DNA simulation benchmarks revealed with the accumulation of high-resolution structures.

DNA carries more than the list of biochemical instructions that drive the basic functions of living systems. The sequence of base pairs includes a multitude of structural and energetic signals that determine the degree to which the long, threadlike molecule moves and how it responds to proteins and other molecules involved in its processing and packaging. The arrangements of successive base pairs in high-resolution protein-DNA crystal structures provide useful benchmarks for atomic-level simulations of double-helical DNA as well as information potentially useful in interpreting the properties of specific DNA sequences. The set of currently available structures has enough examples to characterize the conformational preferences of the DNA base-pair steps within the context of their immediate neighbors, i.e., in the context of tetramers, and reveals surprising effects of certain neighbors on local chain properties. The proteins in contact with DNA present various microenvironments that sense and/or induce the observed spatial forms. The cumulative buildup of amino-acid atoms in different protein-DNA complexes produces a binding cloud around the double helix with subtle sequence-dependent features. While the microenvironment presented by each protein to DNA is highly unique, the overall composition of amino-acid atoms within close range of DNA in a broad collection of structures is fairly uniform. The buildup of protein atoms of different types around the DNA provides new information for the improvement of nucleic acid force fields and fresh ideas for the exploration of the properties of DNA in solution.

Challenges of Protein-Protein Docking of the Membrane Proteins.

Despite the recent advances in the determination of high-resolution membrane protein (MP) structures, the structural and functional characterization of MPs remains extremely challenging, mainly due to the hydrophobic nature, low abundance, poor expression, purification, and crystallization difficulties associated with MPs. Whereby the major challenges/hurdles for MP structure determination are associated with the expression, purification, and crystallization procedures. Although there have been significant advances in the experimental determination of MP structures, only a limited number of MP structures (approximately less than 1% of all) are available in the Protein Data Bank (PDB). Therefore, the structures of a large number of MPs still remain unresolved, which leads to the availability of widely unplumbed structural and functional information related to MPs. As a result, recent developments in the drug discovery realm and the significant biological contemplation have led to the development of several novel, low-cost, and time-efficient computational methods that overcome the limitations of experimental approaches, supplement experiments, and provide alternatives for the characterization of MPs. Whereby the fine tuning and optimizations of these computational approaches remains an ongoing endeavor.Computational methods offer a potential way for the elucidation of structural features and the augmentation of currently available MP information. However, the use of computational modeling can be extremely challenging for MPs mainly due to insufficient knowledge of (or gaps in) atomic structures of MPs. Despite the availability of numerous in silico methods for 3D structure determination the applicability of these methods to MPs remains relatively low since all methods are not well-suited or adequate for MPs. However, sophisticated methods for MP structure predictions are constantly being developed and updated to integrate the modifications required for MPs. Currently, different computational methods for (1) MP structure prediction, (2) stability analysis of MPs through molecular dynamics simulations, (3) modeling of MP complexes through docking, (4) prediction of interactions between MPs, and (5) MP interactions with its soluble partner are extensively used. Towards this end, MP docking is widely used. It is notable that the MP docking methods yet few in number might show greater potential in terms of filling the knowledge gap. In this chapter, MP docking methods and associated challenges have been reviewed to improve the applicability, accuracy, and the ability to model macromolecular complexes.

Benchmarking medical laboratory performance on a global scale.

