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Summary: Opioid receptors, including the kappa opioid receptor (KOR), exert control over thermoregulation and feeding behavior. Notably, activation of KOR stimulates food intake, leading to postulation that KOR signaling plays a central role in managing energy intake. KOR has also been proposed as a target for treating obesity. Herein, we report studies examining how roles for KOR signaling in regulating thermogenesis, feeding, and energy balance may be interrelated using pharmacological interventions, genetic tools, quantitative thermal imaging, and metabolic profiling. Our findings demonstrate that activation of KOR in the central nervous system causes increased energy expenditure via brown adipose tissue activation. Importantly, pharmacologic, or genetic inhibition of brown adipose tissue thermogenesis prevented the elevated food intake triggered by KOR activation. Furthermore, our data reveal that KOR-mediated thermogenesis elevation is reversibly disrupted by chronic high-fat diet, implicating KOR signaling as a potential mediator in high-fat diet-induced weight gain.

Stable isotope tracer studies of apoprotein flux in rodent models present difficulties as they require working with small volumes of plasma. We demonstrate the ability to measure apoprotein flux by administering either 2H- or 18O-labeled water to mice and then subjecting samples to LC-MS/MS analyses; we were able to simultaneously determine the labeling of several proteolytic peptides representing multiple apoproteins. Consistent with relative differences reported in the literature regarding apoprotein flux in humans, we found that the fractional synthetic rate of apoB is greater than apoA1 in mice. In addition, the method is suitable for quantifying acute changes in protein flux: we observed a stimulation of apoB production in mice following an intravenous injection of Intralipid and a decrease in apoB production in mice treated with an inhibitor of microsomal triglyceride transfer protein. In summary, we demonstrate a high-throughput method for studying apoprotein kinetics in rodent models. Although notable differences exist between lipoprotein profiles that are observed in rodents and humans, we expect that the method reported here has merit in studies of dyslipidemia as i) rodent models can be used to probe target engagement in cases where one aims to modulate apoprotein production and ii) the approach should be adaptable to studies in humans.

Increased serum apolipoprotein (apo)B and associated LDL levels are well-correlated with an increased risk of coronary disease. ApoE–/– and low density lipoprotein receptor (LDLr)–/– mice have been extensively used for studies of coronary atherosclerosis. These animals show atherosclerotic lesions similar to those in humans, but their serum lipids are low in apoB-containing LDL particles. We describe the development of a new mouse model with a human-like lipid profile. Ldlr CETP+/– hemizygous mice carry a single copy of the human CETP transgene and a single copy of a LDL receptor mutation. To evaluate the apoB pathways in this mouse model, we used novel short-interfering RNAs (siRNA) formulated in lipid nanoparticles (LNP). ApoB siRNAs induced up to 95% reduction of liver ApoB mRNA and serum apoB protein, and a significant lowering of serum LDL in Ldlr CETP+/– mice. ApoB targeting is specific and dose-dependent, and it shows lipid-lowering effects for over three weeks. Although specific triglycerides (TG) were affected by ApoB mRNA knockdown (KD) and the total plasma lipid levels were decreased by 70%, the overall lipid distribution did not change. Results presented here demonstrate a new mouse model for investigating additional targets within the ApoB pathways using the siRNA modality.

Reducing circulating LDL-cholesterol (LDL-c) reduces the risk of cardiovascular disease in people with hypercholesterolemia. Current approaches to reduce circulating LDL-c include statins, which inhibit cholesterol synthesis, and ezetimibe, which blocks cholesterol absorption. Both elevate serum PCSK9 protein levels in patients, which could attenuate their efficacy by reducing the amount of cholesterol cleared from circulation. To determine whether PCSK9 inhibition could enhance LDL-c lowering of both statins and ezetimibe, we utilized small interfer­ing RNAs (siRNAs) to knock down Pcsk9, together with ezetimibe, rosuvastatin, and an ezetimibe/rosuvastatin combination in a mouse model with a human-like lipid profile. We found that ezetimibe, rosuvastatin, and ezetimibe/rosuvastatin combined lower serum cholesterol but induce the expression of Pcsk9 as well as the Srebp-2 hepatic cholesterol biosynthesis pathway. Pcsk9 knockdown in combination with either treatment led to greater reductions in serum non-HDL with a near-uniform reduction of all LDL-c subfractions. In addition to reducing serum cholesterol, the combined rosuvastatin/ezetimibe/Pcsk9 siRNA treatment exhibited a significant reduction in serum APOB protein and triglyceride levels. Taken together, these data provide evidence that PCSK9 inhibitors, in combination with current therapies, have the potential to achieve greater reductions in both serum cholesterol and triglycerides.

Objective: Poor glycemic control in the perioperative period has been reported to be associated with early and late major adverse limb events (MALEs). However, these studies were mostly from large databases or lacked long-term outcomes. We examined the long-term effects of high hemoglobin A1c (HbA1c) level on patency, MALE, limb salvage (LS) and survival after lower extremity revascularization procedures in patients with diabetes., Methods: Patients with diabetes who underwent revascularization for Rutherford class 3 to 6 ischemia between May 2002 and December 2018 were identified. Patients with an HbA1c of ≤7% were compared with those with an HbA1c of >7% for patency, MALE, survival, LS, and amputation-free survival., Results: Of 706 patients, 699 had HbA1c data (775 limbs), with 311 (357 limbs) in the HbA1c ≤7% and 388 (418 limbs) in the HbA1c >7% groups. Patients with an HbA1c of >7% were younger (69.9 ± 10.2 years vs 71.7 ± 9.5 years; P = .011), had higher lipid levels, insulin use (70% vs 49%; P < .01), American Society of Anesthesiologists classification of 4, and had a lower prevalence of chronic kidney disease (32% v s41%; P = .023). Patients with an HbA1c of >7% were more likely to present with chronic limb-threatening ischemia (CLTI) (79% vs 72%; P = .019) and undergo infrapopliteal interventions (49% vs 42%; P = .005), with no difference in anatomical complexity (TransAtlantic Inter Society Consensus class C/D, 75% vs 77%; P = .72) or type of revascularization (24% vs 18% open, 66% vs 70% endovascular, 10% vs 12% hybrid; P = .236). Patency and freedom from MALE were significantly lower in patients with an HbA1c of >7% for infrainguinal revascularizations, whereas amputation-free survival and overall survival were similar. In patients with chronic limb-threatening ischemia, LS rates at 5 years were significantly lower in patients undergoing open revascularization (HbA1c > 7%: 64% ± 6% vs HbA1c < 7%:86% ± 5%; P = .020), whereas it was similar after endovascular interventions (HbA1c > 7%:79% ± 4% vs HbA1c < 7%:77% ± 3%; P = .631). Seventy patients with an HbA1c of >7% lost limbs vs 38 patients with an HbA1c of ≤7% (P = .007). In multivariate analysis, HbA1c was associated significantly with primary patency. HbA1c, insulin use, level of intervention, and angiotensin-converting enzyme inhibitor use were associated with MALE., Conclusions: A perioperative HbA1c of >7% is associated with poorer patency rates and increased MALE, especially at the infrainguinal level revascularization in patients with diabetes, with no significant impact on survival. LS is impacted after open, but not after endovascular revascularization., Competing Interests: Disclosures None., (Copyright © 2024. Published by Elsevier Inc.)

