Optogenetic control of kinesin-1, -2, -3 and dynein reveals their specific roles in vesicular transport.

Each cargo in a cell employs a unique set of motor proteins for its transport. To dissect the roles of each type of motor, we developed optogenetic inhibitors of endogenous kinesin-1, -2, -3 and dynein motors and examined their effect on the transport of early endosomes, late endosomes, and lysosomes. While kinesin-1, -3, and dynein transport vesicles at all stages of endocytosis, kinesin-2 primarily drives late endosomes and lysosomes. Transient optogenetic inhibition of kinesin-1 or dynein causes both early and late endosomes to move more processively by relieving competition with opposing motors. Kinesin-2 and -3 support long-range transport, and optogenetic inhibition reduces the distances that their cargoes move. These results suggest that the directionality of transport is controlled through regulating kinesin-1 and dynein activity. On vesicles transported by several kinesin and dynein motors, modulating the activity of a single type of motor on the cargo is sufficient to direct motility.

Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.

Low rates of complications and ß-lactam resistance in viridans group streptococci bloodstream infection among cancer patients receiving chemotherapy.

BACKGROUND: Viridans group streptococci (VGS) bloodstream infection (BSI) frequently occurs in cancer patients receiving chemotherapy, and is associated with infective endocarditis (IE) in up to 20% of cases in the general population. OBJECTIVES: In cancer patients receiving chemotherapy with VGS BSI, we aimed to: (i) determine the incidence of infective complications including IE, (ii) assess the utility of echocardiography in this patient population, (iii) determine the duration and type of antimicrobial therapy received for monomicrobial infections, and (iv) determine the evolution of antimicrobial resistance. METHODS: VGS BSIs (excluding Streptococcus pneumoniae and Streptococcus pseudopneumoniae) in cancer patients receiving chemotherapy were identified from a statewide public pathology database between 2013 and 2022 at our tertiary centre. Medical records were accessed for clinical, microbiological and radiological data. RESULTS: Of 581 patient episodes screened, 183 episodes involving 171 patients met inclusion criteria. Of these, 51% were bone marrow transplantation (BMT) patients, 40% were non-BMT haematology patients, and 8% were solid organ malignancy patients. The median age was 55 years, and 96% were neutropenic at the time of blood culture collection. A transthoracic echocardiogram was performed for 71% of episodes, and one patient met modified Duke's criteria for definite IE, although this diagnosis was not suspected on clinical grounds. Other complications were uncommon. Benzylpenicillin resistance was rare (2.9%) and did not change over time. Most episodes (75%) were treated with piperacillin/tazobactam. For monomicrobial BSIs, the median antibiotic duration was 5 days (IQR 2-7) post-neutropenia resolution. CONCLUSIONS: Infective complications and antimicrobial resistance are rare in cancer patients with VGS BSI. This may provide a safe opportunity to limit both investigations (e.g. echocardiogram) and prolonged exposure to broad-spectrum antimicrobials.

Preoperative visualization of the greater occipital nerve with magnetic resonance imaging in candidates for occipital nerve decompression for headaches.

Occipital nerve decompression is effective in reducing headache symptoms in select patients with migraine and occipital neuralgia. Eligibility for surgery relies on subjective symptoms and responses to nerve blocks and Onabotulinum toxin A (Botox) injections. No validated objective method exists for detecting occipital headache pathologies. The purpose of the study is to explore the potential of high-resolution Magnetic Resolution Imaging (MRI) in identifying greater occipital nerve (GON) pathologies in chronic headache patients. The MRI protocol included three sequences targeting fat-suppressed fluid-sensitive T2-weighted signals. Visualization of the GON involved generating 2-D image slices with sequential rotation to track the nerve course. Twelve patients underwent pre-surgical MRI assessment. MRI identified four main pathologies that were validated against intra-operative examination: GON entanglement by the occipital artery, increased nerve thickness and hyperintensity suggesting inflammation compared to the non-symptomatic contralateral side, early GON branching with rejoining at a distal point, and a connection between the GON and the lesser occipital nerve. MRI possesses the ability to visualize the GON and identify suspected trigger points associated with headache symptoms. This case series highlights MRI's potential to provide objective evidence of nerve pathology. Further research is warranted to establish MRI as a gold standard for diagnosing extracranial contributors in headaches.

