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The objective of this paper is to explore sources of diagnostic error in musculoskeletal oncology and potential strategies for mitigating them using case examples. As musculoskeletal tumors are often obvious, the diagnostic errors in musculoskeletal oncology are frequently cognitive. In our experience, the most encountered cognitive biases in musculoskeletal oncologic imaging are as follows: (1) anchoring bias, (2) premature closure, (3) hindsight bias, (4) availability bias, and (5) alliterative bias. Anchoring bias results from failing to adjust an early impression despite receiving additional contrary information. Premature closure is the cognitive equivalent of "satisfaction of search." Hindsight bias occurs when we retrospectively overestimate the likelihood of correctly interpreting the examination prospectively. In availability bias, the radiologist judges the probability of a diagnosis based on which diagnosis is most easily recalled. Finally, alliterative bias occurs when a prior radiologist's impression overly influences the diagnostic thinking of another radiologist on a subsequent exam. In addition to cognitive biases, it is also important for radiologists to acknowledge their feelings when making a diagnosis to recognize positive and negative impact of affect on decision making. While errors decrease with radiologist experience, the lack of application of medical knowledge is often the primary source of error rather than a deficiency of knowledge, emphasizing the need to foster clinical reasoning skills and assist cognition. Possible solutions for reducing error exist at both the individual and the system level and include (1) improvement in knowledge and experience, (2) improvement in clinical reasoning and decision-making skills, and (3) improvement in assisting cognition.

The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability.A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group.Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality in the United States. Subcutanous unfractionated heparin (UFH) has been used for decades for VTE prophylaxis and under many obstetric quality of care initiatives, hospitalized antepartum patients now receive doses as high as 10,000 units every 12 hours. This practice increases the likelihood of UFH administration around the time that epidural labor analgesia is requested or neuraxial analgesia for cesarean delivery is needed. To clarify the effect of UFH on coagulation, we reviewed the care of hospitalized antepartum patients receiving VTE prophylaxis with UFH to determine the incidence of concurrent abnormal activated partial thromboplastin time (aPTT) values and associated risk factors.This retrospective cohort study used data from the University of Chicago Pharmacy database to identify hospitalized antepartum patients receiving subcutaneous UFH from June 1, 2016 to July 1, 2019. Our institutional protocol states that all patients hospitalized for antepartum conditions should receive pharmacologic prophylaxis empirically unless contraindicated. For patients receiving UFH, dosing was based on gestational age: 5000 units every 12 hours for first trimester antepartum patients, 7500 units every 12 hours for second trimester patients, and 10,000 units every 12 hours for patients in the third trimester. As per protocol, aPTT values were obtained 2 hours after the third dose of heparin, and platelet counts after 4 days. Data collection included demographics, comorbidities, heparin doses, aPTT values, platelet counts, creatinine if available, and anesthetic type and complications. Logistic regression was performed to determine the association between elevated aPTT40 seconds and study variables.Of the 321 antepartum patients who received subcutaneous UFH, 33 (10.3%) had an aPTT40 seconds, 4 of those 33 patients (12.1%) received 5000 units every 12 hours, 14 (42.2%) received 7500 units every 12 hours, and 15 (45.5%) received 10,000 units every 12 hours. The likelihood of a patient having aPTT40 seconds was 2.8% with 5000 units every 12 hours, 18.9% with 7500 units every 12 hours, and 14.6% with 10,000 units every 12 hours.Elevated aPTT values are likely with total daily doses of 15,000 or 20,000 units subcutaneous UFH in hospitalized antepartum patients.

Patient information corresponding to patients included in Supplementary Figure 5.

Supplementary Figure 8 from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Figure 4 from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

