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Objectives: The present review aimed to synthesize evidence from randomized controlled trials (RCTs) that compared outcomes of pars plana vitrectomy (PPV) with and without a supplementary scleral buckle (SB) for management of rhegmatogenous retinal detachment (RRD). Methods: The authors searched MEDLINE, Embase, and CENTRAL to identify RCTs in English that compared PPV with and without supplemental SB. Risk of bias was assessed according to the Cochrane Risk of Bias 2 tool. We present risk ratios (RRs), mean differences (MDs), and 95% confidence intervals (CIs) estimated using random-effects meta-analyses. Results: We identified 6 RCTs involving 705 eyes. Primary reattachment (6 studies, 345 eyes PPV, 324 eyes PPV + SB; RR 0.99, 95% CI 0.93–1.06, I2 = 0%, p = 0.78) and final anatomic success rates (4 studies, 272 eyes PPV, 267 eyes PPV + SB; RR 1.00, 95% CI 0.98–1.02, I2 = 0%, p = 0.89) were similar between the 2 groups. Postoperative visual acuity improvement (5 studies, 244 eyes PPV, 222 eyes PPV + SB; MD 6.09 letters, 95% CI -0.47–12.64, I2 = 69%, p = 0.07) and frequency of adverse events (6 studies, 1,294 observations PPV, 1,221 observations PPV + SB; RR 0.76, 95% CI 0.57–1.01, I2 = 25%, p = 0.06) likewise did not differ significantly between the treatment groups. Conclusion: Low-certainty evidence from RCTs did not demonstrate a benefit in placement of a supplemental SB during vitrectomy for management of RRD in the current analysis. Additional high-quality trials are needed to provide more precise estimates of the effect.

AimsThe aims of this network meta-analysis (NMA) were to examine nonunion rates and functional outcomes following various operative and nonoperative treatments for displaced mid-shaft clavicle fractures.MethodsInitial search strategy incorporated MEDLINE, PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials (RCTs). Four treatment arms were created: nonoperative (NO); intramedullary nailing (IMN); reconstruction plating (RP); and compression/pre-contoured plating (CP). A Bayesian NMA was conducted to compare all treatment options for outcomes of nonunion, malunion, and function using the Disabilities of the Arm Shoulder and Hand (DASH) and Constant-Murley Shoulder Outcome scores.ResultsIn all, 19 RCTs consisting of 1,783 clavicle fractures were included in the NMA. All surgical options demonstrated a significantly lower odds ratio (OR) of nonunion in comparison to nonoperative management: CP versus NO (OR 0.08; 95% confidence interval (CI) 0.04 to 0.17); IMN versus NO (OR 0.07; 95% CI 0.02 to 0.19); RP versus NO (OR 0.07; 95% CI: 0.01 to 0.24). Compression plating was the only treatment to demonstrate significantly lower DASH scores relative to NO at six weeks (mean difference -10.97; 95% CI -20.69 to 1.47).ConclusionSurgical fixation demonstrated a lower risk of nonunion compared to nonoperative management. Compression plating resulted in significantly less disability early after surgery compared to nonoperative management. These results demonstrate possible early improved functional outcomes with compression plating compared to nonoperative treatment. Surgical fixation of mid-shaft clavicle fractures with compression plating may result in quicker return to activity by rendering patients less disabled early after surgery. Cite this article: Bone Jt Open 2021;2(8):646–654.

Background Non-union occurs in approximately 5 to 10% of fracture patients, with certain bones at greater risk of failing to heal. Non-unions have a significant impact on socioeconomic costs and the patients short and long-term quality of life. Low intensity pulsed ultrasound (LIPUS) is a non-invasive therapy for non-union treatment that can improve the long-term outcome. The purpose of this study is to summarize the available literature assessing LIPUS potential to improve the union rate in instrumented, infected, and fragility non-unions. Methods A literature search was conducted in the MEDLINE, EMBASE, and CINAHL databases for all relevant literature on the healing rates of LIPUS utilized in instrumented, infected, and fragility non-unions. Study characteristics were summarized for each of the included studies. The percentage of healed patients (healing rate), for instrumented, infected, and fragility fracture non-union patients were pooled from each included study. Results The literature search identified a total of 326 articles, while searching reference lists and grey literature identified an additional 3 articles. There was a total of 29 articles included in this review, with 20 articles included within the quantitative synthesis of healing rates. The most common design of included studies was case series (17 articles), followed by case reports (9 articles). Studies were primarily retrospective (18 studies), with an additional 10 prospective studies. Non-union healing rates were 82% (95% CI: 76 to 87%) in instrumented, 82% (95% CI: 70 to 95%) in infected, and 91% (95% CI: 87 to 95%) in fragility fracture patients with non-unions. Conclusion This study has provided a thorough overview of the current literature on LIPUS treatment for instrumented, infected, and fragility fracture non-unions. The healing rates for non-unions in these subgroups were comparable to healing rates observed with LIPUS use in general non-union literature. LIPUS treatment should be considered as a conservative non-surgical treatment option to potentially reduce the socioeconomic impact and improve the quality of life of these unfortunate patients. Level of evidence 4 (systematic review of primarily case series data)

Objectives The objective of the study was to develop an inventory summarizing all anchor-based minimal important difference (MID) estimates for patient-reported outcome measures (PROMs) available in the medical literature. Study Design and Setting We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database internal library (January 1989–October 2018). We included primary studies empirically calculating an anchor-based MID estimate for any PROM in adults and adolescents. Pairs of reviewers independently screened and selected studies, extracted data, and evaluated the credibility of the MIDs. Results We identified 585 eligible studies, the majority conducted in Europe (n = 211) and North America (n = 179), reporting 5,324 MID estimates for 526 distinct PROMs. Investigators conducted their studies in the context of patients receiving surgical (n = 105, 18%), pharmacological (n = 85, 15%), rehabilitation (n = 65, 11%), or a combination of interventions (n = 194, 33%). Of all MID estimates, 59% (n = 3,131) used a global rating of change anchor. Major credibility limitations included weak correlation (n = 1,246, 23%) or no information regarding the correlation (n = 3,498, 66%) between the PROM and anchor and imprecision in the MID estimate (n = 2,513, 47%). Conclusion A large number of MIDs for assisting in the interpretation of PROMs exist. The MID inventory will facilitate the use of MID estimates to inform the interpretation of the magnitude of treatment effects in clinical research and guideline development.

PurposeThere are a number of developments in intra-articular therapies that have been determined to be differentiating factors within the classes of treatments. This study evaluated the efficacy and safety of intra-articular treatments of primary knee osteoarthritis in the short term (3 months follow-up), using a network meta-analysis design, while taking within-class differentiating factors into consideration.MethodsA literature search of MEDLINE (through OVID), EMBASE (through OVID), Cochrane Central Register of Controlled Trials for all trials comparing intra-articular therapies was conducted on November 12, 2018. The treatments assessed were high molecular weight and low molecular weight hyaluronic acid injections, extended-release corticosteroids, standard-release corticosteroids, platelet-rich plasma, and saline. A frequentist network meta-analysis was conducted for each outcome.ResultsSixty-four articles (9710 patients) met the inclusion criteria. High molecular weight hyaluronic acid (− 0.53, 95% CI − 0.81 to − 0.25) and PRP (− 0.79, 95% CI − 1.32 to − 0.26) were the only treatments with a confidence interval that lay completely above the MID threshold; however, PRP results varied within sensitivity analyses. For the function analysis, high molecular weight hyaluronic acid (SMD − 0.76, 95% CI − 1.30 to − 0.22) was the only treatment with a confidence interval entirely above the MID. Extended-release corticosteroid demonstrated a possible benefit in functional improvement (SMD − 0.98, 95% CI − 1.79 to − 0.17) compared to that of standard-release corticosteroid (SMD − 0.14, 95% CI − 0.72 to 0.44).ConclusionHigh molecular weight HA was the only treatment to surpass the MID for both pain and function outcomes. Extended-release corticosteroids may provide additional clinical benefit over standard-release corticosteroids. Platelet-rich plasma demonstrated possibly beneficial results; however, wide confidence intervals and sensitivity analyses made the conclusions of efficacy uncertain.Level of evidenceLevel 1. Systematic review of level 1 evidence.

