Biologic and clinical analysis of childhood gamma delta T-ALL identifies LMO2/STAG2 rearrangements as extremely high-risk.

Acute lymphoblastic leukemia expressing the gamma delta T cell receptor (yo T-ALL) is a poorly understood disease. We studied 200 children with yo T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. yo T-ALL diagnosed in children under three years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by Poly(ADP-ribose) polymerase (PARP) inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric yo T-ALL.

Immunogenicity of COVID-19 vaccines in patients with follicular lymphoma receiving frontline chemoimmunotherapy.

Immune responses to primary COVID-19 vaccination were investigated in 58 patients with follicular lymphoma (FL) as part of the PETReA trial of frontline therapy (EudraCT 2016-004010-10). COVID-19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after cytoreductive treatment comprising rituximab (depletes B cells) and either bendamustine (depletes CD4+ T cells) or cyclophosphamide-based chemotherapy. Blood samples obtained after vaccine doses 1 and 2 (V1, V2) were analysed for antibodies and T cells reactive to the SARS-CoV-2 spike protein using the Abbott Architect and interferon-gamma ELISpot assays respectively. Compared to 149 healthy controls, patients with FL exhibited lower antibody but preserved T-cell responses. Within the FL cohort, multivariable analysis identified low pre-treatment serum IgA levels and V2 administration during induction or maintenance treatment as independent determinants of lower antibody and higher T-cell responses, and bendamustine and high/intermediate FLIPI-2 score as additional determinants of a lower antibody response. Several clinical scenarios were identified where dichotomous immune responses were estimated with >95% confidence based on combinations of predictive variables. In conclusion, the immunogenicity of COVID-19 vaccines in FL patients is influenced by multiple disease- and treatment-related factors, among which B-cell depletion showed differential effects on antibody and T-cell responses.

A Qualitative Enquiry of On-Farm Rules About Quad Bikes (ATVs): How Rules Are Determined and Implemented at a Farm Level in Rural Australia.

OBJECTIVE: Quad bikes are a leading cause of death and incident-related injury on farms, yet little is understood about rules used by farmers to ensure their safe operation. This study explored rules about quad bikes set by those who live or work on farms. Through the case of quad bikes, this study sought to understand how rules are determined and implemented at the farm level. SETTING: A mix of farm types and locations in rural Australia including Queensland, South Australia, and New South Wales. PARTICIPANTS: Eight farmers were interviewed and recruited from information sheets at farmers' markets, through a local health organisation, and a media release. DESIGN: Thematic analysis was used to transform data from eight semi-structured interviews with farmers in rural Australia. RESULTS: Data were distilled into two themes - "Rule content" described the explicit rules farmers had set on their properties, while the theme "Underlying rule principles" explored the values and norms which underpinned the creation and implementation of these rules. CONCLUSIONS: Through the case of quad bike rules, this study illustrated how rules are determined and implemented at the farm level. Perceptions of risk were tied to farmers being experts in their own environment and therefore able to mitigate risk. In contrast to injury data, reckless use of quad bikes was perceived to cause incidents, and this was the basis of rules for adults and children.

Exploring the impact of solar radiation on skin microbiome to develop improved photoprotection strategies.

The skin microbiome undergoes constant exposure to solar radiation (SR), with its effects on health well-documented. However, understanding SR's influence on host-associated skin commensals remains nascent. This review surveys existing knowledge on SR's impact on the skin microbiome and proposes innovative sun protection methods that safeguard both skin integrity and microbiome balance. A team of skin photodamage specialists conducted a comprehensive review of 122 articles sourced from PubMed and Research Gateway. Key terms included skin microbiome, photoprotection, photodamage, skin cancer, ultraviolet radiation, solar radiation, skin commensals, skin protection, and pre/probiotics. Experts offered insights into novel sun protection products designed not only to shield the skin but also to mitigate SR's effects on the skin microbiome. Existing literature on SR's influence on the skin microbiome is limited. SR exposure can alter microbiome composition, potentially leading to dysbiosis, compromised skin barrier function, and immune system activation. Current sun protection methods generally overlook microbiome considerations. Tailored sun protection products that prioritize both skin and microbiome health may offer enhanced defense against SR-induced skin conditions. By safeguarding both skin and microbiota, these specialized products could mitigate dysbiosis risks associated with SR exposure, bolstering skin defense mechanisms and reducing the likelihood of SR-mediated skin issues.

