bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure‐based design, synthesis, and evaluation of Bcl‐2/Mcl‐1 dual inhibitors
Authors: Zhu Junjie , Wang Ziqian , Guo Zongwei , Zhang Xiaodong , Song Ting , Guo Yafei , Ji Tong , Zhang Zhichao
Published: March 2020

Based on our previously reported Bcl‐2/Mcl‐1 dual inhibitor 4‐thiomorpholinyl‐2‐cyano‐3‐amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl‐2 and Mcl‐1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure–activity relationship resulted in a new derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1, with Ki values determined by fluorescence polarization assay (FPAs) improving to 0.31 μM for Bcl‐2 and 0.16 μM for Mcl‐1. Furthermore, B4 exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (–)‐gossypol on a Bcl‐2/Mcl‐1‐dependent cancer cell line and killed an Mcl‐1‐dependent cell line which is resistant to ABT‐199 treatment.
Fabrication of Current Collectors and Binder‐Free Electrodes on Separators Used in Lithium‐Ion Batteries
Authors: Delaporte Nicolas , Ossonon Diby B. , Zaghib Karim , Bélanger Daniel
Published: March 2020

We report the fabrication of a composite electrode through the deposition of electrode materials directly onto a separator to avoid the use of a metallic current collector. In addition to being an active electrode material, this method employs only graphene as both a carbon additive and a binder. A major achievement is the elimination of heavy and inactive current collector, harmful solvents, and resistive binder. The deposition of the composite film electrode was applied through the filtrated dispersion of a redox active material and graphene through a separator (Celgard), which is commonly used in battery. The electronic conductivity of LiFePO4/Celgard electrodes was ∼10 times higher than that of conventional electrodes spread onto an aluminum current collector. The electrochemical performances of LiFePO4/C (LFP) and Li4Ti5O12 (LTO) half‐cells fabricated according to this process and a conventional method were compared. A clear improvement in the electrochemical performance for electrodes fabricated using the new method was observed, particularly at high C‐rates. LiFePO4/Celgard electrodes deliver specific capacities of up to 125 mAh.g−1electrode corresponding to more than 6 times the gravimetric capacity of an LFP electrode coated on Al foil. A LiFePO4/Li4Ti5O12 full cell made using film electrodes deposited on a Celgard membrane shows stable specific capacities during the cycling at various C‐rates and delivers a specific capacity of 106 mAh.g−1electrode at a C/10 rate.
Laboratory Notes, Laboratory Experiences, and Conceptual Analysis: Understanding the Making of Ohm's First Law in Electricity
Authors: Heering Peter , Keck Julian , Rohlfs Gerhard A.
Published: March 2020

Georg Simon Ohm's work in the field of electricity led to what is now considered to be the most fundamental law of electrical circuits, Ohm's Law. Much less known is that only months earlier, Ohm had published another law—one that differed significantly from the now accepted one. The latter entailed a logarithmic relation between the length of the conductor and a parameter that Ohm called “loss of force.” This paper discusses how Ohm came up with an initial law that he felt compelled to correct a few months later. We analyze Ohm's publication as well as his laboratory notes, relating them to our own laboratory experiences while using the replication method to study his work. We also discuss the conceptual background of Ohm's work. We conclude that he was significantly influenced by French studies in the field of electricity, most notably the ones by Charles Augustin Coulomb.
Commensal Rats and Humans: Integrating Rodent Phylogeography and Zooarchaeology to Highlight Connections between Human Societies
Authors: Puckett Emily E. , Orton David , Munshi‐South Jason
Published: March 2020

Phylogeography and zooarchaeology are largely separate disciplines, yet each interrogates relationships between humans and commensal species. Knowledge gained about human history from studies of four commensal rats (Rattus rattus, R. tanezumi, R. exulans, and R. norvegicus) is outlined, and open questions about their spread alongside humans are identified. Limitations of phylogeographic and zooarchaeological studies are highlighted, then how integration would increase understanding of species’ demographic histories and resultant inferences about human societies is discussed. How rat expansions have informed the understanding of human migration, urban settlements, trade networks, and intra‐ and interspecific competition is reviewed. Since each rat species is associated with different human societies, they identify unique ecological and historical/cultural conditions that influenced their expansion. Finally, priority research areas including nuclear genome based phylogeographies are identified using archaeological evidence to understand R. norvegicus expansion across China, multi‐wave colonization of R. rattus across Europe, and competition between R. rattus and R. norvegicus.
Circular Nucleic Acids: Discovery, Functions and Applications
Authors: Li Jiuxing , Mohammed‐Elsabagh Mostafa , Paczkowski Freeman , Li Yingfu
Published: March 2020

