Miracle-dz/UniFAR-FTUs huggingface dataset:
The Effects of Amphetamine and Methamphetamine on the Release of Norepinephrine, Dopamine and Acetylcholine From the Brainstem Reticular Formation

Amphetamine (AMPH) and methamphetamine (METH) are widely abused psychostimulants, which produce a variety of psychomotor, autonomic and neurotoxic effects. The behavioral and neurotoxic effects of both compounds (from now on defined as AMPHs) stem from a fair molecular and anatomical specificity for catecholamine-containing neurons, which are placed in the brainstem reticular formation (RF). In fact, the structural cross-affinity joined with the presence of shared molecular targets between AMPHs and catecholamine provides the basis for a quite selective recruitment of brainstem catecholamine neurons following AMPHs administration. A great amount of investigations, commentary manuscripts and books reported a pivotal role of mesencephalic dopamine (DA)-containing neurons in producing behavioral and neurotoxic effects of AMPHs. Instead, the present review article focuses on catecholamine reticular neurons of the low brainstem. In fact, these nuclei add on DA mesencephalic cells to mediate the effects of AMPHs. Among these, we also include two pontine cholinergic nuclei. Finally, we discuss the conundrum of a mixed neuronal population, which extends from the pons to the periaqueductal gray (PAG). In this way, a number of reticular nuclei beyond classic DA mesencephalic cells are considered to extend the scenario underlying the neurobiology of AMPHs abuse. The mechanistic approach followed here to describe the action of AMPHs within the RF is rooted on the fine anatomy of this region of the brainstem. This is exemplified by a few medullary catecholamine neurons, which play a pivotal role compared with the bulk of peripheral sympathetic neurons in sustaining most of the cardiovascular effects induced by AMPHs.
Preferential Consolidation of Emotional Memory During Sleep: A Meta-Analysis

It is uncertain whether sleep preferentially consolidates emotional over neutral material. Some studies suggest that sleep enhances emotional memory (i.e., that there are large differences in strength of memory for valenced material compared to neutral material after a sleep-filled interval, but that this difference is smaller after a wake-filled interval). Others find no such effect. We attempted to resolve this uncertainty by conducting a meta-analysis that compared valenced to neutral material after both sleep- and wake-filled delays. Standard search strategies identified 31 studies (containing 36 separate datasets) that met our inclusion criteria. Using random effects modeling, we conducted separate analyses for datasets comparing (a) negative vs. neutral material, (b) positive vs. neutral material, or (c) combined negative and positive vs. neutral material. We then specified several subgroup analyses to investigate potential moderators of the relationship between sleep and emotional memory consolidation. Results showed no overall effect for preferential sleep-dependent consolidation of emotional over neutral material. However, moderation analyses provided evidence for stronger effects when (a) studies used free recall rather than recognition outcome measures, or (b) delayed recall or recognition outcomes were controlled for initial learning. Those analyses also suggested that other methodological features (e.g., whether participants experience a full night of sleep and a regular daytime waking control condition rather than a nap and a night-time sleep deprivation control condition) and sample characteristics (e.g. all-male or not, young adult or not) should be carefully addressed in future research in this field. These findings suggest that sleep does enhance emotional memory, but that in the laboratory the effect is only observed under particular methodological conditions. The conditions we identify as being critical to consider are consistent with general theories guiding scientific understanding of memory consolidation during sleep.
US Resource Company Environmental Disclosure Practices: What, Where And How?

This study examines the voluntary environmental reporting practices of US companies over five mediums namely, hard copy annual reports, hard copy environmental reports, internet annual reports, internet environmental reports and additional environmental disclosures on the Internet of 135 US resource companies listed on the New York Stock Exchange over the 1999-2000 fiscal year. These resource companies were chosen on the basis of their operations having a very large impact on the environment. The results of this study indicate that US resource companies on average disclose low levels of environmental information in all mediums examined. The majority of US resource companies primarily adopt hard copy annual reports and internet-based annual reports to report environmental disclosures and hence fail to exploit the power of other mediums for environmental disclosures. This study attributes the conservative levels of environmental disclosure on different motivations that US resource companies have in disclosing in different mediums.
Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial.