Biomechanical Comparison of Impaction Techniques and Cross-Sectional Femoral Stem Shapes for Cementless Total Hip Arthroplasty.

Introduction: Traditional mallet broaching and stem seating in cementless total hip arthroplasty (THA) can result in femoral stem misalignment, potentially reducing implant longevity. This study aimed to compare the pullout strength of cementless THA femoral stems with different cross-sectional designs achieved through the powered impactor method versus the traditional mallet method. Methods: The authors utilized 24 polyurethane foam femurs and two femoral bone preservation stems with different proximal cross-sectional shapes (double taper: ACTIS®, size 5; flat taper: TRI-LOCK®, size 5). A single orthopedic surgeon broached each femur from size 0 to size 5 using either the powered impactor or mallet impaction methods. Broaching time and component implantation times were recorded. A load-to-failure pullout strength test was conducted, and the ultimate pullout load was recorded. Results: The broaching time for the TRI-LOCK® stem showed a statistically significant difference between the two impaction methods (powered: 37±7 seconds, mallet: 75±29 seconds, F[3, 20] = 4.56, p = 0.002), but no statistically significant difference was detected for the ACTIS® stem between the two impaction methods (powered: 47±22 seconds, mallet: 59±9 seconds, F[3, 20] = 4.56, p = 0.304). There was a statistically significant difference in pullout strength between the two impaction groups, and this strength was influenced by the implant cross-sectional shape (ACTIS®: 774±75N versus 679±22N, F(3,20) = 16.38, p = 0.018; TRI-LOCK®: 616±57N versus 859±85N, F(3, 20) = 16.38, p <0.001). Conclusions: The technique used for femoral bone preparation (powered impactor versus mallet) and the cross-sectional design of the cementless femoral stem are crucial factors that affect initial stem stability and operation time.

Phaseolus vulgaris STP13.1 is an H+-coupled monosaccharide transporter, present in source leaves and seed coats, with higher substrate affinity at depolarized potentials.

Sugar transport proteins (STPs) are high-affinity H+-coupled hexose symporters. Recently, the contribution of STP13 to bacterial and fungal pathogen resistance across multiple plant species has garnered significant interest. Quantitative PCR analysis of source leaves, developing embryos, and seed coats of Phaseolus vulgaris L. (common bean) revealed that PvSTP13.1 was expressed in source leaves and seed coats throughout seed development. In contrast, PvSTP13.1 transcripts were detected at exceedingly low levels in developing embryos. To characterize the transport mechanism, PvSTP13.1 was expressed in Xenopus laevis oocytes, and inward-directed currents were analyzed using two-electrode voltage clamping. PvSTP13.1 was shown to function as an H+-coupled monosaccharide symporter exhibiting a unique high affinity for hexoses and aldopentoses at depolarized membrane potentials. Specifically, of the 31 assessed substrates, which included aldohexoses, deoxyhexoses, fructose, 3-O-methyl-D-glucose, aldopentoses, polyols, glycosides, disaccharides, trisaccharides, and glucuronic acid, PvSTP13.1 displayed the highest affinity (K 0.5) for glucose (43 µM), mannose (92 µM), galactose (145 µM), fructose (224 µM), xylose (1.0 mM), and fucose (3.7 mM) at pH 5.6 at a depolarized membrane potential of -40 mV. The results presented here suggest PvSTP13.1 contributes to retrieval of hexoses from the apoplasmic space in source leaves and coats of developing seeds.

Obesity Differs from Diabetes Mellitus in Antibody and T Cell Responses Post COVID-19 Recovery.

Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.

Efficacy and tolerability of a depigmenting gel serum comprising tranexamic acid, niacinamide, 4-butylresorcinol, phytic acid, and a mixture of hydroxy acids that targets the biological processes regulating skin melanogenesis.