Circular nucleic acids (CNAs) are nucleic acid molecules with a closed‐loop structure. This feature comes with a number of advantages including complete resistance to exonuclease degradation, much better thermodynamic stability, and the capability of being replicated by a DNA polymerase in a rolling circle manner. Circular functional nucleic acids, CNAs containing at least a ribozyme/DNAzyme or a DNA/RNA aptamer, not only inherit the advantages of CNAs but also offer some unique application opportunities, such as the design of topology‐controlled or enabled molecular devices. This article will begin by summarizing the discovery, biogenesis, and applications of naturally occurring CNAs, followed by discussing the methods for constructing artificial CNAs. The exploitation of circular functional nucleic acids for applications in nanodevice engineering, biosensing, and drug delivery will be reviewed next. Finally, the efforts to couple functional nucleic acids with rolling circle amplification for ultra‐sensitive biosensing and for synthesizing multivalent molecular scaffolds for unique applications in biosensing and drug delivery will be recapitulated.
Probing the Brønsted Acidity of the External Surface of Faujasite‐Type Zeolites
Authors: Lakiss Louwanda , Vicente Aurélie , Gilson Jean‐Pierre , Valtchev Valentin , Mintova Svetlana , Vimont Alexandre , Bedard Robert , Abdo Suheil , Bricker Jeffery
Published: March 2020

We outline two methodologies to selectively characterize the Brønsted acidity of the external surface of FAU‐type zeolites by IR and NMR spectroscopy of adsorbed basic probe molecules. The challenge and goal are to develop reliable and quantitative IR and NMR methodologies to investigate the accessibility of acidic sites in the large pore FAU‐type zeolite Y and its mesoporous derivatives often referred to as ultra‐stable Y (USY). The accessibility of their Brønsted acid sites to probe molecules (n‐alkylamines, n‐alkylpyridines, n‐alkylphosphine‐ and phenylphosphine‐oxides) of different molecular sizes is quantitatively monitored either by IR or 31P NMR spectroscopy. It is now possible, for the first time to quantitatively discriminate between the Brønsted acidity located in the microporosity and on the external surface of large pore zeolites. For instance, the number of external acid sites on a Y (LZY‐64) zeolite represents 2 % of its total acid sites while that of a USY (CBV760) represents 4 % while the latter has a much lower framework Si/Al ratio.
Clinical Interpretation of Sequence Variants
Authors: Zhang Junyu , Yao Yanyi , He Haixian , Shen Jun
Published: March 2020

Clinical interpretation of DNA sequence variants is a critical step in reporting clinical genetic testing results. Application of next‐generation sequencing technology in molecular genetic testing has facilitated diagnoses of genetic disorders in clinical practice. However, the large number of DNA sequence variants detected in clinical specimens, many of which have never been seen before, make clinical interpretation challenging. Recommendations by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) have been widely adopted by clinical laboratories around the world to guide clinical interpretation of sequence variants. The ClinGen Sequence Variant Interpretation Working Group and various disease‐specific variant curation expert panels have also developed specifications for the ACMG/AMP recommendations. Despite these efforts to standardize variant interpretation in clinical practice, different laboratories may subjectively use professional judgment to determine which criteria are applicable when classifying a variant. In addition, clinicians and researchers who are not familiar with the variant interpretation process may have difficulty understanding clinical genetic reports and communicating the clinical significance of genetic testing results. Here we provide a step‐by‐step protocol for clinical interpretation of sequence variants, including practical examples. By following this protocol, clinical laboratory geneticists can interpret the clinical significance of sequence variants according to the ACMG/AMP recommendations and ClinGen framework. Furthermore, this article will help clinicians and researchers to understand variant classification in clinical genetic testing reports and evaluate the quality of the reports. © 2020 by John Wiley & Sons, Inc.

Basic Protocol: Interpreting the clinical significance of sequence variants

Support Protocol: Reevaluating the clinical significance of sequence variants
Ex Vivo Imaging of Mitochondrial Dynamics and Trafficking in Astrocytes
Authors: Farnan Julia K. , Green Kayla K. , Jackson Joshua G.
Published: March 2020

Mitochondria are essential organelles involved in energy supply and calcium homeostasis. The regulated distribution of mitochondria in polarized cells, particularly neurons, is thought to be essential to these roles. Altered mitochondrial function and impairment of mitochondrial distribution and dynamics is implicated in a number of neurologic disorders. Several recent reports have described mechanisms regulating the activity‐dependent distribution of mitochondria within astrocyte processes and the functional consequences of altered mitochondrial transport. Here we provide an ex vivo method for monitoring the transport of mitochondria within the processes of astrocytes using organotypic “slice” cultures. These methods can be easily adapted to investigate a wide range of mitochondrial behaviors, including fission and fusion dynamics, mitophagy, and calcium signaling in astrocytes and other cell types of the central nervous system. © 2020 by John Wiley & Sons, Inc.

