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The institutional history of the United States Congress has lagged in recent decades as historians of American political development have focused on the history of administration and defined the state in terms of the autonomy of bureaucratic government institutions. In this article, I argue that the history of both Congress and the American state would benefit from analyzing Congress as an institution of the democratic state—an ongoing historical project in which the American people and their representatives in Congress have shaped American democracy and the creation, evolution, and administration of the American state.

Introduction The modern understanding of the comorbidities associated with erectile dysfunction (ED) has been shaped by the findings of decades-old survey-based epidemiologic studies. The demographic structure and comorbidities of the United States population have since changed. A contemporary assessment of the comorbidity profile of men with ED is timely and indispensable for the efficient care of these men. Objective The objectives are to describe the comorbidity profile of a contemporary cross-section of men with erectile dysfunction, to identify clinically meaningful health trends, and to evaluate whether clusters of men with distinct comorbidity profiles can be discerned. Methods A cross-sectional analysis of the MarketScan® administrative claims database from 2008 to 2019 was performed. Inclusion criteria were men 18 to 64 years of age with a diagnosis of ED or phosphodiesterase type 5 inhibitor (PDE5i) prescription with at least 1 year of enrollment before the index date, as well as age-matched controls without an ED diagnosis or related prescription. Comorbidities were extracted by ICD-9/10 diagnosis codes and categorized by the Elixhauser Comorbidity Index. The trends in prevalence of comorbidities and odds of comorbidity diagnosis, overall and by age group, were analyzed. To elucidate the relationships between common comorbidities, a novel comorbidity network was performed with comorbidity strength estimated by observed-to-expected ratio (OER) of disease (prevalence > 0.01) in pairs with a comorbid prevalence > 0.001. Results The prevalence of all comorbidities in men with and without ED increased over the study period. The five most prevalent comorbidities (and percentage increase) among men with ED were hypertension (108%), diabetes without complication (78%), obesity (357%), chronic pulmonary disease (124%), and depression (164%) (Figure 1). The association of ED with comorbidities such as complicated diabetes and paralysis tended to be more pronounced among men in the younger cohort (18-45 years of age, vs 46-64 years of age) (Figure 2). Between 2008 and 2014, a generalized increase in the strength of association of ED with prevalent comorbidities is observed (Figure 3). Conclusions The comorbidity profile of men with ED has evolved since its initial characterization nearly 30 years ago. Increases in comorbidities associated with obesity and metabolic syndrome, as well as mental health disorders, are particularly notable. The findings illustrate the complex interplay of chronic health conditions in men with ED, and serve to justify the comprehensive evaluation of men of all ages who present with ED. Disclosure No

Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking., Acute stress transiently disrupts reward-seeking behaviour and repeated stress exposure produces lasting anhedonia-like behaviour in rodents. Here, the authors show that stress triggers GABAergic activity in the ventral tegmental area which blunts reward-seeking behaviour in mice.

Students often struggle to identify correlations among various concepts in STEM courses, such as energy, mechanics, and cellular communication. Integrative learning incorporates numerous concepts and subjects to aid understanding and enhance critical thinking. This research describes an integrative learning approach in a General Biology I course where key physics-based concepts that are connected to biological topics were emphasized. In addition, students’ knowledge and their beliefs towards biology in all General Biology I classes were assessed using American Association of Colleges and Universities’ Integrative Learning VALUE Rubric and the Colorado Learning Attitudes about Science Survey (CLASS). It was found that correlations existed between students’ attitudes towards biology and their overall content knowledge. The results of this study support that integrative learning is a powerful approach to aid in the understanding of physical and biological concepts, leading to improved student success.

Dietary manipulation with high-protein or high-carbohydrate content are frequently employed during elite athletic training, aiming to enhance athletic performance. Such interventions are likely to impact upon gut microbial content. This study explored the impact of acute high-protein or high-carbohydrate diets on measured endurance performance and associated gut microbial community changes. In a cohort of well-matched, highly trained endurance runners, we measured performance outcomes, as well as gut bacterial, viral (FVP), and bacteriophage (IV) communities in a double-blind, repeated-measures design randomized control trial (RCT) to explore the impact of dietary intervention with either high-protein or high-carbohydrate content. High-dietary carbohydrate improved time-trial performance by +6.5% (P

SummaryIn their seminal findings, Hubel and Wiesel identified sensitive periods in which experience can exert lasting effects on adult visual cortical functioning and behavior via transient changes in neuronal activity during development. Whether comparable sensitive periods exist for non-sensory cortices, such as the prefrontal cortex, in which alterations in activity determine adult circuit function and behavior is still an active area of research. Here, we demonstrate that inhibition of prefrontal parvalbumin-expressing interneurons during the juvenile and adolescent period, results in persistent impairments in adult prefrontal circuit connectivity, in vivo network function and behavioral flexibility that can be reversed by targeted activation of parvalbumin interneurons in adulthood. In contrast, transient suppression of parvalbumin interneuron activity in adulthood produces no lasting effects. These findings identify an activity-dependent sensitive period for prefrontal circuit maturation and highlight how abnormal parvalbumin interneuron activity during development alters adult prefrontal circuit function and cognitive behavior.

