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Resistance of acute lymphoblastic leukemia (ALL) cells to chemotherapy, whether present at diagnosis or acquired during treatment, is a major cause of treatment failure. Primary ALL cells are accessible for drug sensitivity testing at the time of new diagnosis or at relapse, but there are major limitations with current methods for determining drug sensitivity ex vivo. Here, we describe a functional precision medicine method using a fluorescence imaging platform to test drug sensitivity profiles of primary ALL cells. Leukemia cells are co-cultured with mesenchymal stromal cells and tested with a panel of 40 anti-leukemia drugs to determine individual patterns of drug resistance and sensitivity ("pharmacotype"). This imaging-based pharmacotyping assay addresses the limitations of prior ex vivo drug sensitivity methods by automating data analysis to produce high-throughput data while requiring fewer cells and significantly decreasing the labor-intensive time required to conduct the assay. The integration of drug sensitivity data with genomic profiling provides a basis for rational genomics-guided precision medicine. Key features Analysis of primary acute lymphoblastic leukemia (ALL) blasts obtained at diagnosis from bone marrow aspirate or peripheral blood. Experiments are performed ex vivo with mesenchymal stromal cell co-culture and require four days to complete. This fluorescence imaging-based protocol enhances previous ex vivo drug sensitivity assays and improves efficiency by requiring fewer primary cells while increasing the number of drugs tested to 40. It takes approximately 2-3 h for sample preparation and processing and a 1.5-hour imaging time. Graphical overview., Competing Interests: Competing interestsAll authors declare no competing interests., (©Copyright : © 2023 The Authors; This is an open access article under the CC BY-NC license.)

Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL. We identified six patient clusters based on ALL pharmacotypes, which were associated with event-free survival, even after adjusting for MRD. Pharmacotyping identified a T cell ALL subset with a poor prognosis that was sensitive to targeted agents, pointing to alternative therapeutic strategies. Our study comprehensively described the pharmacological heterogeneity of ALL, highlighting opportunities for further individualizing therapy for this most common childhood cancer., (© 2023. The Author(s).)