Basic Protocol 1: Preparation of brain slices

Basic Protocol 2: Preparation of gene gun bullets

Basic Protocol 3: Gene gun transfection of slices

Basic Protocol 4: Visualization and tracking of mitochondrial movement

Alternate Protocol: Transduction of EGFP‐mito via viral injection of the neonatal mouse brain
Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets
Authors: Lu Jingli , Liu Jiyun , Li Lulu , Lan Yan , Liang Yan
Published: March 2020

Cytokines play crucial roles in orchestrating complex multicellular interactions between pancreatic β cells and immune cells in the development of type 1 diabetes (T1D) and are thus potential immunotherapeutic targets for this disorder. Cytokines that can induce regulatory functions—for example, IL‐10, TGF‐β and IL‐33—are thought to restore immune tolerance and prevent β‐cell damage. By contrast, cytokines such as IL‐6, IL‐17, IL‐21 and TNF, which promote the differentiation and function of diabetogenic immune cells, are thought to lead to T1D onset and progression. However, targeting these dysregulated cytokine networks does not always result in consistent effects because anti‐inflammatory or proinflammatory functions of cytokines, responsible for β‐cell destruction, are context dependent. In this review, we summarise the current knowledge on the involvement of well‐known cytokines in both the initiation and destruction phases of T1D and discuss advances in recently discovered roles of cytokines. Additionally, we emphasise the complexity and implications of cytokine modulation therapy and discuss the ways in which this strategy has been translated into clinical trials.
Synthesis of novel N‐substitutedphenyl‐6‐oxo‐3‐phenylpyridazine derivatives as cyclooxygenase‐2 inhibitors
Authors: Khan Abida , Diwan Anupama , Thabet Hamdy K , Imran Mohd
Published: March 2020

Some novel non‐ulcerogenic N‐substitutedphenyl‐6‐oxo‐3‐phenylpyridazines as COX‐2 inhibitors have been developed (Supplementary material Appendix 1). The novel aldehyde 3 was prepared by reacting 6‐phenylpyridazin‐3(2H)‐one with 4‐fluorobenzaldehyde. The aldehyde 3 was reacted with different hydrazines and thiazolidin‐4‐ones to obtain the novel N‐substitutedphenyl‐6‐oxo‐3‐phenylpyridazine derivatives. These were assessed for their anti‐inflammatory potential and gastric ulcerogenic effects. The molecular docking investigations were also undertaken. The spectroscopic data were coherent with the allocated structures of the compounds. The compounds 4a (IC50 = 17.45 nm; p < .05), 4b (IC50 = 17.40 nm; p < .05), 5a (IC50 = 16.76 nm; p < .05), and 10 (IC50 = 17.15 nm; p < .05) displayed better COX‐2 inhibitory activity than celecoxib (IC50 = 17.79 nm; p < .05). These findings were consistent with the molecular docking investigations of 4a, 4b, 5a, and 10. The in vivo anti‐inflammatory profile of 4a, 4b, 5a, and 10 was also superior to celecoxib and indomethacin. The compounds 4b, 5a, and 10 revealed no gastric ulcerogenic effects, wherein the compound 4a produced almost negligible gastric ulcerogenic effects than celecoxib and indomethacin. The compounds 4a, 4b, 5a, and 10 have been postulated as promising non‐ulcerogenic COX‐2 inhibitors.
Genetic determinants of circulating VEGF levels in major depressive disorder and electroconvulsive therapy response
Authors: Maffioletti Elisabetta , Gennarelli Massimo , Magri Chiara , Bocchio‐Chiavetto Luisella , Bortolomasi Marco , Bonvicini Cristian , Abate Maria , Trabucchi Luigi , Ulivi Sheila , Minelli Alessandra
Published: March 2020

Alterations in peripheral vascular endothelial growth factor (VEGF) levels were observed in major depressive disorder and relative treatments and were shown to be influenced by genetic variants. The study objective was to explore, at a genome‐wide level, possible interplaying effects between the genetic background and major depressive disorder in regulating VEGF levels. Moreover, we aimed to investigate the association between these variants and response to electroconvulsive therapy. A genome‐wide association study was carried out both on controls and patients with major depressive disorder (n = 145; n = 121) in correlation with serum VEGF levels determined by ELISA. Five SNPs not included in SNP arrays were additionally genotyped. Seventy‐one patients with treatment‐resistant depression underwent electroconvulsive therapy and were evaluated as responders/nonresponders. An association between VEGF levels and a locus in 6p21.1, downstream the VEGF gene, was evidenced both in controls (best SNP: FDR‐corrected p = 2.4 × 10−5) and in patients with major depressive disorder (best SNP: FDR‐corrected p = 2.6 × 10–3). The alleles associated with lower VEGF concentrations in patients were also associated with nonresponse to electroconvulsive therapy (p = .01). These results confirm a role of SNPs in 6p21.1 locus as major influencers of circulating VEGF levels also in patients affected by major depressive disorder and indicate a possible implication in response to electroconvulsive therapy.
Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update)
Authors: Bus Sicco A. , Lavery Lawrence A. , Monteiro‐Soares Matilde , Rasmussen Anne , Raspovic Anita , Sacco Isabel C.N. , van Netten Jaap J. ,   on behalf of the International Working Group on the Diabetic Foot
Published: March 2020