Rationale: Ambient air pollution (AAP) is linked to asthma outcomes, but predicting individual risk remains challenging. Understanding genetic contributors to AAP sensitivity may help overcome this gap., Objectives: To determine if single nucleotide polymorphisms (SNPs) are associated with AAP sensitivity in children with asthma., Methods: We complete a GWAS in pediatric patients with asthma frequently exposed to AAP, comparing patients with exacerbations following spikes in AAP to patients without this temporal association and calculate a polygenic risk score (PRS) for PM 2.5 . This PRS was validated using internal data and data from the All of Us cohort., Measurements and Results: We included 6023 patients in the GWAS, restricted to the African ancestry cohort due to the association between AAP exposure and race. Three loci reached genome-wide significance, including rs111970601, associated with CO sensitivity (odds ratio [OR] 6.58; P = 1.63 × 10 -8 ) and rs9836522 with PM 2.5 sensitivity (OR 0.75; P = 3,87 × 10 -9 ), both externally validated. PRS z-scores were associated with increased asthma exacerbations in patients frequently exposed to poor air quality (β = 0.15; P = 2.67 × 10⁻⁵). Spirometry data from 4138 patients showed that having a high PRS was associated with lower FVC z-scores in patients frequently exposed to AAP (β = -0.44; P = 0.035). External validation confirmed a significant interaction between high PRS and frequent AAP exposure (β = 0.30; P = 0.012) CONCLUSIONS: We associate specific SNPs with AAP-related asthma exacerbations and introduce a PM 2.5 sensitivity PRS, paving the way for future research aimed at protecting genetically predisposed patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The effect of nonnutritive sweeteners (NNSs) on the body mass index [BMI (in kg/m 2 )] of children and adolescents remains unclear despite rising consumption. Detailed systematic evaluations are warranted. We aimed to summarize evidence on NNS consumption and BMI sex- and age-specific absolute changes (kg/m 2 ) in pediatric populations, by NNS type, study design, duration, analysis type, conflicts of interest (COI), geographical region, age, sex, and baseline BMI. We searched randomized controlled trials (RCTs) and prospective cohort studies in children (2-9 y), adolescents (10-24 y), and young adults (20-24 y). Pooled estimates derived from random-effects meta-analysis for BMI changes, and the evidence quality was evaluated overall and by subgroup. From 2789 results, we included 4 RCTs [n = 1372; mean follow-up = 42.6 wk (standard deviation = 18.4); 2 (50%) with COI], and 8 prospective cohort studies [n = 35,340; median follow-up 2.5 y (interquartile range = 1.7-6.3), 2 (25%) with COI]. No identified studies evaluated NNS in food, NNS beverages compared with water, or participants aged 20-24 y. Random allocation to NNS beverages (25-2400 mg/d, from beverages) showed less BMI gain [mean difference = -0.114 kg/m 2 (95% confidence interval [CI]: -0.207, -0.021); I 2 = 87.02%] compared with sugar-sweetened beverages (SSBs). Stratified estimates resulted in less BMI gain in adolescents, participants with baseline obesity, consumers of mixed NNS, longer trials, and trials without COI. Pooled estimates from prospective cohorts showed a nonsignificant association between NNS beverages and BMI gain [0.05 kg/m 2 (95% CI: -0.03, 0.13); I 2 = 75.06%; per daily 355 mL serving]. Stratified estimates remained consistent. Removing studies with COI attenuated estimates. Evidence had low to moderate quality. In summary, pooled results from RCTs comparing NNS beverages compared with SSBs showed less BMI gain in adolescents with obesity. Meta-analyses of long-term cohort studies did not display a significant association between NNS beverages and BMI changes. This trial was registered at PROSPERO as CRD42022352284., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Osteoblast-derived extracellular vesicles (EVs) have demonstrated therapeutic utility for bone repair as transporters of key biomolecules capable of accelerating biomineralisation and tissue repair. The clinical translation of these biologically derived nanoparticles, however remains limited due to scalability, heterogeneity and standardisation issues. Herein we investigate the generation of nanovesicles (NVs) from mineralising osteoblasts by extrusion directly compared against natural EV counterparts from the same parental cells. Mineralising osteoblast-derived EVs (MO-EVs) were isolated via ultracentrifugation from cell culture media. The parental osteoblasts were then processed via serial extrusion to <200 nm. EVs and NVs were characterised by comparing their size, concentration and morphology. The presence of tetraspanin markers was detected by Single Particle Interferometric Reflectance Imaging Sensor (SP-IRIS). Osteoblasts viability and metabolic activity was assessed after both EV and NV-treatment before comparing their mineralising potency via alizarin red staining. EVs and NVs exhibited similar diameters of approximately 100 nm with a vesicular morphology. EVs were found to be richer in proteins and exhibited a significantly more negative ζ-potential compared to NVs. SP-IRIS analysis confirmed the presence of CD9, CD63 and CD81 in EVs. At both 1 and 10 μg/mL, EVs and NVs reduced the metabolic activity of osteoblasts, however, this was not associated with any cytotoxic effects. The biomineralisation study performed using osteoblasts showed that only EVs significantly increased mineral deposition (p < 0.05) compared to untreated control. In this study, we have established for the first time the biofabrication of cell-derived nanovesicles as a promising alternative to extracellular vesicles derived from mineralising osteoblasts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

There is concern that trauma memory processing in psychological therapies leads to PTSD symptom exacerbation. We compared PTSD symptoms at mid-treatment in trauma-focused psychological therapy to control groups. We systematically searched multiple databases and searched grey literature. We included randomised controlled trials involving adults comparing trauma-focused psychological interventions with active non-trauma-focused interventions or waitlist conditions. Twenty-three studies met our inclusion criteria. We found no evidence of PTSD symptom exacerbation at mid-treatment in trauma-focused interventions compared to control groups (g=-.16, [95 % confidence interval, CI, -.34,.03]). Sensitivity analyses with high quality studies (risk of bias assessment ≥ 7; g=-.25; [95 % CI -.48, -.03], k = 12) and studies with passive controls (g=-.32; [95 % CI -.59, -.05], k = 8) yielded small effect sizes favouring trauma-focused interventions. At post-treatment, trauma-focused interventions yielded a medium effect on PTSD symptoms compared to all controls (g=-.57; [CI -.79, -.35], k = 23). Regarding depression, trauma-focused interventions yielded a small effect size compared to controls at mid-treatment (g=-.23; [95 % CI -.39, -.08], k = 12) and post-treatment (g=-.45; [CI -.66, -.25], k = 12). This meta-analysis found no evidence that trauma-focused psychotherapies elicit symptom exacerbation at mid-treatment in terms of PTSD or depression symptoms. Instead, this meta-analysis suggests that the benefits of trauma-focused interventions can be experienced through improved depression and possibly PTSD before the conclusion of therapy. However, it is possible that symptom exacerbation occurred before mid-treatment and/or that people who experience symptom exacerbation drop out of studies and so are not included in the analysis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. RMS & DT train mental health professionals in the use of trauma-focused cognitive-behavioural therapies for the treatment of PTSD. All other authors