BACKGROUND: The diverse causes of hyperpigmentation and complex nature of melanogenesis make it a challenge to manage. Current approaches either fail to deliver effective pigmentation control or have undesirable safety profiles that preclude their long-term use. AIMS: To evaluate the capacity of a cosmetic gel serum comprising tranexamic acid, niacinamide, 4-butylresorcinol, phytic acid, and a mixture of hydroxy acids that was designed to target the biological processes regulating skin melanogenesis to attenuate melanin production in vitro and reduce hyperpigmentation clinically. METHODS: Capacity to reduce melanin production in vitro was determined in melanocyte-containing reconstructed human epidermis (RHEm). Clinical efficacy and skin tolerability following twice daily application were assessed in 35 subjects with slight to moderate facial hyperpigmentation by instrumental (VISIA®-CR, Mexameter®) and clinical (mMASI, clinical score, IGA for hyperpigmentation) evaluation on D14, D28, D56, and D84. Maintenance of pigmentation control was followed up 1 month after cessation of treatment on D112. RESULTS: In RHEm in vitro, melanin production was reduced by 50.0% from baseline (D0) on D14 (p < 0.001) and by 67.0% on D21 (p < 0.001). Clinical reductions from baseline in brown spots count (-9.0%; p < 0.05), brown spots area (-16.7%; p < 0.001), and the melanin index (-11.4%; p < 0.001) were observed within 14 days of use. Statistically significant improvements in all clinical parameters were achieved by D28. By the end of treatment on D84, the number and surface area of brown spots were reduced by 28.4% and 40.3% compared to D0, respectively (p < 0.001, both), the melanin index was reduced by 31.1% (p < 0.001), mMASI was reduced by 63.0% (p < 0.001), and skin luminosity was increased by 79.0% (p < 0.001). IGA was reduced from 2.3 on D0 to 1.3 on D84 (p < 0.001). Improvements to all these parameters were maintained until D112, 1 month after termination of treatment. The product also demonstrated very good skin tolerability. CONCLUSION: A gel serum comprising tranexamic acid, niacinamide, 4-butylresorcinol, and hydroxy acids, designed to target the biological processes regulating skin melanogenesis, demonstrates rapid, robust, and sustained pigmentation control in this cohort.

Targeted metagenomics reveals association between severity and pathogen co-detection in infants with respiratory syncytial virus.

Respiratory syncytial virus (RSV) is the leading cause of hospitalisation for respiratory infection in young children. RSV disease severity is known to be age-dependent and highest in young infants, but other correlates of severity, particularly the presence of additional respiratory pathogens, are less well understood. In this study, nasopharyngeal swabs were collected from two cohorts of RSV-positive infants <12 months in Spain, the UK, and the Netherlands during 2017-20. We show, using targeted metagenomic sequencing of >100 pathogens, including all common respiratory viruses and bacteria, from samples collected from 433 infants, that burden of additional viruses is common (111/433, 26%) but only modestly correlates with RSV disease severity. In contrast, there is strong evidence in both cohorts and across age groups that presence of Haemophilus bacteria (194/433, 45%) is associated with higher severity, including much higher rates of hospitalisation (odds ratio 4.25, 95% CI 2.03-9.31). There is no evidence for association between higher severity and other detected bacteria, and no difference in severity between RSV genotypes. Our findings reveal the genomic diversity of additional pathogens during RSV infection in infants, and provide an evidence base for future causal investigations of the impact of co-infection on RSV disease severity.

Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

PURPOSE: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease. METHODS: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts. RESULTS: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], P =9.5 x 10 -5 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], P =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating LMO2 activation and inactivating STAG2 inactivation ( STAG2/LMO2 ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine. CONCLUSION: γδ T-ALL in children under the age of three is extremely high-risk and enriched for STAG2/LMO2 ALL. STAG2 loss perturbs chromatin conformation and differentiation, and STAG2/LMO2 ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL. SUPPORT: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.

Secure key distribution exploiting error rate criticality for radio frequency links.