For a subpopulation of acute myeloid leukemia (AML) patients, the constitutively activated tyrosine kinase, mutant FLT3, has emerged as a promising target for therapy. The development of drug resistance, however, is a growing concern for mutant FLT3 inhibitors, such as PKC412. Potential therapeutic benefit can arise from the combination of two structurally diverse inhibitors that target—but bind differently to—the same protein or from two inhibitors with completely different mechanisms of action. Thus, there is a need for identification and development of novel FLT3 inhibitors that have the ability to positively combine with PKC412 or standard chemotherapeutic agents used to treat AML as a way to suppress the development of drug resistance and consequently prolong disease remission. Here, we report the effects of the novel type II ATP-competitive inhibitors, HG-7-85-01 and HG-7-86-01, which potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3-ITD or FLT3 kinase domain point mutants via induction of apoptosis and cell cycle inhibition. Antileukemic activity of HG-7-85-01 was shown in vivo to be comparable with that observed with PKC412 in a bioluminescence assay using NCr nude mice harboring Ba/F3-FLT3-ITD-luc+ cells. HG-7-85-01 was also observed to override PKC412 resistance. Finally, HG-7-85-01 and HG-7-86-01 synergized with PKC412 and standard chemotherapeutic agents against mutant PKC412-sensitive and some PKC412-resistant, FLT3-positive cells. Thus, we present a structurally novel class of FLT3 inhibitors that warrants consideration for clinical testing against drug-resistant disease in AML patients. Mol Cancer Ther; 9(9); 2468–77. ©2010 AACR.

Supplementary Table 2 from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Figure 3A-3B from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Figure 5A-5E from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Figure 7 from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Figure 2 from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Figure 6 from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Figure 3C-3F from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Table 1 from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Figure 5F from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Supplementary Figure Legends from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors

Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) are approved for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS and active secondary progressive MS. However, real-world data on cladribine tablets are limited. CLICK-MS and MASTER-2 are single arm, observational, 30-month, Phase IV studies in the US evaluating the effectiveness and safety of cladribine tablets 3.5 mg/kg in patients with relapsing-remitting MS or active secondary progressive MS who had suboptimal response to prior injectable (CLICK-MS), or infusion/oral (MASTER-2) disease-modifying therapy. The primary end point is 24-month annualized relapse rate. Key secondary end points include patient-reported outcomes on quality of life measures, treatment adherence and adverse events. Studies began in 2019 and are expected to be completed in 2023. Trial registration number • CLICK-MS: NCT03933215 (ClinicalTrials.gov) Full title; CLadribine tablets: observational evaluation of effectIveness and patient-reported outcomes in suboptimally Controlled patients previously taKing injectable disease-modifying drugs for relapsing forms of Multiple Sclerosis • MASTER-2: NCT03933202 (ClinicalTrials.gov) Full title; Cladribine tablets: observational evaluation of effectiveness and patient-reported outcomes in suboptiMAlly controlled patientS previously Taking oral or infusion disEase-modifying dRugs for relapsing forms of multiple sclerosis

Elucidation of the mechanisms by which the microbiota-gut-brain axis influences behavior requires understanding the anatomical relationship of bacteria with mucosal elements. We herein report that microbes were mainly associated with food or fecal matter in the intestinal lumen. In the small intestine, bacterial density increased from proximal-to-distal levels and was much higher in the large intestine. A mucus layer was present between the mucosal epithelium and fecal boluses in the large intestine, but not between food and the mucosal epithelium in the small intestine. In contrast, in all intestinal regions lacking food or fecal boluses, the lumen was small, or absent, and contained little or no bacteria or mucus. The association of bacteria with food was tested in the small intestine by examining the effect of fasting on it. Bacterial density was equivalent in the ileum of fasted and fed mice, but fasting greatly reduced the amount of food containing bacteria, suggesting the amount of bacteria was reduced. Critically, this study provides evidence that the vast majority of the microbiota in the intestines are associated with the food matrix thereby raising questions regarding how the gut microbiota can potentially signal the brain and influence behavior. Given their spatial location within the lumen, which keeps them at a great distance from neuronal elements in the mucosa, combined with immune and mucus barriers, microbiota more likely to influence behavior through secretion of bacterial products that can traverse the spatial difference to interact with gut neurons and not through direct physical association.