A deep-learning framework to predict cancer treatment response from histopathology images through imputed transcriptomics.

Advances in artificial intelligence have paved the way for leveraging hematoxylin and eosin-stained tumor slides for precision oncology. We present ENLIGHT-DeepPT, an indirect two-step approach consisting of (1) DeepPT, a deep-learning framework that predicts genome-wide tumor mRNA expression from slides, and (2) ENLIGHT, which predicts response to targeted and immune therapies from the inferred expression values. We show that DeepPT successfully predicts transcriptomics in all 16 The Cancer Genome Atlas cohorts tested and generalizes well to two independent datasets. ENLIGHT-DeepPT successfully predicts true responders in five independent patient cohorts involving four different treatments spanning six cancer types, with an overall odds ratio of 2.28 and a 39.5% increased response rate among predicted responders versus the baseline rate. Notably, its prediction accuracy, obtained without any training on the treatment data, is comparable to that achieved by directly predicting the response from the images, which requires specific training on the treatment evaluation cohorts.

Genetic and environmental determinants of bone quality: a cross-sectional analysis of the Hungarian Twin Registry.

There is abundant evidence that bone mineral content is highly heritable, while the heritability of bone quality (i.e. trabecular bone score [TBS] and quantitative ultrasound index [QUI]) is rarely investigated. We aimed to disentangle the role of genetic, shared and unique environmental factors on TBS and QUI among Hungarian twins. Our study includes 82 twin (48 monozygotic, 33 same-sex dizygotic) pairs from the Hungarian Twin Registry. TBS was determined by DXA, QUI by calcaneal bone ultrasound. To estimate the genetic and environmental effects, we utilized ACE-variance decomposition. For the unadjusted model of TBS, an AE model provided the best fit with > 80% additive genetic heritability. Adjustment for age, sex, BMI and smoking status improved model fit with 48.0% of total variance explained by independent variables. Furthermore, there was a strong dominant genetic effect (73.7%). In contrast, unadjusted and adjusted models for QUI showed an AE structure. Adjustments improved model fit and 25.7% of the total variance was explained by independent variables. Altogether 70-90% of the variance in QUI was related to additive genetic influences. We found a strong genetic heritability of bone quality in unadjusted models. Half of the variance of TBS was explained by age, sex and BMI. Furthermore, the adjusted model suggested that the genetic component of TBS could be dominant or an epistasis could be present. In contrast, independent variables explained only a quarter of the variance of QUI and the additive heritability explained more than half of all the variance.

Exploring the cross-sectional association between the strength of school vaping policies and student vaping behaviours using data from the 2021-2022 COMPASS Study.

OBJECTIVES: Youth vaping is a concern in Canada. While school-level policies influence student behaviours, few studies have investigated the association between school vaping policies and student vaping. This study reviewed and scored the comprehensiveness of school vaping policies and investigated the association between school vaping policy scores and student vaping. METHODS: Online policy documents from n = 39 schools in Ontario, Alberta, and British Columbia, Canada, participating in the 2021-2022 wave of the COMPASS study were collected, reviewed, and scored for comprehensiveness (/39) using the School Tobacco Policy Index (STPI) rating form. The mean and range of scores for each domain of the STPI were calculated. School policy scores were linked to student vaping data from the COMPASS study. Multilevel logistic regression analyses identified the association between school vaping policy score and student lifetime and current (past 30-day) vaping. RESULTS: The mean total policy score was 10.2/39 (range 0‒24), and 28% of schools scored 0/39. The majority of school policies did not identify enforcement approaches or available preventive or cessation resources. Increasing STPI score was not associated with the odds of student lifetime or current vaping in multilevel logistic regression analyses. CONCLUSION: The STPI quickly identified components of school vaping policies that were missing. The overall score of most school vaping policies in our sample was low and most school vaping policies lacked many important components. Future studies should explore factors associated with adolescent vaping and identify effective prevention measures.