declare they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Exposure to xylazine has been associated with wounds distinct from typical injection-related skin and soft tissue infections. We sought to understand drug use and wound care practices, and treatment experiences of people who use drugs (PWUD) in a high-prevalence area of xylazine adulteration., Methods: In August 2023, we surveyed adult PWUD reporting at least one past-year drug use-related wound across three Massachusetts syringe service programs. Using a representative illustration, participants indicated if they had experienced a xylazine wound in the past 90 days. We compared demographic, drug use factors, wound care, and medical treatment experiences among those with and without xylazine wounds. We also conducted additional content analysis of open-ended responses., Results: Of the 171 respondents, 87 % (n=148) had a xylazine wound in the past 90 days. There were no statistically significant demographic differences between those with and without xylazine wounds. Among those primarily injecting (n=155), subcutaneous injection was nearly ten times more likely among people with xylazine wounds. For those with xylazine wounds (n=148), many engaged in heterogeneous wound self-treatment practices, and when seeking medical care, 74 % experienced healthcare stigma and 58 % had inadequate pain and withdrawal management., Conclusion: People with self-identified xylazine wounds were more likely to engage in subcutaneous injection and faced several barriers seeking medical wound treatment. Programs serving people exposed to xylazine should work to support safer injection practices, including alternatives to injecting and improving access to high-quality, effective wound care. Further study is warranted to understand the causes, promoters, and prevention of xylazine-related wounds., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Mitochondria, pivotal organelles crucial for energy generation, apoptosis regulation, and cellular metabolism, have spurred remarkable advancements in targeted material development. This review surveys recent breakthroughs in targeted mitochondrial nanomaterials, illuminating their potential in drug delivery, disease management, and biomedical imaging. This review approaches from various application perspectives, introducing the specific applications of mitochondria-targeted materials in cancer treatment, probes and imaging, and diseases treated with mitochondria as a therapeutic target. Addressing extant challenges and elucidating potential therapeutic mechanisms, it also outlines future development trajectories and obstacles. By comprehensively exploring the diverse applications of targeted mitochondrial nanomaterials, this review aims to catalyze innovative treatment modalities and diagnostic approaches in medical research. STATEMENT OF SIGNIFICANCE: This review presents the latest advancements in mitochondria-targeted nanomaterials for biomedical applications, covering diverse fields such as cancer therapy, bioprobes, imaging, and the treatment of various systemic diseases. The novelty and significance of this work lie in its systematic analysis of the intricate relationship between mitochondria and different diseases, as well as the ingenious design strategies employed to harness the therapeutic potential of nanomaterials. By providing crucial insights into the development of mitochondria-targeted nanomaterials and their applications, this review offers a valuable resource for researchers working on innovative treatment modalities and diagnostic approaches. The scientific impact and interest to the readership lie in the identification of promising avenues for future research and the potential for clinical translation of these cutting-edge technologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background Aims: The production of commercial autologous cell therapies such as chimeric antigen receptor T cells requires complex manual manufacturing processes. Skilled labor costs and challenges in manufacturing scale-out have contributed to high prices for these products., Methods: We present a robotic system that uses industry-standard cell therapy manufacturing equipment to automate the steps involved in cell therapy manufacturing. The robotic cluster consists of a robotic arm and customized modules, allowing the robot to manipulate a variety of standard cell therapy instruments and materials such as incubators, bioreactors, and reagent bags. This system enables existing manual manufacturing processes to be rapidly adapted to robotic manufacturing, without having to adopt a completely new technology platform. Proof-of-concept for the robotic cluster's expansion module was demonstrated by expanding human CD8+ T cells., Results: The robotic cultures showed comparable cell yields, viability, and identity to those manually performed. In addition, the robotic system was able to maintain culture sterility., Conclusions: Such modular robotic solutions may support scale-up and scale-out of cell therapies that are developed using classical manual methods in academic laboratories and biotechnology companies. This approach offers a pathway for overcoming manufacturing challenges associated with manual processes, ultimately contributing to the broader accessibility and affordability for personalized immunotherapies., Competing Interests: Declaration of competing interest BS, ALJ, YA, AR, DC, ED, KP, KH, DS, US, VB, AS, NK, AH, MG and AT, wish to disclose that they are current employees of Multiply Labs, Inc. or were employed with the company at the time of this study's execution. They hold equity in the company; AM and FP wish to disclose that they are co-founders of Multiply Labs, Inc. and hold the position of Chief Scientific Officer and Chief Executive Officer, respectively; SC wishes to disclose that she is employed by Cytiva, which is a company active in the cell therapy manufacturing space; MH wishes to disclose that he is employed by Charles River Laboratories, which is a company active in the cell therapy manufacturing space; HA and XJ wishes to disclose that they are employed by Thermo Fisher Scientific, which is a company active in the cell therapy manufacturing space; BDR is a paid advisor to Multiply Labs, Inc. and holds equity in the company; JHE is a paid advisor to and receives sponsored research funding from Multiply Labs, Inc. He serves on its scientific advisory board and holds equity in the company. He receives sponsored research funding from Lonza, Inc. for the development of cellular therapy manufacturing devices., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Concerns regarding retraumatisation have been identified as a barrier to delivering trauma-focused therapy for post-traumatic stress disorder (PTSD). We explored clinicians' understanding of what constitutes potential signs of retraumatisation (PSoR), reported incidences of witnessing retraumatisation, use of (and confidence in) therapies for PTSD, fear of retraumatisation during therapy for PTSD, and whether having witnessed retraumatisation was associated with these variables. We surveyed 348 clinicians. There was variation in what clinicians viewed as PSoR. Retraumatisation was reported by clinicians in 3.4 % of patients undergoing trauma-focused therapy for PTSD. A variety of trauma-focused and non-trauma-focused therapies were routinely used, yet 14.4 % reported not using trauma-focused therapy. There was a significant negative correlation between participants' highest reported confidence in trauma-focused therapy and endorsement of PSoR (r = -.25) and fear of retraumatisation (r = -.28). Mean fear of retraumatisation was 30.3 (SD=23.4; a score we derived from asking participants out of 100 how much they worry about trauma-focused therapy being harmful in its own right/leading to a worsening of