The radiation response of TaO x -based resistive memory (RRAM) devices fabricated in academic (Set A) and industrial (Set B) settings was compared. Ionization damage from a 60Co gamma source did not cause any changes in device resistance for either device type, up to 45 Mrad(Si). Displacement damage from a heavy ion beam caused a decrease in resistance at $1 \times 10 ^{21}$ oxygen displacements per cm3 in Set B devices in the high-resistance state (HRS); meanwhile, Set A devices did not exhibit any decrease in resistance due to displacement damage. Both types of devices exhibited an increase in resistance around $3 \times 10 ^{22}$ oxygen displacements per cm3, possibly due to the damage at the oxide/metal interfaces. These extremely high levels of damage represent near-total atomic disruption, and if this level of damage was ever reached, other circuit elements would likely fail before the RRAM devices in this article. Overall, both sets of devices were much more resistant to radiation effects than the similar devices reported in the literature. Displacement damage effects were only observed in the Set A devices once the displacement-induced oxygen vacancies surpassed the intrinsic vacancy concentration in the devices, suggesting that high oxygen vacancy concentration played a role in the devices’ high tolerance to displacement damage.

STUDY QUESTION Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children? SUMMARY ANSWER In this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children. WHAT IS KNOWN ALREADY DNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day. STUDY DESIGN, SIZE, DURATION This observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (45 years of age at conception). PARTICIPANTS/MATERIALS, SETTING, METHODS Whole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing. MAIN RESULTS AND THE ROLE OF CHANCE No significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10−7), with on average 71 DNMs in the genomes of children born to young fathers (45 years of age). LIMITATIONS, REASONS FOR CAUTION This is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results. WIDER IMPLICATIONS OF THE FINDINGS This pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.

Impaired cortical maturation is a postulated mechanism in the etiology of neurodevelopmental disorders, including schizophrenia. In sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. Whether thalamic activity also shapes prefrontal cortical maturation is unknown. Here, we show that inhibiting the midline thalamus during adolescence leads to a long-lasting decrease in thalamo-prefrontal projection density and cortical excitation. Adolescent thalamic inhibition also causes prefrontal-dependent cognitive deficits during adulthood that are associated with disrupted prefrontal cross-correlations and task outcome encoding. In contrast, thalamic inhibition during adulthood has no long-lasting consequences. Strikingly, exciting the thalamus in adulthood during a cognitive task rescues prefrontal cross-correlations, task outcome encoding, and cognitive deficits. These data point to adolescence as a sensitive window of thalamo-cortical circuit maturation. Furthermore, by supporting prefrontal network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders.

Impaired cortical maturation is a postulated mechanism in the etiology of neurodevelopmental disorders, including schizophrenia. In the sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. Whether thalamic activity also shapes prefrontal cortical maturation is unknown. We show that inhibiting the mediodorsal and midline thalamus in mice during adolescence leads to a long-lasting decrease in thalamo-prefrontal projection density and reduced excitatory drive to prefrontal neurons. It also caused prefrontal-dependent cognitive deficits during adulthood associated with disrupted prefrontal cross-correlations and task outcome encoding. Thalamic inhibition during adulthood had no long-lasting consequences. Exciting the thalamus in adulthood during a cognitive task rescued prefrontal cross-correlations, task outcome encoding and cognitive deficits. These data point to adolescence as a sensitive window of thalamocortical circuit maturation. Furthermore, by supporting prefrontal network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders.

Background Although not legally allowed to consume alcohol, adolescents account for 11% of all alcohol use in the United States and approximately 90% of adolescent intake is in the form of an alcohol binge. The adolescent intermittent ethanol (AIE) model developed by the NADIA consortium produces binge-like EtOH exposure episodes. The current experiment examined the effects of AIE on the reinforcing properties of EtOH and genetic expression of cholinergic and dopaminergic factors within the posterior ventral tegmental area (pVTA) in Wistar male and female rats and in male alcohol-preferring (P) rats. Methods Rats were exposed to the AIE or water during adolescence, and all testing occurred during adulthood. Wistar control and AIE rats were randomly assigned to groups that self-administered 0 to 200 mg% EtOH. Male P rats self-administered 0 to 100 mg%. Results The data indicated that exposure to AIE in both Wistar male and female rats (and male P rats) resulted in a significant leftward shift in dose-response curve for EtOH self-administration into the pVTA. TaqMan array indicated that AIE exposure had divergent effects on the expression of nicotinic receptors (increased a7, reduction in a4 and a5). There were also sex-specific effects of AIE on gene expression; male only reduction in D3 receptors. Conclusion Binge-like EtOH exposure during adolescence enhances the sensitivity to the reinforcing properties of EtOH during adulthood which could be part of biological sequelae that are the basis for the deleterious effects of adolescent alcohol consumption on the rate of alcoholism during adulthood.