IMPORTANCE Hyperkalemia is a common electrolyte abnormality that may be difficult to manage because of a lack of effective therapies. Sodium zirconium cyclosilicate is a nonabsorbed cation exchanger that selectively binds potassium in the intestine. OBJECTIVE To evaluate the efficacy and safety of zirconium cyclosilicate for 28 days in patients with hyperkalemia. DESIGN, SETTING, AND PARTICIPANTS HARMONIZE was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating zirconium cyclosilicate in outpatients with hyperkalemia (serum potassium ≥5.1 mEq/L) recruited from 44 sites in the United States, Australia, and South Africa (March-August 2014). INTERVENTIONS Patients (n = 258) received 10 g of zirconium cyclosilicate 3 times daily in the initial 48-hour open-label phase. Patients (n = 237) achieving normokalemia (3.5-5.0 mEq/L) were then randomized to receive zirconium cyclosilicate, 5 g (n = 45 patients), 10 g (n = 51), or 15 g (n = 56), or placebo (n = 85) daily for 28 days. MAIN OUTCOMES AND MEASURES The primary end point was mean serum potassium level in each zirconium cyclosilicate group vs placebo during days 8-29 of the randomized phase. RESULTS In the open-label phase, serum potassium levels declined from 5.6 mEq/L at baseline to 4.5 mEq/L at 48 hours. Median time to normalization was 2.2 hours, with 84% of patients (95% CI, 79%-88%) achieving normokalemia by 24 hours and 98% (95% CI, 96%-99%) by 48 hours. In the randomized phase, serum potassium was significantly lower during days 8-29 with all 3 zirconium cyclosilicate doses vs placebo (4.8 mEq/L [95% CI, 4.6-4.9], 4.5 mEq/L [95% CI, 4.4-4.6], and 4.4 mEq/L [95% CI, 4.3-4.5] for 5 g, 10 g, and 15 g; 5.1 mEq/L [95% CI, 5.0-5.2] for placebo; P < .001 for all comparisons). The proportion of patients with mean potassium <5.1 mEq/L during days 8-29 was significantly higher in all zirconium cyclosilicate groups vs placebo (36/45 [80%], 45/50 [90%], and 51/54 [94%] for the 5-g, 10-g, and 15-g groups, vs 38/82 [46%] with placebo; P < .001 for each dose vs placebo). Adverse events were comparable between zirconium cyclosilicate and placebo, although edema was more common in the 15-g group (edema incidence: 2/85 [2%], 1/45 [2%], 3/51 [6%], and 8/56 [14%] patients in the placebo, 5-g, 10-g, and 15-g groups). Hypokalemia developed in 5/51 (10%) and 6/56 patients (11%) in the 10-g and 15-g zirconium cyclosilicate groups, vs none in the 5-g or placebo groups. CONCLUSIONS AND RELEVANCE Among outpatients with hyperkalemia, open-label sodium zirconium cyclosilicate reduced serum potassium to normal levels within 48 hours; compared with placebo, all 3 doses of zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days. Further studies are needed to evaluate the efficacy and safety of zirconium cyclosilicate beyond 4 weeks and to assess long-term clinical outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02088073.
Two Distinct Scene-Processing Networks Connecting Vision and Memory

Visual Abstract A number of regions in the human brain are known to be involved in processing natural scenes, but the field has lacked a unifying framework for understanding how these different regions are organized and interact. We provide evidence from functional connectivity and meta-analyses for a new organizational principle, in which scene processing relies upon two distinct networks that split the classically defined parahippocampal place area (PPA). The first network of strongly connected regions consists of the occipital place area/transverse occipital sulcus and posterior PPA, which contain retinotopic maps and are not strongly coupled to the hippocampus at rest. The second network consists of the caudal inferior parietal lobule, retrosplenial complex, and anterior PPA, which connect to the hippocampus (especially anterior hippocampus), and are implicated in both visual and nonvisual tasks, including episodic memory and navigation. We propose that these two distinct networks capture the primary functional division among scene-processing regions, between those that process visual features from the current view of a scene and those that connect information from a current scene view with a much broader temporal and spatial context. This new framework for understanding the neural substrates of scene-processing bridges results from many lines of research, and makes specific functional predictions.
CATEGORICAL VERSUS DIMENSIONAL DIAGNOSIS OF GENERALIZED ANXIETY DISORDER: HOW WELL DO THEY PREDICT RESPONSE TO TREATMENT?

The present investigation examined three questions related to the diagnosis and treatment of generalized anxiety disorder (GAD). First, is a continuous GAD diagnosis better able to predict the treatment response of worried individuals than a categorical GAD diagnosis? Second, can the known benefits of stimulus control and problem solving interventions for worry be improved by the addition of relaxation training and cognitive restructuring commonly used in the treatment of GAD? Third, does the GAD status of a worried individual interact with the number of therapy components that are received to predict treatment outcome? To address these questions, 72 highly worried individuals were diagnosed under both a categorical (DSM-IV) and a dimensional (severity) GAD model and then provided with one of two brief cognitivebehavioral interventions for severe worry. The two interventions were compared using an additive methodological design and involved a single, group-administered treatment session followed by approximately four weeks of self-guided skills rehearsal and application using a therapy workbook. Participants were assessed for GAD, worry, anxiety, depression, global functioning, and quality of life before and after treatment. Results revealed the dimensional GAD diagnosis to predict some important treatment outcomes more powerfully than the categorical GAD diagnosis, particularly the symptoms and functioning observed at the end of treatment. Results also showed both of the inexpensive, stimulus-control-based anxiety treatments to yield substantial improvement in worrying and associated pathology, with relaxation training and cognitive restructuring providing a small but consistent increment in treatment benefit that appeared especially helpful for non-GAD worriers. Finally, results revealed that while GADdiagnosed and nondiagnosed high worriers benefited considerably from these worry-focused treatments, GAD worriers generally evidenced greater improvement—but poorer endstate
Neural Processing of Respiratory Sensations when Breathing Becomes More Difficult and Unpleasant

