, or the co-receptor, Klotho, are phenocopies with both showing rapid and premature development of multiple aging-like abnormalities. Such similarity in phenotype, suggests that FGF-23 and Klotho have co-dependent systemic functions. Recent reports revealed inverse central nervous system (CNS) effects of Klotho deficiency or Klotho overexpression on hippocampal synaptic, neurogenic, and cognitive functions. However, it is unknown whether FGF-23 deficiency effects function of the hippocampus. We report that, similar to Klotho-deficient mice, FGF-23-deficient mice develop dose-dependent, hippocampal-dependent cognitive impairment. However, FGF-23-deficient brains had no gross structural or developmental defects, no change in hippocampal synaptic plasticity, and only minor impairment to postnatal hippocampal neurogenesis. Together, these data provide evidence that FGF-23 deficiency impairs hippocampal-dependent cognition but otherwise results in a brain phenotype that is distinct from the KL-deficient mouse.

Eastern Canadian Colorectal Cancer Consensus Conference 2017.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2017 was held in St. John's, Newfoundland and Labrador, 28-30 September. Experts in radiation oncology, medical oncology, surgical oncology, and cancer genetics who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of gastric, rectal, and colon cancer, including ■ identification and management of hereditary gastric and colorectal cancer (crc);■ palliative systemic therapy for metastatic gastric cancer;■ optimum duration of preoperative radiation in rectal cancer-that is, short- compared with long-course radiation;■ management options for peritoneal carcinomatosis in crc;■ implications of tumour location for treatment and prognosis in crc; and■ new molecular markers in crc.

Tuneable dielectric and optical characteristics of tailor-made inorganic electro-chromic materials.

Electro-chromic materials (EC) are a new class of electronically reconfigurable thin films that have the ability to reversibly change optical properties by electric charge insertion/extraction. Since their discovery by Deb, they have been employed in applications related to display technology, such as smart windows and mirrors and active optical filters. In this sense, a variety of studies related to the tuneable optical characteristics of EC materials have recently been reported, however, their microwave tuneable dielectric characteristics have been left somewhat unexplored. In 2016 Bulja showed that dc bias voltage induced modulation of the optical characteristics of an inorganic Conductor/WO3/LiNbO3/NiO/Conductor EC cell isaccompanied by the modulation of its high frequency (1-20 GHz) dielectric characteristics. In general, according to the state of the art, cells of different material compositions are needed to produce devices of tailor made characteristics. Here, we report the discovery that the microwave dielectric and the optical characteristics of an EC cell can be engineered to suit a variety of applications without changing their material composition. The obtained results indicate the potential for producing novel, tuneable and tailor-engineered materials that can be used to create next generation agile microwave-optical devices.

Recovery and immune priming modulate the evolutionary trajectory of infection-induced reproductive strategies.

In response to parasite exposure, organisms from a variety of taxa undergo a shift in reproductive investment that may trade off with other life-history traits including survival and immunity. By suppressing reproduction in favour of somatic and immunological maintenance, hosts can enhance the probability of survival and recovery from infection. By plastically enhancing reproduction through terminal investment, on the other hand, hosts under the threat of disease-induced mortality could enhance their lifetime reproductive fitness through reproduction rather than survival. However, we know little about the evolution of these strategies, particularly when hosts can recover and even bequeath protection to their offspring. In this study, we develop a stochastic agent-based model that competes somatic maintenance and terminal investment strategies as they trade off differentially with lifespan, parasite resistance, recovery and transgenerational immune priming. Our results suggest that a trade-off between reproduction and recovery can drive directional selection for either terminal investment or somatic maintenance, depending on the cost of reproduction to lifespan. However, some conditions, such as low virulence with a high cost of reproduction to lifespan, can favour diversifying selection for the coexistence of both strategies. The introduction of transgenerational priming into the model favours terminal investment when all strategies are equally likely to produce primed offspring, but favours somatic maintenance if it confers even a slight priming advantage over terminal investment. Our results suggest that both immune priming and recovery may modulate the evolution of reproductive shift diversity and magnitude upon exposure to parasites.