Background: The use of titanium-coated polypropylene mesh (TCPM) is an alternative to a-cellular dermal matrix for the implant based breast reconstruction by providing extra implant coverage especially in the lower half. The aim of our study was to analyze short-term outcomes of TCPM based implant breast reconstruction and compare the patient- and procedure-related factors to implant loss and surgical complications. Methods: Between 2013and 2016, implant breast reconstructions after conservative mastectomies using TCMP was performed in 50 patients (with 58 reconstructions). Complications were divided into major (need for additional surgery), minor (conservative treatment), and implant loss. Univariate analyses were performed to determine the influence of the patient- and procedure-related factors on postoperative complications and implant loss. Results: Fifty patients had therapeutic mastectomies with 8 of them also had contra lateral risk reducing mastectomies. With median follow-up of 17.5 months, four of 50 patients had implant loss. Reasons for implant loss were skin necrosis in 2 cases, infection in 1 case and necrosis with infection in another case. One of these patients had a revised reconstruction one year later. One additional patient required implant replacement because of capsule contracture. No risk factors were observed for patient-associated complications. Univariate analysis revealed an increased risk for implant loss in patients with skin necrosis (p < 0.01). Conclusions: This titanium-coated polypropylene mesh shows acceptable complication rates and its use in immediate implant breast reconstruction is safe and effective. Citation Format: Munir A, Holt S, Huws A, Khan S, Shariaha Y, Khawaja S. Titanium-coated polypropylene mesh for immediate implant-based breast reconstruction – Our initial experience [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-16-17.

The 2015 European Guidelines on Pulmonary Hypertension did not only cover pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase‑5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians sometimes feel inclined to treat other forms of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Paediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were created, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The 2018 updated recommendations of this working group are summarized in the present paper.

IntroductionDe novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness1. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00×10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01×10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing2. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

Bradykinin increases skin blood flow via a cGMP mechanism but its role in sweating in vivo is unclear. There is a current need to translate cell culture and nonhuman paw pad studies into in vivo human preparations to test for therapeutic viability for disorders affecting sweat glands. Protocol 1: physiological sweating was induced in 10 healthy subjects via perfusing warm (46–48°C) water through a tube-lined suit while bradykinin type 2 receptor (B2R) antagonist (HOE-140; 40 μM) and only the vehicle (lactated Ringer’s) were perfused intradermally via microdialysis. Heat stress increased sweat rate (HOE-140 = +0.79 ± 0.12 and vehicle = +0.64 ± 0.10 mg/cm2/min), but no differences were noted with B2R antagonism. Protocol 2: pharmacological sweating was induced in 6 healthy subjects via intradermally perfusing pilocarpine (1.67 mg/mL) followed by the same B2R antagonist approach. Pilocarpine increased sweating (HOE-140 = +0.38 ± 0.16 and vehicle = +0.32 ± 0.12 mg/cm2/min); again no differences were observed with B2R antagonism. Last, 5 additional subjects were recruited for various control experiments which identified that a functional dose of HOE-140 was utilized and it was not sudorific during normothermic conditions. These data indicate B2R antagonists do not modulate physiologically or pharmacologically induced eccrine secretion volumes. Thus, B2R agonist/antagonist development as a potential therapeutic target for hypo- and hyperhidrosis appears unwarranted.