Background and aims: Laboratory performance as a relative concept needs repetitive benchmarking for continuous improvement of laboratory procedures and medical processes. Benchmarking as such establishes reference levels as a basis for improvements efforts for healthcare institutions along the diagnosis cycle, with the patient at its center. But while this concept seems to be generally acknowledged in laboratory medicine, a lack of practical implementation hinders progress at a global level. The aim of this study was to examine the utility of a specific combination of indicators and survey-based data collection approach, and to establish a global benchmarking dataset of laboratory performance for decision makers in healthcare institutions. Methods: The survey consisted of 44 items relating to laboratory operations in general and three subscales identified in previous studies. A global sample of laboratories was approached by trained professionals. Results were analyzed with standard descriptive statistics and exploratory factor analysis. Dimensional reduction of specific items was performed using confirmatory factor analysis, resulting in individual laboratory scores for the three subscales of "Operational performance," "Integrated clinical care performance," and "Financial sustainability" for the high-level concept of laboratory performance. Results and conclusions: In total, 920 laboratories from 55 countries across the globe participated in the survey, of which 401 were government hospital laboratories, 296 private hospital laboratories, and 223 commercial laboratories. Relevant results include the need for digitalization and automation along the diagnosis cycle. Formal quality management systems (ISO 9001, ISO 15189 etc.) need to be adapted more broadly to increase patient safety. Monitoring of key performance indicators (KPIs) relating to healthcare performance was generally low (in the range of 10-30% of laboratories overall), and as a particularly salient result, only 19% of laboratories monitored KPIs relating to speeding up diagnosis and treatment. Altogether, this benchmark elucidates current practice and has the potential to guide improvement efforts and standardization in quality & safety for patients and employees alike as well as sustainability of healthcare systems around the globe.

Responding to the workforce crisis: consensus recommendations from the Second Workforce Summit of the American Society of Pediatric Nephrology.

IMPORTANCE: Pediatric patients with complex medical problems benefit from pediatric sub-specialty care; however, a significant proportion of children live greater than 80 mi. away from pediatric sub-specialty care. OBJECTIVE: To identify current knowledge gaps and outline concrete next steps to make progress on issues that have persistently challenged the pediatric nephrology workforce. EVIDENCE REVIEW: Workforce Summit 2.0 employed the round table format and methodology for consensus building using adapted Delphi principles. Content domains were identified via input from the ASPN Workforce Committee, the ASPN's 2023 Strategic Plan survey, the ASPN's Pediatric Nephrology Division Directors survey, and ongoing feedback from ASPN members. Working groups met prior to the Summit to conduct an organized literature review and establish key questions to be addressed. The Summit was held in-person in November 2023. During the Summit, work groups presented their preliminary findings, and the at-large group developed the key action statements and future directions. FINDINGS: A holistic appraisal of the effort required to cover inpatient and outpatient sub-specialty care will help define faculty effort and time distribution. Most pediatric nephrologists practice in academic settings, so work beyond clinical care including education, research, advocacy, and administrative/service tasks may form a substantial amount of a faculty member's time and effort. An academic relative value unit (RVU) may assist in creating a more inclusive assessment of their contributions to their academic practice. Pediatric sub-specialties, such as nephrology, contribute to the clinical mission and care of their institutions beyond their direct billable RVUs. Advocacy throughout the field of pediatrics is necessary in order for reimbursement of pediatric sub-specialist care to accurately reflect the time and effort required to address complex care needs. Flexible, individualized training pathways may improve recruitment into sub-specialty fields such as nephrology. CONCLUSIONS AND RELEVANCE: The workforce crisis facing the pediatric nephrology field is echoed throughout many pediatric sub-specialties. Efforts to improve recruitment, retention, and reimbursement are necessary to improve the care delivered to pediatric patients.

Auditing Abbreviated Breast MR Imaging: Clinical Considerations and Implications.

Abbreviated breast MR (AB-MR) imaging is a relatively new breast imaging tool, which maintains diagnostic accuracy while reducing image times compared with full-protocol breast MR (FP-MR) imaging. Breast imaging audits involve calculating individual and organizational metrics, which can be compared with established benchmarks, providing a standard against which performance can be measured. Unlike FP-MR imaging, there are no established benchmarks for AB-MR imaging but studies demonstrate comparable performance for cancer detection rate, positive predictive value 3, sensitivity, and specificity with T2. We review the basics of performing an audit, including strategies to implement if benchmarks are not being met.

Bridging Requirements, Planning, and Evaluation: A Review of Social Robot Navigation.