RéSUMé: OBJECTIFS: Le vapotage des jeunes est préoccupant au Canada. Les politiques scolaires influencent les comportements des élèves, mais il y a peu d'études sur l'association entre les politiques scolaires sur le vapotage et le vapotage des élèves. Nous avons passé en revue des politiques scolaires sur le vapotage et noté leur complétude, puis étudié l'association entre les notes attribuées aux politiques scolaires sur le vapotage et le vapotage des élèves. MéTHODE: Les documents de politique accessibles en ligne de n = 39 écoles de l'Ontario, de l'Alberta et de la Colombie-Britannique, au Canada, ayant participé au cycle 2021-2022 de l'étude COMPASS ont été collectés, passés en revue et notés selon leur complétude (/39) à l'aide du formulaire de notation de l'indice School Tobacco Policy Index (STPI). La moyenne et l'intervalle des notes attribuées pour chaque élément de l'indice STPI ont été calculés. Les notes des politiques scolaires ont été maillées aux données sur le vapotage des élèves de l'étude COMPASS. Des analyses de régression logistique multiniveaux ont repéré l'association entre les notes attribuées aux politiques scolaires sur le vapotage et le vapotage des élèves à un moment de leur vie et récemment (au cours des 30 jours précédents). RéSULTATS: La note totale moyenne attribuée aux politiques a été de 10,2/39 (intervalle : 0‒24), et 28 % des écoles ont obtenu une note de 0/39. La majorité des politiques scolaires ne mentionnaient pas d'approches ou de ressources de prévention et d'arrêt disponibles. Les notes STPI plus élevées n'étaient pas associées à la probabilité de vapotage récemment ou à un moment de la vie des élèves dans les analyses de régression logistique multiniveaux. CONCLUSION: L'indice STPI a rapidement repéré les lacunes dans les politiques scolaires sur le vapotage. La note globale de la plupart des politiques scolaires sur le vapotage de l'échantillon était faible, et il manquait d'importants éléments dans la plupart des politiques. Les études futures devraient explorer les facteurs associés au vapotage des adolescents et identifier des mesures de prévention efficaces.

An Interventional Radiologist's Guide to Lung Cancer.

Lung cancer continues to be the third leading cause of cancer and the leading cause of cancer deaths. As the field of interventional oncology continues to grow, interventional radiologists are increasingly treating lung cancer patients. Involvement begins with tissue diagnosis for which biomarkers and immunohistochemistry are used to guide selective and advanced medical therapies. An interventional radiologist must be aware of the rationale behind tissue diagnosis and techniques to minimize biopsy complications. Staging is an important part of tumor board conversations and drives treatment pathways. Surgical therapy remains the gold standard for early-stage disease but with an aging population the need for less invasive treatments such as radiation therapy and ablation continue to grow. The interventionalist must be aware of the indications, techniques, and pre- and posttherapy managements for percutaneous ablation. Endovascular therapy is broadly divided into therapeutic treatment of lung cancer, which is gaining traction, and treatment of lung cancer complications such as hemoptysis. This review aims to provide a good basis for interventional radiologists treating lung cancer patients.

Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells.

Long-term reconstituting haematopoietic stem cells (LT-HSCs) are used to treat blood disorders via stem cell transplantation. The very low abundance of LT-HSCs and their rapid differentiation during in vitro culture hinders their clinical utility. Previous developments using stromal feeder layers, defined media cocktails, and bioengineering have enabled HSC expansion in culture, but of mostly short-term HSCs and progenitor populations at the expense of naive LT-HSCs. Here, we report the creation of a bioengineered LT-HSC maintenance niche that recreates physiological extracellular matrix organisation, using soft collagen type-I hydrogels to drive nestin expression in perivascular stromal cells (PerSCs). We demonstrate that nestin, which is expressed by HSC-supportive bone marrow stromal cells, is cytoprotective and, via regulation of metabolism, is important for HIF-1α expression in PerSCs. When CD34+ve HSCs were added to the bioengineered niches comprising nestin/HIF-1α expressing PerSCs, LT-HSC numbers were maintained with normal clonal and in vivo reconstitution potential, without media supplementation. We provide proof-of-concept that our bioengineered niches can support the survival of CRISPR edited HSCs. Successful editing of LT-HSCs ex vivo can have potential impact on the treatment of blood disorders.

Simple Incisionless Temporary Stabilization: An Adjunct to Lower Blepharoplasty.