STUDY QUESTION What are the causative genetic variants in patients with male infertility due to severe sperm motility disorders? SUMMARY ANSWER We identified high confidence disease-causing variants in multiple genes previously associated with severe sperm motility disorders in 10 out of 21 patients (48%) and variants in novel candidate genes in seven additional patients (33%). WHAT IS KNOWN ALREADY Severe sperm motility disorders are a form of male infertility characterised by immotile sperm often in combination with a spectrum of structural abnormalities of the sperm flagellum that do not affect viability. Currently, depending on the clinical sub-categorisation, up to 50% of causality in patients with severe sperm motility disorders can be explained by pathogenic variants in at least 22 genes. STUDY DESIGN, SIZE, DURATION We performed exome sequencing in 21 patients with severe sperm motility disorders from two different clinics. PARTICIPANTS/MATERIALS, SETTING, METHOD Two groups of infertile men, one from Argentina (n = 9) and one from Australia (n = 12), with clinically defined severe sperm motility disorders (motility MAIN RESULTS AND ROLE OF CHANCE In 10 of 21 patients (48%), we identified pathogenic variants in known sperm assembly genes: CFAP43 (3 patients); CFAP44 (2 patients), CFAP58 (1 patient), QRICH2 (2 patients), DNAH1 (1 patient) and DNAH6 (1 patient). The diagnostic rate did not differ markedly between the Argentinian and the Australian cohort (55% and 42%, respectively). Furthermore, we identified patients with variants in the novel human candidate sperm motility genes: DNAH12, DRC1, MDC1, PACRG, SSPL2C and TPTE2. One patient presented with variants in four candidate genes and it remains unclear which variants were responsible for the severe sperm motility defect in this patient. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION In this study, we described patients with either a homozygous or two heterozygous candidate pathogenic variants in genes linked to sperm motility disorders. Due to unavailability of parental DNA, we have not assessed the frequency of de novo or maternally inherited dominant variants and could not determine the parental origin of the mutations to establish in all cases that the mutations are present on both alleles. WIDER IMPLICATIONS OF THE FINDINGS Our results confirm the likely causal role of variants in six known genes for sperm motility and we demonstrate that exome sequencing is an effective method to diagnose patients with severe sperm motility disorders (10/21 diagnosed; 48%). Furthermore, our analysis revealed six novel candidate genes for severe sperm motility disorders. Genome-wide sequencing of additional patient cohorts and re-analysis of exome data of currently unsolved cases may reveal additional variants in these novel candidate genes. STUDY FUNDING/COMPETING INTEREST(S) This project was supported in part by funding from the Australian National Health and Medical Research Council (APP1120356) to M.K.O.B., J.A.V. and R.I.M.L., The Netherlands Organisation for Scientific Research (918-15-667) to J.A.V., the Royal Society and Wolfson Foundation (WM160091) to J.A.V., as well as an Investigator Award in Science from the Wellcome Trust (209451) to J.A.V. and Grants from the National Research Council of Argentina (PIP 0900 and 4584) and ANPCyT (PICT 9591) to H.E.C. and a UUKi Rutherford Fund Fellowship awarded to B.J.H.

Bradykinin increases skin blood flow via a cGMP mechanism but its role in sweating in vivo is unclear. There is a current need to translate cell culture and non-human paw pad studies into in vivo human preparations to test for therapeutic viability for disorders affecting sweat glands. Protocol 1: physiological sweating was induced in 10 healthy subjects via perfusing warm (46-48°C) water through a tube-lined suit while bradykinin type 2 receptor (B2R) antagonist (HOE-140; 40 μM) and only the vehicle (lactated Ringer’s) were perfused intradermally via microdialysis. Heat stress increased sweat rate (HOE-140 = +0.79±0.12 and vehicle = +0.64±0.10 mg/cm2/min), but no differences were noted with B2R antagonism. Protocol 2: pharmacological sweating was induced in 6 healthy subjects via intradermally perfusing pilocarpine (1.67 mg/ml) followed by the same B2R antagonist approach. Pilocarpine increased sweating (HOE-140 = +0.38±0.16 and vehicle = +0.32±0.12 mg/cm2/min); again no differences were observed with B2R antagonism. Lastly, 5 additional subjects were recruited for various control experiments which identified that a functional dose of HOE-140 was utilized and it was not sudorific during normothermic conditions. These data indicate B2R antagonists do not modulate physiologically-or pharmacologically-induced eccrine secretion volumes. Thus, B2R agonist/antagonist development as a potential therapeutic target for hypo- and hyperhidrosis appears unwarranted.

The medial prefrontal cortex (mPFC) integrates inputs from multiple subcortical regions including the mediodorsal nucleus of the thalamus (MD) and the ventral hippocampus (vHPC). How the mPFC differentially processes these inputs is not known. One possibility is that these two inputs target discreet populations of mPFC cells. Alternatively, individual prefrontal cells could receive convergent inputs but distinguish between both inputs based on synaptic differences, such as communication frequency. To address this, we utilized a dual wavelength optogenetic approach to stimulate MD and vHPC inputs onto single, genetically defined mPFC neuronal subtypes. Specifically, we compared the convergence and synaptic dynamics of both inputs onto mPFC pyramidal cells, and parvalbumin (PV)- and vasoactive intestinal peptide (VIP)-expressing interneurons. We found that all individual pyramidal neurons in layer 2/3 of the mPFC receive convergent input from both MD and vHPC. In contrast, PV neurons receive input biased from the MD, while VIP cells receive input biased from the vHPC. Independent of the target, MD inputs transferred information more reliably at higher frequencies (20 Hz) than vHPC inputs. Thus, MD and vHPC projections converge functionally onto mPFC pyramidal cells, but both inputs are distinguished by frequency-dependent synaptic dynamics and preferential engagement of discreet interneuron populations.

