Signatures of hierarchical temporal processing in the mouse visual system.

A core challenge for the brain is to process information across various timescales. This could be achieved by a hierarchical organization of temporal processing through intrinsic mechanisms (e.g., recurrent coupling or adaptation), but recent evidence from spike recordings of the rodent visual system seems to conflict with this hypothesis. Here, we used an optimized information-theoretic and classical autocorrelation analysis to show that information- and correlation timescales of spiking activity increase along the anatomical hierarchy of the mouse visual system under visual stimulation, while information-theoretic predictability decreases. Moreover, intrinsic timescales for spontaneous activity displayed a similar hierarchy, whereas the hierarchy of predictability was stimulus-dependent. We could reproduce these observations in a basic recurrent network model with correlated sensory input. Our findings suggest that the rodent visual system employs intrinsic mechanisms to achieve longer integration for higher cortical areas, while simultaneously reducing predictability for an efficient neural code.

Computing Generalized Convolutions Faster Than Brute Force.

In this paper, we consider a general notion of convolution. Let D be a finite domain and let Dn be the set of n-length vectors (tuples) of D. Let f:D×D→D be a function and let ⊕f be a coordinate-wise application of f. The f-Convolution of two functions g,h:Dn→{-M,…,M} is (g⊛fh)(v):=∑vg,vh∈Dns.t.v=vg⊕fvhg(vg)·h(vh)for every v∈Dn. This problem generalizes many fundamental convolutions such as Subset Convolution, XOR Product, Covering Product or Packing Product, etc. For arbitrary function f and domain D we can compute f-Convolution via brute-force enumeration in O~(|D|2n·polylog(M)) time. Our main result is an improvement over this naive algorithm. We show that f-Convolution can be computed exactly in O~((c·|D|2)n·polylog(M)) for constant c:=3/4 when D has even cardinality. Our main observation is that a cyclic partition of a function f:D×D→D can be used to speed up the computation of f-Convolution, and we show that an appropriate cyclic partition exists for every f. Furthermore, we demonstrate that a single entry of the f-Convolution can be computed more efficiently. In this variant, we are given two functions g,h:Dn→{-M,…,M} alongside with a vector v∈Dn and the task of the f-Query problem is to compute integer (g⊛fh)(v). This is a generalization of the well-known Orthogonal Vectors problem. We show that f-Query can be computed in O~(|D|ω2n·polylog(M)) time, where ω∈[2,2.372) is the exponent of currently fastest matrix multiplication algorithm.

Discovery of Potent Agonists for the Predominant Variant of the Orphan MAS-Related G Protein-Coupled Receptor X4 (MRGPRX4).

The MAS-related Gq protein-coupled receptor X4 (MRGPRX4) is poorly investigated. MRGPRX4 has been proposed to be involved in pain transmission, itch, inflammation, wound healing, and cancer. However, so far only a few moderately potent, nonselective MRGPRX4 agonists have been described, most of which appear to preferably activate the minor receptor variant MRGPRX4-83L but not the main variant 83S. In the present study, we discovered a xanthine derivative bearing a phosphate substituent that activates the main variant of MRGPRX4. Optimization resulted in analogs with high potency and metabolic stability. The best compounds of the present series include 8-(m-methoxyphenethyl)-1-propargylxanthine substituted with a butyl linker in the 3-position containing a terminal phosphonate (30d, PSB-22034, EC50 Ca2+ assay/ß-arrestin assay, 11.2 nM/32.0 nM) and its N7-methyl derivative 31d (PSB-22040, EC50, 19.2/30.0 nM) showing high selectivity versus all other MRGPRX subtypes. They present promising tool compounds for exploring the potential of MRGPRX4 as a future drug target.

Length of Stay per Total Body Surface Area Burn Relative to Mechanism: A Pediatric Injury Quality Improvement Collaborative Study.

Studies on length of stay (LOS) per total body surface area (TBSA) burn in pediatric patients are often limited to single institutions and are grouped in ranges of TBSA burn which lacks specific detail to counsel patients and families. A LOS to TBSA burn ratio of 1 has been widely accepted but not validated with multi-institution data. The objective of this study is to describe the current relationship of LOS per TBSA burn and LOS per TBSA burn relative to burn mechanism with the use of multi-institutional data. Data from the Pediatric Injury Quality Improvement Collaborative (PIQIC) were obtained for patients across five pediatric burn centers from July 2018 to September 2020. LOS per TBSA burn ratios were calculated. Descriptive statistics and generalized linear regression which modeled characteristics associated with LOS per TBSA ratio are described. Among the 1267 pediatric burn patients, the most common mechanism was scald (64%), followed by contact (17%) and flame (13%). The average LOS/TBSA burn ratio across all cases was 1.2 (SD = 2.1). In adjusted models, scald burns and chemical burns had similar LOS/TBSA burn ratios of 0.8 and 0.9, respectively, whereas all other burns had a significantly higher LOS/TBSA burn ratio (p<0.0001). LOS/TBSA burn ratios were similar across races, although Hispanics had a slightly higher ratio at 1.4 days. These data establish a multi-institution LOS per TBSA ratio across PIQIC centers and demonstrate a significant variation in the LOS per TBSA burn relative to the burn mechanism sustained.