PTSD symptoms). Participants who had witnessed retraumatisation reported significantly greater endorsement of PSoR (d=.69 [95 % CI .37, 1.02]) and fear of retraumatisation (d=.94 [95 % CI .61, 1.26]). Confidence in using therapies for PTSD was varied and related to how clinicians understood retraumatisation. Retraumatisation is uncommon, but there is variability in clinicians' interpretation of what retraumatisation is, and its utility warrants research., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GB, NG, SE-L and RMS occasionally give paid workshops on CT-PTSD. All other authors declare they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Anabolic steroid therapy has been associated with tendon injury, but there is a paucity of evidence associating physiologic testosterone replacement therapy (TRT) with tenosynovitis of the hand, specifically trigger finger and de Quervain tenosynovitis. The purpose of this study was to evaluate the relationship between TRT and tenosynovitis of the hand., Methods: This was a one-to-one exact matched retrospective cohort study using a large nationwide claims database. Records were queried between 2010 and 2019 for adult patients who filled a prescription for TRT for 3 consecutive months. Rates of new onset trigger finger and de Quervain tenosynovitis and subsequent steroid injection or surgery were identified using ICD-9, ICD-10, and Current Procedural Terminology billing codes. Single-variable chi-square analyses and multivariable logistic regression were used to compare rates in the TRT and control cohorts while controlling for potential confounding variables. Both unadjusted and adjusted odds ratios (OR) are reported for each comparison., Results: In the adjusted analysis, patients undergoing TRT were more than twice as likely to develop trigger finger compared to their matched controls. TRT was also associated with an increased likelihood of experiencing de Quervain tenosynovitis. Of the patients diagnosed with either trigger finger or de Quervain tenosynovitis over the 2-year period, patients with prior TRT were roughly twice as likely to undergo steroid injections or surgical release for both trigger finger and de Quervain tenosynovitis compared to the controls., Conclusions: TRT is associated with an increased likelihood of both trigger finger and de Quervain tenosynovitis, and an increased likelihood of requiring surgical release for both conditions., Type of Study/level of Evidence: Prognostic II., Competing Interests: Conflicts of Interest No benefits in any form have been received or will be received related directly to this article., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine how regulatory structures and processes focused on antimicrobial stewardship and antimicrobial resistance are experienced by hospital managers and clinicians., Methods: Forty-two hospital managers and clinicians working within accreditation and antimicrobial stewardship teams in three Australian hospitals participated in individual in-depth interviews. Thematic analysis was performed., Results: Thematic analysis revealed participants' experiences of hospital antimicrobial regulation and their perceptions of what would be required for meaningful antimicrobial optimisation. Theme 1: Experience of regulation of antimicrobials within hospitals: Participants described an increased profile of antimicrobial resistance with inclusion in regulatory requirements, but also the risks of bureaucratic manoeuvring to meet standards rather than governance-inducing systemic changes. Theme 2: Growth of accreditation processes and hospitals over time: Both regulatory requirements and hospitals were described as evolving over time, each manoeuvring in response to each other (e.g. development of short notice accreditation). Theme 3: Perceived requirements for change: Participants perceived a need for top-down buy-in, resource prioritisation, complex understanding of power and influence on clinician behaviour, and a critical need for medical engagement., Conclusions: This study around antimicrobials shows the tension and dynamic relationship between regulatory processes and hospital responses, bringing to light the enduring balance of a system that positions itself to meet regulatory requirements and emerging "demands", without necessarily addressing the key underlying concerns. Antimicrobial resistance-related solutions are perceived as likely to require further resourcing and buy-in across multiple levels, engagement across professional streams and require strategies that consider complex systems change in order for regulatory structures to have potency., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The goal of this study was to evaluate the image quality provided by a novel cone beam computed tomography (CBCT) platform (HyperSight, Varian Medical Systems), a platform with enhanced reconstruction algorithms as well as rapid acquisition times. Image quality was compared with both status quo CBCT for image guidance, and to fan beam CT (FBCT) acquired on a CT simulator (CTsim)., Methods and Materials: In a clinical study, 30 individuals were recruited for whom either deep inspiration (DIBH) or deep exhalation breath hold (DEBH) was used during imaging and radiation treatment of tumors involving liver, lung, breast, abdomen, chest wall, and pancreatic sites. All subjects were imaged during breath hold with CBCT on a standard image guidance platform (TrueBeam 2.7, Varian Medical Systems) and FBCT CT (CTsim, GE Optima). HyperSight imaging with both breath hold (HSBH) and free breathing (HSFB) was performed in a single session. The 4 image sets thus acquired were registered and compared using metrics quantifying artifact index, image nonuniformity, contrast, contrast-to-noise ratio, and difference of Hounsfield unit (HU) from CTsim., Results: HSBH provided less severe artifacts compared with both HSFB and TrueBeam. The severity of artifacts in HSBH images was similar to that in CTsim images, with statistically similar artifact index values. CTsim provided the best image uniformity; however, HSBH provided improved uniformity compared with both HSFB and TrueBeam. CTsim demonstrated elevated contrast compared with HyperSight imaging, but both HSBH and HSFB imaging showed superior contrast-to-noise ratio characteristics compared with TrueBeam. The median HU difference of HSBH from CTsim was within 1 HU for muscle/fat tissue, 12 HU for bone, and 14 HU for lung., Conclusions: The HyperSight system provides 6-second CBCT acquisition with image artifacts that are significantly reduced compared with TrueBeam and comparable to those in CTsim FBCT imaging. HyperSight breath hold imaging was of higher quality compared with free breathing imaging on the same system. The median HU value in HyperSight breath hold imaging is within 15 HU of that in CTsim imaging for muscle, fat, bone, and lung tissue types, indicating the utility of image data for direct dose calculation in adaptive workflows., Competing Interests: Disclosures James L. Robar, Amanda Cherpak, and Robert Lee MacDonald report honoraria, consulting fees, and support for attending meetings, and hold research grants with financial support from Varian Medical Systems. James L. Robar also cochairs the Varian Intelligent Imaging Consortium with a focus on HyperSight technology., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate the incidence of Y chromosome microdeletions in male newborns conceived by intracytoplasmic sperm injection (ICSI), in vitro fertilization (IVF), and natural conception (NC)., Methods: A total of 186 male newborns were recruited, including 35 conceived by ICSI, 37 conceived by IVF, and 114 conceived naturally. DNA was extracted from umbilical cord blood after birth. The Yq genetic status of the newborns was determined according to 18 Y-specific sequence tagging