Rounds Of Modifications Research Articles

Achieving Consensus: Severity-Graded Definitions of Fontan-Associated Complications to Characterize Fontan Circulatory Failure

BackgroundFontan physiology leads to chronic changes in other organ systems that may affect long-term survival and the success of heart transplantation. Inadequate assessment and treatment of the extra-cardiac effects of Fontan may contribute to poor outcomes. Severity-graded/ordinal consensus definitions of Fontan complications are lacking, which limits understanding of how Fontan-specific morbidity affects patients’ outcomes. Methods and ResultsA panel of Fontan patient and physiology experts, including pediatric, adult congenital, heart failure, and critical-care cardiology as well as pediatric nephrology, hepatology and psychology, convened to develop definitions of Fontan complications. Definitions were created by using a severity-graded ordinal scale: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, disabling or life threatening. Following definition creation, a second panel of 21 experts in Fontan circulatory failure used a modified Delphi methodology to modify and vote on definitions until consensus (> 90% agreement without recommended further modification) was reached on final definitions. After 3 rounds of modifications and voting, consensus agreement was achieved on all Fontan-specific definitions. The defined complications and morbidities of Fontan include: anatomic Fontan pathway obstruction, cyanosis, systemic venous abnormalities resulting from venous insufficiency, atrial arrhythmia, ventricular arrhythmia, bradycardia, chronic pleural effusions, chronic ascites, protein-losing enteropathy, plastic bronchitis, hemoptysis and pulmonary hemorrhage, sleep apnea, Fontan-associated liver disease, portal and hepatic variceal disease, acute kidney injury affecting clinical treatment, polycythemia, thrombotic disease, recurrent or severe bacterial infection, skin atrophy, adrenal insufficiency, physical impact of previous stroke, mood/behavior disorder, and neurodevelopmental disorder. ConclusionConsensus and severity-graded definitions of Fontan-specific cardiac and extra-cardiac complications were achieved and are available for use in research. They will allow future robust analyses of Fontan patient outcomes.

QUAPAS: An Adaptation of the QUADAS-2 Tool to Assess Prognostic Accuracy Studies.

Whereas diagnostic tests help detect the cause of signs and symptoms, prognostic tests assist in evaluating the probable course of the disease and future outcome. Studies to evaluate prognostic tests are longitudinal, which introduces sources of bias different from those for diagnostic accuracy studies. At present, systematic reviews of prognostic tests often use the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool to assess risk of bias and applicability of included studies because no equivalent instrument exists for prognostic accuracy studies.QUAPAS (Quality Assessment of Prognostic Accuracy Studies) is an adaptation of QUADAS-2 for prognostic accuracy studies. Questions likely to identify bias were evaluated in parallel and collated from QUIPS (Quality in Prognosis Studies) and PROBAST (Prediction Model Risk of Bias Assessment Tool) and paired to the corresponding question (or domain) in QUADAS-2. A steering group conducted and reviewed 3 rounds of modifications before arriving at the final set of domains and signaling questions.QUAPAS follows the same steps as QUADAS-2: Specify the review question, tailor the tool, draw a flow diagram, judge risk of bias, and identify applicability concerns. Risk of bias is judged across the following 5 domains: participants, index test, outcome, flow and timing, and analysis. Signaling questions assist the final judgment for each domain. Applicability concerns are assessed for the first 4 domains.The authors used QUAPAS in parallel with QUADAS-2 and QUIPS in a systematic review of prognostic accuracy studies. QUAPAS improved the assessment of the flow and timing domain and flagged a study at risk of bias in the new analysis domain. Judgment of risk of bias in the analysis domain was challenging because of sparse reporting of statistical methods.

Seismic design of low-rise steel building frames with self-centering hybrid damping connections

This paper develops a practice-oriented seismic design procedure for an emerging lateral force resisting system. The system combines the favorable re-centering feature with the attractive hybrid damping capacity. The system overcomes the detrimental frame expansion effect that occurs in conventional self-centering building frames without the cost of building space. Following the proposed design procedure, multiple designs with different parameters to achieve performance objectives were performed for a representative three-story building in which the considered lateral force resisting system is used to resist the seismic forces. Nonlinear response history analyses were performed for the designs to evaluate the applicability and adequacy of the proposed design approach. Based on the analyses conducted in this research, it was found that the considered system designed using the proposed approach can meet both transient and residual inter-story drift requirements specified for the selected performance objectives. While an initial design per the proposed design approach may be inadequate, the re-design strategy recommended can help transform the design to an acceptable one after only one round of modification. Moreover, the composition of hybrid damping may affect the maximum floor acceleration responses. In this study, the maximum floor acceleration can be reduced 12.75% at most by replacing hysteretic damping with viscous damping. This should be included in design consideration in the proposed approach through adjusting the hybrid damping composition.