OBJECTIVE To investigate treat-and-extend (T&E) regimens of anti-vascular endothelial growth factor (anti-VEGF) therapy for the treatment of macular oedema secondary to retinal vein occlusions (RVOs). METHODS Ovid MEDLINE, Ovid EMBASE and CENTRAL were searched on 25 February 2021. Randomized controlled trials, cohort studies, case-control studies and case series were included. The primary outcome was the change in Early Treatment Diabetic Retinopathy Score (ETDRS) letters from baseline. Conversions from Snellen to ETDRS letters were performed utilizing a published protocol. Secondary outcomes included improvement in retinal thickness from baseline, number of anti-VEGF injections and frequency of adverse events. Outcomes were examined at 12 and 24 months. Certainty of evidence was assessed utilizing GRADE (Grading of Recommendations Assessments, Development and Evaluations) guidelines. RESULTS Seven hundred eighty-six eyes from 16 studies were included. Meta-analysis demonstrated a mean improvement of 15.7 (95% CI: 13.3-18.0) ETDRS letters at 12 months. Central retinal thickness improved 269.7 μm (95% CI: 233.64-305.90) at 12 months. Injections were performed 8.1 (95% CI: 7.4-8.7) and 13.1 (95% CI: 9.4-16.8) times at 12 and 24 months respectively. Adverse events were infrequent across all studies. Grading of Recommendations Assessments, Development and Evaluations (GRADE) certainty of evidence was very low across all outcomes. CONCLUSIONS The results support the viability of T&E regimens for the treatment of macular oedema secondary to RVOs.

The capacity to link records associated with the same individual across data sets is a key challenge for data-driven research. The challenge is exacerbated by the potential inclusion of both genomic and clinical data in data sets that may span multiple legal jurisdictions, and by the need to enable re-identification in limited circumstances. Privacy-Preserving Record Linkage (PPRL) methods address these challenges. In 2016, the Interdisciplinary Committee of the International Rare Diseases Research Consortium (IRDiRC) launched a task team to explore approaches to PPRL. The task team is a collaboration with the Global Alliance for Genomics and Health (GA4GH) Regulatory and Ethics and Data Security Work Streams, and aims to prepare policy and technology standards to enable highly reliable linking of records associated with the same individual without disclosing their identity except under conditions in which the use of the data has led to information of importance to the individual's safety or health, and applicable law allows or requires the return of results. The PPRLTask Force has examined the ethico-legal requirements, constraints, and implications of PPRL, and has applied this knowledge to the exploration of technology methods and approaches to PPRL. This paper reports and justifies the findings and recommendations thus far.

PURPOSE: The current process for radiotherapy treatment plan quality assurance relies on human inspection of treatment plans, which is time‐consuming, error prone and oft reliant on inconsistently applied professional judgments. A previous proof‐of‐principle paper describes the use of a Bayesian network (BN) to aid in this process. This work studied how such a BN could be expanded and trained to better represent clinical practice. METHODS: We obtained 51 540 unique radiotherapy cases including diagnostic, prescription, plan/beam, and therapy setup factors from a de‐identified Elekta oncology information system from the years 2010–2017 from a single institution. Using a knowledge base derived from clinical experience, factors were coordinated into a 29‐node, 40‐edge BN representing dependencies among the variables. Conditional probabilities were machine learned using expectation maximization module using all data except a subset of 500 patient cases withheld for testing. Different classes of errors that were obtained from incident learning systems were introduced to the testing set of cases which were withheld from the dataset used for building the BN. Different sizes of datasets were used to train the network. In addition, the BN was trained using data from different length epochs as well as different eras. Its performance under these different conditions was evaluated by means of Areas Under the receiver operating characteristic Curve (AUC). RESULTS: Our performance analysis found AUCs of 0.82, 0.85, 0.89, and 0.88 in networks trained with 2‐yr, 3‐yr 4‐yr and 5‐yr windows. With a 4‐yr sliding window, we found AUC reduction of 3% per year when moving the window back in time in 1‐yr steps. Compared to the 4‐yr window moved back by 4 yrs (2010–2013 vs 2014–2017), the largest component of overall reduction in AUC over time was from the loss of detection performance in plan/beam error types. CONCLUSIONS: The expanded BN method demonstrates the ability to detect classes of errors commonly encountered in radiotherapy planning. The results suggest that a 4‐yr training dataset optimizes the performance of the network in this institutional dataset, and that yearly updates are sufficient to capture the evolution of clinical practice and maintain fidelity.

Simple Summary This reseach explored the safety and feasibility of combining local chemotherapy with fluorescence-guided resection in patients with a brain cancer, glioblastoma. The aim was to determine if the combination of fluorescence-guided surgery using 5-aminolevulinic acid and BCNU wafers left in the tumour cavity at the end of the operation was safe and did not prevent patients getting subsequent chemo-radiotherapy. The results showed that combining local chemotherapy with fluorescence-guided resection was tolerable in terms of surgical morbidity and overall toxicity. However, any potential therapeutic benefit requires further investigation, preferably with improved local delivery technologies. Abstract Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity (n = 3), death (n = 3), lost to follow-up/withdrew (n = 3), clinical decision (n = 1), poor performance status (n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4–9.8) and median overall survival was 14.7 months (95% CI: 11.7–16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies.

The ESA-JAXA BepiColombo mission to Mercury will provide simultaneous measurements from two spacecraft, offering an unprecedented opportunity to investigate magnetospheric and exospheric particle dynamics at Mercury as well as their interactions with solar wind, solar radiation, and interplanetary dust. The particle instrument suite SERENA (Search for Exospheric Refilling and Emitted Natural Abundances) is flying in space on-board the BepiColombo Mercury Planetary Orbiter (MPO) and is the only instrument for ion and neutral particle detection aboard the MPO. It comprises four independent sensors: ELENA for neutral particle flow detection, Strofio for neutral gas detection, PICAM for planetary ions observations, and MIPA, mostly for solar wind ion measurements. SERENA is managed by a System Control Unit located inside the ELENA box. In the present paper the scientific goals of this suite are described, and then the four units are detailed, as well as their major features and calibration results. Finally, the SERENA operational activities are shown during the orbital path around Mercury, with also some reference to the activities planned during the long cruise phase.

We introduce the modular and scalable design of Kartta Labs, an open source, open data, and scalable system for virtually reconstructing cities from historical maps and photos. Kartta Labs relies on crowdsourcing and artificial intelligence consisting of two major modules: Maps and 3D models. Each module, in turn, consists of sub-modules that enable the system to reconstruct a city from historical maps and photos. The result is a spatiotemporal reference that can be used to integrate various collected data (curated, sensed, or crowdsourced) for research, education, and entertainment purposes. The system empowers the users to experience collaborative time travel such that they work together to reconstruct the past and experience it on an open source and open data platform.

