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This article, based upon pedagogical experimentation in development in a master-level architecture studio at the ULB School of Architecture (Brussels), focuses on the concept of a linear city in a metropolitan context. This concept is proposed by the Grand Tetouan (North Morocco) spatial development scheme as a framework to think about the future of this territory. The interest of the concept lies in its being both a descriptive and project-oriented tool, which allows working with students on the intricate relationship between these two moments of urban design. The coastal region has been the subject of a proposal for a “linear garden city” by a follower of Soria y Mata, Hilarión González del Castillo (1929), a project that left traces on the “palimpsest” (Corboz, 1983/2001) of the actual territory. The idea of the linear city, which has been, throughout the 20th century, a recurrent thematic in urban planning theory and practice dealing with the issue of industrial development of the modern city can be, in the specific case of the Grand Tetouan region, re-examined through the lens of tourism as an industry. The exploration is based on an analytical approach by the use of the notion of urban material (Boeri, Lanzani, & Marini, 1993; Viganò, 1999), an approach that creates the conditions of understanding (describing/designing) the existing territory through the mapping of its physical elements, a description that can then be used to develop an analysis of the forms of production of these elements and the complexity of their uses: how the city is, formally and socially, built (Secchi, 1989).

Abstract Many theoretical models predict when genetic evolution and phenotypic plasticity allow adaptation to changing environmental conditions. These models generally assume stabilizing selection around some optimal phenotype. We however often ignore how optimal phenotypes change with the environment, which limit our understanding of the adaptive value of phenotypic plasticity. Here, we propose an approach based on our knowledge of the causal relationships between climate, adaptive traits, and fitness to further these questions. This approach relies on a sensitivity analysis of the process‐based model Phenofit, which mathematically formalizes these causal relationships, to predict fitness landscapes and optimal budburst dates along elevation gradients in three major European tree species. Variation in the overall shape of the fitness landscape and resulting directional selection gradients were found to be mainly driven by temperature variation. The optimal budburst date was delayed with elevation, while the range of dates allowing high fitness narrowed and the maximal fitness at the optimum decreased. We also found that the plasticity of the budburst date should allow tracking the spatial variation in the optimal date, but with variable mismatch depending on the species, ranging from negligible mismatch in fir, moderate in beech, to large in oak. Phenotypic plasticity would therefore be more adaptive in fir and beech than in oak. In all species, we predicted stronger directional selection for earlier budburst date at higher elevation. The weak selection on budburst date in fir should result in the evolution of negligible genetic divergence, while beech and oak would evolve counter‐gradient variation, where genetic and environmental effects are in opposite directions. Our study suggests that theoretical models should consider how whole fitness landscapes change with the environment. The approach introduced here has the potential to be developed for other traits and species to explore how populations will adapt to climate change.

Abstract Background Evidence from clinical trials suggests that the addition of bevacizumab to chemotherapy in the first-line treatment of patients with HER2-negative metastatic breast cancer improves progression-free survival (PFS) but not overall survival (OS). However, a retrospective analysis of real-world data from the French Comprehensive Cancer Centers (FCCC) through the Epidemiological Strategy and Medical Economics (ESME) Research Program, suggested that in this setting, the addition of bevacizumab may confer a significant benefit in terms of both PFS and OS. A cost-effectiveness analysis was performed to determine the cost-effectiveness of bevacizumab plus paclitaxel versus paclitaxel alone in the first-line treatment of HER2-negative metastatic breast cancer at specialist oncology centers in France. Methods The analysis was performed using a three-state Markov model and clinical input data from N = 3426 HER2-negative metastatic breast cancer patients treated with bevacizumab plus paclitaxel or paclitaxel alone. The analysis was performed from a third party payer perspective over a 10-year time horizon; future costs and clinical outcomes were discounted at 4% per annum. Results In the overall population, the addition of bevacizumab to paclitaxel led to incremental gain of 0.72 life years and 0.48 quality-adjusted life years (QALYs) relative to paclitaxel alone. The incremental lifetime cost of the addition of bevacizumab was EUR 27,390, resulting in an incremental cost-effectiveness ratio (ICER) of EUR 56,721 per QALY gained for bevacizumab plus paclitaxel versus paclitaxel alone. In a subgroup of triple negative patients the ICER was EUR 66,874 per QALY gained. Conclusions The analysis indicated that the combination of bevacizumab plus paclitaxel is likely to be cost-effective compared with paclitaxel alone for the first-line treatment of HER2-negative metastatic breast cancer in specialized oncology centers in France.

