Utility of Cellular Measurements of Non-Specific Endocytosis to Assess the Target-Independent Clearance of Monoclonal Antibodies.

Past studies have demonstrated higher clearance for monoclonal antibodies possessing increased rates of non-specific endocytosis. However, this metric is oftentimes evaluated indirectly using biophysical techniques or cell surface binding studies that may not provide insight into the specific rates of cellular turnover. Furthermore, few examples evaluating non-specific endocytosis have been reported for a therapeutic antibody that reached clinical assessment. In the current report, we evaluated a therapeutic human immunoglobulin G2 monoclonal antibody targeted against the interleukin-4 receptor alpha chain (IL-4Rα) that exhibited elevated target independent clearance in previous Phase 1 and 2 studies. We confirmed high non-specific clearance of the anti-IL-4Rα antibody as compared to a reference antibody during pharmacokinetic assessments in wild type mice where target-mediated disposition was absent. We then developed a cell-based method capable of measuring cellular protein endocytosis and demonstrated the anti-IL-4Rα antibody exhibited marked non-specific uptake relative to the reference compound. Antibody homology modeling identified the anti-IL-4Rα antibody possessed positive charge patches whose removal via targeted mutations substantially reduced its non-specific endocytosis. We then expanded the scope of the study by evaluating panels of both preclinical and clinically relevant monoclonal antibodies and demonstrate those with the highest rates of non-specific uptake in vitro exhibited elevated target independent clearance, low subcutaneous bioavailability, or both. Our results support the observation that high non-specific endocytosis is a negative attribute in monoclonal antibody development and demonstrate the utility of a generic cell-based screen as a quantitative tool to measure non-specific endocytosis of protein therapeutics at the single-cell level.

Paediatric strategy forum for medicinal product development of PI3-K, mTOR, AKT and GSK3ß inhibitors in children and adolescents with cancer.

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.

Outcomes of Selective Arthrodesis Based on Joints Affected in 33 Feet With Müller-Weiss Disease.

No consensus exists regarding operative treatment of Müller-Weiss disease (MWD). Its only classification is based solely on Méary's angle and serves neither as guide to management nor prognosis. We report on 33 feet that underwent surgery following failed conservative management. Treatment was directed towards joint(s) involved, as determined by clinical examination, plain radiography and SPECT-CT. Thus, surgery consisted of isolated talonavicular in 6 feet, triple in 8, subtalar and talonavicular in 7, talonaviculocuneiform in 4, talonaviculocuneiform with interpositional tricortical iliac crest graft in 6 and pantalar arthrodesis in 2. PROMIS scores for pain interference and depression decreased significantly (p < .001) with significant accompanying increase in physical function (p = .003). Union occurred in 31 of 33 feet (94%) with complete resolution of pain at an average follow-up of 84 months. Of the 2 nonunions, 1 had fracture through the lateral navicular, and the other marked sclerosis and avascularity of the lateral navicular. We describe our pathways for selecting arthrodesis based on the joints affected. Isolated talonavicular arthrodesis was performed in early stages of MWD, which begins at the talonavicular articulation. When disease extended to both sides of the navicular, we performed talonaviculocuneiform arthrodesis. When considering isolated talonavicular, double medial or triple arthrodesis, there should be adequate cancellous bone stock remaining in the lateral part of the navicular, as determined on medial oblique radiographs and CT scan. In case of inadequate bone stock or fracture through the lateral navicular, talonaviculocuneiform arthrodesis with interpositional iliac crest bone graft is recommended.

Mind the Anterior Tibial Tendon in Oblique Distal Third Tibial Fractures with Anterior Inferior Proximal Spike: A Case Report.

CASE: An oblique fracture of the distal third of the tibia, treated nonoperatively in a 14-year-old adolescent boy, did not unite because of ensnarement of the anterior tibial tendon (ATT) around an anterior inferior bony spike from the proximal tibial fragment. Computed tomography scan with 3-dimensional volume rendering aided in preoperative diagnosis. Surgical extraction of the tendon from within the fracture site and internal fixation led to successful union and full painless function. CONCLUSION: Beware of possible ATT entrapment as a cause of irreducibility of oblique distal third tibial fractures with an anterior inferior bony spike of the proximal fragment.

Regorafenib plus Vincristine and Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors: An Innovative Therapy for Children with Cancer Study.

PURPOSE: This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan. PATIENTS AND METHODS: Patients aged 6 months to <18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8, and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model. RESULTS: We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9-14.8] and median overall survival was 8.7 months (95% CI, 5.5-16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day). CONCLUSIONS: Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (ClinicalTrials.gov NCT02085148).

