A mechanical task for measuring sign- and goal-tracking in humans: A proof-of-concept study.

Cue-based associative learning (i.e., Pavlovian conditioning) is a foundational component of behavior in almost all forms of animal life and may provide insight into individual differences in addiction liability. Cues can take on incentive-motivational properties (i.e., incentive salience) through Pavlovian learning. Extensive testing with non-human animals (primarily rats) has demonstrated significant variation among individuals in the behaviors this type of learning evokes. So-named "sign-trackers" and "goal-trackers" have been examined in many studies of non-human animals, but this work in humans is still a nascent area of research. In the present proof-of-concept study, we used a Pavlovian conditioned approach task to investigate human sign- and goal-tracking in emerging adults. Conditioned behaviors that developed over the course of the task were directed toward the reward-cue and toward the reward location. Participants' eye-gaze and behavior during the task were submitted to a latent profile analysis, which revealed three groups defined as sign-trackers (n = 10), goal-trackers (n = 4), and intermediate responders (n = 36). Impulsivity was a significant predictor of the sign-tracking group relative to the goal-tracking group. The present study provides preliminary evidence that a simple procedure can produce learned Pavlovian conditioned approach behavior in humans. Though further investigation is required, findings provide a promising step toward the long-term goal of translating important insights gleaned from basic research into treatment strategies that can be applied to clinical populations.

Zonisamide safety in pregnancy: Data from the UK and Ireland epilepsy and pregnancy register.

BACKGROUND: Animal data suggest teratogenic effects with zonisamide use and risk of pregnancy losses. Human data following zonisamide exposure are presently limited, but suggest low risk of malformation with elevated risk of low birth weight. OBJECTIVE: To calculate the major congenital malformation (MCM) rate of zonisamide in human pregnancy and assess for a signal of any specific malformation pattern and associations with birth weight. METHODS AND MATERIALS: Data were obtained from the UK and Ireland Epilepsy and Pregnancy register (UKIEPR) which is an observational, registration, and follow up study from December 1996 to July 2020. Eligibility criteria were use of zonisamide and to have been referred to the UKIEPR before the outcome of the pregnancy was known. Primary outcome was evidence of MCM. RESULTS: From December 1996 through July 2020 there were 112 cases of first trimester exposure to zonisamide, including 26 monotherapy cases. There were 3 MCM for monotherapy cases (MCM rate 13.0% (95% confidence interval 4.5-32.1)), and 5 MCM for polytherapy cases (MCM rate 6.9% (95% confidence interval 3.0-15.2)). While the median birth weight was on 71st and 44th centile for monotherapy and polytherapy cases respectively, there was a high rate of infants born small for gestational age (21% for both). CONCLUSION: These data raise concerns about a signal for potential teratogenicity with zonisamide in human pregnancy. Given the low numbers reported, further data will be required to adequately counsel women who use zonisamide in pregnancy.

Considerations and practical protocols for using virtual reality in psychological research and practice, as evidenced through exposure-based therapy.

Everyday client stressors are often challenging to replicate in clinical and research environments, which hinders the ability to reliably reproduce clinical outcomes. To overcome this obstacle, tools that can bridge the inherent disconnect between these settings and the real-world experiences of clients are urgently needed. Virtual reality (VR) promises to provide immersive experiences within controlled laboratory or clinical settings. While the potential opportunities and challenges of VR applications have been scientifically reviewed, clinical adoptions into psychology are hampered by a paucity of practical and methodological publications. This paper intends to address that gap, by providing a four-step process for decision-making considerations, including practical recommendations and an applied case study of developing an exposure-based system for obsessive-compulsive disorder. We provide a framework to make VR accessible for clinician-researchers to create similar systems that realise the promise while encouraging ongoing scientific rigour.

ScribeMD: Mixed-methods analysis of a pen pal program in undergraduate medical education.