Defining Benchmarks in Pediatric Burn Care: Inception of the Pediatric Injury Quality Improvement Collaborative.

Pediatric burn care is highly variable nationwide. Standardized quality and performance benchmarks are needed for guiding performance improvement within pediatric burn centers. A network of pediatric burn centers was established to develop and evaluate pediatric-specific best practices. A multi-disciplinary team including pediatric surgeons, nurses, advanced practice providers, pediatric intensivists, rehabilitation staff, and child psychologists from five pediatric burn centers established a collaborative to share and compare performance improvement data, evaluate outcomes, and exchange best care practices. In December 2016, the Pediatric Injury Quality Improvement Collaborative (PIQIC) was established. PIQIC members chose quality improvement indicators, drafted and approved a memorandum of understanding (MOU), data use agreement (DUA) and charter, formalized the multidisciplinary membership, and established a steering committee. Since inception, PIQIC has conducted monthly teleconferences and biannual in-person or virtual group meetings. A centralized data repository has been established where data is collated and analyzed for benchmarking in a blinded fashion. PIQIC has shown the feasibility of multi-institutional data collection, implementation of performance improvement metrics, publication of research, and enhancement of aggregate and institution-specific pediatric burn care.

Embedding optimization reveals long-lasting history dependence in neural spiking activity.

Information processing can leave distinct footprints on the statistics of neural spiking. For example, efficient coding minimizes the statistical dependencies on the spiking history, while temporal integration of information may require the maintenance of information over different timescales. To investigate these footprints, we developed a novel approach to quantify history dependence within the spiking of a single neuron, using the mutual information between the entire past and current spiking. This measure captures how much past information is necessary to predict current spiking. In contrast, classical time-lagged measures of temporal dependence like the autocorrelation capture how long-potentially redundant-past information can still be read out. Strikingly, we find for model neurons that our method disentangles the strength and timescale of history dependence, whereas the two are mixed in classical approaches. When applying the method to experimental data, which are necessarily of limited size, a reliable estimation of mutual information is only possible for a coarse temporal binning of past spiking, a so-called past embedding. To still account for the vastly different spiking statistics and potentially long history dependence of living neurons, we developed an embedding-optimization approach that does not only vary the number and size, but also an exponential stretching of past bins. For extra-cellular spike recordings, we found that the strength and timescale of history dependence indeed can vary independently across experimental preparations. While hippocampus indicated strong and long history dependence, in visual cortex it was weak and short, while in vitro the history dependence was strong but short. This work enables an information-theoretic characterization of history dependence in recorded spike trains, which captures a footprint of information processing that is beyond time-lagged measures of temporal dependence. To facilitate the application of the method, we provide practical guidelines and a toolbox.

Social Decision Making in Autistic Adolescents: The Role of Theory of Mind, Executive Functioning and Emotion Regulation.

Social decision making is often challenging for autistic individuals. Twenty autistic adolescents made decisions in the socially interactive context of a one-shot ultimatum game, and performance was compared to a large matched typical reference sample. Theory of mind, executive functioning and emotion regulation were measured via direct assessments, self- and parent report. Relative to the reference sample, autistic adolescents proposed fewer fair offers, and this was associated with poorer theory of mind. Autistic adolescents responded similarly to the reference sample when making decisions about offers proposed to them, however they did not appear to down regulate their negative emotion in response to unfair treatment in the same way. Atypical processes may underpin even apparently typical decisions made by autistic adolescents.

Simulation studies for characterizing ultrashort bunches using novel polarizable X-band transverse deflection structures.

Transverse deflection structures are useful devices for characterizing the longitudinal properties of bunches in electron accelerators. With efforts to produce ever-shorter bunches for applications such as external injection into novel accelerator structures, e.g. plasma cells or dielectric structures, the applicability of deflection structures to measuring ultrashort bunches has been considered. In this paper, charge-density and bunch-length measurements of femtosecond and subfemtosecond bunches at the ARES linac at the SINBAD facility at DESY are studied with simulations and the limitations discussed in detail. The novel polarizable X-band transverse deflection structure (PolariX-TDS) will allow the streaking of bunches at all transverse angles, making a 3D charge-density reconstruction of bunches possible, in addition to the standard 1D charge-density reconstruction and bunch-length measurements. These various measurements of the charge-density distributions of bunches have been simulated, and it is shown that useful information about ultrashort bunches down to subfemtosecond lengths may be obtained using the setup planned for the ARES linac.