The Solar Orbiter mission seeks to make connections between the physical processes occurring at the Sun or in the solar corona and the nature of the solar wind created by those processes which is subsequently observed at the spacecraft. The mission also targets physical processes occurring in the solar wind itself during its journey from its source to the spacecraft. To meet the specific mission science goals, Solar Orbiter will be equipped with both remote-sensing and in-situ instruments which will make unprecedented measurements of the solar atmosphere and the inner heliosphere. A crucial set of measurements will be provided by the Solar Wind Analyser (SWA) suite of instruments. This suite consists of an Electron Analyser System (SWA-EAS), a Proton and Alpha particle Sensor (SWA-PAS), and a Heavy Ion Sensor (SWA-HIS) which are jointly served by a central control and data processing unit (SWA-DPU). Together these sensors will measure and categorise the vast majority of thermal and suprathermal ions and electrons in the solar wind and determine the abundances and charge states of the heavy ion populations. The three sensors in the SWA suite are each based on the top hat electrostatic analyser concept, which has been deployed on numerous space plasma missions. The SWA-EAS uses two such heads, each of which have 360° azimuth acceptance angles and ±45° aperture deflection plates. Together these two sensors, which are mounted on the end of the boom, will cover a full sky field-of-view (FoV) (except for blockages by the spacecraft and its appendages) and measure the full 3D velocity distribution function (VDF) of solar wind electrons in the energy range of a few eV to ∼5 keV. The SWA-PAS instrument also uses an electrostatic analyser with a more confined FoV (−24° to +42° × ±22.5° around the expected solar wind arrival direction), which nevertheless is capable of measuring the full 3D VDF of the protons and alpha particles arriving at the instrument in the energy range from 200 eV/q to 20 keV/e. Finally, SWA-HIS measures the composition and 3D VDFs of heavy ions in the bulk solar wind as well as those of the major constituents in the suprathermal energy range and those of pick-up ions. The sensor resolves the full 3D VDFs of the prominent heavy ions at a resolution of 5 min in normal mode and 30 s in burst mode. Additionally, SWA-HIS measures 3D VDFs of alpha particles at a 4 s resolution in burst mode. Measurements are over a FoV of −33° to +66° × ±20° around the expected solar wind arrival direction and at energies up to 80 keV/e. The mass resolution (m/Δm) is > 5. This paper describes how the three SWA scientific sensors, as delivered to the spacecraft, meet or exceed the performance requirements originally set out to achieve the mission’s science goals. We describe the motivation and specific requirements for each of the three sensors within the SWA suite, their expected science results, their main characteristics, and their operation through the central SWA-DPU. We describe the combined data products that we expect to return from the suite and provide to the Solar Orbiter Archive for use in scientific analyses by members of the wider solar and heliospheric communities. These unique data products will help reveal the nature of the solar wind as a function of both heliocentric distance and solar latitude. Indeed, SWA-HIS measurements of solar wind composition will be the first such measurements made in the inner heliosphere. The SWA data are crucial to efforts to link the in situ measurements of the solar wind made at the spacecraft with remote observations of candidate source regions. This is a novel aspect of the mission which will lead to significant advances in our understanding of the mechanisms accelerating and heating the solar wind, driving eruptions and other transient phenomena on the Sun, and controlling the injection, acceleration, and transport of the energetic particles in the heliosphere.

Picking a programme management software tool is probably one of the least important decisions people makes when implementing successful programme management. This comes from several decades of experience. The author presents three cases such as, XYZ company, Jill, and his own experience. XYZ is an extremely large, global smartphone and computer manufacturer. Over the course of a year or so they were looking for a new programme management software tool to support one of their global lines of business. Together the tool makers and the XYZ company uncovered valuable intersections of the tool makers' technology and XYZ's ideal programme management approach. Jill wanted to create a picture of the executives' ideal state for how the company should operate when programme management was taken seriously. She put together Visio drawings and PowerPoint presentations describing the current state, the future state and a detailed plan on how to get from the current state to the future state.

ObjectiveIntra-articular (IA) injections represent a commonly used modality in the treatment of hip osteoarthritis (OA). Commonly used injections include corticosteroids (CCS), hyaluronic acid (HA) and platelet-rich plasma (PRP). A network meta-analysis allows for comparison among more than two treatment arms and uses both direct and indirect comparisons between interventions. The objective of this network meta-analysis is to compare the efficacy of the various IA injectable treatments in treating hip OA at up to 6 months of follow-up.DesignThis is a systematic review and network meta-analysis. Bayesian random-effects model was performed to assess the direct and indirect comparisons of all treatment options.Data sourcesPubMed, Embase, Cochrane Central Register of Controlled Trials, Scopus and Web of Science, from inception to October 2019.Eligibility criteria for selected studiesRandomised controlled trials assessing the efficacy of CCS, HA, PRP and placebo in the form of IA saline injection for patients with hip OA.ResultsEleven randomised controlled trials comprising 1353 patients were included. For pain outcomes at both 2–4 and 6 months, no intervention significantly outperformed placebo IA injection. For functional outcomes at both 2–4 and 6 months, no intervention significantly outperformed placebo IA injection. Regarding change from baseline at 2–4 months and 6 months, pooled data demonstrated that all interventions (including placebo), with the exception of HA+PRP, led to a clinically important improvement in both pain, exceeding the minimal clinically important difference.ConclusionEvidence suggests that IA hip saline injections performed as well as all other injectable options in the management of hip pain and functional outcomes.

Background: Surgical specialties face unique challenges caused by SARS-COV-2 (COVID-19). These disruptions will call on clinicians to have greater consideration for non-operative treatment options to help manage patient symptoms and provide therapeutic care in lieu of the traditional surgical management course of action. This study aimed to summarize the current guidance on elective surgery during the COVID-19 pandemic, assess how this guidance may impact orthopaedic care, and review any recommendations for non-operative management in light of elective surgery disruptions. Methods: A systematic search was conducted, and included guidance were categorized as either “Selective Postponement” or “Complete Postponement” of elective surgery. Selective postponement was considered as guidance that suggested elective cases should be evaluated on a case-by-case basis, whereas complete postponement suggested that all elective procedures be postponed until after the pandemic, with no case-by-case consideration. In addition, any statements regarding conservative/non-operative management were summarized when provided by included reports. Results: A total of 11 reports from nine different health organizations were included in this review. There were seven (63.6%) guidance reports that suggested a complete postponement of non-elective surgical procedures, whereas four (36.4%) reports suggested the use of selective postponement of these procedures. The guidance trends shifted from selective to complete elective surgery postponement occurred throughout the month of March. The general guidance provided by these reports was to have an increased consideration for non-operative treatment options whenever possible and safe. As elective surgery begins to re-open, non-operative management will play a key role in managing the surgical backlog caused by the elective surgery shutdown. Conclusion: Global guidance from major medical associations are in agreement that elective surgical procedures require postponement in order to minimize the risk of COVID-19 spread, as well as increase available hospital resources for managing the influx of COVID-19 patients. It is imperative that clinicians and patients consider non-operative, conservative treatment options in order to manage conditions and symptoms until surgical management options become available again, and to manage the increased surgical waitlists caused by the elective surgery shutdowns.

The evolution of genomic research and its integration into clinical practice, as they become international—even global—endeavors, has brought us to a place where scientists and clinicians may now only ignore the rules governing international data sharing at their own peril. Open data policies, on the one hand, increasingly require custodians of others’ genomic data to make it as widely available as feasible, including to researchers in other countries. Data protection law, on the other, has become a significant hurdle to the sharing of personal data across jurisdictional borders. The space between these two competing duties is narrowing. In contrast with the other texts in this volume, which explore the present and future of data sharing and data protection, this article’s focus is on the past. It centres on the historical development of the data protection rules regarding the international transfer of personal data up to the present. The article’s aim is to bring into focus the underlying objectives that have influenced and that will continue to influence the way that data protection rules are applied to the fields of genomics and health, as well as future developments in data protection generally. The first part of this article describes the development of international data-sharing data protection rules since 1970. The second considers difficulties in applying general data protection rules to the specific context of genomics and health. The third and final part compares the options available to comply with the international transfer restrictions set out in the standard-setting EU General Data Protection Regulation from a genomics perspective.