Stressful experiences frequently precede depressive episodes1. Depression results in anhedonia, or disrupted reward-seeking, in most patients2. In humans3,4 and rodents5,6, stress can disrupt reward-seeking, providing a potential mechanism by which stress can precipitate depression7-9. Yet despite decades investigating how stress modulates dopamine neuron transmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc), the underpinnings of the stress-anhedonia transition remain elusive10-13. Here we show that during restraint stress, VTA GABA neurons drive low frequency NAc LFP oscillations, rhythmically modulating NAc firing rates. The strength of these stress-induced NAc oscillations predict the degree of impaired reward-seeking upon release from restraint. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and reverses the effect of stress on reward-seeking. By contrast, mimicking these oscillations with rhythmic VTA GABA stimulation in the absence of stress blunts subsequent reward-seeking. These experiments demonstrate that VTA GABA inputs to the NAc are both necessary and sufficient for stress-induced decreases in reward seeking behavior, elucidating a key circuit-level mechanism underlying stress-induced anhedonia.

Cognitive functions, such as working memory, are disrupted in most psychiatric disorders. Many of these processes are believed to depend on the medial prefrontal cortex (mPFC). Traditionally, maze-based behavioral tasks, which have a strong exploratory component, have been used to study the role of the mPFC in working memory in mice. In maze tasks, mice navigate through the environment and require a significant amount of time to complete each trial, thereby limiting the number of trials that can be run per day. Here, we show that an operant-based delayed nonmatch to sample (DNMS) working memory task, with shorter trial lengths and a smaller exploratory component, is also mPFC-dependent. We created excitotoxic lesions in the mPFC of mice and found impairments in both the acquisition of the task, with no delay, and in the performance with delays introduced. Importantly, we saw no differences in trial length, reward collection, or lever-press latencies, indicating that the difference in performance was not due to a change in motivation or mobility. Using this operant DNMS task will facilitate the analysis of working memory and improve our understanding of the physiology and circuit mechanisms underlying this cognitive process. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Improved screening methods for women with dense breasts are needed because of their increased risk of breast cancer and of failed early diagnosis by screening mammography.To compare the screening performance of abbreviated breast magnetic resonance imaging (MRI) and digital breast tomosynthesis (DBT) in women with dense breasts.Cross-sectional study with longitudinal follow-up at 48 academic, community hospital, and private practice sites in the United States and Germany, conducted between December 2016 and November 2017 among average-risk women aged 40 to 75 years with heterogeneously dense or extremely dense breasts undergoing routine screening. Follow-up ascertainment of cancer diagnoses was complete through September 12, 2019.All women underwent screening by both DBT and abbreviated breast MRI, performed in randomized order and read independently to avoid interpretation bias.The primary end point was the invasive cancer detection rate. Secondary outcomes included sensitivity, specificity, additional imaging recommendation rate, and positive predictive value (PPV) of biopsy, using invasive cancer and ductal carcinoma in situ (DCIS) to define a positive reference standard. All outcomes are reported at the participant level. Pathology of core or surgical biopsy was the reference standard for cancer detection rate and PPV; interval cancers reported until the next annual screen were included in the reference standard for sensitivity and specificity.Among 1516 enrolled women, 1444 (median age, 54 [range, 40-75] years) completed both examinations and were included in the analysis. The reference standard was positive for invasive cancer with or without DCIS in 17 women and for DCIS alone in another 6. No interval cancers were observed during follow-up. Abbreviated breast MRI detected all 17 women with invasive cancer and 5 of 6 women with DCIS. Digital breast tomosynthesis detected 7 of 17 women with invasive cancer and 2 of 6 women with DCIS. The invasive cancer detection rate was 11.8 (95% CI, 7.4-18.8) per 1000 women for abbreviated breast MRI vs 4.8 (95% CI, 2.4-10.0) per 1000 women for DBT, a difference of 7 (95% CI, 2.2-11.6) per 1000 women (exact McNemar P = .002). For detection of invasive cancer and DCIS, sensitivity was 95.7% (95% CI, 79.0%-99.2%) with abbreviated breast MRI vs 39.1% (95% CI, 22.2%-59.2%) with DBT (P = .001) and specificity was 86.7% (95% CI, 84.8%-88.4%) vs 97.4% (95% CI, 96.5%-98.1%), respectively (P .001). The additional imaging recommendation rate was 7.5% (95% CI, 6.2%-9.0%) with abbreviated breast MRI vs 10.1% (95% CI, 8.7%-11.8%) with DBT (P = .02) and the PPV was 19.6% (95% CI, 13.2%-28.2%) vs 31.0% (95% CI, 17.0%-49.7%), respectively (P = .15).Among women with dense breasts undergoing screening, abbreviated breast MRI, compared with DBT, was associated with a significantly higher rate of invasive breast cancer detection. Further research is needed to better understand the relationship between screening methods and clinical outcome.ClinicalTrials.gov Identifier: NCT02933489.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and nonhuman primates have demonstrated that the N-methyl-d-aspartate antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The PK profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-hydroxydopamine rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct-effect maximum possible effect model. Results from the PK/PD model were compared with amantadine plasma concentrations and antidyskinetic effect in a phase 2 study in patients with Parkinson's disease treated with ADS-5102, an extended-release amantadine capsule formulation. Outcomes from each of the species evaluated indicate that the EC50 of amantadine for reducing dyskinesia range from 1025 to 1633 ng/ml (1367 ng/ml for an all-species model). These data are consistent with the mean amantadine plasma concentrations observed in patients with Parkinson's disease (∼1500 ng/ml) treated with ADS-5102 at doses that demonstrated a statistically significant reduction in dyskinesia. These results demonstrate that the EC50 of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of ∼1400 ng/ml to achieve therapeutic efficacy.