Objectives: To explore information seeking behavior on medical innovations., Background: While autologous and alloplastic options for breast reconstruction are well established, it is the advent of the combination of 3D printing technology and the biocompatible nature of a highly porous biodegradable implants that offers new treatment options for the future. While this type of prosthesis is not yet clinically available understanding how patients, surgeons, and nurses take up new medical innovations is of critical importance for efficient healthcare provision., Materials and Methods: Using the largest ever combined sample of breast cancer patients (n = 689), specialist surgeons (n = 53), and breast care nurses (n = 101), we explore participants preference for a new surgical treatment concept rooted in 3D printed and biodegradable implant technologies in the context of breast reconstruction., Results: We find that patients overwhelmingly favor information from a successful patient of the proposed new technology when considering transitioning. Surgeons and nurses instead favor regulatory body advice, peer-reviewed journals, and witnessing the procedure performed (either in person or online). But while 1 in 4 nurses nominated talking to a successful patient as an information source, not a single surgeon chose the same. Our multinomial logit analysis exploring patient preference (controlling for individual differences) showed statistically significant results for both the type of surgical treatment and choice to undergo reconstruction. Women who underwent a type of mastectomy procedure (compared with lumpectomy patients) were more likely to choose a former patient than a surgeon for seeking information relating to a new breast implant technology. Further, women who chose to undergo a reconstruction procedure, compared with those who did not, where more likely to prefer a surgeon for information relating to a new breast implant technology, rather than a successful patient. For medical professionals, we find no statistically significant relationship between medical professionals' preference and their age, nor the number of other medical professionals they work with daily, nor the average number of breast procedures performed in their practice on a weekly basis., Conclusions: As our findings show large variation exists (both within our patient group and compared with medical professionals) in where individuals favor information on new medical innovations, future behavioral research is warranted., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Understanding how medical experts and their patients process and transfer information is of critical importance for efficient health care provision. Behavioral economics has explored similar credence markets where economic incentives, information asymmetry, and cognitive bias can impact patient and surgeon choice. The aim of the current study is to explore how framing and behavioral bias affect elective restorative surgery decision-making, such as breast reconstruction following cancer treatment., Methods: The authors' study uses a cross-sectional survey data set of specialist surgeons (n = 53), breast care nurses (n = 101), and former or current breast cancer patients (n = 689). Data collected include participant demographics, medical history, a battery of cognitive bias tests, and a behavioral framing experiment., Results: This study finds statistically significant differences in breast reconstruction surgery preference by patients and nurses when decision options are framed in different ways (i.e., positively versus negatively). The authors' analysis of surgeons, nurses, and patients shows no statistically significant difference across eight common forms of cognitive bias. Rather, the authors find that the behavioral biases are prevalent to the same extent in each group. This may indicate that differences in experience and education seem not to mitigate biases that may affect patient choices and medical professional's recommendations. The authors' multivariate analysis identifies patient age (p < 0.0001), body mass index, and self-perceived health (p < 0.05) as negative correlates for choice of implant-based reconstruction., Conclusion: For surgeons, nurses, and patients, the authors find uniform evidence of cognitive bias; more specifically, for patients and nurses, the authors find inconsistency in preference for type of surgical therapy chosen when alternative procedures are framed in different ways (i.e., framing bias)., Competing Interests: Disclosure:Dr. Hutmacher is a founder and shareholder of BellaSeno GmbH. All other authors declare no financial or material conflict of interest. Data and code are available on request of the corresponding author. There is no external funding to declare., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Aberrant activation of the JAK-STAT signaling pathway has been implicated in the pathogenesis of a range of hematological malignancies and autoimmune disorders. Here we describe the design, synthesis, and characterization of JAK2/3 PROTACs utilizing a phenyl glutarimide (PG) ligand as the cereblon (CRBN) recruiter. SJ10542 displayed high selectivity over GSPT1 and other members of the JAK family and potency in patient-derived ALL cells containing both JAK2 fusions and CRLF2 rearrangements., Competing Interests: The authors declare the following competing financial interest(s): J.J.Y. receives research funding from Takeda Pharmaceutical Company. C.G.M. has received research funding from AbbVie and Pfizer; consulting fees from Illumina and speaking fees and holds equity in Amgen. Z.R. receives consulting fees from Revolution Medicines, Orum Therapeutics, and Nyrada, Inc., (© 2022 American Chemical Society.)

Currently there are limited implant-based options for cosmetic breast augmentation, and problems associated with those have been increasingly appreciated, most commonly capsular contracture, which occurs due to a chronic foreign body reaction against non-degradable implant materials such as silicone and polyurethane leading to scar tissue formation, pain, and deformity. The underlying biomechanical concepts with implants create a reciprocal stress-strain relationship with local tissue, whilst acting as a deforming force. This means that with time, as the implant continues to have an effect on surrounding tissue the implant and host's biomechanical properties diverge, making malposition, asymmetry, and other complications more likely. Research directed towards development of alternative therapies based on tissue engineering and regenerative medicine seeks to optimize new tissue formation through modulation of tissue progenitors and facilitating tissue regeneration. Scaffolds can guide the process of new tissue formation by providing both an implant surface and a three-dimensional space that promotes the development of a microenvironment that guides attachment, migration, proliferation, and differentiation of connective tissue progenitors. Important to scaffold design are the architecture, surface chemistry, mechanical properties, and biomaterial used. Scaffolds provide a void in which vascularization, new tissue formation, and remodelling can sequentially occur. They provide a conduit for delivery of the different cell types required for tissue regeneration into a graft site, facilitating their retention and distribution. Whilst recent research from a small number of groups is promising, there are still ongoing challenges to achieving clinical translation. This article summarizes the biomechanical principles of breast implants, how these impact outcomes, and progress in scaffold-guided tissue engineering approaches to cosmetic breast augmentation. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