sites (STS) markers covering 3 azoospermia factor (AZF) sub-regions and internal control sequences., Results: Partial AZF microdeletions were identified in 8 of 35 (22.9%) ICSI newborns, 4 of 37 (10.8%) IVF newborns, and 1 of 114 (0.9%) NC newborns. There was a statistically significant difference in the proportion of newborns with partial Y chromosome microdeletions between the ICSI, IVF, and NC groups. When analyzed individually, only the SY114 and SY152 STS markers showed a statistically significant difference in incidence between the 3 cohorts., Conclusions: Our study indicates that the population of male children conceived through assisted reproductive technologies (ART), particularly ICSI, is at an increased risk of genetic defect in the form of partial Y chromosome microdeletions. The growing population of ART-conceived children emphasizes the importance of studying the genetic repercussions of these procedures regarding the future fertility of males conceived in vitro., (Copyright © 2024 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Pteropine orthoreovirus (PRV) causes respiratory tract infections in humans. Despite its emergence as a zoonotic and respiratory virus, little is known about its cell tropism, which hampers progress in fully understanding its pathogenesis in humans. Hek293 cells are most susceptible to PRV infection, while HeLa cells are the least. Human cytokeratin 1 (CK1) was identified as the protein that interacts with PRV. The immunofluorescence assay and qPCR results revealed prior treatment with anti-CK1 may provide Hek293 cells protection against PRV. The KRT1-knockout Hek293 cells were less susceptible to PRV infection. Further study into the pathogenesis of PRV in humans is needed., Competing Interests: Declaration of competing interest The authors declare no competing interests exist., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Since many COVID-19 publications lack consensus reviews or controls, interpretive accuracy is unclear; abdominal processes unique or infrequent during the pandemic remain unknown. The incidence and nature of CT findings accounting for abdominal complaints in COVID patients, reader agreement and overcalling will be determined., Methods: A retrospective study was performed on COVID patients with abdominal complaints from 3/15/2020-5/31/2020 and 11/1/2020-4/15/2021 including matched controls. Reviewers blinded to initial reads interpreted abdominopelvic CT exams, with discordant cases resolved in consensus. Reader agreement was measured by Cohen's Kappa, differences between cohorts by permutation tests and factors affecting false positive/negative rates by Fisher's Exact Test and logistic regression., Results: 116 first wave (average age 65 years [±15.3], 63 [54%] women) and 194 second wave COVID cases (average age 64 years [±16.3], 103 [53%] women) including 116 wave 1 and 194 wave 2 prepandemic controls were included. Concordance was lower among COVID cases than controls (Cohen's Kappa of 0.58 vs. 0.82 [p ≤ 0.001]) and among wave 1 than wave 2 cases (Cohen's Kappa of 0.45 vs. 0.66 [p = 0.052]). With true positives defined as consensus between the initial reader and study reader, false positive rates were higher among COVID cases than controls (OR = 0.42, p = 0.003) and for initial than study reader (OR = 0.36, p ≤ 0.001), but lower in wave 2 than 1 (OR = 0.5, p = 0.028)., Conclusion: Greater reader disagreement occurred during COVID than prepandemic with no reader bias as both initial and study readers called more false positives among COVID cases than controls. More overcalling occurred during COVID with colitis and cystitis most common., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sexual and gender minorities have a higher risk for health and nutrition-related disparities across the life course compared to the heterosexual or cisgender population. Experiences of stigmatization and discrimination are associated with diminished mental health quality and psychological distress, which are risk factors for developing various eating disorders. Other nutrition disparities include increased risk for food insecurity, body dissatisfaction, and weight complications, such as those experienced by the transgender population in association with gender-affirming hormone therapies. Despite the need for tailored nutrition recommendations that address the unique needs of the lesbian, gay, bisexual, transgender, queer/questioning (LGBTQ+) community, there are currently no such guidelines in North America. The purpose of this review is to summarize major LGBTQ+ nutrition disparities and highlight the need for tailored recommendations. We examine the evidence on mental health and social disparities in this group, including vulnerabilities to disordered eating, food insecurity, and healthcare provider discrimination. Importantly, we identify a scarcity of literature on dietary concerns and nutrition care guidelines for LGBTQ+ groups, including studies that address intersectionality and differences among specific gender and sexual orientations. These gaps underline the urgency of prioritizing nutrition for LGBTQ+ health needs and for developing tailored public health nutrition recommendations for this underserved population. Our review suggests that future LGBTQ+ health and nutrition research agendas should include personalized and precision nutrition, social determinants of health, diet quality, body image, and healthcare provider cultural competency and responsiveness. Moreover, the current evidence on LGBTQ+ nutrition and health will be strengthened when research studies (including clinical trials) with robust methodologies amplify inclusion and representation of this community to elucidate health and nutrition disparities in sexual and gender minorities., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Prosthetic joint infections (PJIs) cause substantial morbidity to patients and are extremely challenging for clinicians. Their management can include multiple operations, antibiotics, and prolonged hospital admissions. Multidisciplinary team meetings (MDTM) are increasingly used for collaborative decision-making around the management of PJIs, but thus far there has been no examination of the role of MDTM in decisions and management. This study aimed to examine interactions in a PJI MDTM to identify the dynamics in decision-making, and inter-specialty relationships more broadly., Methods: Twelve MDTMs over 7 months at an Australian tertiary referral hospital were video recorded, transcribed, and thematic analysis was performed., Results: Thematic analysis revealed four key areas of collaborative discussion 1. Achieving Inter-specialty Balance: The role of the multidisciplinary team discussion in providing balance between specialty views, and traversing the barriers between specialty interactions. 2. Negotiating Grey zones: there was frequent discussion of the limits of tests, interpretation of symptoms, and the limits of proposed operative strategies, and the resultant tensions of balancing ideal care vs pragmatic decision-making, and divergent goals of care. 3. Tailoring Treatment: identification of individual patient factors (both physiological and behavioural) and risks into collaborative decision-making. 4. Affording Failure: creating affordances in communication to openly discuss 'failure' to eliminate infection and likely negative outcomes., Conclusions: MDTM in the management of prosthetic joint infections serve multiple functions including: achieving interdisciplinary balance; effective grey zone management, tailoring reconfigured care; and most critically, recognition of 'failure' to eliminate infection, a communicative affordance most likely leading to better care., (Copyright © 2023 Australasian College for Infection Prevention and Control. Published by Elsevier B.V. All rights reserved.)