Summary Background In conflict settings, data to guide humanitarian and development responses are often scarce. Although geospatial analyses have been used to estimate health-care access in many countries, such techniques have not been widely applied to inform real-time operations in protracted health emergencies. Doing so could provide a more robust approach for identifying and prioritising populations in need, targeting assistance, and assessing impact. We aimed to use geospatial analyses to overcome such data gaps in Yemen, the site of one of the world's worst ongoing humanitarian crises. Methods We derived geospatial coordinates, functionality, and service availability data for Yemen health facilities from the Health Resources and Services Availability Monitoring System assessment done by WHO and the Yemen Ministry of Public Health and Population. We modelled population spatial distribution using high-resolution satellite imagery, UN population estimates, and census data. A road network grid was built from OpenStreetMap and satellite data and modified using UN Yemen Logistics Cluster data and other datasets to account for lines of conflict and road accessibility. Using this information, we created a geospatial network model to deduce the travel time of Yemeni people to their nearest health-care facilities. Findings In 2018, we estimated that nearly 8·8 million (30·6%) of the total estimated Yemeni population of 28·7 million people lived more than 30-min travel time from the nearest fully or partially functional public primary health-care facility, and more than 12·1 million (42·4%) Yemeni people lived more than 1 h from the nearest fully or partially functional public hospital, assuming access to motorised transport. We found that access varied widely by district and type of health service, with almost 40% of the population living more than 2 h from comprehensive emergency obstetric and surgical care. We identified and ranked districts according to the number of people living beyond acceptable travel times to facilities and services. We found substantial variability in access and that many front-line districts were among those with the poorest access. Interpretation These findings provide the most comprehensive estimates of geographical access to health care in Yemen since the outbreak of the current conflict, and they provide proof of concept for how geospatial techniques can be used to address data gaps and rigorously inform health programming. Such information is of crucial importance for humanitarian and development organisations seeking to improve effectiveness and accountability. Funding Global Financing Facility for Women, Children, and Adolescents Trust Fund; Development and Data Science grant; and the Yemen Emergency Health and Nutrition Project, a partnership between the World Bank, UNICEF, and WHO.

Summary Background Satralizumab, a humanised monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) when added to immunosuppressant therapy. This study assessed the safety and efficacy of satralizumab monotherapy in patients with the disorder. Methods In this phase 3, double-blind, placebo-controlled, parallel-group trial, we enrolled adults aged 18–74 years with aquaporin-4 antibody seropositive or seronegative NMOSD at 44 investigational sites in 13 countries. Eligible participants had experienced at least one documented NMOSD attack or relapse in the past 12 months and had a score of 6·5 or less on the Expanded Disability Status Scale. Exclusion criteria included clinical relapse 30 days or fewer before baseline. Participants were randomly assigned (2:1) to receive satralizumab 120 mg or visually matched placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Taking immunosuppressants concomitantly was prohibited. The primary endpoint was time to the first protocol-defined relapse, based on the intention-to-treat population and analysed with stratification for two randomisation factors (previous therapy for prevention of attacks and nature of the most recent attack). Safety was assessed in all participants who received at least one dose of satralizumab or placebo. The double-blind phase was due to last until 44 protocol-defined relapses occurred or 1·5 years after random assignment of the last patient enrolled, whichever occurred first; participants could enter an open-label phase after the occurrence of a protocol-defined relapse or at the end of the double-blind phase. The study is registered with ClinicalTrials.gov , NCT02073279 . Findings 95 (57%) of 168 screened participants were randomly assigned to treatment (63 to satralizumab; 32 to placebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapses occurred in 19 (30%) patients receiving satralizumab and 16 (50%) receiving placebo (hazard ratio 0·45, 95% CI 0·23–0·89; p=0·018). 473·9 adverse events per 100 patient-years occurred in the satralizumab group, as did 495·2 per 100 patient-years in the placebo group; the incidence of serious adverse events and adverse events leading to withdrawal was similar between groups. Interpretation Satralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favourable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD. Funding Chugai Pharmaceutical (Roche).

Background: Ublituximab, a novel monoclonal antibody (mAb) targeting a unique epitope on the CD20 antigen, is glycoengineered for enhanced B-cell targeting through antibody-dependent cellular cytotoxicity (ADCC). Greater ADCC may allow lower doses and shorter infusion times versus other anti-CD20 mAbs. Objective: The objective was to determine optimal dose, infusion time, and activity of ublituximab in relapsing multiple sclerosis. Methods: This is a phase 2, placebo-controlled study. Patients received three ublituximab infusions (150 mg over 1–4 hours on day 1 and 450–600 mg over 1–3 hours on day 15 and week 24) in six dosing cohorts. The primary endpoint was B-cell depletion. Results: In all cohorts ( N = 48), median B-cell depletion was >99% by week 4, maintained at weeks 24 and 48. Most common adverse events (AEs) were infusion-related reactions (all grade 1–2), with no apparent increased incidence at shorter infusion times. There were no AE-related discontinuations. At weeks 24 and 48, no T1 gadolinium-enhancing lesions ( p = 0.003) and a 10.6% decrease in T2 lesion volume ( p = 0.002) were detected. The annualized relapse rate was 0.07; 93% remained relapse free on study. Overall, 74% of patients had no evidence of disease activity (NEDA). Conclusion: Ublituximab was safely infused as rapid as 1 hour, producing robust B-cell depletion and profound reductions in magnetic resonance imaging (MRI) activity and relapses.