Introduction: A growing emphasis on humanistic medical care has led to the development of programs to imbue more humanistic values into training physicians. The ScribeMD intra-class pen pal program is a narrative medicine tool designed to meet this need with a focus on the journey through medical education. This study intends to evaluate the efficacy of this novel program on the participants' professional identity formation (PIF), emotional intelligence development (EID), and narrative competency improvement (NCI).Methods: This program evaluation involved quantitative and qualitative survey solicitations from first and second-year medical student participants and controls. An efficacy-triangulation model was developed as a quantitative outcome-measuring tool linking objective, writing prompts, and survey data.Results: The quantitative results showed statistically significant improvements in line with the Efficacy Triangulation Model in the participant group. Qualitatively, reflective and insight-driven gains were elicited, as were notable themes of personal and community improvements.Conclusion: ScribeMD poses a unique avenue for the development of more humanistic physicians during their medical education. We recommend additional development of the Efficacy Triangulation Model as well as the program design itself. We also recommend the piloting of this program in other healthcare-education settings both with medical education and other health professions.

Head and Neck Lymphedema: Treatment Response to Single and Multiple Sessions of Advanced Pneumatic Compression Therapy.

Ten head and neck cancer survivors diagnosed with head and neck lymphedema (HNL) were imaged using near-infrared fluorescence lymphatic imaging (NIRFLI) prior to and immediately after an initial advance pneumatic compression device treatment and again after 2 weeks of daily at-home use. Images assessed the impact of pneumatic compression therapy on lymphatic drainage. Facial composite measurement scores assessed reduction/increase in external swelling, and survey results were obtained. After a single pneumatic compression treatment, NIRFLI showed enhanced lymphatic uptake and drainage in all subjects. After 2 weeks of daily treatment, areas of dermal backflow disappeared or were reduced in 6 of 8 subjects presenting with backflow. In general, reductions in facial composite measurement scores tracked with reductions in backflow and subject-reported improvements; however, studies are needed to determine whether longer treatment durations can be impactful and whether advanced pneumatic compression can be used to ameliorate backflow characteristic of HNL.

Notes from the Field: Clostridium perfringens Gastroenteritis Outbreak Associated with a Catered Lunch - North Carolina, November 2015.

During November 2015, the North Carolina Division of Public Health was notified by the Pitt County Health Department (PCHD) that approximately 40 persons who attended a catered company Thanksgiving lunch the previous day were ill with diarrhea and abdominal pain. The North Carolina Division of Public Health and PCHD worked together to investigate the source of illness and implement control measures. Within hours of notification, investigators developed and distributed an online survey to all lunch attendees regarding symptoms and foods consumed and initiated a cohort study. A case of illness was defined as abdominal pain or diarrhea in a lunch attendee with illness onset <24 hours after the event. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated for all menu items. Among 80 attendees, 58 (73%) completed the survey, including 44 respondents (76%) who reported illnesses meeting the case definition; among these, 41 (93%) reported diarrhea, and 40 (91%) reported abdominal pain. There were no hospitalizations. Symptom onset began a median of 13 hours after lunch (range = 1-22 hours). Risk for illness among persons who ate turkey or stuffing (38 of 44; 86%), which were plated and served together, was significantly higher than risk for illness among those who did not eat turkey or stuffing (six of 14; 43%) (RR = 2.02; 95% CI = 1.09-3.73).

The University of Minnesota Donor Lung Quality Index: A Consensus-Based Scoring Application Improves Donor Lung Use.

BACKGROUND: A simplified and consensus-based donor scoring process could improve donor lung use. METHODS: To develop the University of Minnesota Donor Lung Quality Index (UMN-DLQI), we used expert opinion to create an online survey that ranked 17 lung donor and recipient factors and graded their importance on a scale of 0 to 10. To arrive at consensus-based weights for each of the 17 factors, we used magnitude estimation (ME) methods. We performed receiver operating characteristic (ROC) analyses to evaluate predictive value. An application (app) was developed to simplify the scoring process. A second review process was instituted for every donor offer with an UMN-DLQI score greater than 40 as of September 2014 (post-donor score era). RESULTS: Worldwide, 11 transplantation centers (including ours) completed our survey. Results showed strong consensus among transplantation physicians across disparate practices. UMN-DLQI scores greater than 40 provided a sensitivity of 89%, a specificity of 55%, and a positive predictive value of 52% for donor offer acceptance. Number of transplants (63 versus 48) and donor lung use (15.1% versus 8.9%; p = 0.02) were significantly better in the post-donor score era without a penalty in transplantation outcomes. There was a trend toward a lower incidence of any primary graft dysfunction within 72 hours (40% versus 75%; p = 0.06) with a UMN-DLQI greater than 40 but no difference in 30-day or 1-year survival. CONCLUSIONS: The UMN-DLQI scoring app is a simple tool for describing the attributes of a donor lung offer. More attention to scores greater than 40 safely improved donor lung use at a single institution.