Introduction: FLT180a (verbrinacogene setparvovec) is an investigational, liver-directed AAV gene therapy for the treatment of patients with hemophilia B (HB). FLT180a consists of a novel, potent, engineered capsid (AAVS3) containing an expression cassette encoding a Factor IX (FIX) gain-of-function protein variant ('Padua'; FIX-R338L). The B-AMAZE study was designed to identify a dose of FLT180a that maintains FIX activity within the normal range (50-150%) and thereby protect patients with severe HB from spontaneous and traumatic bleeds. Methods: B-AMAZE was a multicentre, open-label Phase 1/2 clinical trial (NCT03369444; sponsored by UCL) that evaluated FLT180a dose levels using an escalating/descending adaptive design in patients with severe (FIX activity Results: Ten HB patients received a single dose of FLT180a. Four FLT180a doses ranging from 3.84e11 vg/kg to 1.28e12 vg/kg were assessed. As of the data cut-off date, all patients have been followed for ≥16 months. FLT180a demonstrated a favorable safety profile, without evidence of inhibitors against FIX, infusion-related or allergic reactions. The most common treatment-related adverse event was transient elevation in alanine aminotransferase. An event of AV fistula thrombosis occurred in a 67-year-old patient who received the highest dose of 1.28e12 vg/kg (total dose of 1.15e14 vg) and had supranormal FIX levels; this patient was treated with anticoagulants. While these FIX levels demonstrate the potency of our proprietary AAVS3 capsid, this dose will not be used in future hemophilia studies. At Week 26 after FLT180a administration, a dose-response relationship was observed with mean FIX activity of 45.0%, 35.5%, 141.5%, and 175.5% for 3.84e11, 6.4e11, 8.32e11, and 1.28e12 vg/kg doses, respectively (Table); FIX activity levels ≥50% were achieved in 7 of 8 patients treated with the three highest doses. One patient (Patient 4) who received 6.4e11 vg/kg lost transgene expression early due to transaminitis and resumed routine factor prophylaxis. The 8.32e11 vg/kg cohort received an extended immune management regimen (9-18 weeks) with prophylactic tacrolimus in addition to prednisolone to prevent breakthrough vector-related transaminitis. However, after cessation of the immune management regimen, transaminitis with concomitant reductions in FIX activity was observed in all patients in the 8.32e11 vg/kg cohort. The combination of prophylactic tacrolimus and prednisolone appeared to have suppressed immune-mediated transaminitis while administered, but recurrence of transaminitis developed soon after cessation. This unique and previously unreported observation suggests that the longer-duration prophylactic immune management regimen may have prevented tolerization to the vector because this was not observed in earlier cohorts where a brief course of tacrolimus was given reactively for breakthrough transaminitis. All patients (including the 8.32e11 vg/kg cohort) have achieved steady state. Patients in the earliest cohort who received the lowest dose (3.84e11 vg/kg) have shown stable FIX activity for >3 years. There were no spontaneous bleeds that required FIX supplementation in patients who maintained FIX activity above 50%; Patient 4 in the 6.4e11 vg/kg cohort experienced two bleeds (cause unknown) after he lost transgene expression, which were treated with exogenous FIX. One patient received exogenous FIX for treatment of a traumatic bleed, but his FIX activity level was 57% at the time of the event. Additional efficacy and safety results with >3.5 years of follow-up will be presented. Conclusions: B-AMAZE is the first HB gene therapy study to achieve normal levels of FIX activity using relatively low vector doses. Results suggest that a dose of 7.7e11 vg/kg, coupled with a short course of prophylactic immune management, has the potential to achieve durable FIX activity in the normal range (50-150%) and thereby prevent spontaneous bleeds and normalize hemostasis in the event of traumatic bleeds. Figure 1 Figure 1. Disclosures Chowdary: Sanofi: Honoraria; Roche: Honoraria; CSL Behring: Honoraria, Research Funding; Freeline: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; SOBI: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Chugai: Honoraria; Spark: Honoraria; Bayer: Honoraria, Research Funding. Shapiro: Roche: Honoraria; CSL Bering: Honoraria; Takeda: Honoraria, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Makris: Freeline: Consultancy. Dolan: Takeda: Speakers Bureau; Roche-Chugai: Speakers Bureau; Spark Therapeutics: Speakers Bureau; Octapharma: Speakers Bureau; CSL: Speakers Bureau; Biomarin: Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Pfizer: Research Funding. Tuddenham: Freeline: Consultancy, Current holder of individual stocks in a privately-held company. Long: Freeline: Current Employment. Krop: Freeline: Current Employment. Nathwani: Freeline: Current holder of individual stocks in a privately-held company, Other: Board of directors.

Purpose/Objective(s) Despite being an integral part of stem cell transplant, the technical aspects of classical total body irradiation (TBI) remain relatively crude. In particular, the implementations of lung and cardiac shielding vary widely between institutions. We hypothesize that the block margins away from anatomical landmarks could substantially alter lung and cardiac dose parameters, and thus affecting the likelihood of TBI-related toxicities such as radiation pneumonitis and late cardiotoxicities. This work seeks to utilize a newly commissioned 3D TBI beam model to determine potential dosimetric effects caused by variations in the choice of shielding parameters to better understand the potential for such detrimental effects. Materials/Methods We commissioned a TBI beam model in a treatment planning system. CT scans of 3 anonymized patients without gross disease are contoured following typical clinical practice. Patients are planned in the classic standing AP/PA at extended distance technique for a total dose of 1200 cGy in 6 fractions to midline at umbilicus level, with 3/6 fractions delivered with lung blocks. Lung blocks are modeled using automated script in the treatment planning system, with varying superior (from clavicles), inferior (from diaphragms), and lateral margins from 0 to 2 cm, as well as cases for which the cardiac silhouette was blocked or unblocked for the study. Dose to lungs and heart were calculated and compared for the following metrics: mean dose, volume receiving 10 Gy (V10 Gy) and 12 Gy (V12 Gy), and point dose behind the blocks. Results The results showed that the point dose behind the blocks is approximately 75% of prescription dose for all patients, with insignificant changes with varying block margins. The dose off the block center increases rapidly that much of the tissue under the blocks receives 80% to 90% of prescription dose. Similar results are observed for mean lung dose. In contrast, the lung V10 Gy increases by nearly two-fold, from approximately 30% to 60% over the 0 to 2 cm block margin range. The mean heart dose increased by approximately 7.5% when the cardiac silhouette is unblocked, while the cardiac V12 Gy increased by approximately 25%. The mean dose to left anterior descending artery (LAD) increases significantly in the unblocked case, with as much as 43% difference. Conclusion This work has shown that margins of lung blocks could affect the dose to lungs and heart substantially, despite the indifference that the commonly used point dose parameter, point dose behind the blocks, indicates. A 3D TBI model could provide more dosimetry data to help future studies to correlate TBI-associated toxicity to the heart and lungs.

Background: There are many clinical practice guidelines (CPGs) for the prevention, diagnosis, and treatment of knee osteoarthritis (OA). They differ by region, considering local health care systems, along with cultural and economic factors. Currently, there are conflicting CPG recommendations across the various publications, which makes it difficult for clinicians to fully understand the optimal treatment decisions for knee OA management. Purpose: To summarize the current published CPG recommendations for the role of injections in the nonoperative management of knee OA, specifically with the use of intra-articular hyaluronic acid (IA-HA), intra-articular corticosteroids (IA-CS), and platelet-rich plasma (PRP). Study Design: Systematic review. Methods: A comprehensive search identified all nonoperative knee OA CPGs within the ECRI (formerly Emergency Care Research Institute) Guidelines Trust database, the Guidelines International Network database, Google Scholar, and the Trip (formerly Turning Research Into Practice) database. Guideline recommendations were categorized into strong, conditional, or uncertain recommendations for or against the use of IA-HA, IA-CS, or PRP. Guideline recommendations were summarized and depicted graphically to identify trends in recommendations over time. Results: The search strategy identified 27 CPGs that provided recommendations. There were 20 recommendations in favor of IA-HA use, 21 recommendations in favor of IA-CS use, and 9 recommendations that were uncertain or unable to make a formal recommendation for or against PRP use based on current evidence. Most recommendations considered IA-HA and IA-CS use for symptom relief when other nonoperative options are ineffective. IA-CS were noted to provide fast and short-acting symptom relief for acute episodes of disease exacerbation, while IA-HA may demonstrate a relatively delayed but prolonged effect in comparison. The CPGs concluded that PRP recommendations currently lack evidence to definitively recommend for or against use. Conclusion: Available CPGs provide recommendations on injectables for knee OA treatment. General guidance from a global perspective concluded that IA-CS and IA-HA are favored for different needed responses and can be utilized within the knee OA treatment paradigm, while PRP currently has insufficient evidence to make a conclusive recommendation for or against its use.