Background: Lateral canthal tightening is indicated for patients undergoing lower eyelid blepharoplasty who have preexisting lower eyelid laxity or ectropion. A canthoplasty or canthopexy is indicated at the time of lower blepharoplasty to avoid postoperative complications, such as eyelid retraction or ectropion. Various surgical techniques are described to accomplish this goal, including canthopexy procedures, which usually access the lateral canthal tendon through an upper eyelid blepharoplasty or lateral canthal incision. Objectives: To describe an incisionless technique adjunctive to lower blepharoplasty, which stabilizes the lower eyelid in the week following blepharoplasty. Methods: This operative technique description and retrospective case series includes 15 patients who underwent a simple incisionless temporary stabilization (SITS) during lower eyelid blepharoplasty. The procedures were performed at the same outpatient office-based surgery center and were performed by the author surgeons. Patients were followed from 3 to 6 months postoperatively. Results: The SITS procedure during lower eyelid blepharoplasty successfully maintained a desirable functional and aesthetic eyelid position with minimal complications. One patient reported tearing postoperatively which was determined to be unrelated to the SITS and resolved by the 1-month follow-up visit. No patient had any other complications during the follow-up period. Conclusions: The SITS procedure was successfully utilized in patients with mild-to-moderate lower eyelid laxity and/or a negative vector to prevent postoperative ectropion and eyelid retraction. It is a more favorable alternative to temporary tarsorrhaphy, as it does not obstruct vision during healing and better secures the eyelid. It should not be used in patients with significant lower eyelid laxity that would place the patient at significant risk of ectropion and lower eyelid retraction related to swelling and inappropriate eyelid position during the early postoperative course.

Impact of blood donation biovigilance and transfusion-transmitted infections on organ transplantation.

Over 118 million blood donations are collected globally each year. Recipients of blood products include those who experience major trauma or surgery, have acute blood loss and anemia, or impaired bone marrow function. Solid organ transplant recipients often require transfusion of blood products which places them at risk of transfusion-associated adverse events including transfusion-transmitted infection. National hemovigilance networks have documented low rates of transfusion-transmitted infection in the general population. Incidence transfusion-transmitted infection continues to occur in solid organ transplant patients and arises mainly from existing gaps in blood donor biovigilance processes. Emerging infectious diseases have highlighted existing gaps in the donor-recipient pathway to administering safe blood products. This article reviews the current process and regulatory oversight of blood donor biovigilance, including donor screening and microbiological testing, highlights cases of transfusion-transmitted infection documented in the literature, and addresses ways in which biovigilance may be improved, with a focus on the impact of solid organ transplantation.

Do sociodemographic risk profiles for adolescents engaging in weekly e-cigarette, cigarette, and dual product use differ?

BACKGROUND: E-cigarette use represents a contemporary mode of nicotine product use that may be changing the risk profile of participating adolescents. Understanding differences in sociodemographic characteristics of adolescents engaging in contemporary e-cigarette use and traditional cigarette use is important for effectively developing and targeting public health intervention programs. The objective of this study was to identify and compare sociodemographic risk profiles for exclusive e-cigarette use and dual-product use among a large sample of Canadian youth. METHODS: A survey of 46,666 secondary school students in the 2021-22 wave of the COMPASS study measured frequency of past month e-cigarette and cigarette use as well as age, sex, gender, racial or ethnic background, spending money, relative family affluence, and having one's own bedroom. Rates of cigarette-only, e-cigarette-only, and dual product use were calculated, and separate classification trees were run using the CART algorithm to identify sociodemographic risk profiles for weekly dual-product use and weekly e-cigarette-only use. RESULTS: Over 13% of adolescents used only e-cigarettes at least weekly, 3% engaged in weekly dual e-cigarette and cigarette use, and less than 0.5% used only cigarettes. Available spending money was a common predictor of dual-product and e-cigarette-only use. Gender diverse youth and youth with lower perceived family affluence were at higher risk for dual-product use, while white and multiethnic adolescents were at greater risk of e-cigarette-only use. Two high-risk profiles were identified for e-cigarette-only use and four high-risk profiles were identified for dual product use. CONCLUSIONS: This study used a novel modelling approach (CART) to identify combinations of sociodemographic characteristics that profile high-risk groups for exclusive e-cigarette and dual-product use. Unique risk profiles were identified, suggesting that e-cigarettes are attracting new demographics of adolescents who have not previously been considered as high-risk for traditional cigarette use.

Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis.