(1) Background: Current vestibular rehabilitation therapy is an exercise-based approach aimed at promoting gaze stability, habituating symptoms, and improving balance and walking in patients with mild traumatic brain injury (mTBI). A major component of these exercises is the adaptation of the vestibulo-ocular reflex (VOR) and habituation training. Due to acute injury, the gain of the VOR is usually reduced, resulting in eye movement velocity that is less than head movement velocity. There is a higher chance for the success of the therapy program if the patient (a) understands the exercise procedure, (b) performs the exercises according to the prescribed regimen, (c) reports pre- and post-exercise symptoms and perceived difficulty, and (d) gets feedback on performance. (2) Methods: The development and laboratory evaluation of VestAid, an innovative, low-cost, tablet-based system that helps patients perform vestibulo-ocular reflex (VORx1) exercises correctly at home without therapist guidance, is presented. VestAid uses the tablet camera to automatically assess patient performance and compliance with exercise parameters. The system provides physical therapists (PTs) with near real-time, objective (head speed and gaze fixation compliance), and subjective (perceived difficulty and pre- and post- exercise symptoms) metrics through a web-based provider portal. The accuracy of the head-angle and eye-gaze compliance metrics was evaluated. The accuracy of estimated head angles calculated via VestAid’s low-complexity algorithms was compared to the state-of-the-art deep-learning method on a public dataset. The accuracy of VestAid’s metric evaluation during the VORx1 exercises was assessed in comparison to the output of an inertial measurement unit (IMU)-based system. (3) Results: There are low mean interpeak time errors (consistently below 0.1 s) across all speeds of the VORx1 exercise, as well as consistently matching numbers of identified peaks. The spatial comparison (after adjusting for the lag measured with the cross-correlation) between the VestAid and IMU-based systems also shows good matching, as shown by the low mean absolute head angle error, in which for all speeds, the mean is less than 10 degrees. (4) Conclusions: The accuracy of the system is sufficient to provide therapists with a good assessment of patient performance. While the VestAid system’s head pose evaluation model may not be perfectly accurate as a result of the occluded facial features when the head moves further towards an extreme in pitch and yaw, the head speed measurements and associated compliance measures are sufficiently accurate for monitoring patients’ VORx1 exercise compliance and general performance.

The radiation environment of space poses a challenge for electronic systems, in particular flash memory, which contains multiple radiation-sensitive parts. Resistive memory (RRAM) devices have the potential to replace flash memory, functioning as an inherently radiation resistant memory device. Several studies indicate significant radiation resistance in RRAM devices to a broad range of radiation types and doses. In this study, we focus on the effect of displacement damage on tantalum oxide-based RRAM devices, as this form of damage is likely a worst-case scenario. An Ar+ (170 keV) ion beam was used to minimize any contribution from ionization damage, maximizing the effect of displacement damage. Fluence levels were chosen to generate enough oxygen vacancies such that devices in the high resistance state (HRS) would likely switch to the low resistance state (LRS). More than half of devices tested at the highest fluence level (1.43E13 ions/cm2) switched from HRS to LRS. The devices were then switched for 50 set/reset cycles, after which the radiation-induced resistance shift disappeared. These results suggest that device switching may mitigate radiation damage by accelerating oxygen vacancy-interstitial recombination.