The use of animals as models of human physiology is, and has been for many years, an indispensable tool for understanding the mechanisms of human disease. In Parkinson's disease, various mouse models form the cornerstone of these investigations. Early models were developed to reflect the traditional histological features and motor symptoms of Parkinson's disease. However, it is important that models accurately encompass important facets of the disease to allow for comprehensive mechanistic understanding and translational significance. Circadian rhythm and sleep issues are tightly correlated to Parkinson's disease, and often arise prior to the presentation of typical motor deficits. It is essential that models used to understand Parkinson's disease reflect these dysfunctions in circadian rhythms and sleep, both to facilitate investigations into mechanistic interplay between sleep and disease, and to assist in the development of circadian rhythm-facing therapeutic treatments. This review describes the extent to which various genetically- and neurotoxically-induced murine models of Parkinson's reflect the sleep and circadian abnormalities of Parkinson's disease observed in the clinic., (© 2021. The Author(s).)

Background: The presentation of a child with an abnormal head shape can be challenging and should be met with an appropriate clinical approach. Craniosynostosis is a common cause of paediatric skull deformity and is best managed by a multispecialty tertiary referral unit with regular follow-up. As craniosynostosis frequently requires time-sensitive surgery, it is important to differentiate between craniosynostosis and common self-limiting conditions such as deformational plagiocephaly., Objective: The aim of this article is to outline the clinical approach to paediatric skull deformity in the general practice setting, and to highlight the importance of early referral if there is clinical suspicion of craniosynostosis., Discussion: Parental concern regarding infant head shape is common. General practitioners (GPs) have an important role in assessment, diagnosis and referral for paediatric skull deformities. GPs are well placed to clinically differentiate between deformational plagiocephaly and craniosynostosis and provide timely referrals to optimise patient outcomes.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia' drug sensitivities ex vivo , we discovered that 44.4% of childhood and 16.7% of adult T-ALL cases exquisitely respond to dasatinib. Applying network-based systems pharmacology analyses to examine signal circuitry, we identified preTCR-LCK activation as the driver of dasatinib sensitivity, and T-ALL-specific LCK dependency was confirmed in genome-wide CRISPR-Cas9 screens. Dasatinib-sensitive T-ALLs exhibited high BCL-XL and low BCL2 activity and venetoclax resistance. Discordant sensitivity of T-ALL to dasatinib and venetoclax is strongly correlated with T-cell differentiation, particularly with the dynamic shift in LCK vs. BCL2 activation. Finally, single-cell analysis identified leukemia heterogeneity in LCK and BCL2 signaling and T-cell maturation stage, consistent with dasatinib response. In conclusion, our results indicate that developmental arrest in T-ALL drives differential activation of preTCR-LCK and BCL2 signaling in this leukemia, providing unique opportunities for targeted therapy.

Background: Children who undergo bi-fronto-orbital advancement (BFOA) frequently develop a contour deformity on the temporal and supra-orbital region, with an incidence reported as high as 55% and 75%, respectively. Up to 20% of patients may require correction. Hydroxyapatite cement (HAC) is a good alternative to autogenous tissue. The available literature on its use focusses on the reconstruction of bone defects, but little has been published on its efficacy and safety as an onlay graft over intact cranium., Objectives: To describe our institution's experience with HAC in the pediatric population., Methods: Retrospective chart review from 1998 to 2018 on all patients from the Craniofacial Unit at the Sydney Children's Hospital who had either coronal or metopic craniosynostosis and underwent BFOA and later in life required cranioplasty with HAC for contour repair., Findings: We have performed 166 BFOA and nineteen secondary cranioplasties for contour repair using onlay HAC. The mean age at the time of operation was 14 years. Bi-coronal craniosynostosis was most frequently associated with secondary cranioplasty and 37% had an associated syndrome. The mean volume of HAC used was 37 mL. There was only 1 patient who had a complication (5.3%) and required partial removal of allograft. The mean length of admission was 2 days. Mean follow up time of 22.4 months., Conclusions: HAC represents a safe option when used correctly, with low rates of complication and satisfactory cosmetic outcomes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