The aim of the study is to evaluate the cost-effectiveness of alectinib for first-line treatment of ALK+ advanced non-small-cell lung cancer compared to crizotinib in the French setting. This study used a partitioned survival model, with three discrete health states (progression-free survival, post-progression survival and death). Survival probabilities were derived from a randomised Phase III clinical trial comparing alectinib to crizotinib (ALEX). Beyond the length of the trial (18 months), the efficacy of both treatments was considered equivalent. Occurrence of adverse events or brain metastases were considered as inter-current events. Utilities (and disutilities for intercurrent adverse events) derived from the EQ-5D were applied. Costs were attributed using standard French national public health tariffs. Projected mean overall survival was 4.62 years for alectinib and 4.18 years for crizotinib. Projected mean progression-free survival was 30.30 months for alectinib and 16.13 months for crizotinib. The total number of quality-adjusted life years projected was 3.40 for alectinib and 2.84 for crizotinib. The projected total cost of treatment over the lifetime of the model was € 246,022 for alectinib and € 195,486 for crizotinib. This extra cost was principally attributable to treatment acquisition costs and management before progression. Alectinib was associated with lower costs related to brain metastases and to management post-progression. The incremental cost per life year gained was 115,334 €/year and the incremental cost-effectiveness ratio was 90,232 €/QALY. First-line treatment of ALK+ NSCLC with alectinib provides superior clinical outcomes to crizotinib and is cost-effective in the French context.

The need for advancements in residential construction and the hazard induced by the shrink–swell reactive soil movement prompted the development of the prefabricated footing system of this study, which was assessed and compared to a conventional waffle raft using a multi-criteria analysis. The assessment evaluates the structural performance, cost efficiency, and sustainability using finite element modelling, life cycle cost analysis, and life cycle assessment, respectively. The structural performance of the developed prefabricated system was found to have reduced the deformation and cracking by approximately 40%. However, the cost, GHG emission, and embodied energy were higher in the prefabricated footing system due to the greater required amount of concrete and steel than that of the waffle raft. The cost difference between the two systems can be reduced to as low as 6% when prefabricated systems were installed in a highly reactive sites with large floor areas. The life cycle assessment further observed that the prefabricated footing systems consume up to 21% more energy and up to 18% more GHG emissions. These can significantly be compensated by reusing the developed prefabricated footing system, decreasing the GHG emission and energy consumption by 75–77% and 55–59% with respect to that of the waffle raft.