The International Working Group on the Diabetic Foot (IWGDF) has published evidence‐based guidelines on the prevention and management of diabetic foot disease since 1999. This guideline is on the prevention of foot ulceration in persons with diabetes and updates the 2015 IWGDF prevention guideline. We followed the GRADE methodology to devise clinical questions and critically important outcomes in the PICO format, to conduct a systematic review of the medical‐scientific literature, and to write recommendations and their rationale. The recommendations are based on the quality of evidence found in the systematic review, expert opinion where evidence was not available, and a weighing of the benefits and harms, patient preferences, feasibility and applicability, and costs related to the intervention. We recommend to screen a person at very low risk for ulceration annually for loss of protective sensation and peripheral artery disease and persons at higher risk at higher frequencies for additional risk factors. For preventing a foot ulcer, educate the at‐risk patient about appropriate foot self‐care and treat any pre‐ulcerative sign on the foot. Instruct moderate‐to‐high risk patients to wear accommodative properly fitting therapeutic footwear, and consider instructing them to monitor foot skin temperature. Prescribe therapeutic footwear that has a demonstrated plantar pressure relieving effect during walking to prevent plantar foot ulcer recurrence. In patients that fail non‐surgical treatment for an active or imminent ulcer, consider surgical intervention; we suggest not to use a nerve decompression procedure. Provide integrated foot care for high‐risk patients to prevent ulcer recurrence. Following these recommendations will help health care professionals to provide better care for persons with diabetes at risk of foot ulceration, to increase the number of ulcer‐free days, and to reduce the patient and health care burden of diabetic foot disease.
Guidelines on the classification of diabetic foot ulcers (IWGDF 2019)
Authors: Monteiro‐Soares Matilde , Russell David , Boyko Edward J. , Jeffcoate William , Mills Joseph L. , Morbach Stephan , Game Fran ,   on behalf of the International Working Group on the Diabetic Foot (IWGDF)
Published: March 2020

The International Working Group on the Diabetic Foot (IWGDF) has been publishing evidence‐based guidelines on the prevention and management of diabetic foot disease since 1999. This publication represents a new guideline addressing the use of classifications of diabetic foot ulcers in routine clinical practice and reviews those which have been published. We only consider systems of classification used for active diabetic foot ulcers and do not include those that might be used to define risk of future ulceration.

The guidelines are based on a review of the available literature and on expert opinion leading to the identification of eight key factors judged to contribute most to clinical outcomes. Classifications are graded on the number of key factors included as well as on internal and external validation and the use for which a classification is intended.

Key factors judged to contribute to the scoring of classifications are of three types: patient related (end‐stage renal failure), limb‐related (peripheral artery disease and loss of protective sensation), and ulcer‐related (area, depth, site, single, or multiple and infection). Particular systems considered for each of the following five clinical situations: (a) communication among health professionals, (b) predicting the outcome of an individual ulcer, (c) as an aid to clinical decision‐making for an individual case, (d) assessment of a wound, with/without infection, and peripheral artery disease (assessment of perfusion and potential benefit from revascularisation), and (d) audit of outcome in local, regional, or national populations.

We recommend: (a) for communication among health professionals the use of the SINBAD system (that includes Site, Ischaemia, Neuropathy, Bacterial Infection and Depth); (b) no existing classification for predicting outcome of an individual ulcer; (c) the Infectious Diseases Society of America/IWGDF (IDSA/IWGDF) classification for assessment of infection; (d) the WIfI (Wound, Ischemia, and foot Infection) system for the assessment of perfusion and the likely benefit of revascularisation; and (e) the SINBAD classification for the audit of outcome of populations.
Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2019 update)
Authors: Bus Sicco A. , Armstrong David G. , Gooday Catherine , Jarl Gustav , Caravaggi Carlo , Viswanathan Vijay , Lazzarini Peter A. ,   on behalf of the International Working Group on the Diabetic Foot (IWGDF)
Published: March 2020

The International Working Group on the Diabetic Foot (IWGDF) has published evidence‐based guidelines on the prevention and management of diabetic foot disease since 1999. This guideline is on the use of offloading interventions to promote the healing of foot ulcers in people with diabetes and updates the previous IWGDF guideline.

We followed the GRADE methodology to devise clinical questions and critically important outcomes in the PICO format, to conduct a systematic review of the medical‐scientific literature, and to write recommendations and their rationale. The recommendations are based on the quality of evidence found in the systematic review, expert opinion where evidence was not available, and a weighing of the benefits and harms, patient preferences, feasibility and applicability, and costs related to the intervention.

For healing a neuropathic plantar forefoot or midfoot ulcer in a person with diabetes, we recommend that a nonremovable knee‐high offloading device is the first choice of offloading treatment. A removable knee‐high and removable ankle‐high offloading device are to be considered as the second‐ and third‐choice offloading treatment, respectively, if contraindications or patient intolerance to nonremovable offloading exist. Appropriately, fitting footwear combined with felted foam can be considered as the fourth‐choice offloading treatment. If non‐surgical offloading fails, we recommend to consider surgical offloading interventions for healing metatarsal head and digital ulcers. We have added new recommendations for the use of offloading treatment for healing ulcers that are complicated with infection or ischaemia and for healing plantar heel ulcers.