Multisession stereotactic radiation therapy is increasingly being seen as a preferred option for intracranial diseases in close proximity to critical structures and for larger target volumes. The objective of this study is to investigate the reproducibility of the Extend system from Elekta. A retrospective review was conducted for all patients treated with multisession Gamma Knife between July 2010 and June 2015, including both malignant and benign lesions. Eighty-four patients were treated in this 5-year span. The average residual daily setup uncertainty was 0.48 (0.19) mm. We compare measurements of setup uncertainty from the Extend system to measurements performed with a linac-based approach previously used in our center. The Extend system has significantly reduced setup uncertainty for fractionated intracranial treatments at our institution. Positive results were observed in a small population of edentulous patients. The Extend system compares favorably with other approaches to delivering intracranial stereotactic radiotherapy and is a robust, simple-to-use, and precise method for treating multisession intracranial lesions.

Monitoring respiratory parameters can help predict COPD exacerbations but sensor coverage is limited to parts of the day or home. Continuous respiratory monitoring is difficult to attain due to unwieldy and limited devices. A low-cost, long-lasting, clothing-adhered device has been designed and built, each of which is adhered to the inside of the patient’s undergarments and does not require recharging. Objective: Evaluate the feasibility of remote recruitment of COPD patients with moderate to severe disease status through social media and evaluate adherence to said device. Materials and Methods: 30 subjects were asked to wear the sensor for 60 days as part of a clinical trial (target N=150; 9 months per patient). Recruitment is social media-based with a single nurse phone interview to verify eligibility. Each patient is asked to wear the sensor daily and to answer a weekly survey. Results: Recruitment and self-initiation with only minimal phone support is achievable. Once enrolled, adherence to wearable device is high: 97.2% of the days enrolled and 84.4% of the hours of days a sensor was worn. Figure 1 compares continuous 1-minute respiratory rate values of the cohort with healthy normals. Conclusion: Remote recruitment of moderate to severe COPD patients can be successful via social media and one phone call. The device provides for high adherence, continuous respiratory monitoring among this population.

As our population ages and increasing numbers of older patients experience major trauma it is important to understand factors that influence outcomes in this patient cohort. The aim of this study is to assess the impact of frailty in older patients who experience major trauma (Injury Severity Score (ISS) greater than 15). A retrospective cohort review using the national trauma registry data (Trauma Audit and Research Network) and an institutional database was carried out on all patients aged 60 years or older with an ISS> 15 who were treated at the regional Major Trauma Centre from 2014 to 2017 following major trauma. Frailty was assessed using the modified frailty index (mFI). Outcomes assessed included mortality, complications, hospital stay, functional outcome and discharge destination. 819 patients were included in the study. The most common mechanism of injury was fall from a height less than 2m (57.4%). 412 (51.3%) patients had a low frailty score, 280 (35%) had an intermediate frailty score and 110 (14%) had high frailty score. Increased frailty was associated with increased mortality at discharge (18.7%, 14.6% and 26.4% for low, intermediate and high frailty groups) and at one year (26.2%, 35.2% and 51%, respectively). Other predictors of mortality included male sex, age >90 years and the occurrence of a serious complication. Increasing frailty was also associated with an increased risk of serious complications including unplanned intubation, infection and progressive renal failure, and discharge to a destination other than home. This is the first study that has delineated the impact of frailty in older patients who experience major trauma and provides important information for patients, their families and healthcare providers. Future studies should focus on identifying care pathways that counteract the impact of frailty in this setting.

The recent explosion in machine learning efforts in the quality assurance (QA) space has produced a variety of proofs-of-concept many with promising results. Expected outcomes of model implementation include improvements in planning time, plan quality, advanced dosimetric QA, predictive machine maintenance, increased safety checks, and developments key for new QA paradigms driven by adaptive planning. In this article, we outline several areas of research and discuss some of the unique challenges each area presents.

Given that organizations need to manage complex situations, multiple organizational climates can coexist and these climates can jointly influence employee behaviors. However, the mechanisms through which the latter relationships operate are poorly understood. We take a multilevel approach to examine the mechanisms that link organizational innovative climate and employee innovative behavior, and the moderating effects of organizational proactive and risk-taking climates on these relationships. Using multisource data from 105 managers and 39 CEOs, we found that innovative climate was positively related to employee innovative behavior indirectly through employee passion for inventing. In addition, the relationship between innovative climate and passion for inventing became stronger as proactive climate increased, and the relationship between passion for inventing and employee innovative behavior became stronger as risk-taking climate increased. Our study contributes to entrepreneurial research by highlighting the interactive effects of multiple organizational climates on employee innovative behavior.

A systematic review was performed to explore the current trends over the last 5 years in femoroacetabular impingement (FAI) literature and compare the quality and sources of publications in the literature to that published previously. We identified 1066 relevant studies including 186,572 patients. The number of publications increased during the reviewed time period with the most dramatic increase from 2011 to 2013. Seventy-three percent (N = 786) of all studies were of levels 4 and 5 quality evidence. The percent of publications which were levels 1, 2 and 3 increased by almost twofold from 16.1 % (N = 26) to 28.7 % (N = 51) between 2011 and 2015. In comparison to previous work, there has been 3.5-fold increase in the number of publications over the past 5 years with a shift towards improving the level of evidence available guiding the arthroscopic management of FAI.IV-Systematic Review.

Purpose Create a cost-effectiveness model comparing preoperative intensity modulated radiation therapy (IMRT) versus 3-dimensional conformal radiation therapy (3DCRT) for extremity soft tissue sarcomas. Methods and Materials Input parameters included 5-year local recurrence rates, rates of acute wound adverse events, and chronic toxicities (edema, fracture, joint stiffness, and fibrosis). Health-state utilities were used to calculate quality-adjusted life years (QALYs). Overall treatment costs per QALY or incremental cost-effectiveness ratio (ICER) were calculated. Roll-back analysis was performed using average costs and utilities to determine the baseline preferred radiation technique. One-way, 2-way, and probabilistic sensitivity analyses (PSA) were performed for input parameters with the largest impact on the ICER. Results Overall treatment costs were $17,515.58 for 3DCRT compared with $22,920.51 for IMRT. The effectiveness was higher for IMRT (3.68 QALYs) than for 3DCRT (3.35 QALYs). The baseline ICER for IMRT was $16,842.75/QALY, making it the preferable treatment. The ICER was most sensitive to the probability of local recurrence, upfront radiation costs, local recurrence costs, certain utilities (no toxicity/no recurrence, grade 1 toxicity/no local recurrence, grade 4 toxicity/no local recurrence), and life expectancy. Dominance patterns emerged when the cost of 3DCRT exceeded $15,532.05 (IMRT dominates) or the life expectancy was under 1.68 years (3DCRT dominates). Furthermore, preference patterns changed based on the rate of local recurrence (threshold: 13%). The PSA results demonstrated that IMRT was the preferred cost-effective technique for 64% of trials compared with 36% for 3DCRT. Conclusions Based on our model, IMRT is the preferred technique by lowering rates of local recurrence, severe toxicities, and improving QALYs. From a third-party payer perspective, IMRT should be a supported approach for extremity soft tissue sarcomas.

IntroductionAthletic groin pain requiring surgery remains a diagnostic and therapeutic challenge. This systematic review aims to identify the most common causes of groin pain in athletes requiring surgery. Additionally, it aims to further characterise their susceptible athlete profiles, common physical examination and imaging techniques, and surgical procedures performed. This will enable the orthopaedic sports medicine clinician/surgeon to best treat these patients.Materials and methodsThe electronic databases MEDLINE, PubMed and EMBASE were searched from database inception to 13 August 2014 for studies in the English language that addressed athletic groin pain necessitating surgery. The search was updated on 4 August 2015 to find any articles published after the original search. The studies were systematically screened and data were abstracted in duplicate, with descriptive data presented.ResultsA total of 73 articles were included within our study, with data from 4655 patients abstracted. Overall, intra-articular and extra-articular causes of groin pain in athletes requiring surgery were equal. The top five causes for pain were: femoroacetabular impingement (FAI) (32%), athletic pubalgia (24%), adductor-related pathology (12%), inguinal pathology (10%) and labral pathology (5%), with 35% of this labral pathology specifically attributed to FAI.ConclusionsGiven the complex anatomy, equal intra-articular and extra-articular contribution, and potential for overlap of clinical entities causing groin pain leading to surgery in athletes, further studies are required to ascertain the finer details regarding specific exam manoeuvres, imaging views and surgical outcomes to best treat this patient population.