Objective: At certain institutions and radiology practices, a routine lumbar radiographic exam may include 3 views: AP, lateral, and coned-down lateral of the lumbosacral junction. The purpose of this study is to determine whether the third coned-down-lateral view adds significant diagnostic information regarding pathology at the L4-L5 and L5-S1 levels., Materials and Methods: This retrospective study includes patients (n = 74) who had a 3-view radiographic exam of the lumbar spine, as well as a CT or MRI within six months. The AP and lateral views were reviewed by three radiologists, both with and without the use of the third, coned-lateral view. Subsequently, the CT and MRI performed within 6 months was reviewed, and the results compared. The primary outcome was detection of abnormal alignment and disc disease at the L4-L5 and L5-S1 levels., Results: For the combined findings of alignment and disc disease at each L4-L5 and L5-S1, there was disagreement between the 2-view and 3-view exams on 18 (of 296) evaluations. Of these 18, the 2-view and the 3-view exam each made positive findings on 9. By the binomial test, there is no evidence that either the 2-view or the 3-view exam tends to make more findings than the other (p = 1). Compared to CT/MRI, the 2-view exam agrees on 74.7 % of evaluations and the 3-view exam agrees on 75.3 %. There is therefore no evidence that the 3-view exam is more accurate than the 2-view exam., Conclusion: Elimination of the coned-down lateral view could reduce radiation exposure and imaging-related costs while maintaining diagnostic quality., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests/conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Purpose: Near-peer teaching within healthcare education has numerous benefits, but there is limited literature to assess the impact that these experiences have on skill development and future teaching roles. This study describes the impact of serving as a near-peer teaching assistant on both former and current pharmacy students., Educational Activity and Setting: The University of Texas at Austin College of Pharmacy implemented the Academic Assistant (AA) program in 2009 to provide an opportunity for students to participate as near-peer educators in a variety of courses. To determine the impact of these AA positions on current and former students, participants from five years of the program were surveyed regarding the impact of the program on skill development and current or future interest in teaching/mentoring., Findings: Current students in the AA program reported that participation increased the likelihood of pursuing a career with teaching/mentoring roles. A majority (65%) of alumni who participated in the program reported being in a current teaching/mentoring role with 42% responding that the AA program was impactful to their career choice. The qualitative analysis showed that direct impact to respondents included validating career goals and increasing interests in teaching/mentoring roles. Those who reported no direct impact on their career still gained valuable professional skills that included: public speaking, time management, broadened perspectives, and increased understanding of academia career expectations., Summary: Providing opportunities for pharmacy students to serve in near-peer teaching roles increased students' interest in pursuing teaching/mentoring roles and offered valuable professional experiences., Competing Interests: Declaration of Competing Interest We, the authors, deny any actual or potential conflicts of interest in relation to this manuscript., (Copyright © 2023. Published by Elsevier Inc.)

The quality of drug products in the United States has been a matter of growing concern. Buyers and payers of pharmaceuticals have limited insight into measures of drug-product quality. Therefore, a quality-score system driven by data collection is proposed to differentiate between the qualities of drug products produced by different manufacturers. The quality scores derived using this proposed system would be based upon public regulatory data and independently-derived chemical data. A workflow for integrating the system into procurement decisions within health care organizations is also suggested. The implementation of such a quality-score system would benefit health care organizations by including the consideration of the quality of products while also considering price as a part of the drug procurement process. Such a system would also benefit the U.S. health care industry by bringing accountability and transparency into the drug supply chain and incentivizing manufacturers to place an increased emphasis on the quality and safety of their drug products., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Obtaining the mechanical properties of soft tissues is critical in many medical fields, such as regenerative medicine and surgical simulation training. Although various tissue-characterization methods have been developed, such as AFM, indentation, and elastography, there remain some limitations on their accuracy and validity for measuring small and fragile soft tissues. This paper presents a tensile testing technique to measure the mechanical properties of soft tissues directly and accurately. Tensile testing was chosen as the primary method because of its simple procedure and ability to derive mechanical properties without requiring many assumptions or complicated models. However, tensile testing on soft tissues presents challenges related to gripping the tissue sample without affecting its inherent properties, applying minuscule forces to the sample, and measuring the cross-section area and strain of the sample. To solve these issues, this study presents a sub-micro scale tensile testing system that uses a flexure mechanism and a novel 3D-printed sample holder for gripping the tissue samples. The system also measures tested samples' cross-section area and strain using two high-resolution cameras. The system was validated by testing standard materials and used to characterize the elastic modulus, yield stress, and yield strain of lung tissue slices from six different mice. The results from the validation tests showed a less than 2.5% error for elastic modulus values measured using the tensile tester. At the same time, results from the mice lung tissue measurements revealed qualitative findings that closely matched those seen in the literature and displayed low coefficient of variation values, demonstrating the high repeatability of the system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: We evaluated limb salvage (LS), amputation-free survival (AFS), and target extremity reintervention (TER) after plain old balloon angioplasty (POBA), stenting, and atherectomy for treatment of infrapopliteal disease (IPD) with chronic limb-threatening ischemia (CLTI)., Methods: All index peripheral vascular interventions for IPD and CLTI were identified from the Vascular Quality Initiative registry. Of the multilevel procedures, the peripheral vascular intervention type was indexed to the infrapopliteal segment. Propensity score matching was used to control for baseline differences between groups. Kaplan-Meier and Cox regression were used to calculate and compare LS and AFS., Results: The 3-year LS for stenting vs POBA was 87.6% vs 81.9% (P = .006) but was not significant on Cox regression analysis (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.56-0.76; P = .08). AFS was superior for stenting vs POBA (78.1% vs 69.5%; P = .001; HR, 0.73; 95% CI, 0.60-0.90; P = .003). LS was similar for POBA and atherectomy (81.9% vs 84.8%; P = .11) and for stenting and atherectomy (87.6% vs 84.8%; P = .23). The LS rate after propensity score matching for POBA vs stenting was 83.4% vs 88.2% (P = .07; HR, 0.71; 95% CI, 0.50-1.017; P = .062). The AFS rate for stenting vs POBA was 78.8% vs 69.4% (P = .005; HR, 0.69; 95% CI, 0.54-0.89; P = .005). No significant differences were found between stenting and atherectomy (P = .21 for atherectomy; and P = .34 for POBA). The need for TER did not differ across the groups but the interval to TER was significantly longer for stenting than for POBA or atherectomy (stenting vs POBA, 12.8 months vs 7.7 months; P = .001; stenting vs atherectomy, 13.5 months vs 6.8 months; P < .001)., Conclusions: Stenting and atherectomy had comparable LS and AFS for patients with IPD and CLTI. However, stenting conferred significant benefits for AFS compared with POBA but atherectomy did not. Furthermore, the interval to TER was nearly double for stenting compared with POBA or atherectomy. These factors should be considered when determining the treatment strategy for this challenging anatomic segment., (Copyright © 2022 Society for Vascular Surgery. All rights reserved.)