Background: In the Western World, it has been stated that breast cancers detected on a screening program are indolent. There have been many recent publications stating that breast screening is overdiagnosing and therefore overtreating patients with breast cancer. With the advent of genomic testing, it can now be determined which patients have an aggressive tumor requiring systemic chemotherapy. We therefore conducted a retrospective study in the UK on patients having oncotype DX testing in both screen detected and symptomatic cancers. Materials and Methods: Patients in our institution undergoing oncotype DX testing for invasive breast cancer which was ER positive and node negative were part of this study. The detection of the breast cancer was documented as either a screening case or a symptomatic one. The recurrence scores of the oncotype DX testing was then compared in the screening versus the symptomatic cohort. Results: 155 patients were included in this study. They underwent Oncotype DX testing between 2008 to 2016. The age of the patients ranged from between 31 years to 78 years. Eighty-nine patients were reported to have a low recurrence score; 45 had an intermediate score; and 21 had a high result. Fifty eight patients were screen detected, while 97 patients were symptomatic presentations. In the screening population, 32 patients had a low recurrence score; 22 had an intermediate result and 4 had a high recurrence score resulting in the latter groups being considered for chemotherapy. In the symptomatic cohort, 57 had a low recurrence score; 23 had an intermediate result; and 17 had a high score. Conclusion: The results of our study depict that even patients in a screeining cohort will have a high number of intermediate recurrence scores and some with a high recurrence score. This shows that the hypothesis that screening detects a majority of breast cancers which are indolent not requiring further systemic treatment should be looked at again in light of our results with genomic testing. Citation Format: Khawaja S, Parab A, Thomas D, Huws A, Munir A, Udayasankar S, Sharaiha Y, Holt S. A comparison of oncotype DX recurrence scores in a screen detected vs a symptomatic cohort of patients with breast cancer: A UK experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-21.

Die 2015 veroffentlichen Europaischen Leitlinien zur Diagnostik und Therapie der pulmonalen Hypertonie (PH) sind nunmehr auch in Deutschland gultig. Wahrend sich die Leitlinien eingehend mit der pulmonal arteriellen Hypertonie (PAH) befassen, wird die haufig vorkommende PH infolge von Linksherzerkrankungen nur relativ kurz behandelt. Aktuell lasst sich in zunehmendem Mase ein unkritischer Einsatz gezielter PAH-Medikamente bei Patienten mit PH infolge von Linksherzerkrankungen beobachten, obwohl keine entsprechenden Wirksamkeitsdaten vorliegen. Diese Entwicklung gibt Anlass zur Sorge, zumal Ressourcen limitiert sind und eine evidenzbasierte Medizin Basis unseres Handles sein muss. Andererseits ist die PH bei Patienten mit Linksherzinsuffizienz ein haufiges Problem welches fur die Morbiditat und Prognose der Patienten bedeutsam ist, so dass sich bei ausgewahlten Patienten die Frage nach einer gezielten Behandlung der PH stellt. Diesbezuglich sind fur die praktische Umsetzung der Europaischen Leitlinien in Deutschland zahlreiche spezifische Gesichtspunkte und bereits wieder neue Daten bedeutsam, die eine ausfuhrliche Kommentierung der Leitlinien und in einigen Punkten eine Aktualisierung notwendig machen. Im Juni 2016 fand in Koln eine Konsensus-Konferenz statt, die von den Arbeitsgruppen PH der Deutschen Gesellschaften fur Kardiologie (DGK), Pneumologie (DGP) und Padiatrische Kardiologie (DGPK) organisiert wurde. Die Konferenz befasste sich mit der Umsetzung der Europaischen Leitlinien in Deutschland. Dazu wurden verschiedene Arbeitsgruppen eingesetzt, von denen sich eine gezielt der PH bei Linksherzerkrankungen widmete. Die Ergebnisse und Empfehlungen dieser Arbeitsgruppe werden in dem vorliegenden Manuskript detailliert beschrieben.

SiC MOSFETs are a leading option for increasing the power density of power electronics; however, for these devices to supersede the Si insulated-gate bipolar transistor, their characteristics have to be further understood. Two SiC vertically oriented planar gate D-MOSFETs rated for 1200 V/150 A were repetitively subjected to pulsed overcurrent conditions to evaluate their failure mode due to this common source of electrical stress. This research supplements recent work that demonstrated the long term reliability of these same devices [1] . Using an RLC pulse-ring-down test bed, these devices hard-switched 600 A peak current pulses, corresponding to a current density of 1500 A/cm2. Throughout testing, static characteristics of the devices such as $B_{{\rm VDSS}}$ , $R_{{\rm DS}({\rm on})}$ , and $V_{{\rm GS}({\rm th})}$ were measured with a high power device analyzer. The experimental results indicated that a conductive path was formed through the gate oxide; TCAD simulations revealed localized heating at the SiC/SiO2 interface as a result of the extreme high current density present in the device's JFET region. However, the high peak currents and repetition rates required to produce the conductive path through the gate oxide demonstrate the robustness of SiC MOSFETs under the pulsed overcurrent conditions common in power electronic applications.