Navigation lies at the core of social robotics, enabling robots to navigate and interact seamlessly in human environments. The primary focus of human-aware robot navigation is minimizing discomfort among surrounding humans. Our review explores user studies, examining factors that cause human discomfort, to perform the grounding of social robot navigation requirements and to form a taxonomy of elementary necessities that should be implemented by comprehensive algorithms. This survey also discusses human-aware navigation from an algorithmic perspective, reviewing the perception and motion planning methods integral to social navigation. Additionally, the review investigates different types of studies and tools facilitating the evaluation of social robot navigation approaches, namely datasets, simulators, and benchmarks. Our survey also identifies the main challenges of human-aware navigation, highlighting the essential future work perspectives. This work stands out from other review papers, as it not only investigates the variety of methods for implementing human awareness in robot control systems but also classifies the approaches according to the grounded requirements regarded in their objectives.

Tenofovir-Diphosphate and Emtricitabine-Triphosphate Adherence Benchmarks in Dried Blood Spots for Persons with HIV Receiving Tenofovir Alafenamide and Emtricitabine-based Antiretroviral Therapy (QUANTI-TAF).

BACKGROUND: QUANTI-TAF aimed to establish tenofovir-diphosphate/emtricitabine-triphosphate (TFV-DP/FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with HIV (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART). METHODS: During a 16-week pharmacokinetic study, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TAF/FTC anabolites (TFV-DP/FTC-TP) in DBS were quantified by LC-MS/MS and summarized at steady-state (week 12 or 16) as median (IQR). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP. RESULTS: 84 participants (86% male, 11% female, and 4% transgender), predominantly receiving bictegravir/TAF/FTC (73%) enrolled. 92% completed week 12 or 16 (94% receiving unboosted ART). TFV-DP for <85% (7/72), ≥85%-<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039-4108), 3117 (2332-3339), and 3344 (2605-4293) fmol/punches. All participants with ≥85% cumulative adherence had TFV-DP ≥1800 fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower BMI, and in non-Blacks. FTC-TP for <85% (14/77), ≥85%-<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64-4.48), 4.58 (4.39-5.06), and 4.96 (4.21-6.26) pmol/punches. All participants with ≥85% 10-day adherence had FTC-TP ≥2.5 pmol/punches. Low-level viremia (HIV-1 RNA ≥20-<200 copies/mL) occurred at 60/335 (18%) visits in 33/84 (39%) participants (range: 20-149 copies/mL), with similar TFV-DP (3177 [2494-4149] fmol/punches) compared with HIV-1 RNA <20 copies/mL visits (3279 [2580-4407] fmol/punches). CONCLUSIONS: We propose PK-based TFV-DP (≥1800 fmol/punches)/FTC-TP (≥2.5 pmol/punches) benchmarks in DBS for PWH receiving unboosted TAF/FTC-based ART with ≥85% adherence. In the setting of high adherence, low-level viremia was common.

HyperPUT: generating synthetic faulty programs to challenge bug-finding tools.

As research in automatically detecting bugs grows and produces new techniques, having suitable collections of programs with known bugs becomes crucial to reliably and meaningfully compare the effectiveness of these techniques. Most of the existing approaches rely on benchmarks collecting manually curated real-world bugs, or synthetic bugs seeded into real-world programs. Using real-world programs entails that extending the existing benchmarks or creating new ones remains a complex time-consuming task. In this paper, we propose a complementary approach that automatically generates programs with seeded bugs. Our technique, called HyperPUT, builds C programs from a "seed" bug by incrementally applying program transformations (introducing programming constructs such as conditionals, loops, etc.) until a program of the desired size is generated. In our experimental evaluation, we demonstrate how HyperPUT can generate buggy programs that can challenge in different ways the capabilities of modern bug-finding tools, and some of whose characteristics are comparable to those of bugs in existing benchmarks. These results suggest that HyperPUT can be a useful tool to support further research in bug-finding techniques-in particular their empirical evaluation.

Elements and development processes for test methods in toxicology and human health-relevant life science research.