Purpose: The final state of the tumor at the end of a radiotherapy course is dependent on the doses given in each fraction during the treatment course. This study investigates the feasibility of using dynamic adaptive radiotherapy (DART) in treatinglungcancers assuming CBCT is available to observe midtreatment tumor states. DART adapts treatment plans using a dynamic programming technique to consider the expected changes of the tumor in the optimization process. Methods: DART is constructed using a stochastic control formalism framework. It minimizes the total expected number of tumor cells at the end of a treatment course, which is equivalent to maximizing tumor control probability, subject to the uncertainty inherent in the tumor response. This formulation allows for nonstationary dose distributions as well as nonstationary fractional doses as needed to achieve a series of optimal plans that are conformal to the tumor over time, i.e., spatiotemporally optimal plans. Sixteen phantom cases with various sizes and locations of tumors and organs-at-risk (OAR) were generated using in-house software. Each case was planned with DART and conventional IMRT prescribing 60 Gy in 30 fractions. The observations of the change in the tumor volume over a treatment course were simulated using a two-level cell population model. Monte Carlo simulations of the treatment course for each case were run to account for uncertainty in the tumor response. The same OAR dose constraints were applied for both methods. The frequency of replanning was varied between 1, 2, 5 (weekly), and 29 times (daily). The final average tumordose and OAR doses have been compared to quantify the potential dosimetric benefits of DART. Results: The average tumor max, min, mean, and D95 doses using DART relative to these using conventional IMRT were 124.0%–125.2%, 102.1%–114.7%, 113.7%–123.4%, and 102.0%–115.9% (range dependent on the frequency of replanning). The average relative maximum doses for the cord and esophagus, mean doses for the heart and lungs, and D05 for the unspecified tissue resulting 84%–102.4%, 99.8%–106.9%, 66.9%–85.6%, 58.2%–78.8%, and 85.2%–94.0%, respectively. Conclusions: It is feasible to apply DART to the treatment of NSCLC using CBCT to observe the midtreatment tumor state. Potential increases in the tumordose and reductions in the OAR dose, particularly for parallel OARs with mean or dose–volume constraints, could be achieved using DART compared to nonadaptive IMRT.

This study evaluated the effectiveness and safety of bone growth stimulation using combined magnetic field (CMF) for the treatment of fracture nonunions. In this prospective multicenter study, patients were assessed monthly for 9 mo, or until they demonstrated a healed nonunion, and were assessed at a final follow-up 3 mo after treatment completion. The primary outcome was the presence or absence of fracture healing at the nonunion site, determined by clinical and radiographic assessment. Enrolled in this study were 112 patients with 116 fracture nonunions. Fifty-two (44.8%) patients demonstrated a healed nonunion between treatment initiation and 12-mo- posttreatment initiation (9 mo of treatment plus 3 mo posttreatment follow-up). Tibial nonunions had a higher percentage of healed fractures compared to other fracture types (78% vs. 46.5%, respectively; p = 0.004). This study demonstrated that noninvasive CMF technology healed 78% of tibial fracture nonunions and 45% of all fracture nonunions (p = 0.004). Additionally, pain at rest, with stress, and on weight bearing all decreased following treatment with CMF, with no adverse events reported. These results indicate that CMF is a beneficial noninvasive treatment modality for nonunions.

Vertebral fractures place significant burdens on patients, caregivers, and the healthcare system at large. Nonunion is a frequent complication following vertebral fracture treatment, often resulting in significant patient pain and morbidity. Bone growth stimulators are an adjunct treatment modality proposed to increase rates of fracture healing. Combined magnetic field (CMF) bone growth stimulators have specifically been shown to increase union rates in patients with vertebral fractures. Certain populations, such as the elderly, postmenopausal women, and smokers, have demonstrated a preferentially greater response to CMF treatment. The present review focuses on the mechanism of action, efficacy, cost effectiveness, indications, contraindications, and safety of CMF treatment as an adjunct treatment for vertebral fractures. Future large high-quality investigations of adjunct CMF treatment for spine fusion patients focusing on patient-important outcomes are warranted.

The term Big Data has come to encompass a number of concepts and uses within medicine. This paper lays out the relevance and application of large collections of data in the radiation oncology community. We describe the potential importance and uses in clinical practice. The important concepts are then described and how they have been or could be implemented are discussed. Impediments to progress in the collection and use of sufficient quantities of data are also described. Finally, recommendations for how the community can move forward to achieve the potential of big data in radiation oncology are provided.

Intimate partner violence (IPV) refers to behavior by an intimate partner or ex-partner that causes physical, sexual or psychological harm, including physical aggression, sexual coercion, psychological abuse, and controlling behaviors.1 IPV is a human rights violation that affects men and women of all walks of life and is pervasive worldwide. More than one third of female homicides globally are perpetrated by an intimate partner,2 and IPV is a prevalent source of non-fatal injury to women.3 To address the need for health care professionals to assist victims of abuse, multiple IPV screening, identification, advocacy, and assistance programs have been developed and implemented across different clinical settings. A variety of research methodologies and outcome measures have been used to evaluate each program’s effectiveness. The results of these studies are often inconclusive and frequently conflicting, resulting in a high level of clinical uncertainty and controversy regarding the merits of IPV screening and assistance programs.4-6 Because of the clinical importance of IPV, controversies in the field, and the need for high quality evidence to resolve these controversies, it is important to focus on the quality of research including reporting quality. Quality of reporting is paramount when presenting clinical findings in published research to ensure that we have the highest quality of evidence on this important topic. Poorly reported clinical findings can result in a number of potential pitfalls, including confusion of the methodology used or selective reporting of study results.7,8 High quality reporting is a key aspect of research transparency. Studies that are inadequately reported may also score poorly on risk of bias assessments due to lack of clarity in the published manuscript.9 The Consolidated Standards of Reporting (CONSORT) checklist is a tool that aims to standardize the way in which randomized trials are reported in the literature to ensure transparency.7 Other checklists for other study designs have also been developed for the same purpose, including Strengthening Reporting of Observational Studies in Epidemiology (STROBE) for observational studies,10,11 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for systematic reviews,12,13 and others. The use of these reporting guidelines and checklists may aid in the appropriate reporting of research, which is of increased importance in fields that have controversies and complex methodological issues, such as intimate partner violence. The primary objective of this systematic review is to assess the reporting quality of published IPV studies. Our overarching goal is to determine which aspects of reporting are commonly deficient so that we can make recommendations to improve the transparency and clarity of IPV research in the future.

Background: Although proton radiation treatments are more costly than photon/X-ray therapy, they may lower overall treatment costs through reducing rates of severe toxicities and the costly management of those toxicities. To study this issue, we created a decision-model comparing proton vs. X-ray radiotherapy for locally advanced non-small cell lung cancer patients. Methods: An influence diagram was created to model for radiation delivery, associated 6-month pneumonitis/esophagitis rates, and overall costs (radiation plus toxicity costs). Pneumonitis (age, chemo type, V20, MLD) and esophagitis (V60) predictors were modeled to impact toxicity rates. We performed toxicity-adjusted, rate-adjusted, risk group-adjusted, and radiosensitivity analyses. Results: Upfront proton treatment costs exceeded that of photons [$16,730.37 (3DCRT), $23,893.83 (IMRT), $41,061.80 (protons)]. Based upon expected population pneumonitis and esophagitis rates for each modality, protons would be expected to recover $1,065.62 and $1,139.63 of the cost difference compared to 3DCRT or IMRT. For patients treated with IMRT experiencing grade 4 pneumonitis or grade 4 esophagitis, costs exceeded patients treated with protons without this toxicity. 3DCRT patients with grade 4 esophagitis had higher costs than proton patients without this toxicity. For the risk group analysis, high risk patients (age 65, carboplatin/paclitaxel) benefited more from proton therapy. A biomarker may allow patient selection for proton therapy, although the AUC alone is not sufficient to determine if the biomarker is clinically useful. Conclusions: The comparison between proton and photon/X-ray radiation therapy for NSCLC needs to consider both the up-front cost of treatment and the possible long term cost of complications. In our analysis, current costs favor X-ray therapy. However, relatively small reductions in the cost of proton therapy may result in a shift to the preference for proton therapy.