Medial unicompartmental knee arthroplasty (UKA) has increased in popularity for the ​treatment of end-stage anteromedial osteoarthritis in part secondary to its quicker recovery, improved function, and decreased risk of medical complications over total knee arthroplasty (TKA). However, despite the success of medial UKA, dilemma still exists over certain patient characteristics as to suitability for undergoing the procedure. In addition to patient age, body mass index (BMI), and the presence, or lack thereof, of an anterior cruciate ligament (ACL), one of the most contentious issues surrounding suitability for medial UKA is the preoperative status of the patellofemoral joint (PFJ). This review aims to look at the historical factors leading to the current dilemma as well as recent evidence surrounding anterior knee pain and preoperative PFJ arthritis on the survivability and outcomes of medial UKA. This article will also evaluate other PFJ factors possibly affecting the outcome of medial UKA such as lateral patellar subluxation and lateral facet grooving, future perspectives that may influence the utilization of medial UKA such as cementless implants, and the choice of mobile versus fixed bearing articulations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Adolph Lombardi, Jr., MD reports a relationship with Zimmer Biomet that includes: consulting or advisory. Adolph Lombardi, Jr., MD (JIS Research Institute) reports a relationship with Total Joint Orthopedics that includes: consulting or advisory. Adolph Lombardi, Jr., MD (JIS Research Institute) reports a relationship with Firstkind that includes: funding grants. Adolph Lombardi, Jr., MD reports a relationship with Parvizi Surgical Innovations Research Institute that includes: equity or stocks and funding grants. Adolph Lombardi, Jr., MD (JIS Research Institute) reports a relationship with Recovery Rx that includes: funding grants. Adolph Lombardi, Jr., MD (JIS Research Institute) reports a relationship with SPR Therapeutics Inc that includes: funding grants. Adolph Lombardi, Jr., MD (JIS Research Institute) reports a relationship with Prescribe Fit that includes: equity or stocks and funding grants. Adolph Lombardi, Jr., MD reports a relationship with Smith and Nephew Inc that includes: funding grants. Adolph Lombardi, Jr., MD reports a relationship with SI-BONE Inc that includes: funding grants. Adolph Lombardi, Jr., MD reports a relationship with JIS Ventures that includes: equity or stocks. Adolph Lombardi, Jr., MD reports a relationship with Joint Development Corporation that includes: equity or stocks. Adolph Lombardi, Jr., MD reports a relationship with Operation Walk USA that includes: board membership. Adolph Lombardi, Jr., MD reports a relationship with Central Ohio Orthopaedic Management Company that includes: board membership. Adolph Lombardi, Jr. MD reports a relationship with Current Concepts in Joint Replacement that includes: board membership. Keith Berend, MD reports a relationship with Medacta USA INC that includes: speaking and lecture fees. Keith Berend, MD reports a relationship with Smith and Nephew Inc that includes: funding grants and speaking and lecture fees. Keith Berend, MD (JIS Research Institute) reports a relationship with Zimmer Biomet that includes: funding grants. Keith Berend (JIS Research Institute) reports a relationship with Total Joint Orthopedics that includes: funding grants. Keith Berend, MD (JIS Research Institute) reports a relationship with Firstkind that includes: funding grants. Keith Berend, MD (JIS Research Institute) reports a relationship with Parvizi Surgical Innovations Research Institute that includes: equity or stocks and funding grants. Keith Berend, MD (JIS Research Institute) reports a relationship with Recovery Rx that includes: funding grants. Keith Berend, MD (JIS Research Institute) reports a relationship with Prescribe Fit that includes: equity or stocks and funding grants. Keith Berend, MD reports a relationship with SPR Therapeutics that includes: funding grants. Keith Berend, MD (JIS Research Institute) reports a relationship with SI-BONE Inc that includes: funding grants. Keith Berend, MD reports a relationship with JIS Ventures that includes: equity or stocks. Keith Berend, MD reports a relationship with Joint Development Corporation that includes: equity or stocks. Adolph Lombardi, Jr., MD has patent with royalties paid to Zimmer Biomet. Adolph Lombardi, Jr., MD has patent with royalties paid to Innomed. Publications Editorial Boards (Adolph Lombardi, Jr., MD): Journal of Arthroplasty; Journal of Bone and Joint Surgery; Clinical Orthopaedics and Related Research; Journal of the American Academy of Orthopaedic Surgeons; Journal of Orthopaedics and Traumatology; Surgical Technology International; The Knee; The Bone & Joint Journal Publications Editorial Boards (Keith Berend, MD): Journal of Arthroplasty; Reconstructive Review. Todd Bertrand, MD, MBA; Patricia Melvin, MD, MBS have no known competing financial interests or personal relationships to declare that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Partner notification services (PNS) offers opportunities to discuss HIV pre-exposure prophylaxis (PrEP) and provide referrals. We evaluated the PrEP care cascade among men who have sex with men (MSM) engaging in PNS within a sexually transmitted infections clinic. Among 121 MSM eligible for PrEP during PNS, 21% subsequently initiated PrEP.

Objectives: PNS is critical to prevent the spread of STIs. We evaluated the feasibility of integrating PNS into an STI clinic focused on MSM., Design/methods: The RI STI Clinic, in partnership with the RIDOH, implemented a PNS program in 2019. Interviews with patients diagnosed with gonorrhea/ syphilis were conducted. RIDOH attempted outreach to partners identified. We utilized interview data among MSM diagnosed with gonorrhea/syphilis in clinic from 1/1/19-12/31/2021. Bivariate analyses/multivariable logistic regression were conducted., Results: 341 MSM were diagnosed with gonorrhea/syphilis during the three-year period, and 233 (68%) interviews were completed. Partner information was provided in 173 (74%) interviews. At least one workable partner was provided in 110 (47%) interviews. No statistically significant associations between provision of workable partners and index patient age/race/ethnicity were found., Conclusions: PNS at an STI clinic was successful, but challenges led to suboptimal information. Research is needed to identify barriers to integrate/optimize PNS in STI clinics.

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients ( n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.

Background: Extraskeletal osteosarcoma is an extremely rare disease, comprising less than 0.1% of all cancers diagnosed in the United States, of which less than 5% occur in the upper extremities. The management of two cases of pediatric upper extremity extraskeletal osteosarcoma is discussed., Case Description: Two children initially noticed painless left upper extremity masses at the ages of 16 and 13, respectively. Following a period of several months, both lesions became symptomatic, necessitating operative intervention, which revealed giant cell-rich extraskeletal osteosarcoma; PET staging following gross total resection revealed no residual or metastatic disease in either patient. After extensive discussion with the patients and family, adjuvant chemotherapy was initiated for one patient, and adjuvant radiation therapy was initiated in both patients., Conclusions: Despite the rarity of these tumors, the importance of radiation therapy has been established by current and ongoing studies such as the Children's Oncology Group study ARST0332. Radiation therapy remains an important component of the multimodality therapy comprising optimal treatment of this disease, despite the relative paucity of long-term outcome data derived from level I evidence., (© 2019 Wiley Periodicals, Inc.)