Many laboratory procedures generate data on properties of chemicals, but they cannot be equated with toxicological "test methods". This apparent discrepancy is not limited to in vitro testing, using animal-free new approach methods (NAM), but also applies to animal-based testing approaches. Here, we give a brief overview of the differences between data generation and the setup or use of a complete test method. While there is excellent literature available on this topic for specialists (GIVIMP guidance; ToxTemp overview), a brief overview and easily-accessible entry point may be useful for a broader community. We provide a single figure to summarize all test method elements and processes required in the development (setup and adaptation) of a test method. The exposure scheme, the endpoint, and the test system are briefly outlined as fundamental elements of any test method. A rationale is provided, why they are not sufficient. We then explain the importance and role of purpose definition (including some information on what is modelled) and the prediction model, aka data interpretation procedure, which depends on the purpose definition, as further essential elements. This connection exemplifies that all fundamental elements are interdependent, and none can be omitted. Finally, discussion is provided on validation as a measure to provide confidence in the reliability, performance, and relevance of a test method. In this sense, validation may be considered a sixth fundamental element for practical use of test methods.

Many laboratory procedures generate data on chemicals, but they cannot be considered complete toxicological "test methods". Here, we give a brief explanation of the fundamental elements of a toxicological test method. We provide an illustration that gives a complete overview of the devel­opment of a test method for non-specialists. We introduce the six fundamental elements, i.e., the exposure scheme, the test endpoint, the test system, the purpose definition and the prediction model and describe how they work together. Finally, we discuss the concept of validation. An understanding of these concepts is important for good-quality scientific research and especially for the development and acceptance of alternatives to animal experiments.

Uncertainty in GNN Learning Evaluations: A Comparison between Measures for Quantifying Randomness in GNN Community Detection.

(1) The enhanced capability of graph neural networks (GNNs) in unsupervised community detection of clustered nodes is attributed to their capacity to encode both the connectivity and feature information spaces of graphs. The identification of latent communities holds practical significance in various domains, from social networks to genomics. Current real-world performance benchmarks are perplexing due to the multitude of decisions influencing GNN evaluations for this task. (2) Three metrics are compared to assess the consistency of algorithm rankings in the presence of randomness. The consistency and quality of performance between the results under a hyperparameter optimisation with the default hyperparameters is evaluated. (3) The results compare hyperparameter optimisation with default hyperparameters, revealing a significant performance loss when neglecting hyperparameter investigation. A comparison of metrics indicates that ties in ranks can substantially alter the quantification of randomness. (4) Ensuring adherence to the same evaluation criteria may result in notable differences in the reported performance of methods for this task. The W randomness coefficient, based on the Wasserstein distance, is identified as providing the most robust assessment of randomness.

Time to define food salt targets in Italy starting with cereal-based products: A safe and practical way to reduce the heavy burden of cardiovascular disease.

BACKGROUND AND AIMS: Excess salt intake is the leading dietary risk factor for cardiovascular disease in most countries, including Italy. While the cost-effectiveness of interventions aimed to reduce salt intake has been proved, the WHO recommendation to reduce salt intake by 30 % at the global level by 2025 is far from being reached. METHODS AND RESULTS: In Italy, two surveys of the general adult population have established that the average salt intake is still almost twice the WHO recommendation although it was reduced by 1.2 g/day between 2008-12 and 2018-19. Previous investigations had shown that non-discretionary salt added by the industry or by local craft producers represents at least 50 % of the total intake and indicated cereal-based products as the main source of non-discretionary salt. Two recent studies conducted by the Italian Society of Human Nutrition "Young Working Group" have provided updated information on the salt content of almost three thousand cereal-based products currently available on the Italian food market and shown that most of the items evaluated had a sodium content much higher than the sodium benchmarks recently proposed by WHO. CONCLUSIONS: Italy has built the foundations of an effective population strategy for salt intake reduction: it is time however to proceed with full commitment to food reformulation if any substantial further progress has to be made. Salt benchmarks for Italy need to be defined for the food categories most relevant to population salt intake and their implementation should ideally be mandatory after consultation with food producers.

Better Accuracy for Better Science . . . Through Random Conclusions.