Development of a valid and reliable pterygium surgery assessment scale for ophthalmology residents

BackgroundMicrosurgery training has become an important part of ophthalmology teaching and one of the main topics of examination. Accurate and effective evaluation of microsurgery skills is vital for the training and teaching of residents. In this study, we aimed to establish a pterygium surgery assessment scale for use by ophthalmic residents and evaluate its reliability and validity.MethodsBased on a literature search, experienced pterygium surgeons developed the preliminary scale according to the standard surgical procedure. The preliminary scale and a questionnaire were sent to teaching and research experts in the field for feedback. Face and content validity and reliability of the scale were determined by rounds of modifications based on expert feedback. For construct validity, existing assessment scales were obtained and a range of factors were tested.ResultsNineteen expert surgeons completed the questionnaire and modifications were made until all surgeons agreed on the final scale. Good construct validity was found by evaluation against 257 existing scales. For reliability, 280 evaluation scales were completed. Inter- and intra-rater reliability analysis both found Intraclass Correlation Coefficient (ICC) > 0.8 for all items and total scores.ConclusionThe pterygium surgery assessment scale developed in this study has good reliability and validity, and is an effective measurement tool for the evaluation of ophthalmology residents’ pterygium surgical skills.

A Census and Categorization Method of Epitranscriptomic Marks.

In the past few years, thorough investigation of chemical modifications operated in the cells on ribonucleic acid (RNA) molecules is gaining momentum. This new field of research has been dubbed “epitranscriptomics”, in analogy to best-known epigenomics, to stress the potential of ensembles of RNA modifications to constitute a post-transcriptional regulatory layer of gene expression orchestrated by writer, reader, and eraser RNA-binding proteins (RBPs). In fact, epitranscriptomics aims at identifying and characterizing all functionally relevant changes involving both non-substitutional chemical modifications and editing events made to the transcriptome. Indeed, several types of RNA modifications that impact gene expression have been reported so far in different species of cellular RNAs, including ribosomal RNAs, transfer RNAs, small nuclear RNAs, messenger RNAs, and long non-coding RNAs. Supporting functional relevance of this largely unknown regulatory mechanism, several human diseases have been associated directly to RNA modifications or to RBPs that may play as effectors of epitranscriptomic marks. However, an exhaustive epitranscriptome’s characterization, aimed to systematically classify all RNA modifications and clarify rules, actors, and outcomes of this promising regulatory code, is currently not available, mainly hampered by lack of suitable detecting technologies. This is an unfortunate limitation that, thanks to an unprecedented pace of technological advancements especially in the sequencing technology field, is likely to be overcome soon. Here, we review the current knowledge on epitranscriptomic marks and propose a categorization method based on the reference ribonucleotide and its rounds of modifications (“stages”) until reaching the given modified form. We believe that this classification scheme can be useful to coherently organize the expanding number of discovered RNA modifications.

Development and Pilot Testing a Self-Reported Pediatric PROMIS App for Young Children Aged 5–7 Years

PurposeThe aims of this study are threefold. Firstly, Using the state of science PROMIS (Patient-Reported Outcomes Measurement Information System) methods to develop a smartphone application to monitor the emotional distress for young children aged 5–7 years old; Secondly, to test the usability of this application; and thirdly, to determine the level of agreement between reports by parents and young children's self-report. Design and methodsA multidisciplinary research team, made up of senior pediatric nurses and doctors, software engineers' team, and pediatric health researchers worked together to develop this application. Three phases of stakeholders and user studies were conducted. Phase 1 focused on prototype development; Phase 2 involved cognitive interview and usability testing; Phases 3 focused on the pilot testing of this application. ResultsWe included the original parent proxy reporting version of Patient Reported Outcome Measurement Information System-emotional distress in the application, as well as self-reporting animated version for young children. After many rounds of modification, all participants felt that this application was easy to use and the animated items were easy to understand for young children aged 5–7 years. Correlations between parents-children reports are significant and moderate, parents underestimated child depression, and overestimated child anger and anxiety compared to child self-report. ConclusionsThis smartphone application and its Web-based administration portal demonstrate good usability and are well accepted by young children aged 5–7 years, which can be used to promote young children's participation when reporting or assessing symptoms of young pediatric patients. Practice implicationsParent reports cannot be substituted for child reports and evaluations of pediatric patients' perspectives regarding treatment outcomes should be included in pediatric clinic. This animated application can be used as a smart measurement to investigate the symptoms for young children aged 5–7 years, so as to amplify young children's voice in clinical care.