Offloading is arguably the most important of multiple interventions needed to heal a neuropathic plantar foot ulcer in a person with diabetes. Following these recommendations will help health care professionals and teams provide better care for diabetic patients who have a foot ulcer and are at risk for infection, hospitalization, and amputation.
Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: A systematic review
Authors: Forsythe Rachael O. , Apelqvist Jan , Boyko Edward J. , Fitridge Robert , Hong Joon Pio , Katsanos Konstantinos , Mills Joseph L. , Nikol Sigrid , Reekers Jim , Venermo Maarit , Zierler R. Eugene , Schaper Nicolaas C. , Hinchliffe Robert J.
Published: March 2020

The accurate identification of peripheral artery disease (PAD) in patients with diabetes and foot ulceration is important, in order to inform timely management and to plan intervention including revascularisation. A variety of non‐invasive tests are available to diagnose PAD at the bedside, but there is no consensus as to the most useful test, or the accuracy of these bedside investigations when compared to reference imaging tests such as magnetic resonance angiography, computed tomography angiography, digital subtraction angiography or colour duplex ultrasound. Members of the International Working Group of the Diabetic Foot updated our previous systematic review, to include all eligible studies published between 1980 and 2018. Some 15 380 titles were screened, resulting in 15 eligible studies (comprising 1563 patients, of which >80% in each study had diabetes) that evaluated an index bedside test for PAD against a reference imaging test. The primary endpoints were positive likelihood ratio (PLR) and negative likelihood ratio (NLR). We found that the most commonly evaluated test parameter was ankle brachial index (ABI) <0.9, which may be useful to suggest the presence of PAD (PLR 6.5) but an ABI value between 0.9 and 1.3 does not rule out PAD (NLR 0.31). A toe brachial index >0.75 makes the diagnosis of PAD less likely (NLR 0.14‐0.24), whereas pulse oximetry may be used to suggest the presence of PAD (if toe saturation < 2% lower than finger saturation; PLR 17.23‐30) or render PAD less likely (NLR 0.2‐0.27). We found that the presence of triphasic tibial waveforms has the best performance value for excluding a diagnosis of PAD (NLR 0.09‐0.28), but was evaluated in only two studies. In addition, we found that beside clinical examination (including palpation of foot pulses) cannot reliably exclude PAD (NLR 0.75), as evaluated in one study. Overall, the quality of data is generally poor and there is insufficient evidence to recommend one bedside test over another. While there have been six additional publications in the last 4 years that met our inclusion criteria, more robust evidence is required to achieve consensus on the most useful non‐invasive bedside test to diagnose PAD.
Performance of prognostic markers in the prediction of wound healing or amputation among patients with foot ulcers in diabetes: A systematic review
Authors: Forsythe Rachael O. , Apelqvist Jan , Boyko Edward J. , Fitridge Robert , Hong Joon Pio , Katsanos Konstantinos , Mills Joseph L. , Nikol Sigrid , Reekers Jim , Venermo Maarit , Zierler R. Eugene , Schaper Nicolaas C. , Hinchliffe Robert J.
Published: March 2020

Clinical outcomes of patients with diabetes, foot ulceration, and peripheral artery disease (PAD) are difficult to predict. The prediction of important clinical outcomes, such as wound healing and major amputation, would be a valuable tool to help guide management and target interventions for limb salvage. Despite the existence of a number of classification tools, no consensus exists as to the most useful bedside tests with which to predict outcome. We here present an updated systematic review from the International Working Group of the Diabetic Foot, comprising 15 studies published between 1980 and 2018 describing almost 6800 patients with diabetes and foot ulceration. Clinical examination findings as well as six non‐invasive bedside tests were evaluated for their ability to predict wound healing and amputation. The most useful tests to inform on the probability of healing were skin perfusion pressure ≥ 40 mmHg, toe pressure ≥ 30 mmHg, or TcPO2 ≥ 25 mmHg. With these thresholds, all of these tests increased the probability of healing by greater than 25% in at least one study. To predict major amputation, the most useful tests were ankle pressure < 50 mmHg, ABI < 0.5, toe pressure < 30 mmHg, and TcPO2 < 25 mmHg, which increased the probability of major amputation by greater than 25%. These indicative values may be used as a guide when deciding which patients are at highest risk for poor outcomes and should therefore be evaluated for revascularization at an early stage. However, this should always be considered within the wider context of important co‐existing factors such as infection, wound characteristics, and other comorbidities.
Diagnosis of infection in the foot in diabetes: a systematic review
Authors: Senneville Éric , Lipsky Benjamin A. , Abbas Zulfiqarali G. , Aragón‐Sánchez Javier , Diggle Mathew , Embil John M. , Kono Shigeo , Lavery Lawrence A. , Malone Matthew , van Asten Suzanne A. , Urbančič‐Rovan Vilma , Peters Edgar J.G.
Published: March 2020

Background

Securing an early accurate diagnosis of diabetic foot infections and assessment of their severity are of paramount importance since these infections can cause great morbidity and potentially mortality and present formidable challenges in surgical and antimicrobial treatment.