We propose a method by which two radio frequency (RF) communication terminals exchange encryption keys or other data securely. This method draws on the approach developed for quantum key distribution (QKD) for detecting eavesdroppers but our method does not use any quantum properties at all. Instead, by exploiting the effects an eavesdropper has on channel stability, we explore a line-of-sight link radio in which data transfer rates are so high as to approach the Shannon limit. With very steep rises in bit error rate accompanying a small degradation of signal-to-noise limits for certain forward error correction codes, it becomes possible to infer the existence of an eavesdropper before they are able to obtain a complete key. We describe our method and analyse one possible implementation using low density parity check codes with quadrature phase shift keying modulation. The proposed technique is in principle far easier to implement than quantum-based approaches for RF and optical wireless links since the required hardware is readily available and the basic principles are well known and well understood. Finally, we show our method to have a higher key rate and spectral efficiency than those of QKD.

The Effect of Bone Quality on Treatment of Intertrochanteric Fractures with Helical Blade Versus Lag Screw Fixation in Cephalomedulary Nails.

Introduction: The specific aim of this retrospective study was to determine whether bone quality has any effect on the complication rates or overall survivorship between helical blades and lag screws in cephalomedullary nails used for intertrochanteric hip fractures. Methods: The authors reviewed clinical charts and radiographic studies of patients between January 2012 and August 2019. We reviewed radiographic images (pre-, intra-, and post-operative) to evaluate fracture fixation type, fracture reduction grade, and post-operative complications. We collected dual energy x-ray absorptiometry scan results (T-score) and serum alkaline phosphatase (ALP) isoenzyme activity values to evaluate patient bone quality. Results: We included 303 cases (helical: 197, screw: 106) in the study. Complications were found in 31 (16%) helical blade cases and 23 (22%) lag screw cases. No statistically significant difference was detected when comparing complication rates with patient bone quality between the two groups. These two groups had similar one-year implant survivorship with respect to T-score, the low ALP level group, and normal ALP level group. The helical blade had higher implant survivorship compared to lag screw in five-year survival rate with respect to osteoporotic group, high ALP level group, and normal ALP level group (osteoporotic: 77% vs 69%, high ALP: 73% vs 67%, normal ALP: 70% vs 64%). Conclusions: Similar complication rates were observed between helical blade and lag screw constructs in cephalomedullary femoral nails when accounting for patient bone quality. However, the helical blade design had a higher five-year survival rate.

HBV001: Phase I study evaluating the safety and immunogenicity of the therapeutic vaccine ChAdOx1-HBV.

Background & Aims: Millions of people worldwide are infected chronically with HBV, which results in significant morbidity and mortality. Therapeutic vaccination is a strategy that aims to induce functional cure by restoring cellular immunity to HBV. Previously we have shown the candidate HBV immunotherapeutic vaccine ChAdOx1-HBV, encoding all major HBV antigens and a genetic adjuvant (shark invariant chain), is highly immunogenic in mice. Methods: Here we report the results of HBV001, a first-in-human, phase I, non-randomised, dose-escalation trial of ChAdOx1-HBV assessed in healthy volunteers and patients with chronic HBV (CHB). Results: Vaccination with a single dose of ChAdOx1-HBV was safe and well tolerated in both healthy and CHB cohorts. Vaccination induced high magnitude HBV-specific T cell responses against all major HBV antigens (core, polymerase, and surface) in healthy volunteers. Responses were detected but lower in patients with CHB. T cells generated by vaccination were cross-reactive between HBV C and D genotypes. Conclusions: ChAdOx1-HBV is safe and immunogenic in healthy volunteers and patients with CHB. In further studies, ChAdOx1-HBV will be used in combination with other therapeutic strategies with an aim to overcome the attenuated immunogenicity in patients with CHB. Impact and implications: Therapeutic vaccine ChAdOx1-HBV, a novel treatment for chronic hepatitis B infection (CHB), has been shown to be immunogenic in preclinical studies. In HBV001, a first-in-human phase I study, we show vaccination with ChAdOx1-HBV is safe and generates high magnitude T cell responses in healthy volunteers and lower levels of responses in patients with CHB. This is an important first step in the development of ChAdOx1-HBV as part of a wider therapeutic strategy to induce hepatitis B functional cure, and is of great interest to patients CHB and clinicians treating the condition. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT04297917).