Quality of recording of diabetes in the UK: how does the GP's method of coding clinical data affect incidence estimates? Cross-sectional study using the CPRD database.

OBJECTIVE: To assess the effect of coding quality on estimates of the incidence of diabetes in the UK between 1995 and 2014. DESIGN: A cross-sectional analysis examining diabetes coding from 1995 to 2014 and how the choice of codes (diagnosis codes vs codes which suggest diagnosis) and quality of coding affect estimated incidence. SETTING: Routine primary care data from 684 practices contributing to the UK Clinical Practice Research Datalink (data contributed from Vision (INPS) practices). MAIN OUTCOME MEASURE: Incidence rates of diabetes and how they are affected by (1) GP coding and (2) excluding 'poor' quality practices with at least 10% incident patients inaccurately coded between 2004 and 2014. RESULTS: Incidence rates and accuracy of coding varied widely between practices and the trends differed according to selected category of code. If diagnosis codes were used, the incidence of type 2 increased sharply until 2004 (when the UK Quality Outcomes Framework was introduced), and then flattened off, until 2009, after which they decreased. If non-diagnosis codes were included, the numbers continued to increase until 2012. Although coding quality improved over time, 15% of the 666 practices that contributed data between 2004 and 2014 were labelled 'poor' quality. When these practices were dropped from the analyses, the downward trend in the incidence of type 2 after 2009 became less marked and incidence rates were higher. CONCLUSIONS: In contrast to some previous reports, diabetes incidence (based on diagnostic codes) appears not to have increased since 2004 in the UK. Choice of codes can make a significant difference to incidence estimates, as can quality of recording. Codes and data quality should be checked when assessing incidence rates using GP data.

High Frequency Dielectric Characteristics of Electrochromic, WO3 and NiO Films with LiNbO3 Electrolyte.

A great deal of attention has been recently focused on Electrochromic (EC) materials and EC based devices, promoting mainly applications related to display technology. In this case, EC based displays are usually actuated by the application of low dc bias voltages, changing their appearance from transparent to opaque. A variety of studies related to the optical characteristics of EC materials have been reported, however, no serious studies so far have been reported on the possible high frequency tunability of the dielectric characteristics of these materials, with the exception of the work by Rose, which presented the operation of a microwave shutter based on conductive polymers operating in the X-band. Here we report tuneable high frequency dielectric characteristics of an Electrochromic (EC) cell with a complimentary structure of Conductor/WO3/LiNbO3/NiO/Conductor in the frequency range from 1 GHz to 20 GHz. The EC cell was prepared using standard semiconductor processing technology, such as lithography, etch and deposition techniques. Our measured results indicate that tunability of high frequency dielectric characteristics as a function of dc bias voltage is achieved, and that a possibility exists for this tunability to be tailored.

Exploring practical approaches to maximising data quality in electronic healthcare records in the primary care setting and associated benefits. Report of panel-led discussion held at SAPC in July 2014.

BACKGROUND: Electronic healthcare records provide information about patient care over time which not only affords the opportunity to improve patient care directly through effective monitoring and identification of care requirements but also offers a unique platform for both clinical and service-model research essential to the longer-term development of the health service. The quality of the recorded data can, however, be variable and can compromise the validity of data use both for primary and secondary purposes. OBJECTIVES: In order to explore the challenges and benefits of and approaches to recording high quality primary care electronic records, a Clinical Practice Research Datalink (CPRD) sponsored workshop was held at the Society of Academic Primary Care (SAPC) conference in 2014 with the aim of engaging GPs and other data users. METHODS: The workshop was held as a structured discussion, led by an expert panel and focused around three questions: (1) What are the data quality priorities for clinicians and researchers? How do these priorities differ or overlap? (2) What challenges might GPs face in provision of good data quality both for treating their patients and for research? Do these aims conflict? (3) What tools (such as data metrics and visualisations or software components) could assist the GP in improving data quality and patient management and could this tie in with analytical processes occurring at the research stage? RESULTS: The discussion highlighted both overlap and differences in the perceived data quality priorities and challenges for different user groups. Five key areas of focus were agreed upon and recommendations determined for moving forward in improving quality. CONCLUSIONS: The importance of good high quality electronic healthcare records has been set forth along with the need for a practical user-considered and collaborative approach to its improvement.