The accurate perception of respiratory sensations is important for the successful management and treatment of respiratory diseases. Previous studies demonstrated that external stimuli such as affective pictures and distracting films can impact the perception and neural processing of respiratory sensations. This study examined the neural processing of respiratory sensations when breathing as an internal stimulus is manipulated and becomes more difficult and unpleasant. Sustained breathing through an inspiratory resistive load was used to increase perceived breathing difficulty in 12 female individuals without respiratory disease. Using high-density EEG, respiratory-related evoked potentials (RREP) to short inspiratory occlusions were recorded at early versus late time points of sustained loaded breathing. Ratings of perceived intensity and unpleasantness of breathing difficulty showed an increase from early to late time points of loaded breathing (p < 0.01 and p < 0.05, respectively). This was paralleled by significant increases in the magnitudes of RREP components N1, P2, and P3 (p < 0.01, p < 0.05, and p < 0.05, respectively). The present results demonstrate increases in the neural processing of respiratory sensations when breathing becomes more difficult and unpleasant. This might reflect a protective neural mechanism allowing effective response behavior when air supply is at risk.
Challenges for the policy representation when applying reinforcement learning in robotics

A summary of the state-of-the-art reinforcement learning in robotics is given, in terms of both algorithms and policy representations. Numerous challenges faced by the policy representation in robotics are identified. Two recent examples for application of reinforcement learning to robots are described: pancake flipping task and bipedal walking energy minimization task. In both examples, a state-of-the-art Expectation-Maximization-based reinforcement learning algorithm is used, but different policy representations are proposed and evaluated for each task. The two proposed policy representations offer viable solutions to four rarely-addressed challenges in policy representations: correlations, adaptability, multi-resolution, and globality. Both the successes and the practical difficulties encountered in these examples are discussed.
Follow-Up of Patients with Multidrug Resistant Tuberculosis Four Years after Standardized First-Line Drug Treatment

Background In 2004, an anti-tuberculosis (TB) drug resistance survey in Heilongjiang province, China, enrolled 1574 (79%) new and 421 (21%) retreatment patients. Multi-drug resistant (MDR) TB was detected in 7.2% of new and 30.4% of retreatment patients. All received treatment with standardized first-line drug (FLD) regimens. Methodology/Principal Findings We report treatment outcomes of the 2004 cohort, and long-term outcomes as assessed in the second half of 2008. The reported cure rate for MDR-TB patients was 83% (94/113) among new and 66% (85/128) among retreatment patients (P<0.001). Ten of the 241 MDR-TB patients died during treatment. Of the remaining 231, 129 (56%) could be traced in 2008. The overall recurrence rates among new and retreatment cases were 46% and 66%, respectively (P = 0.03). The overall death rates among new and retreatment cases were 25% and 46%, respectively (P = 0.02). Forty percent of the traced new cases and 24% of the retreatment cases were alive and without recurrent TB (P = 0.01). Of the 16 patients who failed or defaulted from treatment in 2004, only two patients were not re-diagnosed with TB by 2008. Of the 111 (86%) patients with an initial successful treatment outcome 63 (57%) had developed recurrent TB, 40 (36%) had died, 27 (24%) of them died of TB. The follow-up period of four years precluded follow-up of all patients. In a highly conservative sensitivity analysis in which we assumed that all non-included patients were alive and did not have recurrent TB, the recurrence and death rate were 33% and 21%. Conclusions/Significance Documentation of cure based on conventional smear microscopy was a poor predictor of long term outcomes. MDR-TB patients in Heilongjiang province in China had high recurrence and death rates four years after treatment with standardized FLD regimens, reinforcing the need for early diagnosis and treatment of MDR-TB, including assessment of treatment outcomes with more sensitive laboratory methods.
#Exploration: A Study of Count-Based Exploration for Deep Reinforcement Learning