The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death.This retrospective, population-based study used the Surveillance, Epidemiology, and End Results database (1980-2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed.There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person-years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100-50,000; P .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR,100; P .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87-76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28-181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82-620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89-102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51-57.09).The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

Background: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. Methods: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. Findings: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86–20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 [95% CI 1·05–23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. Interpretation: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Funding: Biogen.

Sciatic nerve impingement via a tumor of or trauma to the proximal subgluteal region creates a considerable surgical challenge that is debated in the literature. The neurosurgery literature favors the infragluteal approach, while in orthopaedics, the transgluteal approach is preferred. The goal of our study was to present an operative technique for the infragluteal approach to the subgluteal region with a step-by-step procedural guide to increase awareness among orthopaedic surgeons of alternative surgical approaches to the sciatic notch. We retrospectively reviewed the case of a 62-year-old female found to have a subgluteal myxoma who underwent the infragluteal approach for tumor excision. We then highlighted the anatomic considerations via cadaveric dissection photographs, artistic renditions, and intra-operative images. Our patient underwent tumor resection and sciatic nerve exploration via the infragluteal approach with a successful outcome. In comparison to other approaches in the literature, the infragluteal approach provides a safer dissection with more options for an extension of the exposure and potentially fewer functional deficits. We conclude that orthopaedic surgeons should strongly consider utilizing this approach to the sciatic notch rather than a transgluteal approach.

We develop a deep learning approach

Background Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up. Methods Fusion sarcomas (2020–2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS). Results Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases). Conclusions Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.

Neurofibromatosis type 1 (NF1) is one of the most common inherited neurological disorders. It can cause plexiform neurofibromas, leading to diffuse enlargement of a nerve or nerves within the body. There are benign in general, however, can cause significant symptoms due to their size, including bony erosion, pain, and joint instability. Unfortunately, they also have the capacity to become malignant by internal transformation into a malignant peripheral nerve sheath tumor (MPNST). The case presented here is a 27-year-old male with NF1 that was followed for years with a pelvic girdle plexiform neurofibroma whose course was complicated by transformation to MPNST and a spontaneous hip dislocation. He underwent excision, Girdlestone procedure, chemotherapy, and radiation. Unfortunately, he subsequently developed lung metastases and is part of a clinical trial with an MDM2 inhibitor and pembrolizumab.

Anti-CD20 therapies have demonstrated considerable efficacy in the treatment of relapsing multiple sclerosis, constituting a high-efficacy treatment approach for reducing relapse risk and mitigating disability progression. These therapies have been shown to strongly deplete circulating B cells and small subsets of CD3+ CD4 and CD8 T cells that express low levels of CD20. While the clinical profiles of the various anti-CD20 monoclonal antibodies used in treating multiple sclerosis are well-described in the literature, greater understanding of the implications of their distinct molecular and pharmacological attributes is needed. In this review, we focus on four anti-CD20 monoclonal antibodies—rituximab, ocrelizumab, ofatumumab, and ublituximab—that are currently used, approved, or in late-stage clinical development for the treatment of multiple sclerosis. We provide clinical perspectives on the potential implications of differences in molecular structures, target epitopes, dosing regimens, mechanisms and impact on B-cell depletion and reconstitution, immunogenicity, administration-related reactions, and infection risks. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00843-8.

Carboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone-muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti-TGFβ antibody (1D11) to prevent carboplatin-induced bone loss and showed similar results to ZA-treated mice. We found that atrogin-1 mRNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin-induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy. © 2019 American Society for Bone and Mineral Research.

