bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Interpretation of Sequence Variants
Authors: Zhang Junyu , Yao Yanyi , He Haixian , Shen Jun 
Published: March 2020

AbstractClinical 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 variantsSupport 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

AbstractMitochondria 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 slicesBasic Protocol 2: Preparation of gene gun bulletsBasic Protocol 3: Gene gun transfection of slicesBasic Protocol 4: Visualization and tracking of mitochondrial movementAlternate 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

AbstractCytokines 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

AbstractSome 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

AbstractAlterations 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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractClinical 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

AbstractBackgroundSecuring 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.MethodsIn 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.ResultsFrom 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.ConclusionThe 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.