Purpose The review of a radiation therapy plan by a physicist prior to treatment is a standard tool for ensuring the quality of treatments. However, little is known about how well this task is performed in practice. The goal of this study is to present a novel method to measure the effectiveness of physics plan review by introducing simulated errors into computerized "mock" treatment charts and measuring the performance of plan review by physicists. Methods We generated six simulated treatment charts containing multiple errors. To select errors, we compiled a list based on events from a departmental incident learning system and an international incident learning system (SAFRON). Seventeen errors with the highest scores for frequency and severity were included in the simulations included six mock treatment charts. Eight physicists reviewed the simulated charts as they would a normal pretreatment plan review, with each chart being reviewed by at least six physicists. There were 113 data points for evaluation. Observer bias was minimized using a simple error vs hidden error approach, using detectability scores for stratification. The confidence interval for the proportion of errors detected was computed using the Wilson score interval. Results Simulated errors were detected in 67% of reviews [58-75%] (95% confidence interval [CI] in brackets). Of the errors included in the simulated plans, the following error scenarios had the highest detection rates: an incorrect isocenter in DRR (93% [70-99%]), a planned dose different from the prescribed dose (92% [67-99%]) and invalid QA (85% [58-96%]). Errors with low detection rates included incorrect CT dataset (0%, [0-39%]) and incorrect isocenter localization in planning system (38% [18-64%]). Detection rates of errors from simulated charts were compared against observed detection rates of errors from a departmental incident learning system. Conclusions It has been notoriously difficult to quantify error and safety performance in oncology. This study uses a novel technique of simulated errors to quantify performance and suggests that the pretreatment physics plan review identifies some errors with high fidelity while other errors are more challenging to detect. These data will guide future work on standardization and automation. The example process studied here was physics plan review, but this approach of simulated errors may be applied in other contexts as well and may also be useful for training and education purposes.

This paper presents an approach to evaluating the potential supply chain benefits of adopting continuous processing technologies for a diverse set of pharmaceutical products. The approach integrates upstream ‘continuous’ processing considerations for the production of active ingredients and final product formulation, with the downstream implications for packing and distribution. Currently, these upstream and downstream operations largely operate as decoupled operations with independent coordination and governance mechanisms, and the approach presented in this paper identifies opportunities for more case-specific integrated end-to-end supply chains enabled by continuous flow technologies. Three specific product (and corresponding processing technology) case studies are used to demonstrate the utility of the approach in assessing the supply network and system integration opportunities that emerge from the continuous processing of pharmaceutical products.

Adhesive capsulitis (AC) of the hip (i.e. 'Frozen Hip'), in part due to its difficulty in diagnosis, is an often overlooked and underappreciated entity of hip morbidity. This review aimed to elucidate a diagnostic approach and the surgical treatment options (with associated outcomes) of employing hip arthroscopy in the setting of AC. Electronic databases (EMBASE, MEDLINE and PubMed) were searched for available sources for all relevant clinical studies addressing the surgical management of AC. Additionally, reference lists of studies were hand-searched to find all relevant articles. Articles were systematically screened in duplicate, with agreement and descriptive statistics presented. Ten studies satisfied inclusion criteria. A total of 40 patients (mean age of 47.1 ± 14.8 years) were included. Diagnosis of AC of the hip commonly encompassed a combination of: decreased joint capacity; hip pain exacerbated by weight bearing or activity; and progressive decrease in global range of motion. Diagnostic arthroscopy was utilized in nine patients, and successful diagnosis of AC was achieved in all nine patients. Common treatments included pressure dilation (11 cases) and manipulation under anesthesia (11 cases). AC continues to be a difficult clinical entity to diagnose. Similarities are seen between hip AC and shoulder AC as diagnosis is often a result of ruling out all other possible conditions, and treatment options and outcomes resemble those of the shoulder counterpart. With successful outcomes harping on timely diagnosis and effective treatment, the use of hip arthroscopy may be of benefit to achieving this.

Purpose: To investigate the impact of using spatiotemporal optimization, i.e., intensity-modulated spatial optimization followed by fractionation schedule optimization, to select the patient-specific fractionation schedule that maximizes the tumor biologically equivalent dose (BED) under dose constraints for multiple organs-at-risk (OARs). Methods: Spatiotemporal optimization was applied to a variety of lung tumors in a phantom geometry using a range of tumor sizes and locations. The optimal fractionation schedule for a patient using the linear-quadratic cell survival model depends on the tumor and OAR sensitivity to fraction size (α/β), the effective tumor doubling time (Td ), and the size and location of tumor target relative to one or more OARs (dose distribution). The authors used a spatiotemporal optimization method to identify the optimal number of fractions N that maximizes the 3D tumor BED distribution for 16 lung phantom cases. The selection of the optimal fractionation schedule used equivalent (30-fraction) OAR constraints for the heart (D mean ≤ 45 Gy), lungs (D mean ≤ 20 Gy), cord (D max ≤ 45 Gy), esophagus (D max ≤ 63 Gy), and unspecified tissues (D 05 ≤ 60 Gy). To assess plan quality, the authors compared the minimum, mean, maximum, and D 95 of tumor BED, as well as the equivalent uniform dose (EUD) for optimized plans to conventional intensity-modulated radiation therapy plans prescribing 60 Gy in 30 fractions. A sensitivity analysis was performed to assess the effects of Td (3–100 days), tumor lag-time (Tk = 0–10 days), and the size of tumors on optimal fractionation schedule. Results: Using an α/β ratio of 10 Gy, the average values of tumor max, min, mean BED, and D 95 were up to 19%, 21%, 20%, and 19% larger than those from conventional prescription, depending on Td and Tk used. Tumor EUD was up to 17% larger than the conventional prescription. For fast proliferating tumors with Td less than 10 days, there was no significant increase in tumor BED but the treatment course could be shortened without a loss in tumor BED. The improvement in the tumor mean BED was more pronounced with smaller tumors (p-value = 0.08). Conclusions: Spatiotemporal optimization of patient plans has the potential to significantly improve local tumor control (larger BED/EUD) of patients with a favorable geometry, such as smaller tumors with larger distances between the tumor target and nearby OAR. In patients with a less favorable geometry and for fast growing tumors, plans optimized using spatiotemporal optimization and conventional (spatial-only) optimization are equivalent (negligible differences in tumor BED/EUD). However, spatiotemporal optimization yields shorter treatment courses than conventional spatial-only optimization. Personalized, spatiotemporal optimization of treatment schedules can increase patient convenience and help with the efficient allocation of clinical resources. Spatiotemporal optimization can also help identify a subset of patients that might benefit from nonconventional (large dose per fraction) treatments that are ineligible for the current practice of stereotactic body radiation therapy.