Streamlining Food Effect Assessment - Are Repeated Food Effect Studies Needed? An IQ Analysis.

Current regulatory guidelines on drug-food interactions recommend an early assessment of food effect to inform clinical dosing instructions, as well as a pivotal food effect study on the to-be-marketed formulation if different from that used in earlier trials. Study waivers are currently only granted for BCS class 1 drugs. Thus, repeated food effect studies are prevalent in clinical development, with the initial evaluation conducted as early as the first-in-human studies. Information on repeated food effect studies is not common in the public domain. The goal of the work presented in this manuscript from the Food Effect PBPK IQ Working Group was to compile a dataset on these studies across pharmaceutical companies and provide recommendations on their conduct. Based on 54 studies collected, we report that most of the repeat food effect studies do not result in meaningful differences in the assessment of the food effect. Seldom changes observed were more than twofold. There was no clear relationship between the change in food effect and the formulation change, indicating that in most cases, once a compound is formulated appropriately within a specific formulation technology, the food effect is primarily driven by inherent compound properties. Representative examples of PBPK models demonstrate that following appropriate validation of the model with the initial food effect study, the models can be applied to future formulations. We recommend that repeat food effect studies should be approached on a case-by-case basis taking into account the totality of the evidence including the use of PBPK modeling.

Towards understanding Müller-Weiss disease from an analysis of 95 cases.

BACKGROUND: The single existing classification of Müller-Weiss Disease (MWD), based solely upon Méary's angle, serves neither as guide for prognosis nor treatment. This accounts for lack of gold standard in its management. METHODS: Navicular compression, medial extrusion, metatarsal lengths, Kite's, lateral and dorsoplantar talo-first metatarsal angles were measured in 95 feet with MWD. Joints involved, presence and location of navicular fracture were recorded. RESULTS: Group 1 "early-onset" MWD feet (n = 11) had greatest compression and medial extrusion, and lowest Kite's angles. All except 1 were index minus and had lateral navicular fracture. Only 1 had moderate degeneration at the talonavicular joint (TNJ) with none requiring surgery yet. Group 2 "Müller-Weissoid" feet (n = 23) had radiologically normal navicular in their fifties and developed MWD on average 5 years later. They had the lowest compression and extrusion, and highest Kite's angles. None had complete fracture. All had TNJ arthritis, with early changes at lateral naviculocuneiform joint (NCJ) in 43%. Group 3 "late-onset" MWD presented in the sixth decade. Only TNJ was involved in Group 3 A (n = 16). Group 3B (n = 20) affected TNJ more than NCJ and had the greatest number of Maceira stage V disease. Group 3 C "reverse Müller-Weiss disease", which affected NCJ more than TNJ (n = 25), had greatest midfoot abduction and overlength of the second metatarsal. No fracture occurred in group 3 A compared to 65% and 32% in groups 3B and 3 C, respectively. CONCLUSIONS: With need to compare like-for-like pathology, the proposed classification provides a common platform for reporting outcomes of different treatments. We theorize pathogenetic pathways in the various groups.

Model-informed approach to support pediatric dosing for the pan-PI3K inhibitor copanlisib in children and adolescents with relapsed/refractory solid tumors.

Copanlisib is an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor which was investigated in pediatric patients with relapsed/refractory solid tumors. A model-informed approach was undertaken to support and confirm an empirically selected starting dose of 28 mg/m2 for pediatric patients ≥1 year old, corresponding to 80% of the adult recommended dose adjusted for body surface area. An adult physiologically based pharmacokinetic (PBPK) model was initially established using copanlisib physicochemical and disposition properties and clinical pharmacokinetics (PK) data and was shown to adequately capture clinical PK across a range of copanlisib doses in adult cancer patients. The adult PBPK model was then extended to the pediatric population through incorporation of age-dependent anatomical and physiological changes and used to simulate copanlisib exposures in pediatric cancer patient age groups. The pediatric PBPK model predicted that the copanlisib 28 mg/m2 dose would achieve similar copanlisib exposures across pediatric ages when compared with historical adult exposures following the approved copanlisib 60 mg dose administered on Days 1, 8, and 15 of a 28-day cycle. Clinical PK were collected from a phase I study in pediatric patients with relapsed/refractory solid tumors (aged ≥4 years). An established adult population PK model was extended to incorporate an allometrically-scaled effect of body surface area and confirmed that the copanlisib maximum tolerated dose of 28 mg/m2 was appropriate to achieve uniform copanlisib exposures across the investigated pediatric age range and consistent exposures to historical data in adult cancer patients. The model-informed approach successfully supported and confirmed the copanlisib pediatric dose recommendation.