Methods

In June 2018, we searched the literature using PuEbMed and EMBASE for published studies on the diagnosis of diabetic foot infection. On the basis of predetermined criteria, we reviewed prospective controlled, as well as noncontrolled, studies in any language, seeking translations for those not in English. We then developed evidence statements on the basis of the included papers.

Results

From the 4242 records screened, we selected 35 papers that met our inclusion criteria. The quality of all but one of the evidence statements was low because of the weak methodology of nearly all of the studies. The available data suggest that diagnosing diabetic foot infections on the basis of clinical signs and symptoms and classified according to the International Working Group of the Diabetic Foot scheme correlates with the patient's likelihood of ulcer healing, of lower extremity amputation, and risk of death. Elevated levels of selected serum inflammatory markers are supportive, but not diagnostic, of soft tissue or bone infection. In patients with suspected diabetic foot osteomyelitis, both a positive probe‐to‐bone test and an elevated erythrocyte sedimentation rate are strongly associated with its presence. Culturing tissue samples of soft tissues or bone, when care is taken to avoid contamination, provides more accurate microbiological information than culturing superficial (swab) samples. Plain X‐ray remains the first‐line imaging examination when there is suspicion of diabetic foot osteomyelitis, but advanced imaging methods help in cases when either the diagnosis or the localization of infection is uncertain.

Conclusion

The results of this first reported systematic review on the diagnosis of diabetic foot infections provide some guidance for clinicians, but there is a need for more prospective controlled studies of high quality.
Interventions in the management of infection in the foot in diabetes: a systematic review
Authors: Peters Edgar J. G. , Lipsky Benjamin A. , Senneville Éric , Abbas Zulfiqarali G. , Aragón‐Sánchez Javier , Diggle Mathew , Embil John M. , Kono Shigeo , Lavery Lawrence A. , Malone Matthew , Urbančič‐Rovan Vilma , Van Asten Suzanne A.
Published: March 2020

The optimal approaches to managing diabetic foot infections remain a challenge for clinicians. Despite an exponential rise in publications investigating different treatment strategies, the various agents studied generally produce comparable results, and high‐quality data are scarce. In this systematic review, we searched the medical literature using the PubMed and Embase databases for published studies on the treatment of diabetic foot infections as of June 2018. This systematic review is an update of previous reviews, the first of which was undertaken in 2010 and the most recent in 2014, by the infection committee of the International Working Group of the Diabetic Foot. We defined the context of literature by formulating clinical questions of interest, then developing structured clinical questions (PICOs) to address these. We only included data from controlled studies of an intervention to prevent or cure a diabetic foot infection. Two independent reviewers selected articles for inclusion and then assessed their relevant outcomes and the methodological quality. Our literature search identified a total of 15 327 articles, of which we selected 48 for full‐text review; we added five more studies discovered by means other than the systematic literature search. Among these selected articles were 11 high‐quality studies published in the last 4 years and two Cochrane systematic reviews. Overall, the outcomes in patients treated with the different antibiotic regimens for both skin and soft tissue infection and osteomyelitis of the diabetic foot were broadly equivalent across studies, except that treatment with tigecycline was inferior to ertapenem (±vancomycin). Similar outcomes were also reported in studies comparing primarily surgical and predominantly antibiotic treatment strategies in selected patients with diabetic foot osteomyelitis. There is insufficient high‐quality evidence to assess the effect of various adjunctive therapies, such as negative pressure wound therapy, topical ointments or hyperbaric oxygen, on infection related outcomes of the diabetic foot. In general, the quality of more recent trial designs are better in past years, but there is still a great need for further well‐designed trials to produce higher quality evidence to underpin our recommendations.
Allocating resources for land protection using continuous optimization: biodiversity conservation in the United States
Authors: Armsworth Paul R. , Benefield Amy E. , Dilkina Bistra , Fovargue Rachel , Jackson Heather B. , Le Bouille Diane , Nolte Christoph
Published: March 2020

Spatial optimization approaches that were originally developed to help conservation organizations determine protection decisions over small spatial scales are now used to inform global or continental scale priority setting. However, the different decision contexts involved in large‐scale resource allocation need to be considered. We present a continuous optimization approach in which a decision‐maker allocates funding to regional offices. Local decision‐makers then use these funds to implement habitat protection efforts with varying effectiveness when evaluated in terms of the funder's goals. We illustrate this continuous formulation by examining the relative priority that should be given to different counties in the coterminous United States when acquiring land to establish new protected areas. If weighting all species equally, counties in the southwest United States, where large areas can be bought cheaply, are priorities for protection. If focusing only on species of conservation concern, priorities shift to locations rich in such species, particularly near expanding exurban areas facing high rates of future habitat conversion (e.g., south‐central Texas). Priorities for protection are sensitive to what is assumed about local ecological and decision‐making processes. For example, decision‐makers who doubt the efficacy of local land protection efforts should focus on a few key areas, while optimistic decision‐makers should disperse funding more widely. Efforts to inform large‐scale conservation priorities should reflect better the types of choice that decision‐makers actually face when working over these scales. They also need to report the sensitivity of recommended priorities to what are often unstated assumptions about local processes affecting conservation outcomes.
Nanosized cation exchanger for the electrophoretic separation and preconcentration of catecholamines and amino acids
Authors: Polikarpova Daria , Makeeva Daria , Kolotilina Nadezhda , Dolgonosov Anatoly , Peshkova Maria , Kartsova Liudmila
Published: March 2020