The purpose of this study is to design and develop a probabilistic network for detecting errors in radiotherapy plans for use at the time of initial plan verification. Our group has initiated a multi-pronged approach to reduce these errors. We report on our development of Bayesian models of radiotherapy plans. Bayesian networks consist of joint probability distributions that define the probability of one event, given some set of other known information. Using the networks, we find the probability of obtaining certain radiotherapy parameters, given a set of initial clinical information. A low probability in a propagated network then corresponds to potential errors to be flagged for investigation. To build our networks we first interviewed medical physicists and other domain experts to identify the relevant radiotherapy concepts and their associated interdependencies and to construct a network topology. Next, to populate the network's conditional probability tables, we used the Hugin Expert software to learn parameter distributions from a subset of de-identified data derived from a radiation oncology based clinical information database system. These data represent 4990 unique prescription cases over a 5 year period. Under test case scenarios with approximately 1.5% introduced error rates, network performance produced areas under the ROC curve of 0.88, 0.98, and 0.89 for the lung, brain and female breast cancer error detection networks, respectively. Comparison of the brain network to human experts performance (AUC of 0.90 ± 0.01) shows the Bayes network model performs better than domain experts under the same test conditions. Our results demonstrate the feasibility and effectiveness of comprehensive probabilistic models as part of decision support systems for improved detection of errors in initial radiotherapy plan verification procedures.

Hip arthroscopy is becoming a common technique for the diagnosis and treatment of ligamentum teres pathologic conditions. This systematic review aims to determine the indications/contraindications, treatments, and surgical outcomes for management of ligamentum teres injuries.We searched EMBASE, MEDLINE, and PubMed databases from 1946 to November 28, 2013 for all relevant English articles pertaining to surgical treatment of the ligamentum teres. A hand search of the reference sections of included articles was performed, and all relevant articles were systematically screened in duplicate, with agreement and descriptive statistics presented.We identified 1,016 studies, 9 of which (4 case series and 5 case reports) met our eligibility criteria. These studies had a total of 87 patients (89 hips) who had undergone either arthroscopic debridement (81 patients, 83 hips) or reconstruction with autografting, allografting, or synthetic grafting (6 patients) of a torn ligamentum teres. Major qualifications for surgery included persistent hip pain despite conservative treatment and mechanical symptoms or instability symptoms (e.g., clicking or locking). Advanced arthritis (i.e., radiographic joint space2 mm) was the only reported contraindication. Patients were followed postoperatively for 1.5 to 60 months and were assessed using subjective methods (i.e., modified Harris Hip Score [mHHS] and Non-Arthritic Hip Score [NAHS]). Overall, both debridement and reconstruction improved the condition of patients, with a 40% increase in reported postoperative functional scores as well as a reported 89% of patients who were able to return to regular activity/sport.Ligamentum teres debridement is indicated for short-term relief of hip pain caused by partial-thickness tears (type 2) failing conservative management, whereas reconstruction with autografts, allografts, or synthetic grafts may be indicated for type 1 (full-thickness) ligamentum teres tears that are deemed "reparable," cause instability, have failed previous debridement, or a combination of these conditions.Level IV, systematic review of Level IV and Level V studies.

The collapse of confidence in anonymization (sometimes also known as de-identification) as a robust approach for preserving the privacy of personal data has incited an outpouring of new approaches that aim to fill the resulting trifecta of technical, organizational, and regulatory privacy gaps left in its wake. In the latter category, and in large part due to the growth of Big Data–driven biomedical research, falls a growing chorus of calls for criminal and penal offences to sanction wrongful re-identification of “anonymized” data. This chorus cuts across the fault lines of polarized privacy law scholarship that at times seems to advocate privacy protection at the expense of Big Data research or vice versa. Focusing on Big Data in the context of biomedicine, this article surveys the approaches that criminal or penal law might take toward wrongful re-identification of health data. It contextualizes the strategies within their respective legal regimes as well as in relation to emerging privacy debates focusing on personal data use and data linkage and assesses the relative merit of criminalization. We conclude that this approach suffers from several flaws and that alternative social and legal strategies to deter wrongful re-identification may be preferable.

To compare Knee Injury and Osteoarthritis Outcome Score (KOOS) and EuroQol-5D (EQ-5D) subscale scores at 2-year follow-up for patients with primary isolated ACL reconstruction with patients undergoing ACL reconstruction and simultaneous meniscal treatment in terms of either resection or repair in the Swedish National Knee Ligament Register (SNKLR). All ACL reconstruction patients within the SNKLR at 2-year follow-up were reviewed. The KOOS and EQ-5D subscales were assessed in four distinct patient groups: isolated ACL reconstruction, ACL reconstruction + medial meniscus resection, ACL reconstruction + lateral meniscus resection, ACL reconstruction + medial meniscus repair, and ACL reconstruction + lateral meniscus repair. The primary analysis was conducted using linear regression with isolated ACL reconstruction designated as the reference group, and was adjusted for patient age, gender, and time from injury to surgery. The included patients consisted of 10,001 (65.0%) individuals with an isolated ACL injury, 588 (3.8%) with ACL injury plus treated with medial meniscus repair, 2307 (15.0%) with ACL injury plus treated with medial meniscus resection, 323 (2.1%) with ACL injury plus treated with lateral meniscus repair, and 2173 (14.1%) with ACL injury plus treated with lateral meniscus resection. Meniscus resection demonstrated significantly worse results with respect to the KOOS Symptoms subscale for both the medial and lateral meniscus resection groups. Medial meniscus resection also demonstrated worse results for the KOOS quality of life (QoL) subscale, while lateral meniscus resection only approached significance. Outcomes were not different between the isolated ACL reconstruction group and the meniscus repair groups. Meniscus resection in addition to ACL reconstruction resulted in worse clinical outcomes than isolated ACL reconstruction patients; a result not seen within the meniscus repair group. This suggests that, when possible, meniscus repair may provide greater clinical outcomes over resection when treating a reparable meniscal tear that presents along with an ACL tear. Clinicians should consider and implement these findings for the management of future meniscus tear patients within their clinical practice. Level III.

© 2017, © The Author(s), 2017. Osteoarthritis (OA) is a chronic condition characterized by a loss of joint cartilage and is a major cause of disability in Canada, with an estimated CN$195 billion annual cost. Knee OA leads to persistent pain and loss of function, and treatment goals primarily focus on symptom relief and retention of function. Intra-articular hyaluronic acid (IAHA) has therapeutic benefits, and numerous recently published meta-analyses (MAs) and commentaries have highlighted new evidence on the role of IAHA therapy for knee OA. A diverse, multidisciplinary group of specialists met independently in closed sessions to review findings from eight MAs with literature search end dates no earlier than 2012 to address controversies surrounding IAHA therapy for mild-to-moderate knee OA within the Canadian treatment context. Outcomes from a total of eight MAs were reviewed, and consistent and statistically significant improvements in pain, function and stiffness up to 26 weeks were found with IAHA therapy compared with IA placebo or controls, regardless of MA size or trial quality. These findings are in line with those of a Cochrane review, another recent systematic review and patient satisfaction survey. Overall, three MAs reported outcomes based on molecular weight (MW), with the two reporting effect sizes showing significantly improved pain outcomes for higher compared with lower MW HAs. Recent evidence suggests that HA therapy is well tolerated with no increased risk of serious adverse events compared with placebo and the full therapeutic effect of IAHA therapy appears to have considerable clinical importance, consisting of the combined IA placebo and HA therapeutic effects. IAHA therapy is a well-tolerated and effective option for patients with mild-to-moderate knee OA failing first-line pharmacological therapy.

The use of noninvasive bone growth stimulators is a nonoperative treatment option for fracture nonunions. The purpose of this study was to evaluate the initial effectiveness of the combined magnetic field (CMF) bone growth stimulation in the treatment of fracture nonunions. Using data from a large nonunion fracture registry, we reviewed fracture-healing-outcome data and healing times for all patients treated with a CMF bone growth stimulator during a 4-yr period. Overall, 75% of the 2370 included patients achieved fracture union. Healing rates ranged from 64.0% in patients with femoral fractures to 89.7% in patients with carpal/metacarpal fractures. The weighted mean time to heal was 4.9 ± 1.0 mo. Patients treated earlier than 6 mo with CMF following injury demonstrated significantly greater healing rates and shorter mean times to heal than patients treated 6 mo or more following injury. These results indicate that CMF bone stimulation is a potentially beneficial noninvasive treatment modality for nonunions; however, high-quality comparative research is required to further evaluate the efficacy, potential prognostic factors, and contraindications for the use of this treatment modality.