Comparing the similarity and differences in MeSH terms associated with spine-specific journals using the forest plot: A bibliometric analysis.

BACKGROUND: A common concern in the literature is the comparison of the similarities and differences between research journals, as well as the types of research they publish. At present, there are no clear methodologies that can be applied to a given article of interest. When authors use an effective and efficient method to locate journals in similar fields, they benefit greatly. By using the forest plot and major medical subject headings (MeSH terms) of Spine (Phila Pa 1976) compared to Spine J, this study: displays relatively similar journals to the target journal online and identifies the effect of the similarity odds ratio of Spine (Phila Pa 1976) compared to Spine J. METHODS: From the PubMed library, we downloaded 1000 of the most recent top 20 most similar articles related to Spine (Phila Pa 1976) and then plotted the clusters of related journals using social network analysis (SNA). The forest plot was used to compare the differences in MeSH terms for 2 journals (Spine (Phila Pa 1976) and Spine J) based on odds ratios. The heterogeneity of the data was evaluated using the Q statistic and the I-square (I2) index. RESULTS: This study shows that: the journals related to Spine (Phila Pa 1976) can easily be presented on a dashboard via Google Maps; 8 journal clusters were identified using SNA; the 3 most frequently searched MeSH terms are surgery, diagnostic imaging, and methods; and the odds ratios of MeSH terms only show significant differences with the keyword "surgery" between Spine (Phila Pa 1976) and Spine J with homogeneity at I2 = 17.7% (P = .27). CONCLUSIONS: The SNA and forest plot provide a detailed overview of the inter-journal relationships and the target journal using MeSH terms. Based on the findings of this research, readers are provided with knowledge and concept diagrams that can be used in future submissions to related journals.

Misdiagnosis of Extraskeletal Osteochondroma in the Foot: A Report of 3 Cases.

CASES: Two women presented with newly growing callosities beneath the first and second metatarsal heads, initially believed to reflect gastrocnemius tightness and plantar plate pathology. In another man, swelling at the posterolateral aspect of the heel was mistaken for a Haglund deformity. Subsequent imaging of each patient led to delayed diagnosis of extraskeletal osteochondroma (ESO). Surgical excision resolved symptoms in all 3 with no recurrence over 12 months later. CONCLUSIONS: Whenever bony prominences newly develop in soft tissues of the foot, ESO should be suspected and appropriate imaging obtained. We describe physical features to help differentiate ESO from other common causes of foot overload.

Paediatric Strategy Forum for medicinal product development of multi-targeted kinase inhibitors in bone sarcomas: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities.

An IQ Consortium Perspective on Connecting Dissolution Methods to In Vivo Performance: Analysis of an Industrial Database and Case Studies to Propose a Workflow.

Assessment of bioperformance to inform formulation selection and development decisions is an important aspect of drug development. There is high demand in the pharmaceutical industry to develop an efficient and streamlined approach for better understanding and predicting drug product performance to support acceleration of clinical timelines. This manuscript presents an effort from the IQ Formulation Bioperformance Prediction Working Group composed of members from 12 pharmaceutical companies under the IQ Consortium to develop a database around the topic of formulation bioperformance prediction and report findings from the database analysis. Six case studies described in the manuscript demonstrate how bioperformance models were used to predict in vivo performance and to provide guidance addressing questions encountered during oral solid dosage form development. The case studies also described findings of a correlation between in vitro dissolution and in vivo performance and how dissolution data can be incorporated into physiologically based biopharmaceutical modeling. Finally, a workflow for how in vitro dissolution data can be utilized to predict clinical bioperformance of oral solid dosage forms is proposed.

Thematic analysis of articles on artificial intelligence with spine trauma, vertebral metastasis, and osteoporosis using chord diagrams: A systematic review and meta-analysis.