Proximal femur fracture fixation with intramedullary nailing relies on stability at the fracture site and integrity of the fixation construct to achieve union. The biomechanics that dictate fracture site stability and implant stress depend on fracture type as well as implant features such as nail length, nail diameter, presence of distal fixation screws, and material composition of the implant. When deciding how to fix a fracture, surgeons have choices in these implant-related design variables. This study models all combinations of a range of implant variables for nine standard AO/OTA proximal femur fractures using finite element analysis. Under simulated maximum load during gait, the maximum stress in the implant and screws as well as interfragmentary motions at the fracture site in the axial and shear directions were computed. The results were separated by fracture type to show the influence of each design variable on measured biomechanical outcomes. Filling the reamed canal with the largest fitting nail diameter reduced axial and shear interfragmentary motion for all fracture types. Nail length was less predictive of shear interfragmentary motion for most simulated fracture types than other construct variables. Furthermore, gapping at the fracture site predisposed the construct to higher implant stresses and larger interfragmentary motions. Clinical significance: Biomechanical outcomes from this computational study can aid in surgical decision-making for optimizing hip fracture fixation with IM nailing. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2358-2366, 2019.

Objective To assess real-world durability of reduction in relapse rates among patients with multiple sclerosis (MS) receiving fingolimod therapy over a longer-term period of follow-up. Methods Patients with MS who initiated fingolimod were identified from a US claims database (January 1, 2009 to September 30, 2016) and followed for 3 years post-initiation. Annualized relapse rates (ARRs) were calculated during the 1-year pre-initiation period, and during each year over the 3-year follow-up period. Time from fingolimod initiation to discontinuation (≥60-day treatment gap) was also summarized. Results Among 1599 fingolimod initiators, 1158 (72%) had continuous fingolimod use up to the start of year 2 and 937 (59%) had continuous fingolimod use up to the start of year 3. The mean baseline ARR during the 1-year pre-initiation period for all initiators was 0.51. After fingolimod initiation, mean ARRs were consistently lower in each year of follow-up: 0.25 (95% CI: 0.22, 0.28) in year 1 for all fingolimod initiators, 0.22 (0.18, 0.25) in year 2 for patients with continuous fingolimod use up to the start of year 2, and 0.23 (0.19, 0.27) in year 3 for patients with continuous fingolimod use up to the start of year 3. Median time on treatment was 33 months for all patients initiating fingolimod. Conclusions Patients with MS who received continuous fingolimod therapy experienced a sustained reduction in relapse rates (>50% vs. baseline) during each year of a 3-year follow-up period.

ObjectiveTo assess the long-term efficacy of ofatumumab treatment for up to ~4 years in patients with relapsing multiple sclerosis (RMS).MethodsThis analysis (data cut-off: 25-Sep-2021) will include cumulative data from patients randomised to ofatumumab/teriflunomide in the ASCLEPIOS I/II trials (core study) and the ongoing, open-label, ALITHIOS extension study. Patients will be analyzed in two groups: those randomised to ofatumumab in the core (continuous group) and those randomised to teriflunomide in the core with potential switch to ofatumumab in the extension (switch group). Annualised relapse rate (ARR), disability worsening (time- to-3-month/6-month confirmed disability worsening), disability improvement (time-to-6-month confirmed disability improvement), and brain MRI outcomes (number of Gd+T1 lesions and annualised T2 lesion rate) will be assessed.ResultsOverall, 1882 patients who were randomised in the ASCLEPIOS I/II trials (ofatumumab/terifluno- mide: 946/936) will be included in the analysis. In total, 690/946 patients treated with ofatumumab and 677/936 patients treated with teriflunomide entered ALITHIOS. Updated efficacy results for up to ~4 years will be presented at the congress.ConclusionsThese analyses will provide insights on the sustained efficacy of continuous ofatumumab treatment for up to 4 years in patients with RMS, and on ofatumumab efficacy in patients newly switched from teriflunomide. Funding: Novartis Pharma AG, Basel, Switzerland.

On behalf of the Networked Digital Library of Theses and Dissertations (NDLTD; see our website with multiple aliases: ndltd.org, theses.org, dissertations.org), I welcome you to the first volume of J-ETD. Now is the time to broadly share through an archival journal some of the most interesting discussions related to the global movement around ETDs. We hope you will find this journal to be of interest, and will spread the word that it is globally accessible as an open access archival forum empowering graduate student researchers and universities to broadly contribute to scholarship, knowledge, education, and understanding. We hope you and your associates will use the articles contained herein to help students, researchers, scholars, administrators, librarians, archivists, publishers, and diverse others to expand and improve learning and scholarly communication. We also encourage you and your colleagues to contribute your works and thoughts to this endeavor, or to offer your assistance in other ways, e.g., if you have interest and skill for reviewing or publicity.