Evaluation of microbial qPCR workflows using engineered Saccharomyces cerevisiae.

AIMS: We describe the development and interlaboratory study of modified Saccharomyces cerevisiae as a candidate material to evaluate a full detection workflow including DNA extraction and quantitative polymerase chain reaction (qPCR). METHODS AND RESULTS: S. cerevisiae NE095 was prepared by stable insertion of DNA sequence External RNA Control Consortium-00095 into S. cerevisiae BY4739 to convey selectivity. For the interlaboratory study, a binomial regression model was used to select three cell concentrations, high (4 × 10(7) cells ml(-1)), intermediate (4 × 10(5) cells ml(-1)) and low (4 × 10(3) cells ml(-1)), and the number of samples per concentration. Seven participants, including potential end users, had combined rates of positive qPCR detection (quantification cycle <37) of 100%, 40%, and 0% for high, intermediate, and low concentrations, respectively. CONCLUSIONS: The NE095 strain was successfully detected by all participants, with the high concentration indicating a potential target concentration for a reference material. SIGNIFICANCE AND IMPACT OF THE STUDY: The engineered yeast has potential to support measurement assurance for the analytical process of qPCR, encompassing the method, equipment, and operator, to increase confidence in results and better inform decision-making in areas of applied microbiology. This material can also support process assessment for other DNA-based detection technologies.

Equine Protozoal Myeloencephalitis: An Updated Consensus Statement with a Focus on Parasite Biology, Diagnosis, Treatment, and Prevention.

Equine protozoal myeloencephalitis (EPM) remains an important neurologic disease of horses. There are no pathognomonic clinical signs for the disease. Affected horses can have focal or multifocal central nervous system (CNS) disease. EPM can be difficult to diagnose antemortem. It is caused by either of 2 parasites, Sarcocystis neurona and Neospora hughesi, with much less known about N. hughesi. Although risk factors such as transport stress and breed and age correlations have been identified, biologic factors such as genetic predispositions of individual animals, and parasite-specific factors such as strain differences in virulence, remain largely undetermined. This consensus statement update presents current published knowledge of the parasite biology, host immune response, disease pathogenesis, epidemiology, and risk factors. Importantly, the statement provides recommendations for EPM diagnosis, treatment, and prevention.

Comparative Mutagenesis Studies of Retinal Release in Light-Activated Zebrafish Rhodopsin Using Fluorescence Spectroscopy.

Rhodopsin is the visual pigment responsible for initiating scotopic (dim-light) vision in vetebrates. Once activated by light, release of all-trans-retinal from rhodopsin involves hydrolysis of the Schiff base linkage, followed by dissociation of retinal from the protein moiety. This kinetic process has been well studied in model systems such as bovine rhodopsin, but not in rhodopsins from cold-blooded animals, where physiological temperatures can vary considerably. Here, we characterize the rate of retinal release from light-activated rhodopsin in an ectotherm, zebrafish (Danio rerio), demonstrating in a fluorescence assay that this process occurs more than twice as fast as bovine rhodopsin at similar temperatures in 0.1% dodecyl maltoside. Using site-directed mutagenesis, we found that differences in retinal release rates can be attributed to a series of variable residues lining the retinal channel in three key structural motifs: an opening in metarhodopsin II between transmembrane helix 5 (TM5) and TM6, in TM3 near E122, and in the "retinal plug" formed by extracellular loop 2 (EL2). The majority of these sites are more proximal to the ß-ionone ring of retinal than the Schiff base, indicating their influence on retinal release is more likely due to steric effects during retinal dissociation, rather than alterations to Schiff base stability. An Arrhenius plot of zebrafish rhodopsin was consistent with this model, inferring that the activation energy for Schiff base hydrolysis is similar to that of bovine rhodopsin. Functional variation at key sites identified in this study is consistent with the idea that retinal release might be an adaptive property of rhodopsin in vertebrates. Our study is one of the few investigating a nonmammalian rhodopsin, which will help establish a better understanding of the molecular mechanisms contributing to vision in cold-blooded vertebrates.

Nevirapine extended-release formulation tablets in HIV-1-infected children--long-term follow-up.