BACKGROUND: Spine trauma, vertebral metastases, and osteoporosis (SVO) can result in serious health problems. If the diagnosis of SVO is delayed, the prognosis may be deteriorated. The use of artificial intelligence (AI) is an essential method for minimizing the diagnostic errors associated with SVO. research achievements (RAs) of SVO on AI are required as a result of the greatest number of studies on AI solutions reported. The study aimed to: classify article themes using visualizations, illustrate the characteristics of SVO on AI recently, compare RAs of SVO on AI between entities (e.g., countries, institutes, departments, and authors), and determine whether the mean citations of keywords can be used to predict article citations. METHODS: A total of 31 articles from SVO on AI (denoted by T31SVOAI) have been found in Web of Science since 2018. The dominant entities were analyzed using the CJAL score and the Y-index. Five visualizations were applied to report: the themes of T31SVOAI and their RAs in comparison for article entities and verification of the hypothesis that the mean citations of keywords can predict article citations, including: network diagrams, chord diagrams, dot plots, a Kano diagram, and radar plots. RESULTS: There were five themes classified (osteoporosis, personalized medicine, fracture, deformity, and cervical spine) by a chord diagram. The dominant entities with the highest CJAL scores were the United States (22.05), the University of Pennsylvania (5.72), Radiology (6.12), and Nithin Kolanu (Australia) (9.88). The majority of articles were published in Bone, J. Bone Miner. Res., and Arch. Osteoporos., with an equal count (=3). There was a significant correlation between the number of article citations and the number of weighted keywords (F = 392.05; P < .0001). CONCLUSION: A breakthrough was achieved by displaying the characteristics of T31SVOAI using the CJAL score, the Y-index, and the chord diagram. Weighted keywords can be used to predict article citations. The five visualizations employed in this study may be used in future bibliographical studies.

Non-target digital ischemia in an ulnar artery distribution following transradial access: Case report and review of best practice techniques.

Transradial access is a safe approach for visceral endovascular interventions, with lower complication rates compared to transfemoral access. This report describes an unusual case of ulnar artery thrombosis following splenic artery aneurysm embolization via left transradial approach, resulting in non-target digital ischemia and eventual amputation of the ring and little finger distal phalanges. Technical considerations to reduce the incidence of access complications are also reviewed, along with practice modifications undertaken at our institution following this case to improve outcomes.

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

Neurothekeoma: Another differential in the diagnosis of a subungual swelling.

CASE: Lesions, which commonly grow and protrude beneath the distal end of a toe nail and present to the podiatrist or foot and ankle surgeon, include subungual exostosis or enchondroma and a Nora lesion. Neurothekeoma is a benign dermal tumour of the peripheral nerve sheath that usually affects the skin of the head, neck, shoulders and arms. It occurs less commonly in the lower limbs and has only been reported twice in a subungual location. A case of subungual neurothekeoma that recurred twice due to inadequate margins of resection is presented. CONCLUSION: Although rare, neurothekeoma should be included in the differential diagnosis of a subungual lesion. Histopathological diagnosis is reached by differential immunostaining. Adequate clear margins of resection are recommended to prevent recurrence.

Treatment response assessment following transarterial radioembolization for hepatocellular carcinoma.

Transarterial radioembolization with yttrium-90 microspheres is an established therapy for hepatocellular carcinoma. Post-procedural imaging is important for the assessment of both treatment response and procedural complications. A variety of challenging treatment-specific imaging phenomena complicate imaging assessment, such as changes in tumoral size, tumoral and peritumoral enhancement, and extrahepatic complications. A review of the procedural steps, emerging variations, and timelines for post-treatment tumoral and extra-tumoral imaging changes are presented, which may aid the reporting radiologist in the interpretation of post-procedural imaging. Furthermore, a description of post-procedural complications and their significance is provided.

Suitability of h- and x-indices for evaluating authors' individual research achievements in a given short period of years: A bibliometric analysis.

BACKGROUND: The h-index of a researcher refers to the maximum number h of his/her publications that has at least h citations via the concept of the square area. The x-index is determined by the maximum area of a rectangle under the curve to interpret authors' individual research achievements (IRAs). However, the properties of both metrics have not been compared and discussed before. This study aimed to investigate whether both metrics of h- and x-index are suitable for evaluating IRAs in a short period of years. METHODS: By searching the PubMed database (Pubmed.com), we used the keyword "PLoS One" (journal) and downloaded 50,000 articles published in 2015 and 2016. A total of 146,346 citations were listed in PubMed Central and 27,035 authors(with h-index ≥1) were divided into 3 parts. Correlation coefficients among metrics (ie, AIF, h, g, Ag, and x-index) were examined. The bootstrapping method used for estimating 95% confidence intervals was applied to compare differences in metrics among author groups. The most cited authors and topic burst were visualized by social network analysis. The most prominent countries/areas were highlighted by the x-index and displayed via choropleth maps. RESULTS: Results demonstrated that, first, the h-index had the least relation to other metrics and failed to differentiate authors' IRAs among groups, particularly in a short time period. Second, the top 3 highest x-index for countries were the United States, China, and the UK but with the productivity-oriented feature. Third, the most cited medical subject headings (ie, MeSH terms) were genome, metabolome, and microbiology, and the most cited author was Lori Newman (whose x-index = 13.52, and h = 2) from Switzerland with the article (PMID = 26646541) cited 291 times. The need for the x-index combined with a visual map for displaying authors' IRAs was verified and recommended. CONCLUSIONS: We verified that the h-index failed to differentiate authors' IRAs among author groups in a short time period. The x-index combined with the Kano map is recommended in research for a better understanding of the authors' IRAs in other journals or disciplines, not just limited to the journal of PloS One as we did in this study.