BACKGROUND: Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR+) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC. METHODS: PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection. The progression of metastases was monitored by bioluminescent imaging. Histological phenotypes of metastases were characterized by immunohistochemistry and immunofluorescence staining. Castration responses were further investigated in two AR-positive models. RESULTS: Our PDX-derived metastasis (PDM) model collection comprises three AR+ adenocarcinomas (ARPC) and one AR- neuroendocrine carcinoma (NEPC). All ARPC models developed bone metastases with either an osteoblastic, osteolytic, or mixed phenotype, while the NEPC model mainly developed brain metastasis. Different mechanisms of castration resistance were observed in two AR+ PDM models with distinct genotypes, such as combined loss of TP53 and RB1 in one model and expression of AR splice variant 7 (AR-V7) expression in another model. Intriguingly, the castration-resistant tumors displayed inter- and intra-tumor as well as organ-specific heterogeneity in lineage specification. CONCLUSION: Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.

Genome size variation in Cape schoenoid sedges (Schoeneae) and its ecophysiological consequences.

PREMISE: Increases in genome size in plants-often associated with larger, low-density stomata and greater water-use efficiency (WUE)-could affect plant ecophysiological and hydraulic function. Variation in plant genome size is often due to polyploidy, having occurred repeatedly in the austral sedge genus Schoenus in the Cape Floristic Region (CFR), while species in the other major schoenoid genus in the region, Tetraria, have smaller genomes. Comparing these genera is useful as they co-occur at the landscape level, under broadly similar bioclimatic conditions. We hypothesized that CFR Schoenus have greater WUE, with lower maximum stomatal conductance (gwmax) imposed by larger, less-dense stomata. METHODS: We investigated relationships between genome size and stomatal parameters in a phylogenetic context, reconstructing a phylogeny of CFR-occurring Schoeneae (Cyperaceae). Species' stomatal and functional traits were measured from field-collected and herbarium specimens. Carbon stable isotopes were used as an index of WUE. Genome size was derived from flow-cytometric measurements of leafy shoots. RESULTS: Evolutionary regressions demonstrated that stomatal size and density covary with genome size, positively and negatively, respectively, with genome size explaining 72-75% of the variation in stomatal size. Larger-genomed species had lower gwmax and C:N ratios, particularly in culms. CONCLUSIONS: We interpret differences in vegetative physiology between the genera as evidence of more-conservative strategies in CFR Schoenus compared to the more-acquisitive Tetraria. Because Schoenus have smaller, reduced leaves, they likely rely more on culm photosynthesis than Tetraria. Across the CFR Schoeneae, ecophysiology correlates with genome size, but confounding sources of trait variation limit inferences about causal relationships between traits.

Sulfoquinovosyl diacylglycerol is required for dimerisation of the Rhodobacter sphaeroides reaction centre-light harvesting 1 core complex.

The reaction centre-light harvesting 1 (RC-LH1) core complex is indispensable for anoxygenic photosynthesis. In the purple bacterium Rhodobacter (Rba.) sphaeroides RC-LH1 is produced both as a monomer, in which 14 LH1 subunits form a C-shaped antenna around 1 RC, and as a dimer, where 28 LH1 subunits form an S-shaped antenna surrounding 2 RCs. Alongside the five RC and LH1 subunits, an additional polypeptide known as PufX provides an interface for dimerisation and also prevents LH1 ring closure, introducing a channel for quinone exchange that is essential for photoheterotrophic growth. Structures of Rba. sphaeroides RC-LH1 complexes revealed several new components; protein-Y, which helps to form the quinone channel; protein-Z, of unknown function and seemingly unique to dimers; and a tightly bound sulfoquinovosyl diacylglycerol (SQDG) lipid that interacts with two PufX arginine residues. This lipid lies at the dimer interface alongside weak density for a second molecule, previously proposed to be an ornithine lipid. In this work we have generated strains of Rba. sphaeroides lacking protein-Y, protein-Z, SQDG or ornithine lipids to assess the roles of these previously unknown components in the assembly and activity of RC-LH1. We show that whilst the removal of either protein-Y, protein-Z or ornithine lipids has only subtle effects, SQDG is essential for the formation of RC-LH1 dimers but its absence has no functional effect on the monomeric complex.

Clear neuroimaging margin at the brain-tumor interface is associated with gross total resection and longer survival in non-enhancing diffuse gliomas.