The treatment of non-syndromic scaphocephaly with spring-activated cranioplasty offers acceptable outcomes with the potential for reduced surgical morbidity when compared with cranial vault remodelling procedures. A disadvantage of this technique is the need for a second operative intervention to remove the implanted devices. There are many descriptions of the surgical technique for performing spring-activated cranioplasty available in the literature; however, little is documented regarding the procedures used for device removal. The published accounts of spring removal demonstrate a wide range of approaches, from the reopening and dissection of the entire previous surgical field, to attempts to limit the incisions and dissection. In this study we describe our technique for the minimally invasive removal of cranial springs used in the treatment of scaphocephaly. Our technique focuses on minimal soft tissue disruption and uses a Kirschner wire cutter to divide the spring at its mid-point so as to relieve any residual internal forces acting on the footplates., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background: Premature fusion of the sagittal (midline) suture between 2 parietal bones is the most common form of craniosynostosis. Surgical correction is mandated to improve head shape and to decrease the risk of raised intracranial pressure. This study evaluated the utility of 3-dimensional (3D) imaging to quantify the volumetric changes of surgical correction. Currently there is no standardized method used to quantify the outcomes of surgery for craniosynostosis, with the cranial index (width: length ratio) being commonly used., Methods: A method for quantification of head shape using 3D imaging is described in which the cranium is divided up into 6 compartments and the volumes of 6 compartments are quantified and analyzed. The method is size invariant, meaning that it can be used to assess the long-term postoperative outcomes of patients through growth. The method is applied to a cohort of sagittal synostosis patients and a normal cohort, and is used to follow up a smaller group of synostotic patients 1, 2, and 3 years postoperatively., Results: Statistical analysis of the results shows that the 6-compartment volume quantification method is more accurate in separating normal from synostotic patient head shapes than the cranial index., Conclusions: Spring-mediated cranioplasty does not return head shape back to normal, but results in significant improvements in the first year following surgery compared with the preoperative sagittal synostosis head shape. 3D imaging can be a valuable tool in assessing the volumetric changes due to surgery and growth in craniosynstosis patients.

The explored kinome was extended with broad profiling using the DiscoveRx and Millipore assay panels. The analysis of the profiling of 3368 selected inhibitors on 456 kinases in the DiscoveRx format delivered several insights. First, the coverage depended on the threshold of the selectivity parameter. Second, the relation between hit confirmation rates and inhibitor selectivity showed unexpectedly that higher selectivity can increase the likelihood of false positives. Third, comparing the coverage of a focused to that of a random library showed that the design based on a maximum number of scaffolds was superior to a limited number of scaffolds. Therefore, selective compounds can be used in target validation, enable the jumpstarting of new kinase drug discovery projects, and chart new biological space via phenotypic screening., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The medical charts of 267 patients who had primary high-superficial musculoaponeurotic system (SMAS) rhytidectomies were reviewed. The depth of the nasolabial fold was used as an indicator of the degree of descent of the subcutaneous cheek mass, as a guide in procedure selection, and as a method of judging the operative results. Fold depth was assigned a score of 0 to 3, with 3 being most severe. According to their preoperative fold depth, patients were operated on using one of three variants of the high-SMAS technique: sub-SMAS dissection up to the nasolabial fold, sub-SMAS dissection up to the nasolabial fold plus transnasal SMAS graft, or sub-SMAS dissection across the nasolabial fold. An independent trained observer rated the postoperative fold depth in each case from photographs taken at the 6-month follow-up visit. Of patients with fold scores of 2 or 3, 97 percent (183 of 189 patients) showed visible improvement in nasolabial crease depth after the operation.