In the optional extension of clinical trial 1100.1518 39/40, human immunodeficiency virus-infected patients (aged 3 to <18 years) received ≥48 weeks of treatment with extended-release nevirapine. By last visit, all patients had undetectable viral loads and no new safety signals, demonstrating the safety and efficacy of a once-daily antiretroviral regimen.

The Microbiome of Field-Caught and Laboratory-Adapted Australian Tephritid Fruit Fly Species with Different Host Plant Use and Specialisation.

Tephritid fruit fly species display a diversity of host plant specialisation on a scale from monophagy to polyphagy. Furthermore, while some species prefer ripening fruit, a few are restricted to damaged or rotting fruit. Such a diversity of host plant use may be reflected in the microbial symbiont diversity of tephritids and their grade of dependency on their microbiomes. Here, we investigated the microbiome of six tephritid species from three genera, including species that are polyphagous pests (Bactrocera tryoni, Bactrocera neohumeralis, Bactrocera jarvisi, Ceratitis capitata) and a monophagous specialist (Bactrocera cacuminata). These were compared with the microbiome of a non-pestiferous but polyphagous tephritid species that is restricted to damaged or rotting fruit (Dirioxa pornia). The bacterial community associated with whole fruit flies was analysed by 16S ribosomal DNA (rDNA) amplicon pyrosequencing to detect potential drivers of taxonomic composition. Overall, the dominant bacterial families were Enterobacteriaceae and Acetobacteraceae (both Proteobacteria), and Streptococcaceae and Enterococcaceae (both Firmicutes). Comparisons across species and genera found different microbial composition in the three tephritid genera, but limited consistent differentiation between Bactrocera species. Within Bactrocera species, differentiation of microbial composition seemed to be influenced by the environment, possibly including their diets; beyond this, tephritid species identity or ecology also had an effect. The microbiome of D. pornia was most distinct from the other five species, which may be due to its ecologically different niche of rotting or damaged fruit, as opposed to ripening fruit favoured by the other species. Our study is the first amplicon pyrosequencing study to compare the microbiomes of tephritid species and thus delivers important information about the turnover of microbial diversity within and between fruit fly species and their potential application in pest management strategies.

Expression patterns of sex-determination genes in single male and female embryos of two Bactrocera fruit fly species during early development.

In tephritids, the sex-determination pathway follows the sex-specific splicing of transformer (tra) mRNA, and the cooperation of tra and transformer-2 (tra-2) to effect the sex-specific splicing of doublesex (dsx), the genetic double-switch responsible for male or female somatic development. The Dominant Male Determiner (M) is the primary signal that controls this pathway. M, as yet uncharacterized, is Y-chromosome linked, expressed in the zygote and directly or indirectly diminishes active TRA protein in male embryos. Here we first demonstrated the high conservation of tra, tra-2 and dsx in two Australian tephritids, Bactrocera tryoni and Bactrocera jarvisi. We then used quantitative reverse transcription PCR on single, sexed embryos to examine expression of the key sex-determination genes during early embryogenesis. Individual embryos were sexed using molecular markers located on the B. jarvisi Y-chromosome that was also introgressed into a B. tryoni line. In B. jarvisi, sex-specific expression of tra transcripts occurred between 3 to 6 h after egg laying, and the dsx isoform was established by 7 h. These milestones were delayed in B. tryoni lines. The results provide a time frame for transcriptomic analyses to identify M and its direct targets, plus information on genes that may be targeted for the development of male-only lines for pest management.

The minimum important difference for the Pelvic Organ Prolapse-Urinary Incontinence Sexual Function Questionnaire.

INTRODUCTION AND HYPOTHESIS: Although the Pelvic Organ Prolapse-Urinary Incontinence Sexual Function Questionnaire (PISQ) is widely used to assess sexual function in women, the minimum important difference (MID) (defined as the smallest difference in scores of a patient-reported outcome measure that is perceived by patients as beneficial or harmful and which would lead the clinician to consider a change in treatment) is not known. The objective was to estimate the MID for the PISQ. METHODS: Two study populations, one of women with overactive bladder (OAB) and urgency UI (UUI) treated with tolterodine in a placebo-controlled trial (cohort I), and one of women treated surgically for prolapse and/or UI (cohort II) were used. Cohort I anchors were the Overactive Bladder Questionnaire (OAB-q), the Patient Perception of Bladder Condition (PPBC), the Patient Perception of Treatment Benefit Questionnaire (PPTBQ), and the change in number of UUI episodes in bladder diaries. Distribution MIDs were also calculated. RESULTS: In the anchor-based analysis, the MID values for changes in PISQ total scores at 3 months in cohort I were 5 points using the UUI anchor (diary-dry women), 5 points using the PPBC anchor, 5 points with the PPTBQ, and 9 points with the OAB-q. In cohort II, the MID at week 12 in PISQ total scores was 7 points in women with improved IIQ-7 scores. The distribution-based MID in PISQ total scores was 5.3 points in cohort I and 5.8 points in cohort II. CONCLUSION: A reasonable estimate of MID for the PISQ total score is 6 points. Improvements that meet these thresholds may be considered clinically important.