BACKGROUND: This study aimed to determine whether the presence of distinct glioma margins on preoperative imaging is correlated with improved intraoperative identification of tumor-brain interfaces and overall improved surgical outcomes of non-enhancing gliomas. METHODS: This is a retrospective study of all primary glioma resections at our institution between 2000-2020. Tumors with contrast enhancement or with final pathology other than diffuse infiltrative glial neoplasm (WHO II or WHO III) were excluded. Tumors were stratified into two groups: those with distinct radiographical borders between tumor and brain, and those with ill-defined radiographical margins. Multivariate analysis was performed to determine the impact of clear preoperative margins on the primary outcome of gross-total resection. RESULTS: Within the study period, 59 patients met inclusion criteria, of which 31 (53%) had distinct margins. These patients were predominantly younger (37.6 vs. 48.1 years, P=0.007). Tumor and other patient characteristics were similar in both cohorts, including gender, laterality, size, location, tumor type, grade, and surgical adjuncts utilized (P>0.05). Multivariate regression identified that distinct preoperative margins correlated with increased rates of gross total resection (P=0.02). Distinct margins on preoperative neuroimaging also correlated positively with surgeon identification of intra-operative margins (P<0.0001), fewer deaths over the study period (P=0.01), and longer overall survival (P=0.03). CONCLUSIONS: Distinct glioma-parenchyma margins on preoperative imaging are associated with improved surgical resection for diffuse gliomas, as distinct margins may correlate with distinguishable glioma-brain interfaces intraoperatively. Further prospective studies may discover additional clinical uses for these findings.

Diagnosis rates, therapeutic characteristics, lifestyle, and cancer screening habits of patients with diabetes mellitus in a highly deprived region in Hungary: a cross-sectional analysis.

Introduction: Low socioeconomic status affects not only diagnosis rates and therapy of patients with diabetes mellitus but also their health behavior. Our primary goal was to examine diagnosis rates and therapy of individuals with diabetes living in Ormánság, one of the most deprived areas in Hungary and Europe. Our secondary goal was to examine the differences in lifestyle factors and cancer screening participation of patients with diagnosed and undiagnosed diabetes compared to healthy participants. Methods: Our study is a cross-sectional analysis using data from the "Ormánság Health Program". The "Ormánság Health Program" was launched to improve the health of individuals in a deprived region of Hungary. Participants in the program were coded as diagnosed diabetes based on diagnosis by a physician as a part of the program, self-reported diabetes status, and self-reported prescription of antidiabetic medication. Undiagnosed diabetes was defined as elevated blood glucose levels without self-reported diabetes and antidiabetic prescription. Diagnosis and therapeutic characteristics were presented descriptively. To examine lifestyle factors and screening participation, patients with diagnosed and undiagnosed diabetes were compared to healthy participants using linear regression or multinomial logistic regression models adjusted for sex and age. Results: Our study population consisted of 246 individuals, and 17.9% had either diagnosed (n=33) or undiagnosed (n=11) diabetes. Metformin was prescribed in 75.8% (n=25) of diagnosed cases and sodium-glucose cotransporter-2 inhibitors (SGLT-2) in 12.1% (n=4) of diagnosed patients. After adjustment, participants with diagnosed diabetes had more comorbidities (adjusted [aOR]: 3.50, 95% confidence interval [95% CI]: 1.34-9.18, p<0.05), consumed vegetables more often (aOR: 2.49, 95% CI: 1.07-5.78, p<0.05), but desserts less often (aOR: 0.33, 95% CI: 0.15-0.75, p<0.01) than healthy individuals. Patients with undiagnosed diabetes were not different in this regard from healthy participants. No significant differences were observed for cancer screening participation between groups. Conclusions: To increase recognition of diabetes, targeted screening tests should be implemented in deprived regions, even among individuals without any comorbidities. Our study also indicates that diagnosis of diabetes is not only important for the timely initiation of therapy, but it can also motivate individuals in deprived areas to lead a healthier lifestyle.

The Impact of Higher BMI on Wound Complications Following Adolescent Breast Reduction: A Retrospective Study of 1215 Cases.