Objective: Sarcopenia, characterized by decreased muscle mass and function, is projected to affect more than 200 million people worldwide by 2060. This study aimed to evaluate the rates of short-term complications following lumbar spine arthrodesis in patients with and without a recent diagnosis of sarcopenia., Methods: The PearlDiver database was queried to evaluate all patients who underwent index lumbar spine arthrodesis from 2012 to 2019. Multivariate logistic regression was used to compare rates of 90-day surgical and medical complications. Kaplan-Meier analysis was performed to compare cumulative rates of reoperation and all-cause hospital readmission. Two sample t testing was used to compare costs of care. Statistical significance was set at P < 0.05 a priori., Results: Of 239,953 patients undergoing lumbar spine arthrodesis, 1087 had a recent diagnosis of sarcopenia (0.45%) before surgery. Patients with sarcopenia were significantly more likely to experience a urinary tract infection (odds ratio = 1.41, P = 0.035) and undergo incision and drainage (odds ratio = 2.66, P = 0.010) within 90 days after lumbar arthrodesis. Patients with sarcopeniawere at a 24% greater risk of 1-year all-cause hospital readmission. The 90-day cost of care was significantly greater in patients with sarcopenia ($37,689.86 vs. $26,635.72; P < 0.001)., Conclusions: In patients undergoing lumbar spine arthrodesis, sarcopenia is associated with an increased risk of postoperative complications, including increased costs of care. Spine surgeons should consider screening patients for sarcopenia preoperatively and counsel them regarding their increased risk of complications. Additionally, surgeons may consider preoperative optimization, like the management of low bone density., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The SARS-CoV-2 infection causes COVID-19 disease, characterized by acute respiratory distress syndrome, bilateral pneumonia, and organ failure. The consequences of maternal SARS-CoV-2 infection for the pregnant woman, fetus, and neonate are controversial. Thus, it is required to determine whether there is viral and non-viral vertical transmission in COVID-19. The disease caused by SARS-CoV-2 leads to functional alterations in asymptomatic and symptomatic pregnant women, the fetoplacental unit and the neonate. Several diseases of pregnancy, including COVID-19, affect the fetoplacental function, which causes in utero programming for young and adult diseases. A generalized inflammatory state and a higher risk of infection are seen in pregnant women with COVID-19. Obesity, diabetes mellitus, and hypertension may increase the vulnerability of pregnant women to infection by SARS-CoV-2. Alpha, Delta, and Omicron variants of SARS-CoV-2 show specific mutations that seem to increase the capacity of the virus to infect the pregnant woman, likely due to increasing its interaction via the virus S protein and angiotensin-converting enzyme 2 receptors. This review shows the literature addressing to what extent COVID-19 in pregnancy affects the pregnant woman, fetoplacental unit, and neonate. Prospective studies that are key in managing SARS-CoV-2 infection in pregnancy are discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Numerical cognition can take place in multiple representational formats, such as Arabic digits (e.g., 1), verbal number words (e.g., "two"), and nonsymbolic (e.g., •••) numerical magnitude. Basic numerical discrimination abilities are key factors underlying the development of arithmetic abilities, acting as an important developmental precursor of adult-level numeracy. While prior research has begun to detail the neural correlates associated with basic numerical discrimination skills in different representational formats, the interactions between functional neural circuits are less understood. A growing body of evidence suggests that the functional networks recruited by number discrimination tasks differ between children and adults, which may provide valuable insights into the development of numerical cognition. To this end, we posed two questions: how do the interactions between functional circuits associated with number processing differ in children and adults? Are differences in functional network connectivity modulated by numerical representational codes? A theoretically motivated 22 ROI analysis indicated significant functional connectivity differences between children and adults across all three codes. Adults demonstrated sparser and more consistent connectivity patterns across codes, indicative of developmental domain-specialization for number processing. Although neural activity in children and adults is similar, the functional connectivity supporting number processing appears subject to substantial developmental maturation effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Health policy and system leaders need to know whether long travel time to a delivery facility adversely affects birth outcomes. In this study, we estimated associations between travel time to delivery and outcomes in low-risk pregnancies., Methods: This population-based cohort included all singleton births without obstetric comorbidities or intrapartum facility transfers in British Columbia, Canada, from 2012 to 2019. Travel time was measured from maternal residential postal code to delivery facility using road network analysis. We estimated associations between travel time and severe maternal morbidity, stillbirth, pre-term birth, and small-for-gestational age (SGA) and large-for-gestational age (LGA) status using logistic regression, adjusted for confounders (adjusted odds ratios [aORs]). To examine variations in associations between travel time and outcomes by antenatal care utilization, we stratified models by antenatal care categories., Results: Of 232 698 births, 3.8% occurred at a facility ≥60 minutes from the maternal residence. Obesity, adolescent age, substance use, inadequate prenatal care, and low socioeconomic status were more frequent among those traveling farther for delivery. Travel time ≥120 minutes was associated with increased risk of stillbirth (aOR 1.8; 95% CI 1.2-2.8), pre-term birth (aOR 2.3; 95% CI 2.1-2.5), LGA (aOR 1.5; 95% CI 1.4-1.6), and severe maternal morbidity (aOR 1.5; 95% CI 1.2-1.8), but not SGA (aOR 1.0; 95% CI 0.8-1.1), when compared with a travel time of 1-29 minutes. Risk of stillbirth was greatest with inadequate and intensive (adequate plus) antenatal care but persisted for severe maternal morbidity, pre-term birth, and LGA across categories., Conclusion: Longer travel time to delivery was associated with increased risk of adverse outcomes in low-risk pregnancies after adjusting for confounding factors. Associations were stronger among those with inadequate antenatal care., (Copyright © 2022 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. All rights reserved.)