Seismic design of low-rise steel building frames with self-centering panels and steel strip braces

This paper develops a practical seismic design approach for an emerging lateral force resisting system consisting of self-centering panels and steel strip braces. The system combines the favorable re-centering feature of conventional self-centering building frames and the energy absorption capacity and high initial stiffness of concentrically braced frames. The system also overcomes the detrimental frame expansion effect that occurs in conventional self-centering building frames. Following the proposed design approach, multiple designs to achieve different performance objectives were performed for a representative three-story building in which the considered lateral force resisting system is used to resist the seismic forces. Nonlinear response history analyses were performed for the designs to evaluate the applicability and adequacy of the proposed design approach. Based on the analyses conducted in this research, it was found that the considered system designed using the proposed approach can meet both transient and residual inter-story drift requirements specified for the selected performance objectives. While an initial design per the proposed design approach may be inadequate, the re-design strategy recommended can help transform the design to an acceptable one after only one round of modification. Moreover, the high-mode effect appears nonnegligible in the considered system and this effect should be considered in the proposed approach through the use of the lateral distribution factor of seismic forces specifically for self-centering systems.

Dual-Responsive Self-Assembled Monolayer for Specific Capture and On-Demand Release of Live Cells.

We report a dual-responsive self-assembled monolayer (SAM) on a well-defined rough gold substrate for dynamic capture and release of live cells. By incorporating 5'-triphosphate (ATP) aptamer into a SAM, we can accurately isolate specific cell types and subsequently release captured cells at either population or desired-group (or even single-cell) levels. On one hand, the whole SAMs can be disassembled through addition of ATP solution, leading to the entire release of the captured cells from the supported substrate. On the other hand, desired cells can be selectively released using near-infrared light irradiation, with relatively high spatial and temporal precision. The proposed dual-responsive cell capture-and-release system is biologically friendly and is reusable with another round of modification, showing great usefulness in cancer diagnosis and molecular analysis.

3-((R)-4-(((R)-6-(2-Bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic Acid (HEC72702), a Novel Hepatitis B Virus Capsid Inhibitor Based on Clinical Candidate GLS4.

The inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. On the basis of the preclinical properties and clinical results of GLS4, we carried out further investigation to seek a better candidate compound with appropriate anti-HBV potency, reduced hERG activity, decreased CYP enzyme induction, and improved pharmacokinetic (PK) properties. To this end, we have successfully found that morpholine carboxyl analogues with comparable anti-HBV activities to that of GLS4 showed decreased hERG activities, but they displayed strong CYP3A4 induction in a concentration-dependent manner, except for morpholine propionic acid analogues. After several rounds of modification, compound 58 (HEC72702), which had an (R)-morpholine-2-propionic acid at the C6 position of its dihydropyrimidine core ring, was found to display no induction of the CYP1A2, CYP3A4, or CYP2B6 enzyme at the high concentration of 10 μM. In particular, it demonstrated a good systemic exposure and high oral bioavailability and achieved a viral-load reduction greater than 2 log in a hydrodynamic-injected (HDI) HBV mouse model and has now been selected for further development.

Cross-cultural adaptation of Jefferson scale of empathy-health professions students version: An experience with developing the Tamil translation.

Empathy is a key cognitive attribute among healthcare professionals that fosters better patient- healthcare provider relationships. The Jefferson scale of empathy (JSE) measures self-rated empathy among various groups of healthcare professionals-health professionals, medical students and health professions students (HPS). The authors present the experience in translating the JSE-HPS version into an Indian regional language with insights into the issues faced in every step. With official permission from the Thomas Jefferson University, the authors embarked on the translation proceeding through forward translation (three rounds of modification), back translation (two independent translates), and synthesis of a final translated version. While targeting literary accuracy, the simplicity and comprehensibility of the instrument by the study population were also ensured. Variations in regional dialects and accents across the population were considered. The back-translated version was evaluated for semantic, content, cultural, and technical equivalence. It was then pretested on ten students followed by a group discussion with them to ensure the comprehensibility of the tool and the differences between written and spoken language were addressed through necessary modifications. The Tamil translation of the HPS version of JSE is now approved by and officially available with the Thomas Jefferson University.