Tropical tephritid fruit fly community with high incidence of shared Wolbachia strains as platform for horizontal transmission of endosymbionts.

Wolbachia are endosymbiotic bacteria that infect 40-65% of arthropod species. They are primarily maternally inherited with occasional horizontal transmission for which limited direct ecological evidence exists. We detected Wolbachia in 8 out of 24 Australian tephritid species. Here, we have used multilocus sequence typing (MLST) to further characterize these Wolbachia strains, plus a novel quantitative polymerase chain reaction method for allele assignment in multiple infections. Based on five MLST loci and the Wolbachia surface protein gene (wsp), five Bactrocera and one Dacus species harboured two identical strains as double infections; furthermore, Bactrocera neohumeralis harboured both of these as single or double infections, and sibling species B. tryoni harboured one. Two Bactrocera species contained Wolbachia pseudogenes, potentially within the fruit fly genomes. A fruit fly parasitoid, Fopius arisanus shared identical alleles with two Wolbachia strains detected in one B. frauenfeldi individual. We report an unprecedented high incidence of four shared Wolbachia strains in eight host species from two trophic levels. This suggests frequent exposure to Wolbachia in this tropical tephritid community that shares host plant and parasitoid species, and also includes species that hybridize. Such insect communities may act as horizontal transmission platforms that contribute to the ubiquity of the otherwise maternally inherited Wolbachia.

In utero exposure to levetiracetam vs valproate: development and language at 3 years of age.

OBJECTIVE: To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy. METHODS: The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled. RESULTS: After controlling for confounding variables, children exposed to LEV in utero (n = 53) did not differ from unexposed control children (n = 131) on any scale administered. Children exposed to VPA (n = 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] -24.5 to -7.1, p < 0.001), 6.4 points below on comprehension language abilities (95% CI -11.0 to -1.8, p = 0.005), and 9.5 points below on expressive language abilities (95% CI -14.7 to -4.4, p < 0.001). CONCLUSION: The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on women's preferred choice of antiepileptic drug.

Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.

OBJECTIVES: Antiepileptic drug (AED) exposure during pregnancy increases the risk of major congenital malformations (MCMs). The magnitude of this risk varies by AED exposure. Here we provide updated results from the UK Epilepsy and Pregnancy Register of the risk of MCMs after monotherapy exposure to valproate, carbamazepine and lamotrigine. METHODS: Fifteen-year prospective observational study from 1996 until 2012. The main outcome measure is the MCM rate. RESULTS: Informative outcomes were available for 5206 cases. 1290 women were exposed to valproate monotherapy, 1718 to carbamazepine monotherapy and 2198 to lamotrigine monotherapy. The MCM risk with valproate monotherapy exposure in utero was 6.7% (95% CI 5.5% to 8.3%) compared with 2.6% with carbamazepine (95% CI 1.9% to 3.5%) and 2.3% with lamotrigine (95% CI 1.8% to 3.1%). A significant dose effect was seen with valproate (p=0.0006) and carbamazepine (p=0.03) exposed pregnancies. A non-significant trend towards higher MCM rate with increasing dose was found with lamotrigine. MCM rate for high-dose lamotrigine (>400 mg daily) was lower than the MCM rate for pregnancies exposed to <600 mg daily of valproate, but this was not significant (3.4% vs 5.0%, p=0.31). CONCLUSIONS: In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001) and carbamazepine (p=0.0001) monotherapy. In contrast to prior findings, high-dose lamotrigine was associated with fewer MCMs than all doses of valproate. While lamotrigine has a favourable profile compared with valproate for adverse pregnancy outcomes, the requirements for seizure control should not be overlooked.