Structural and Conformational Studies on Carboxamides of 5,6-Diaminouracils-Precursors of Biologically Active Xanthine Derivatives.

8-Arylethynylxanthine derivatives are potent, selective adenosine A2A receptor antagonists, which represent (potential) therapeutics for Parkinson's disease, Alzheimer's dementia, and the immunotherapy of cancer. 6-Amino-5-amidouracil derivatives are important precursors for the synthesis of such xanthines. We noticed an unexpected duplication of NMR signals in many of these uracil derivatives. Here, we present a detailed analytical study of structurally diverse 6-amino-5-carboxamidouracils employing dynamic and two-dimensional NMR spectroscopy, density functional theory calculations, and X-ray analysis to explain the unexpected properties of these valuable drug intermediates.

Fast, Efficient, and Versatile Synthesis of 6-amino-5-carboxamidouracils as Precursors for 8-Substituted Xanthines.

Substituted xanthine derivatives are important bioactive molecules. Herein we report on a new, practical synthesis of 6-amino-5-carboxamidouracils, the main building blocks for the preparation of 8-substituted xanthines, by condensation of 5,6-diaminouracil derivatives and various carboxylic acids using the recently developed non-hazardous coupling reagent COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate). Optimized reaction conditions led to the precipitation of pure products after only 5 to 10 min of reaction time. The method tolerates a variety of substituted 5,6-diaminouracil and carboxylic acid derivatives as starting compounds resulting in most cases in more than 80% isolated yield. Regioselectivity of the reaction yielding only the 5-carboxamido-, but not the 6-carboxamidouracil derivatives, was unambiguously confirmed by single X-ray crystallography and multidimensional NMR experiments. The described method represents a convenient, fast access to direct precursors of 8-substituted xanthines under mild conditions without the necessity of hazardous coupling or chlorinating reagents.

Four Needles in a Haystack: A Systematic Review Assessing Quality of Health Care in Specialty Practice by Practice Type.

Specialists, who represent 60% of physicians in the United States, are consolidating into large group practices, but the degree to which group practice type facilitates the delivery of high quality of care in specialty settings is unknown. We conducted a systematic literature review to identify the impact of group practice type on the quality of care among specialty providers. The search resulted in 913 articles, of which only 4 met inclusion criteria. Studies were of moderate methodological quality. From the limited evidence available, we hypothesize that solo specialists deliver care that is inferior to their peers in group practice, whether measured by patient satisfaction ratings or adherence to guideline-based care. However, solo specialists and multidisciplinary group specialists may be more likely to provide some specialized services compared with their single-specialty group peers. Insufficient research compares quality of care among different practice types in specialty care. Substantial opportunity exists to test the degree to which organizational factors, whether size of practice or the mix of providers within the practice, influence quality of care in specialty settings.

Nursing preference of topical silver sulfadiazine versus collagenase ointment for treatment of partial thickness burns in children: survey follow-up of a prospective randomized trial.

We performed a nursing survey to inquire about nursing preferences toward the use of silver sulfadiazine (SSD) and collagenase (CO). We performed a survey between September 2012 and December 2012 asking nurses to rate the application/removal of both products and provide a description of their preferences. Ten study nurses (83%) preferred CO over SSD (P < .001). Two nurses (17%) had no preference. Negative comments on SSD were pseudoeschar (50%), difficult application burns (25%), messiness (67%), and increased number of dressing changes (25%). Negative comments on CO were the need for an additional antimicrobial agent (58%), although 1 nurse noted the higher expense with CO. Nurses preferred CO because of cleanliness of dressing (17%), lack of pseudoeschar (25%), and less pain with dressing changes (8%). Despite no difference in outcomes between SSD and CO, experienced burn nurses prefer CO because of perceptions of decreased trauma and frequency of dressing changes.

Parameterized Complexity of Eulerian Deletion Problems.

We study a family of problems where the goal is to make a graph Eulerian, i.e., connected and with all the vertices having even degrees, by a minimum number of deletions. We completely classify the parameterized complexity of various versions: undirected or directed graphs, vertex or edge deletions, with or without the requirement of connectivity, etc. The collection of results shows an interesting contrast: while the node-deletion variants remain intractable, i.e., W[1]-hard for all the studied cases, edge-deletion problems are either fixed-parameter tractable or polynomial-time solvable. Of particular interest is a randomized FPT algorithm for making an undirected graph Eulerian by deleting the minimum number of edges, based on a novel application of the color coding technique. For versions that remain NP-complete but fixed-parameter tractable we consider also possibilities of polynomial kernelization; unfortunately, we prove that this is not possible unless NP⊆coNP/poly.