Tackling the problem of blood culture contamination in the intensive care unit using an educational intervention.

Blood culture contamination (BCC) has been associated with unnecessary antibiotic use, additional laboratory tests and increased length of hospital stay thus incurring significant extra hospital costs. We set out to assess the impact of a staff educational intervention programme on decreasing intensive care unit (ICU) BCC rates to <3% (American Society for Microbiology standard). BCC rates during the pre-intervention period (January 2006-May 2011) were compared with the intervention period (June 2011-December 2012) using run chart and regression analysis. Monthly ICU BCC rates during the intervention period were reduced to a mean of 3.7%, compared to 9.5% during the baseline period (P < 0.001) with an estimated potential annual cost savings of about £250,100. The approach used was simple in design, flexible in delivery and efficient in outcomes, and may encourage its translation into clinical practice in different healthcare settings.

Classification of brain tumours from MR spectra: the INTERPRET collaboration and its outcomes.

The INTERPRET project was a multicentre European collaboration, carried out from 2000 to 2002, which developed a decision-support system (DSS) for helping neuroradiologists with no experience of MRS to utilize spectroscopic data for the diagnosis and grading of human brain tumours. INTERPRET gathered a large collection of MR spectra of brain tumours and pseudo-tumoural lesions from seven centres. Consensus acquisition protocols, a standard processing pipeline and strict methods for quality control of the aquired data were put in place. Particular emphasis was placed on ensuring the diagnostic certainty of each case, for which all cases were evaluated by a clinical data validation committee. One outcome of the project is a database of 304 fully validated spectra from brain tumours, pseudotumoural lesions and normal brains, along with their associated images and clinical data, which remains available to the scientific and medical community. The second is the INTERPRET DSS, which has continued to be developed and clinically evaluated since the project ended. We also review here the results of the post-INTERPRET period. We evaluate the results of the studies with the INTERPRET database by other consortia or research groups. A summary of the clinical evaluations that have been performed on the post-INTERPRET DSS versions is also presented. Several have shown that diagnostic certainty can be improved for certain tumour types when the INTERPRET DSS is used in conjunction with conventional radiological image interpretation. About 30 papers concerned with the INTERPRET single-voxel dataset have so far been published. We discuss stengths and weaknesses of the DSS and the lessons learned. Finally we speculate on how the INTERPRET concept might be carried into the future.

"Tiers of delay": warfarin, hip fractures, and target-driven care.

Anticoagulation reversal is a common cause of operative delay. We sought to establish for the first time the impact this has on best practice tariff (BPT) for patients with hip fracture admitted on warfarin. All patients with hip fracture treated operatively over a 32-month period were reviewed. Basic demographics, time to theater, length of stay, and mortality were recorded for all patients. Independent samples t-tests were used to identify statistically significant differences between patients on warfarin and those not taking the drug. A total of 83 patients were admitted anticoagulated with a mean international normalized ratio of 2.65 and a median time to theater of 49.7 hours. Of these patients, 79% breached BPT, incurring significant financial loss. In the control group, 908 patients took a median 24.5 hours, a 28% breach of BPT (P < .01). Length of stay, Nottingham Hip Fracture Score, and predicted 30-day mortality were similar for both the groups. As well as affecting clinical outcome following hip fracture, delay due to anticoagulation causes considerable loss of BPT. Potential loss of revenue due to delays over the study period was £80 000, inspiring the establishment of an "early trigger" anticoagulation protocol. Although it is accepted that there are limitations to this work, it should raise awareness of the real impact of warfarin on patients with hip fracture both in terms of outcome and for the first time, loss of potential revenue.