Conducting research with human subjects can be difficult because of limited sample sizes and small empirical effects. We demonstrate that this problem can yield patterns of results that are practically indistinguishable from flipping a coin to determine the direction of treatment effects. We use this idea of random conclusions to establish a baseline for interpreting effect-size estimates, in turn producing more stringent thresholds for hypothesis testing and for statistical-power calculations. An examination of recent meta-analyses in psychology, neuroscience, and medicine confirms that, even if all considered effects are real, results involving small effects are indeed indistinguishable from random conclusions.

Performance measurement part II: A guide to developing dermatology performance measures.

Throughout the 21st century, national and local governments, private health sectors, health insurance companies, healthcare professionals, labor unions, and consumers have been striving to develop an effective approach to evaluate, report, and improve the quality of healthcare. As medicine improves and health systems grow to meet patient needs, the performance measurement system of care effectiveness must also evolve. Continual efforts should be undertaken to effectively measure quality of care to create a more informed public, improve health outcomes, and reduce healthcare costs. As such, recent policy reform has necessitated that performance systems be implemented in healthcare, with the "performance measure" being the foundation of the system in which all of healthcare must be actively engaged in to ensure optimal care for patients. The development of performance measures can be highly complex, particularly when creating specialty-specific performance measures. To help dermatologists understand the process of creating dermatology-specific performance measures to engage in creating or implementing performance measures at the local or national levels, this article in the two-part continuing medical education series reviews the types, components, and process of developing, reviewing, and implementing performance measures.

Setting sodium targets for pre-packaged foods in China - an exploratory study.

Introduction: Setting sodium targets for pre-packaged food has been a priority strategy for reducing population sodium intake. This study aims to explore the attitudes and considerations of researchers and key stakeholders toward implementing such policy in China. Methods: An exploratory study comprising a survey and a focus group discussion was conducted among 27 purposively selected participants including 12 researchers, 5 consumers, 4 administrators, 3 industry association representatives and 3 food producers. The survey/discussion covered the key questions considered when developing/promoting sodium targets. Free-text responses were manually classified and summarized using thematic analysis. Results: Two-thirds of the participants supported target-setting policy. Researchers and administrators were most supportive, and food producers and associations were least supportive. Adapted WHO food categorization framework was well accepted to underpin target-setting to ensure international comparability and applicability for Chinese products. Maximum values were the most agreed target type. The WHO benchmarks were thought to be too ambitious to be feasible given the current food supply in China but can be regarded as long-term goals. Initially, a reduction of sodium content by 20% was mostly accepted to guide the development of maximum targets. Other recommendations included implementing a comprehensive strategy, strengthening research, engaging social resources, establishing a systematic monitoring/incentive system, maintaining a fair competitive environment, and developing a supportive information system. Target-setting policy was acceptable by most stakeholders and should be implemented alongside strategies to reduce discretionary salt use. Discussion: Our findings provide detailed guidance for the Chinese government when developing a target-setting strategy. The methods and results of this study also provide meaningful references for other countries to set sodium targets for pre-packaged foods and implement other salt reduction strategies simultaneously.

Eye movement corpora in Adyghe and Russian: an eye-tracking study of sentence reading in bilinguals.

The present study expands the eye-tracking-while reading research toward less studied languages of different typological classes (polysynthetic Adyghe vs. synthetic Russian) that use a Cyrillic script. In the corpus reading data from the two languages, we confirmed the widely studied effects of word frequency and word length on eye movements in Adyghe-Russian bilingual individuals for both languages. We also confirmed morphological effects in Adyghe reading (part-of-speech class and the number of lexical affixes) that were previously shown in some morphologically-rich languages. Importantly, we demonstrated that bilinguals' reading in Adyghe does differ quantitatively (the effect of language on reading times) and qualitatively (different effects of landing and previous/upcoming words on the eye movements within a current word) from their reading in Russian.

Universal Newborn Hearing Screening Program: 10-Year Outcome and Follow-Up from a Screening Center in Germany.