The first example of application of nanosized polystyrene‐based cation exchanger (NSCE) with sulfo groups as a dynamic coating of capillary walls was demonstrated. The conditions of dynamic coating formation were optimized and ensured the long‐term stability of the coating. Capillary‐to‐capillary and day‐to‐day repeatabilities were 4% and 3%, correspondingly. The NSCE coating stability at various pH and influence of pH on the EOF mobility were investigated. The developed NSCE‐modified coated capillaries provided improved resolution (Rs = 0.9–3.2 for catecholamines and Rs = 1.7–2.8 for amino acids) and efficiencies (330–520 ×103 t.p./m) of basic analytes, which are 1.5 times higher compared to untreated capillary. The optimized conditions were as follows: 50 mM phosphate buffer solution at pH 2.2 with 5 μM NSCE. The effect of the NSCE concentration in BGE on the electrophoretic mobilities of the analytes was investigated. The various online concentration techniques were tested in order to decrease the LODs. The simultaneous application of NSCE capillaries and field‐amplified sample stacking provided the lowest LODs of catecholamines and amino acids and allowed to determine these analytes in human urine.
The uniqueness of flow in probing the aggregation behavior of clinically relevant antibodies
Authors: Willis Leon F. , Kumar Amit , Jain Tushar , Caffry Isabelle , Xu Yingda , Radford Sheena E. , Kapur Nikil , Vásquez Maximiliano , Brockwell David J.
Published: March 2020

The development of therapeutic monoclonal antibodies (mAbs) can be hindered by their tendency to aggregate throughout their lifetime, which can illicit immunogenic responses and render mAb manufacturing unfeasible. Consequently, there is a need to identify mAbs with desirable thermodynamic stability, solubility, and lack of self‐association. These behaviors are assessed using an array of in silico and in vitro assays, as no single assay can predict aggregation and developability. We have developed an extensional and shear flow device (EFD), which subjects proteins to defined hydrodynamic forces which mimic those experienced in bioprocessing. Here, we utilize the EFD to explore the aggregation propensity of 33 IgG1 mAbs, whose variable domains are derived from clinical antibodies. Using submilligram quantities of material per replicate, wide‐ranging EFD‐induced aggregation (9‐81% protein in pellet) was observed for these mAbs, highlighting the EFD as a sensitive method to assess aggregation propensity. By comparing the EFD‐induced aggregation data to those obtained previously from 12 other biophysical assays, we show that the EFD provides distinct information compared with current measures of adverse biophysical behavior. Assessing a candidate's liability to hydrodynamic force thus adds novel insight into the rational selection of developable mAbs that complements other assays.
Impact of model free parameters and sea‐level rise uncertainties on 20‐years shoreline hindcast: the case of Truc Vert beach (SW France)
Authors: D'Anna Maurizio , Idier Déborah , Castelle Bruno , Le Cozannet Gonéri , Rohmer Jeremy , Robinet Arthur
Published: March 2020

Shoreline change is driven by various complex processes interacting at a large range of temporal and spatial scales, making shoreline reconstructions and predictions challenging and uncertain. Despite recent progress in addressing uncertainties related to the physics of sea‐level rise, very little effort is made towards understanding and reducing the uncertainties related to wave‐driven shoreline response. To fill this gap, the uncertainties associated with the long‐term modelling of shoreline change are analysed at a high‐energy cross‐shore transport dominated site. Using the state‐of‐the‐art LX‐Shore shoreline change model, we produce a probabilistic shoreline reconstruction, based on 3000 simulations over the past 20 years at Truc Vert beach, southwest France, whereby sea‐level rise rate, depth of closure and three model free parameters are considered uncertain variables. We further address the relative impact of each source of uncertainty on the model results performing a Global Sensitivity Analysis. This analysis shows that the shoreline changes are mainly sensitive to the three parameters of the wave‐driven model, but also that the sensitivity to each of these parameters is strongly modulated seasonally and interannually, in relation with wave energy variability, and depends on the time scale of interest. These results have strong implications on the model skill sensitivity to the calibration period as well as for the predictive skill of the model in a context of future climate change affecting wave climate and extremes. © 2020 John Wiley & Sons, Ltd.
Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis
Authors: Ueno Kazuko , Aiba Yoshihiro , Hitomi Yuki , Shimoda Shinji , Nakamura Hitomi , Gervais Olivier , Kawai Yosuke , Kawashima Minae , Nishida Nao , Kohn Seik‐Soon , Kojima Kaname , Katsushima Shinji , Naganuma Atsushi , Sugi Kazuhiro , Komatsu Tatsuji , Mannami Tomohiko , Matsushita Kouki , Yoshizawa Kaname , Makita Fujio , Nikami Toshiki , Nishimura Hideo , Kouno Hiroshi , Kouno Hirotaka , Ohta Hajime , Komura Takuya , Tsuruta Satoru , Yamauchi Kazuhiko , Kobata Tatsuro , Kitasato Amane , Kuroki Tamotsu , Abiru Seigo , Nagaoka Shinya , Komori Atsumasa , Yatsuhashi Hiroshi , Migita Kiyoshi , Ohira Hiromasa , Tanaka Atsushi , Takikawa Hajime , Nagasaki Masao , Tokunaga Katsushi , Nakamura Minoru ,   PBC‐GWAS Consortium in Japan
Published: March 2020