Despite the high value of electronic theses and dissertations (ETDs), the global collection has seen limited use. To extend such use, a new approach to building digital libraries (DLs) is needed. Fortunately, recent decades have seen that a vast amount of “gray literature” has become available through a diverse set of institutional repositories as well as regional and national libraries and archives. Most of the works in those collections include ETDs and are often freely available in keeping with the open-access movement, but such access is limited by the services of supporting information systems. As explained through a set of scenarios, ETDs can better meet the needs of diverse stakeholders if customer discovery methods are used to identify personas and user roles as well as their goals and tasks. Hence, DLs, with a rich collection of services, as well as newer, more advanced ones, can be organized so that those services, and expanded workflows building on them, can be adapted to meet personalized goals as well as traditional ones, such as discovery and exploration.

Introduction: Osteoporosis affects nearly half of the U.S. population. Screening methods are improving but remain inadequate, leaving the disease underdiagnosed and undertreated. The purpose of this study is to determine the effectiveness of an EMR implemented system that identifies patients at risk for osteoporosis via an OST (osteoporosis screening tool) score in prompting patients toward osteoporosis evaluation. Methods: OST scores are generated on every patient 50 years of age and older that is admitted to the Penn State Hershey Medical Center (PSHMC) and recorded in their electronic medical record. An OST score < 2 indicates that a patient has a potential risk for osteoporosis. Information Technology (IT) implemented the EMR OST calculation, which currently generates a daily filtered list of all patients with an OST score Results: In the intervention group, 67 (58.26%) of 115 did not schedule a follow-up, while the remaining 48 (41.74%) did seek a follow-up. Thus, the patient follow-up response rate improved with letter intervention using the OST score as an indicator (P < .0001) compared to historical controls (14.29%). Conclusion: Implementing an EMR OST score which identifies patients at risk for osteoporosis, which generates an automatic letter to the patient, significantly promotes patient driven osteoporosis evaluation compared to historical controls.

In clinical trials, disability progression in multiple sclerosis (MS) is measured by the Kurtzke expanded disability status scale (EDSS), which is not captured in routine clinical care in the U.S. This study developed a claims-based disability score (CDS) based on the EDSS for assigning MS disability level in a U.S. claims database.This retrospective cohort study of patients with MS in the U.S., utilized adjudicated health plan claims data linked to electronic medical records (EMRs) data. Patients were identified between 1 January 2012 and 31 December 2016 and indexed on the first date of MS diagnosis. The CDS was developed to assign disability level at baseline using claims and ambulatory EMR records observed over the 1-year baseline period. All-cause healthcare costs were assessed by baseline disability level to validate the CDS.In total, 45,687 patients were identified in claims (full sample) and 1,599 linked to EMR (core sample). Over half of patients in both samples were classified with mild disability at baseline. Adjusted healthcare costs in patients with moderate and severe disability were 15% (The CDS is the first claims-based measure of MS disability utilizing data from EMR. This novel measure advances the opportunity to examine outcomes by disability accumulation in the absence of standard markers of disease progression. Although formal validation of the CDS was not possible due to lack of available EDSS in the EMR, the economic burden results align with prior publications and show that healthcare costs increase with increasing disability. Future validation studies of the CDS are warranted.

Background: Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS). Objective: This exploratory analysis examined the effects of ocrelizumab on confirmed progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO. Methods: Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ⩾120 weeks. The Nine-Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ⩾20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT. Results: Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ⩾20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses. Conclusion: Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS.

B cell depletion therapy has been shown to be beneficial in multiple sclerosis (MS). However, the mechanism by which B cell depletion mediates its beneficial effects in MS is still unclear. To better understand how B cell depletion may benefit patients with a disease previously thought to be primarily mediated by CD4 T cells, immune profiles were monitored in 48 patients in a phase II trial of ublituximab, a glycoengineered CD20 monoclonal antibody, at 18 time points over a year. As we previously described there was a significant shift in the percentages of T cells, NK cells, and myeloid cells following the initial dose of ublituximab, but this shift normalized within a week and these populations remained stable for the duration of the study. However, T cell subsets changed with an increase in the percentage of naive CD4 and CD8 T cells and a decline in memory T cells. Importantly, the percentage of Th1 and CD4+GM-CSF+ T cells decreased, while the percentage of Tregs continued to increase over the year. Ublituximab not only depleted CD20+ B cells, but also CD20+ T cells. The favorable changes in the T cell subsets may contribute to the beneficial effects of B cell depletion therapy.