The authors report an osteoblastoma-like variant of osteosarcoma of the right ischial tuberosity in a 14-year-old boy. Radiographs initially showed a bone-forming lesion of the right ischial tuberosity. The patient underwent biopsy with curettage and bone grafting, with final pathology revealing osteoblastoma. Two years after the initial procedure, he presented with exuberant bone formation about the operative site concerning for recurrence. He underwent a second biopsy that showed transformation into a high-grade osteoblastoma-like osteosarcoma. Results from staging studies were negative for distant metastatic disease. The patient was treated with standard 3-drug chemotherapy along with wide resection of the right ischium with periacetabular reconstruction and total hip arthroplasty. [Orthopedics. 2019; 42(3):e343-e345.]., (Copyright 2019, SLACK Incorporated.)

Calcaneal tuberosity fractures comprise only 1% to 2% of all calcaneal fractures. Treatment of these injuries has traditionally included open reduction and internal fixation with various means including lag screws, suture anchors, and K-wires. This article reports on a series of cases treated with excision of the tuberosity fragment with repair of the Achilles tendon supplemented by a flexor hallucis longus tendon transfer.

Background: Long-term survival for all patients with osteosarcoma using current aggressive adjuvant chemotherapy and surgical resection is between 60% and 70%. In patients who present with nonmetastatic, high-grade extremity osteosarcoma of bone, limb salvage surgery is favored, when appropriate, over amputation to preserve the limb, because limb salvage may lead to a superior quality of life compared with amputation. However, concern remains that in the attempt to preserve the limb, close or microscopically positive surgical margins may have an adverse effect on event-free survival., Questions/purposes: (1) Does a positive or close surgical margin increase the likelihood of a local recurrence? (2) Does a positive or close surgical margin adversely affect the development of metastatic disease? (3) What is the relationship of surgical margin on overall survival?, Methods: With institutional review board approval, we retrospectively evaluated 241 patients treated at our institution between 1999 and 2011. Exclusion criteria included nonextremity locations, metastatic disease at initial presentation, low- or intermediate-grade osteosarcoma, treatment regimens that did not follow National Comprehensive Cancer Network (NCCN) guidelines, incomplete medical records, and any part of treatment performed outside of Moffitt Cancer Center or All Children's Hospital. Fifty-one patients were included in the final analysis, of whom 31 (61%) had followup data at a minimum of 2 years or whose clinical status was known but had died before 2 years of followup. Margin status was defined as (1) microscopically positive; (2) negative ≤ 1 mm; and (3) negative > 1 mm. Margin status, histologic response (tumor percent necrosis), type of osteosarcoma, type of surgery, presence of local recurrence, metastatic disease, and overall survival were recorded for each patient. The mean age was 22 years (range, 12-74 years) and the mean followup was 3 years (range, 0.1-14 years). Margin status was positive in 10% (five of 51), negative ≤ 1 mm 26% (13 of 51), and negative > 1 mm 65% (33 of 51)., Results: Local recurrence was noted to be 14% (seven of 51) at 3.4 years. After controlling for relevant confounding variables, the presence of a positive margin compared with a negative margin > 1 mm was the only independent predictor of local recurrence (hazard ratio [HR], 8.006; 95% confidence interval [CI], 1.314-48.781; p = 0.0241). At a mean of 3.4 years, 29% (15 of 51) of the patients developed metastatic disease with no difference with the numbers available in the probability of developing metastatic disease among the three margin groups (p = 0.614). Overall survival at 3.8 years was 75% (38 of 51). After controlling for relevant confounding variables, we found that patients with positive margins were more likely to die from disease than those with negative margins (HR, 6.26; 95% CI, 1.50-26.14; p = 0.0119); no other independent predictors of survival were identified., Conclusions: With the numbers of patients we had, we observed that patients with extremity, nonmetastatic, high-grade osteosarcoma who had positive margins showed a higher probability of local recurrence in comparison to those with negative surgical margins. Given that positive margins appear to be associated with poorer survival in patients with high-grade osteosarcoma of the extremities, surgeons should strive to achieve negative margins, but larger studies are needed to confirm these findings., Level of Evidence: Level III, therapeutic study.