Genome‐wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease‐susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single‐nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type–specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune‐related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon‐gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer–like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type–specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets.
Methods for Postdisaster Impact Assessment: A Case Study of the Impacts of the Fundão Dam Failure on Terrestrial Species Threatened with Extinction
Authors: Knopff Kyle , Bede Lucio Cadaval , Arruda Leandro , Alves Thiago , Simons Brock
Published: March 2020

The Fundão tailings dam held back approximately 50 million cubic meters of tailings from an Fe ore mine in the state of Minas Gerais, Brazil. The dam failed on 5 November 2015, releasing tailings into the Rio Doce watershed and causing an environmental disaster in a biodiversity hotspot. To guide conservation action following the event, Brazilian authorities demanded an impact assessment focused on terrestrial species threatened by extinction. Postdisaster impact assessment is substantially more challenging than predevelopment impact assessment. Predisaster baseline data were sparse, and much was unknown about how the Fundão dam failure impacted terrestrial species threatened with extinction. Baseline reconstruction and impact pathway validation and characterization was critical. Ecosystem reconstruction revealed that 1580 ha of terrestrial ecosystems were destroyed, including approximately 480 ha of Atlantic rainforest. Collaboration with local experts identified 346 species of vertebrates, invertebrates, and vascular plants threatened with extinction that were impacted or potentially impacted. Species composition and impacts varied within 4 distinct segments of the Rio Doce watershed. Nine potential impact pathways were identified using data and literature review combined with information provided by regulators, experts, and media. Not all were valid. Validating and characterizing each pathway within each watershed segment involved data evaluation, an ecological risk screening, and field assessments. Impact pathway evaluation proved critical to dispelling misconception, accurately understanding postdisaster impacts, and directing conservation action; the importance of this step cannot be overemphasized. Integr Environ Assess Manag 2020;16:676–680. © 2020 SETAC
Composite nanocellulose‐based hydrogels with spatially oriented degradation and retarded release of macromolecules
Authors: Maestri Cecilia Ada , Motta Antonella , Moschini Lorenzo , Bernkop‐Schnürch Andreas , Baus Randi Angela , Lecca Paola , Scarpa Marina
Published: March 2020

The oral delivery of macromolecular therapeutics to the intestinal tract requires novel, robust, and controlled formulations. Here, we report on fabrication by molding of composite hydrogel cylinders made of cellulose nanocrystals (CNCs) and chitosan (Cht) and their performance as delivery vehicles. CNCs provide excellent mechanical and chemical stress resistance, whereas Cht allows scaffold degradation by enzyme digestion. The release of a representative medium size protein (bovine serum albumin) dispersed in the hydrogel is slow and shows a sigmoidal profile; meanwhile, the hydrogel scaffold degrades according to a preferred route, that is the cylinder is eroded along the vertical axis. The cup‐like, scarcely interconnected porous network, with a gradient of hardness along the cylinder axis, and the compact skin‐like layer covering the lateral wall which stayed in contact with the mold during gelification, explain the preferred erosion direction and the long‐term protein release. The possible effect of the molding process on hydrogel structure suggests that molding could be a simple and cheap way to favor surface compaction and directional scaffold degradation.
Stability, electronic, and optical properties of two‐dimensional phosphoborane
Authors: Steglenko Dmitriy V. , Tkachenko Nikolay V. , Boldyrev Alexander I. , Minyaev Ruslan M. , Minkin Vladimir I.
Published: March 2020

The structure and properties of two‐dimensional phosphoborane sheets were computationally investigated using Density Functional Theory calculations. The calculated phonon spectrum and band structure point to dynamic stability and allowed characterization of the predicted two‐dimensional material as a direct‐gap semiconductor with a band gap of ~1.5 eV. The calculation of the optical properties showed that the two‐dimensional material has a relatively small absorptivity coefficient. The parameters of the mechanical properties characterize the two‐dimensional phosphoborane as a relatively soft material, similar to the monolayer of MoS2. Assessment of thermal stability by the method of molecular dynamics indicates sufficient stability of the predicted material, which makes it possible to observe it experimentally.