Background Ocrelizumab, an anti-CD20 humanized monoclonal antibody, reduced disease progression in pivotal trials of patients with relapsing (OPERA I, OPERA II) and primary progressive (ORATORIO) multiple sclerosis (MS). These effects may be particularly important among patients with increased disability. Objective In this post hoc exploratory analysis, we evaluated the efficacy of ocrelizumab on disability progression among a subgroup of patients with MS who had increased baseline disability levels (Expanded Disability Status Scale scores ≥4.0) in the pivotal trials. Methods During the double-blind period, patients received ocrelizumab 600 mg intravenously every 24 weeks for 96 weeks in the OPERA trials (versus interferon β-1a 44 μg subcutaneously three times per week) and for 120 weeks in ORATORIO (versus placebo). Kaplan–Meier and Cox survival analyses were used to assess disability outcome measures. Results Baseline demographic, disease, and treatment characteristics were generally comparable across treatment groups in patients with increased disability from the OPERA and ORATORIO trials. Ocrelizumab treatment numerically, and in some instances significantly, reduced confirmed disability progression versus the comparator in these patients. Conclusions In patients with increased baseline disability, ocrelizumab reduced the risk of confirmed disability progression versus interferon β-1a in patients with relapsing-onset MS and versus placebo in patients with progression-onset MS.

ObjectiveTo evaluate lymphocyte counts and incidences of infections in patients with primary progressive MS (PPMS) receiving fingolimod 0.5 mg/d or placebo over 5 years during the INFORMS study, to assess infection rates with longer-term treatment.MethodsINFORMS was a randomized, multicenter, double-blind, placebo-controlled, parallel-group, phase 3 study of the sphingosine 1-phosphate receptor modulator fingolimod in patients with PPMS. Lymphocyte counts and incidences of infections were compared in patients receiving fingolimod or placebo. Infection rates were assessed in patients receiving fingolimod according to nadir and mean absolute lymphocyte count (ALC).ResultsOverall, 336 patients received fingolimod 0.5 mg/d (total exposure: 908.1 patient-years), and 487 received placebo (1,423.5 patient-years). In patients receiving fingolimod, mean ALC decreased by approximately 70% in the 2 weeks following treatment initiation and remained stable throughout the study. The incidences of all infections in the fingolimod and placebo groups were similar (53.6 vs 51.9 per 100 patient-years). The most common infections in patients receiving fingolimod were urinary tract infections (5.7 per 100 patient-years), upper respiratory tract infections (4.2 per 100 patient-years), and influenza (3.2 per 100 patient-years); incidences were similar in the placebo group (5.9, 4.2, and 3.1 per 100 patient-years, respectively). There was no apparent association between nadir or mean ALC and incidence of infection-related adverse events.ConclusionsIn patients with PPMS, long-term treatment with fingolimod 0.5 mg/d for up to 5 years led to an expected decrease of approximately 70% in mean ALC and did not appear to correlate with increased risk of infection.Classification of evidenceBecause this is a secondary analysis, this study provides Class II evidence that long-term PPMS treatment with fingolimod decreased mean ALC by approximately 70%, but did not significantly increase infection risk.

This paper explores the benefits and the costs of strengthening infrastructure assets to make them more resilient, reducing the repair costs and infrastructure disruptions caused by natural hazards. Strengthening infrastructure assets in low- and middle-income countries would increase investment needs in power, transport, and water and sanitation by between $11 billion and $65 billion a year, i.e. 3 percent of baseline infrastructure investment needs. The uncertainty pertaining to the costs and benefits of infrastructure resilience makes it difficult to provide a single estimate for the benefit-cost ratio of strengthening exposed infrastructure assets. To manage this uncertainty, this paper explores the benefit-cost ratio in 3,000 scenarios, combining uncertainties in all parameters of the analysis. The benefit-cost ratio is higher than 1 in 96 percent of the scenarios, larger than 2 in 77 percent of them, and higher than 4 in half of them. The net present value of these investments over the lifetime of new infrastructure assets -- or, equivalently, the cost of inaction -- exceeds $2 trillion in 75 percent of the scenarios and $4.2 trillion in half of them. Moreover, climate change makes the strengthening of infrastructure assets even more important, doubling the median benefit-cost ratio.