Count-based exploration algorithms are known to perform near-optimally when used in conjunction with tabular reinforcement learning (RL) methods for solving small discrete Markov decision processes (MDPs). It is generally thought that count-based methods cannot be applied in high-dimensional state spaces, since most states will only occur once. Recent deep RL exploration strategies are able to deal with high-dimensional continuous state spaces through complex heuristics, often relying on optimism in the face of uncertainty or intrinsic motivation. In this work, we describe a surprising finding: a simple generalization of the classic count-based approach can reach near state-of-the-art performance on various high-dimensional and/or continuous deep RL benchmarks. States are mapped to hash codes, which allows to count their occurrences with a hash table. These counts are then used to compute a reward bonus according to the classic count-based exploration theory. We find that simple hash functions can achieve surprisingly good results on many challenging tasks. Furthermore, we show that a domain-dependent learned hash code may further improve these results. Detailed analysis reveals important aspects of a good hash function: 1) having appropriate granularity and 2) encoding information relevant to solving the MDP. This exploration strategy achieves near state-of-the-art performance on both continuous control tasks and Atari 2600 games, hence providing a simple yet powerful baseline for solving MDPs that require considerable exploration.
Validation of the IHE Cohort Model of Type 2 Diabetes and the Impact of Choice of Macrovascular Risk Equations

Background Health-economic models of diabetes are complex since the disease is chronic, progressive and there are many diabetic complications. External validation of these models helps building trust and satisfies demands from decision makers. We evaluated the external validity of the IHE Cohort Model of Type 2 Diabetes; the impact of using alternative macrovascular risk equations; and compared the results to those from microsimulation models. Methods The external validity of the model was analysed from 12 clinical trials and observational studies by comparing 167 predicted microvascular, macrovascular and mortality outcomes to the observed study outcomes. Concordance was examined using visual inspection of scatterplots and regression-based analysis, where an intercept of 0 and a slope of 1 indicate perfect concordance. Additional subgroup analyses were conducted on ‘dependent’ vs. ‘independent’ endpoints and microvascular vs. macrovascular vs. mortality endpoints. Results Visual inspection indicates that the model predicts outcomes well. The UKPDS-OM1 equations showed almost perfect concordance with observed values (slope 0.996), whereas Swedish NDR (0.952) and UKPDS-OM2 (0.899) had a slight tendency to underestimate. The R 2 values were uniformly high (>0.96). There were no major differences between ‘dependent’ and ‘independent’ outcomes, nor for microvascular and mortality outcomes. Macrovascular outcomes tended to be underestimated, most so for UKPDS-OM2 and least so for NDR risk equations. Conclusions External validation indicates that the IHE Cohort Model of Type 2 Diabetes has predictive accuracy in line with microsimulation models, indicating that the trade-off in accuracy using cohort simulation might not be that large. While the choice of risk equations was seen to matter, each were associated with generally reasonable results, indicating that the choice must reflect the specifics of the application. The largest variation was observed for macrovascular outcomes. There, NDR performed best for relatively recent and well-treated patients, while UKPDS-OM1 performed best for the older UKPDS cohort.
Internal Medicine

It has taken a long time to plan for this November issue in Internal Medicine. The topic is so wide and often neglected as the specialties take prominence. However, we do recognize a need for the general physician and this issue of the Annals highlights recent advances in some fields of internal medicine. We hope it would serve to generate interest in Internal Medicine and, at the same time, serve as a quick update for most of us. Much has been said about the economy class syndrome, deep vein thrombosis (DVT) and sudden death. Though this was thought to have been not significant in Asia, research and ongoing studies are proving otherwise. The article by Gallus et al reviews the pathways to coagulation, the incidence of DVTs and new drugs for treatment. With increasing prevalence of obesity in Singapore, obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is increasingly well recognized. The article from Douglas serves to emphasize this problem. He notes that patients with undiagnosed OSAHS are heavy users of healthcare, are predisposed towards hypertension and road traffic accidents. It is enlightening to note that continuous positive airway pressure therapy goes a long way in treating this condition. The paper by Fong, on the use of immunology in the treatment of various conditions from diabetes mellitus to the usual array of autoimmune conditions, is an eye opener . Unfortunately, there will still be problems with side effects and we can expect more to come with more ongoing trials. There are two papers on the use of computers in medicine. This will be an important part of our work and will serve to cut down on errors in prescribing/dosing. However, we note that the human touch must always be there as machines can never replace a doctor. There are also clinical updates on the management of stroke and type 2 diabetes mellitus. I find this issue on Internal Medicine very useful and hope it makes enjoyable reading to all our Fellows and other doctors. I would also like to take the opportunity to thank all our contributors, the editorial staff and the Annals Editorial Board, without which this would not have been possible.
Supersymmetric virial expansion for time-reversal invariant disordered systems

We develop a supersymmetric virial expansion for two-point correlation functions of almost diagonal Gaussian random matrix ensembles (ADRMT) of the orthogonal symmetry. These ensembles have multiple applications in physics and can be used to study the universal properties of time-reversal invariant disordered systems which are either insulators or close to the Anderson localization transition. We derive a two-level contribution to the correlation functions of the generic ADRMT and apply these results to the critical (multifractal) power law banded ADRMT. Analytical results are compared with numerical ones.