Regular reporting of quality control is important in newborn hearing screening, ensuring early diagnosis and intervention. This study reports on a population-based newborn hearing screening program in North-Rhine, Germany and a hospital-based screening at a University Hospital for 2007-2016. The two-staged 'screening' and 'follow-up' program involving TEOAE and AABR recruited newborns through participating birth facilities. Results were sent to the regional tracking center, and the data were analyzed based on recommended benchmarks. The percentage of newborns from the participating birth facilities in the region increased from 1.4% in 2007 to 57.5% in 2016. The 10-year coverage rate for these newborns was 98.7%, the referral rate after a failed two-step screening was 3.4%, and the lost-to-follow-up rate was 1%. At the hospital, >95% of the screened newborns completed screening within 30 days, the 10-year referral rate was 5%, and 64% were referred within 3 months of age. The median time for screening completion was 6 days after birth, for referral it was 74 days after birth, and for diagnosis it was 55 days after birth. Regional-centralized tracking centers with uniform structure are necessary for proper quality control. Obligatory participation of birthing facilities and quality reports may improve performance, but the recommended quality criteria need considerable financial and infrastructural expenditure.

Acceptance criteria for new approach methods in toxicology and human health-relevant life science research - part I.

Every test procedure, scientific and non-scientific, has inherent uncertainties, even when performed according to a standard operating procedure (SOP). In addition, it is prone to errors, defects, and mistakes introduced by operators, laboratory equipment, or materials used. Adherence to an SOP and comprehensive validation of the test method cannot guarantee that each test run produces data within the acceptable range of variability and with the precision and accuracy determined during the method validation. We illustrate here (part I) why controlling the validity of each test run is an important element of experimental design. The definition and application of acceptance criteria (AC) for the validity of test runs is important for the setup and use of test methods, particularly for the use of new approach methods (NAM) in toxicity testing. AC can be used for decision rules on how to handle data, e.g., to accept the data for further use (AC fulfilled) or to reject the data (AC not fulfilled). The adherence to AC has important requirements and consequences that may seem surprising at first sight: (i) AC depend on a test method's objectives, e.g., on the types/concentrations of chemicals tested, the regulatory context, the desired throughput; (ii) AC are applied and documented at each test run, while validation of a method (including the definition of AC) is only performed once; (iii) if AC are altered, then the set of data produced by a method can change. AC, if missing, are the blind spot of quality assurance: Test results may not be reliable and comparable. The establishment and uses of AC will be further detailed in part II of this series.

Expanding the utility of robotics for pancreaticoduodenectomy: a 10-year review and comparison to international benchmarks in pancreatic surgery.

BACKGROUND: Robotic pancreaticoduodenectomy (RPD) is an emerging alternative to open pancreaticoduodenectomy (OPD). Although RPD offers various theoretical advantages, it is used in less than 10% of all pancreaticoduodenectomies. The aim of this study was to report our 10-year experience and compare RPD outcomes with international benchmarks for OPD. METHODS: A retrospective review of a prospectively maintained institutional database was performed of consecutive patients who underwent RPD between January 2011 and December 2021. Patients were categorized into low-risk and high-risk groups according to the selection criteria set by the benchmark study. Their outcomes were compared to the international benchmark cut off values. Outcomes were then evaluated over time to identify improvements in practice and establish a learning curve. RESULTS: Of 201 RPDs, 36 were low-risk and 165 high-risk patients. Compared to the OPD benchmarks, outcomes of low-risk patients were within the cutoff values. High-risk patients were outside the cutoff for blood transfusions (26% vs. ≤ 23%), overall complications (78% vs. ≤ 73%), grade I-II complications (68% vs. ≤ 62%), and readmissions (22% vs ≤ 21%). Oncologic outcomes for high-risk patients were within benchmark cutoffs. Cases at the end of the learning curve included more pancreatic cancer (42% from 17%) and fewer low-risk patients (10% from 24%) than those at the beginning. After 41 RPD there was a decline in conversion rates and operative time. Between 95 and 143 cases operative time, transfusion rates, and LOS declined significantly. Complications did not differ over time. CONCLUSION: RPD yields results comparable to the established benchmarks in OPD in both low- and high-risk patients. Along the learning curve, RPD evolved with the inclusion of more high-risk cases while outcomes remained within benchmarks. Addition of a robotic HPB surgery fellowship did not compromise outcomes. These results suggest that RPD may be an option for high-risk patients at specialized centers.