Introduction: A synthetic 2D mammogram (C-view) can be created by combining the individual optimally enhanced 1mm slices of a digital breast tomosynthesis (DBT). Studies show that screening with 2D mammography and DBT increases the cancer detection rate by about 40% and reduces the recall rate by about 25% but it doubles the x-ray exposure to the patient and reading time for the radiologist compared to standard 2D screening. The use of a synthetic 2D instead of a standard 2D film may theoretically overcome these problems by avoiding a second exposure and presenting the detail normally available in DBT in one picture. The hypothesis we wished to test is, "if the synthetic 2D is normal/benign, is there any advantage in also viewing the DBTs?" Method: We prospectively collected data on 2500 unselected cases presenting symptomatically or at follow up, all of whom underwent DBT on a Hologic® Dimensions machine. From the 3D data sets synthetic 2D mammograms were constructed (Hologic C-view). One breast radiologist with 13 years experience of interpreting mammograms and 5 years with DBTs was asked to review the 2D synthetic mammograms (CC and MLO) and report them before then reviewing the DBTs and issuing a final report. The mammograms were reported M1 to M5 using the standard BIRADs criteria. The BIRADs scores for each breast were recorded prospectively. Similarly the breast density as assessed by eye was recorded (fatty/average density/dense). Results: 2500 patients were studied between October 2013 and October 2014. The average age of the women was 58.4 years (range 28-95). Of these some were under follow up after mastectomies so in total there were 4589 individual mammogram sets reported. Table 1 summarises the correlation between the synthetic 2D and DBT reports. BIRADS Classification - Synthetic 2D v DBT Synthetic 2D M1M2M3M4M5 M115874000 M2827051510DBTM32810140 M4015480 M5001396 The correlation is very close, but there were 11 patients in whom the synthetic 2D was reported normal or benign (M1 or M2) but the DBT was reported as M3. Of these 10 were benign on assessment and one malignant. There was one patient reported as M2 on synthetic 2D but M4 on DBT. Assessment confirmed malignancy. Sixteen cases reported as suspicious of malignancy (M3/4) by synthetic 2D were subsequently downgraded to benign after review of the DBT. We estimate that 2D mammography alone would have detected only 68 of the 94 detected by synthetic 2D. Of the 4589 examinations, 1131 (25%) were assessed as fatty, 1851 (40%) as average density and 1607 (35%) as dense. One cancer was missed in an averagely dense and one in a dense breast. Conclusion: In a symptomatic and follow up clinic, our study suggests that much radiologist's time and x-ray exposure to the patient could be saved by using synthetic 2D mammograms rather than using 2D/3D combinations. Only if the synthetic 2D is reported M3, 4 or 5 is it necessary to review the DBT. Whilst a similar trial is required to confirm these findings in a screening population, this trial suggests that synthetic 2D mammography could be cost effective compared to combination 2D/3D. Citation Format: Holt SD, Sharaiha YM, Moalla A, Williams HR, Thomas D, Huws AM. A comparison of the diagnostic performance of 2D synthetic mammography versus digital breast tomosynthesis in 2500 patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-09.

Background: Prognostic factors have been used for years to determine the benefit of adjuvant chemotherapy in breast cancer. However, reporting of the size and grade of the tumor are affected by interobserver variability in reporting. This can result in a change in the results of adjuvant online and an impact on decision making of chemotherapy. On the contrary, genomic testing such as oncotype Dx is reproducible. The purpose of our study was to assess the effect of pathological discordance on the adjuvant online results on a cohort of patients who also underwent oncotype Dx testing. Materials and Methods: A total of 143 patients' histologies were included in this study. The results of the Phase III WSG-Plan B trial concerning central vs. local grade discrepancy rates were utilized to randomly change the grade of the tumors. 61 percent of grade 1 cancers were upgraded to grade 2 and 2% upgraded to grade 3. 4 percent of grade 2 cancers were downgraded to grade 1 and 26% were upgraded to grade 3. 1 percent of grade 3 cancers were downgraded to grade 1 and 25% were downgraded to grade 2. Likewise, change was made in the size of the tumor in 20 percent of patients. 8 to 10mm, 18-20, 28-30, and 48-50mm changed to 11, 21, 31 and 51mm respectively. 11-13mm, 21-23, 31-33, and 51-53mm was changed to 10, 20, 30, and 50mm. Ten percent of patients had the ER and Her 2 status changed. Results: The simulation results showed that when the grade was only altered, the spearman correlation of the predicted 10 year mortality on adjuvant online with the original data was significantly changed from 1 to a result of 0.788. When the changed size was additionally added, the coefficient was 0.836. With the altered ER status, the result was 0.749 and with the Her 2 change, the spearman correlation was minimally changed to 0.742. The scattergrams showed a large number of outliers when the alteration in size was added to the altered grade. Conclusion: Our simulation study confirms that with minimal changes in the clinical parameters because of the lack of perfect correlation between pathologist's results, there is a significant difference in the 10 year predicted mortality on adjuvant online. This is one step further in understanding the lack of correlation between adjuvant online and oncotype Dx, and the inconsistency of chemotherapy decision making with the sole use of adjuvant online. Citation Format: Khawaja S, Thomas D, Udayasankar S, Munir A, Huws A, Sharaiha Y, Holt S. A simulation study depicting the inconsistency of adjuvant online compared to genomic testing when determining the benefit of chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-12.