CD4+ and CD8+ T cells and antibodies are associated with protection against Delta vaccine breakthrough infection: a nested case-control study within the PITCH study.

IMPORTANCE: Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral correlates of protection, but the role of T cells in protection is still unclear. In this study, we explore antibody and T cell immune responses associated with protection against Delta variant vaccine breakthrough infection in a well-characterized cohort of UK Healthcare Workers (HCWs). We demonstrate evidence to support a role for CD4+ and CD8+ T cells as well as antibodies against Delta vaccine breakthrough infection. In addition, our results suggest a potential role for cross-reactive T cells in vaccine breakthrough.

Specification, validation, and adherence of quality indicators to optimize the safe use of nonsteroidal anti-inflammatory drugs for knee osteoarthritis pain in the primary care setting.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) used for osteoarthritis (OA) in primary care may cause gastrointestinal or renal injury. This study estimated adherence to two quality indicators (QIs) to optimize NSAID safety: add proton pump inhibitors (PPI) to NSAIDs for patients with gastrointestinal (GI) risk (QI #1 NSAID-PPI) and avoid oral NSAIDs in chronic kidney disease (CKD) stage G4 or G5 (QI #2 NSAID-CKD). METHODS: This retrospective study included index primary care clinic visits for knee OA at our health system in 2019. The validation cohort consisted of a random sample of 60 patients. The remainder were included in the expanded cohort. Analysis of structured data extracts was validated against chart review of clinic visit notes (validation cohort) and estimated QI adherence (expanded cohort). RESULTS: Among 60 patients in the validation cohort, analysis of data extracts was validated against chart review for QI #1 NSAID-PPI (100% sensitivity and 91% specificity) and QI #2 NSAID-CKD (100% accuracy). Among 335 patients in the expanded cohort, 44% used NSAIDs, 27% used PPIs, 73% had elevated GI risk, and only 2% had CKD stage 4 or 5. Twenty-one percent used NSAIDs and had elevated GI risk but were not using PPIs. Therefore, adherence to QI #1 NSAID-PPI was 79% (95% CI, 74-83%). No patients with CKD stage 4 or 5 used NSAIDs. Therefore, adherence to QI #2 NSAID-CKD was 100%. CONCLUSION: A substantial proportion of knee OA patients with GI risk factors did not receive PPI with NSAID therapy during primary care visits.

Natural Retinol Analogs Potentiate the Effects of Retinal on Aged and Photodamaged Skin: Results from In Vitro to Clinical Studies.

INTRODUCTION: Plants are a source of natural ingredients with retinol-like properties that can deliver anti-aging benefits without the side effects typically associated with retinoid use. We hypothesized that by combining two such analogs, bakuchiol (BAK) and Vigna aconitifolia extract (VAE), with the potent retinoid retinal (RAL), the anti-photoaging potential of RAL could be enhanced without compromising its skin irritation profile. The purpose of this study was to demonstrate that BAK and VAE potentiate the anti-photoaging activity of RAL. METHODS: Gene expression profiling of full-thickness reconstructed skin was first used to examine the impact of BAK or VAE in combination with RAL on skin biology. Next, the irritative potential of this combination, and its capacity to reverse key signs of photoaging in an ex vivo model was assessed. Finally, a proof-of-concept open label clinical study was performed to evaluate the anti-photoaging capacity and skin compatibility of a cosmetic formulation (tri-retinoid complex; 3RC) containing this complex in combination with other well characterized anti-photoaging ingredients. RESULTS: In vitro profiling suggested that combining 0.1% RAL with BAK or VAE potentiates the effect of RAL on keratinocyte differentiation and skin barrier function without affecting its skin irritation profile. When formulated with other anti-photoaging ingredients, such as niacinamide and melatonin, 3RC reversed ultraviolet radiation-induced deficits in structural components of the dermal extracellular matrix, including hyaluronic acid and collagen. In vivo, it led to a reversal of clinical signs of age and photodamage, with statistically significant improvement to skin firmness (+5.6%), skin elasticity (+13.9%), wrinkle count (-43.2%), and skin tone homogeneity (+7.0%), observed within 28 days of once nightly use. Notably, the number of crow's feet wrinkles was reduced in 100% of subjects. Furthermore, 3RC was very well tolerated. CONCLUSION: These data suggest that 3RC is a highly effective and well-tolerated treatment for photoaging.