IS-LM Paradigm in Macroeconomics: A Survey and Evaluation

This paper analyzes many serious defects existing in traditional aggregate demand/aggregate supply paradigm based on IS-LM model. Those defects cause the situation that IS-LM model declines gradually, but it is still not dead, and continuously revives through modification. This paper distinguishes from rounds of modification on traditional aggregate demand/aggregate supply paradigm. The first round of modification was just introducing the dynamic ad hoc IS-LM model of rational expectation which started from the end of 1970s and the beginning of 1980s. Because the micro-foundation problems are not solved and the rational expectation carries out extreme judgment on monetary neutrality and ineffectiveness of macroeconomic policy, the first modification fails to realize big success. The second round of modification is just happening; through introducing rational expectation and New Phillips Curve (NPC), the powerful improvement has been made in micro-foundation, dynamic form, and monetary policy rules, and the model is called IS-LM/ MP-NPC model. This paper also points out some limitations which are not solved in the second modification.

Pressure‐reduction and preservation in custom‐made footwear of patients with diabetes and a history of plantar ulceration

To assess the value of using in-shoe plantar pressure analysis to improve and preserve the offloading properties of custom-made footwear in patients with diabetes. Dynamic in-shoe plantar pressures were measured in new custom-made footwear of 117 patients with diabetes, neuropathy, and a healed plantar foot ulcer. In 85 of these patients, high peak pressure locations (peak pressure > 200 kPa) were targeted for pressure reduction (goal: > 25% relief or below an absolute level of 200 kPa) by modifying the footwear. After each of a maximum three rounds of modifications, pressures were measured. In a subgroup of 32 patients, pressures were measured and, if needed, footwear was modified at 3-monthly visits for 1 year. Pressures were compared with those measured in 32 control patients who had no footwear modifications based on pressure analysis. At the previous ulcer location and the highest and second highest pressure locations, peak pressures were significantly reduced by 23%, 21% and 15%, respectively, after modification of footwear. These lowered pressures were maintained or further reduced over time and were significantly lower, by 24-28%, compared with pressures in the control group. The offloading capacity of custom-made footwear for high-risk patients can be effectively improved and preserved using in-shoe plantar pressure analysis as guidance tool for footwear modification. This provides a useful approach to obtain better offloading footwear that may reduce the risk for pressure-related diabetic foot ulcers.

Evaluation and Optimization of Therapeutic Footwear for Neuropathic Diabetic Foot Patients Using In-Shoe Plantar Pressure Analysis

OBJECTIVETherapeutic footwear for diabetic foot patients aims to reduce the risk of ulceration by relieving mechanical pressure on the foot. However, footwear efficacy is generally not assessed in clinical practice. The purpose of this study was to assess the value of in-shoe plantar pressure analysis to evaluate and optimize the pressure-reducing effects of diabetic therapeutic footwear.RESEARCH DESIGN AND METHODSDynamic in-shoe plantar pressure distribution was measured in 23 neuropathic diabetic foot patients wearing fully customized footwear. Regions of interest (with peak pressure >200 kPa) were selected and targeted for pressure optimization by modifying the shoe or insole. After each of a maximum of three rounds of modifications, the effect on in-shoe plantar pressure was measured. Successful optimization was achieved with a peak pressure reduction of >25% (criterion A) or below an absolute level of 200 kPa (criterion B).RESULTSIn 35 defined regions, mean peak pressure was significantly reduced from 303 (SD 77) to 208 (46) kPa after an average 1.6 rounds of footwear modifications (P < 0.001). This result constitutes a 30.2% pressure relief (range 18–50% across regions). All regions were successfully optimized: 16 according to criterion A, 7 to criterion B, and 12 to criterion A and B. Footwear optimization lasted on average 53 min.CONCLUSIONSThese findings suggest that in-shoe plantar pressure analysis is an effective and efficient tool to evaluate and guide footwear modifications that significantly reduce pressure in the neuropathic diabetic foot. This result provides an objective approach to instantly improve footwear quality, which should reduce the risk for pressure-related plantar foot ulcers.

SUMOylation and cell signalling

SUMOylation is a highly transient post-translational protein modification. Attachment of SUMO to target proteins occurs via a number of specific activating and ligating enzymes that form the SUMO-substrate complex, and other SUMO-specific proteases that cleave the covalent bond, thus leaving both SUMO and target protein free for the next round of modification. SUMO modification has major effects on numerous aspects of substrate function, including subcellular localisation, regulation of their target genes, and interactions with other molecules. The modified SUMO-protein complex is a very transient state, and it thus facilitates rapid response and actions by the cell, when needed. Like phosphorylation, acetylation and ubiquitination, SUMOylation has been associated with a number of cellular processes. In addition to its nuclear role, important sides of mitochondrial activity, stress response signalling and the decision of cells to undergo senescence or apoptosis, have now been shown to involve the SUMO pathway. With ever increasing numbers of reports linking SUMO to human disease, like neurodegeneration and cancer metastasis, it is highly likely that novel and equally important functions of components of the SUMOylation process in cell signalling pathways will be elucidated in the near future.