Radiographic analysis of Müller-Weiss disease.

BACKGROUND: The only classification of Müller-Weiss disease (MWD) is based primarily on Méary's talo-first metatarsal angle. It describes increasing sag of the medial longitudinal arch with greater degrees of compression and fragmentation of the navicular. Purportedly, the talar head pushes the subtalar joint into varus and drives the medial pole of the navicular medially, as it protrudes inferiorly and laterally. Its authors stipulated heel varus as a pre-requisite, coining the term 'paradoxical pes planus varus' to define heel varus and flatfoot as hallmark deformities of the condition. METHODS: We measured Méary's and Kite's talocalcaneal angles, heel offset, anteroposterior thickness of the navicular at each naviculocuneiform (NC) joint, medial extrusion of the navicular and calculated percentage compression at each NC joint in 68 consecutive feet presenting with MWD. Morphology and activity at the various peri-navicular joints were studied using SPECT-CT in 45 feet. RESULTS: Inverse relationships between Méary's angle and degree of navicular compression reach statistical significance at NC2 but not at NC3. Strong correlation exists between medial extrusion and percentage compression at NC2 and NC3. Medial extrusion is significantly greater on the affected side in unilateral cases and on the more compressed side in bilateral cases. Significant inverse relationships exist between Kite's angle and percentage compression at both NC2 and NC3 and degree of medial extrusion of the navicular. No correlation was detected between Kite's angle and either heel offset or Méary's angle. Varus heel offset was present in only 33% of cases. The combination of heel varus and negative Méary's angle was present in just 26% of cases, the commonest combination being heel valgus with sagging at 56%. CONCLUSION: Our findings confirm part of Maceira's hypothesized pathomechanism of MWD. Reductions in Kite's talocalcaneal angle confirm that lateral and inferior protrusion of the talar head causes increasing compression and medial extrusion of the navicular. However, such shift of the talar head does not always lead to heel varus. As such, we caution against universal advocacy of lateral displacement calcaneal osteotomy, as the heel is not always in varus in MWD.

Predicting article citations using data of 100 top-cited publications in the journal Medicine since 2011: A bibliometric analysis.

BACKGROUND: Publications regarding the 100 top-cited articles in a given discipline are common, but studies reporting the association between article topics and their citations are lacking. Whether or not reviews and original articles have a higher impact factor than case reports is a point for verification in this study. In addition, article topics that can be used for predicting citations have not been analyzed. Thus, this study aims to METHODS:: We searched PubMed Central and downloaded 100 top-cited abstracts in the journal Medicine (Baltimore) since 2011. Four article types and 7 topic categories (denoted by MeSH terms) were extracted from abstracts. Contributors to these 100 top-cited articles were analyzed. Social network analysis and Sankey diagram analysis were performed to identify influential article types and topic categories. MeSH terms were applied to predict the number of article citations. We then examined the prediction power with the correlation coefficients between MeSH weights and article citations. RESULTS: The citation counts for the 100 articles ranged from 24 to 127, with an average of 39.1 citations. The most frequent article types were journal articles (82%) and comparative studies (10%), and the most frequent topics were epidemiology (48%) and blood and immunology (36%). The most productive countries were the United States (24%) and China (23%). The most cited article (PDID = 27258521) with a count of 135 was written by Dr Shang from Shandong Provincial Hospital Affiliated to Shandong University (China) in 2016. MeSH terms were evident in the prediction power of the number of article citations (correlation coefficients  = 0.49, t = 5.62). CONCLUSION: The breakthrough was made by developing dashboards showing the overall concept of the 100 top-cited articles using the Sankey diagram. MeSH terms can be used for predicting article citations. Analyzing the 100 top-cited articles could help future academic pursuits and applications in other academic disciplines.