Minimally invasive stabilization of pelvic metastatic bone disease: A review of an emerging technique.

Percutaneous pelvic stabilization is an emerging technique that provides mechanical stability to pathologic fractures of the pelvic ring and acetabulum. Variability exists in procedural technique among institutions; however, early case series consistently demonstrate an acceptable complication profile and significant improvement in patients' pain and function. This minimally invasive approach is less morbid than traditional, open acetabular and pelvic reconstructions. Therefore, this procedure is an encouraging palliative intervention for a growing patient population in need.

Ex vivo Drug Sensitivity Imaging-based Platform for Primary Acute Lymphoblastic Leukemia Cells.

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.

Experience-based codesign approach to improve care in Australian emergency departments for complex consumer cohorts: the MyED project protocol, Stages 1.1-1.3.

INTRODUCTION: Emergency department (ED) care must adapt to meet current and future demands. In Australia, ED quality measures (eg, prolonged length of stay, re-presentations or patient experience) are worse for older adults with multiple comorbidities, people who have a disability, those who present with a mental health condition, Indigenous Australians, and those with a culturally and linguistically diverse (CALD) background. Strengthened ED performance relies on understanding the social and systemic barriers and preferences for care of these different cohorts, and identifying viable solutions that may result in sustained improvement by service providers. A collaborative 5-year project (MyED) aims to codesign, with ED users and providers, new or adapted models of care that improve ED performance, improve patient outcomes and improve patient experience for these five cohorts. METHODS AND ANALYSIS: Experience-based codesign using mixed methods, set in three hospitals in one health district in Australia. This protocol introduces the staged and incremental approach to the whole project, and details the first research elements: ethnographic observations at the ED care interface, interviews with providers and interviews with two patient cohorts-older adults and adults with a CALD background. We aim to sample a diverse range of participants, carefully tailoring recruitment and support. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Western Sydney Local Health District Human Research Ethics Committee (2022/PID02749-2022/ETH02447). Prior informed written consent will be obtained from all research participants. Findings from each stage of the project will be submitted for peer-reviewed publication. Project outputs will be disseminated for implementation more widely across New South Wales, Australia.

Quality indicators for osteoarthritis pain management in the primary care setting.

BACKGROUND: Development of valid and feasible quality indicators (QIs) is needed to track quality initiatives for osteoarthritis pain management in primary care settings. METHODS: Literature search identified published guidelines that were reviewed for QI extraction. A panel of 14 experts was assembled, including primary care physicians, rheumatologists, orthopedic surgeons, pain specialists, and outcomes research pharmacists. A screening survey excluded QIs that cannot be reliably extracted from the electronic health record or that are irrelevant for osteoarthritis in primary care settings. A validity screening survey used a 9-point Likert scale to rate the validity of each QI based on predefined criteria. During expert panel discussions, stakeholders revised QI wording, added new QIs, and voted to include or exclude each QI. A priority survey used a 9-point Likert scale to prioritize the included QIs. RESULTS: Literature search identified 520 references published from January 2015 to March 2021 and 4 additional guidelines from professional/governmental websites. The study included 41 guidelines. Extraction of 741 recommendations yielded 115 candidate QIs. Feasibility screening excluded 28 QIs. Validity screening and expert panel discussion excluded 73 QIs and added 1 QI. The final set of 15 prioritized QIs focused on pain management safety, education, weight-management, psychological wellbeing, optimizing first-line medications, referral, and imaging. CONCLUSION: This multi-disciplinary expert panel established consensus on QIs for osteoarthritis pain management in primary care settings by combining scientific evidence with expert opinion. The resulting list of 15 prioritized, valid, and feasible QIs can be used to track quality initiatives for osteoarthritis pain management.