BACKGROUND: Macromastia is a physically and psychologically distressing condition for adolescents. While reduction mammaplasty is often the best treatment, risk factors for adolescent wound complications remain unclear. This study aims to investigate the impact of obesity and other predictors of postoperative wound complications following adolescent reduction mammaplasty using a national database. METHODS: The 2012-2019 National Surgical Quality Improvement Program Pediatric (NSQIP-P) databases were reviewed to identify primary reduction mammaplasty encounters. World Health Organization Body Mass Index (BMI), alongside patient and case characteristics, were assessed for association for 30-day wound disruption or surgical site complications. Statistical analyses were performed to identify independent predictors for complications and determine a potential BMI cutoff for risk stratification. RESULTS: There were 1215 patients with an average age of 16.6 years. The average BMI was 30.7 kg/m2, and 593 (48.8%) patients were nonobese while 622 (51.2%) were obese. The incidence of complications was 5.27%. Independent predictors of complications included a BMI 35-39.9, BMI > 40, and an American Society of Anesthesiologists (ASA) Classification > 3. A receiver operating characteristic curve determined that a BMI of 34.6 can be a potential cutoff for increased complication risk. CONCLUSIONS: Higher obesity increases risk of wound complications; however, complication rates remain low. A BMI of 34.6 is a potential screening metric for counseling and monitoring patients. Reduction mammaplasty should remain a viable option as it can significantly improve quality of life. LEVEL OF EVIDENCE III: 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 Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Recruitment and baseline characteristics of young adults at risk of early-onset knee osteoarthritis after ACL reconstruction in the SUPER-Knee trial.

Objectives: The study aims to (1) report the process of recruiting young adults into a secondary knee osteoarthritis prevention randomised controlled trial (RCT) after anterior cruciate ligament reconstruction (ACLR); (2) determine the number of individuals needed to be screened to include one participant (NNS) and (3) report baseline characteristics of randomised participants. Methods: The SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER)-Knee RCT compares SUPER and minimal intervention for young adults (aged 18-40 years) with ongoing symptoms (ie, mean score of <80/100 from four Knee injury and Osteoarthritis Outcome Score subscales (KOOS4)) 9-36 months post-ACLR. The NNS was calculated as the number of prospective participants screened to enrol one person. At baseline, participants provided medical history, completed questionnaires (demographic, injury/surgery, rehabilitation characteristics) and underwent physical examination. Results: 1044 individuals were screened to identify 567 eligible people, from which 184 participants (63% male) enrolled. The sample of enrolled participants was multicultural (29% born outside Australia; 2% Indigenous Australians). The NNS was 5.7. For randomised participants, mean±SD age was 30±6 years. The mean body mass index was 27.3±5.2 kg/m2, with overweight (43%) and obesity (21%) common. Participants were, on average, 2.3 years post-ACLR. Over half completed <8 months of postoperative rehabilitation, with 56% having concurrent injury/surgery to meniscus and/or cartilage. The most affected KOOS (0=worst, 100=best) subscale was quality of life (mean 43.7±19.1). Conclusion: Young adults post-ACLR were willing to participate in a secondary osteoarthritis prevention trial. Sample size calculations should be multiplied by at least 5.7 to provide an estimate of the NNS. The SUPER-Knee cohort is ideally positioned to monitor and intervene in the early development and trajectory of osteoarthritis. Trial registration number: ACTRN12620001164987.

Stem cell dynamics and cellular heterogeneity across lineage subtypes of castrate-resistant prostate cancer.

To resist lineage-dependent therapies such as androgen receptor inhibition, prostate luminal epithelial adenocarcinoma cells often adopt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. Castrate-resistant prostate adenocarcinoma can transition to neuroendocrine (NE) and occasionally to amphicrine, co-expressed luminal and NE, phenotypes. We developed castrate-resistant prostate cancer (CRPC) patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model displaying a range of luminal and NE phenotypes. To gain biological insight and to identify potential treatment targets within heterogeneous tumor cell populations, we assessed the lineage hierarchy and molecular characteristics of various CRPC tumor subpopulations. Transcriptionally similar stem/progenitor (St/Pr) cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent St/Pr cells that produced mainly quiescent differentiated amphicrine progeny. By contrast, adenocarcinoma CRPC progeny originated from St/Pr cells and self-renewing differentiated luminal cells. Neuroendocrine prostate cancer (NEPC) was composed almost exclusively of self-renewing St/Pr cells. Amphicrine subpopulations were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures that characterize clinical progression. Finally, the amphicrine St/Pr subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. These data illuminate distinct stem cell (SC) characteristics for subtype-specific CRPC in addition to demonstrating a context for targeting differentiation-competent prostate SCs.