Introduction/background: Multiple Myeloma (MM) is a plasma cell derived clonal disorder that represents around 1% of all newly diagnosed neoplasms. Limited data regarding MM treatment in Latin America is available, and access to novel agents for a substantial portion of the population is limited by their high costs., Materials (or Patients) and Methods: RENEHOC is a bidirectional (retrospective and prospective) multicenter observational registry of hematological malignancies in Colombia. MM patients included up to July 2020 were analyzed on this report., Results: 890 are reported with a median follow-up of 18 months (IQR: 7-42 months). Patients were classified by age group (≤ or > 65 years). Median age at diagnosis was 67 years (IQR: 59-75 years) and 47.1% of patients were women. 709 patients (79.6%) received Bortezomib-based schemes as part of the first line. Two hundred and fifty-two patients (28.3%) were consolidated with Autologous Stem Cell Transplantation (ASCT) in first-line. ASCT consolidation and age were the main independent factors influencing outcomes; in the non-ASCT cohort, 5-year overall survival was 48.7% (CI 41.8-55.2) compared to 80.7% (CI 73-86.4) in ASCT patients., Conclusion: This data depicts the reality of MM in Colombia, which likely reflects other Latin American countries, where access barriers to diagnosis and treatment are echoed in advanced stage diagnosis and a low rate of transplants. These seem to negatively impact survival despite the availability of most novel drugs approved for this disease. Thus, emphasizing the paradox that prevails in most of the region: availability without equitable access., (Copyright © 2021. Published by Elsevier Inc.)

The fast degradation of collagen-based membranes in the biological environment remains a critical challenge, resulting in underperforming Guided Bone Regeneration (GBR) therapy leading to compromised clinical results. Photoactive atelocollagen (AC) systems functionalised with ethylenically unsaturated monomers, such as 4-vinylbenzyl chloride (4VBC), have been shown to generate mechanically competent materials for wound healing, inflammation control and drug delivery, whereby control of the molecular architecture of the AC network is key. Building on this platform, the sequential functionalisation with 4VBC and methacrylic anhydride (MA) was hypothesised to generate UV-cured AC hydrogels with reduced swelling ratio, increased proteolytic stability and barrier functionality for GBR therapy. The sequentially functionalised atelocollagen precursor (SAP) was characterised via TNBS and ninhydrin colourimetric assays, circular dichroism and UV-curing rheometry, which confirmed nearly complete consumption of collagen's primary amino groups, preserved triple helices and fast (< 180 s) gelation kinetics, respectively. Hydrogel's swelling ratio and compression modulus were adjusted depending on the aqueous environment used for UV-curing, whilst the sequential functionalisation of AC successfully generated hydrogels with superior proteolytic stability in vitro compared to both 4VBC-functionalised control and the commercial dental membrane Bio-Gide®. These in vitro results were confirmed in vivo via both subcutaneous implantation and a proof-of-concept study in a GBR calvarial model, indicating integrity of the hydrogel and barrier defect, as well as tissue formation following 1-month implantation in rats. STATEMENT OF SIGNIFICANCE: Collagen-based membranes remain a key component in Guided Bone Regeneration (GBR) therapy, but their properties, e.g. proteolytic stability and soft tissue barrier functionality, are still far from optimal. This is largely attributed to the complex molecular configuration of collagen, which makes chemical accessibility and structure-function relations challenging. Here, we fabricated a UV-cured hydrogel network of atelocollagen, whereby triple helices were sequentially functionalised with two distinct ethylenically unsaturated monomers. The effects of the sequential functionalisation and UV-curing on the macroscopic properties, degradation behaviour and GBR capability were investigated in vitro and in vivo. The results highlight the key role of the sequential functionalisation and provide important insights for the design of future, longer-lasting resorbable membranes for GBR therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. G. Tronci, S.J. Russell and D.J. Wood are named inventors on a patent related to the fabrication of collagen-based materials., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Pineal region metastases are rare but often cause severe neurologic deficits. Surgical resection and chemoradiotherapy can provide therapeutic benefit. We investigated the literature to analyze clinical characteristics, management strategies, and survival of adult patients with pineal region metastases., Methods: PubMed, Embase, Scopus, and Cochrane were searched following the PRISMA guidelines, including studies reporting clinical outcomes of patients with pineal region metastases. Clinical presentation, management, and survival were reviewed., Results: We included 31 studies comprising 47 patients. Lung cancer (29.8%) and carcinomas of unknown origin (14.9%) were the most frequent primary tumors. In 48.9% of patients, symptomatic pineal metastases preceded primary tumor diagnosis. Headache (67.4%) and confusion (46.5%) were the most common symptoms. Parinaud syndrome (46.5%) and hydrocephalus (87.2%) were noted. Biopsy (65.9%) was preferred over resection (34.1%), and shunting strategies used were endoscopic third ventriculostomy (43.9%) and ventriculoperitoneal (26.8%). Eleven patients (32.3%) received adjuvant chemotherapy and 32 (68%) received radiotherapy. Posttreatment improvement in symptoms (56.6%) and hydrocephalus (80.5%) were noted. In patients who received adjuvant chemotherapy/radiotherapy, significant improvement in posttreatment performance status occurred with both biopsy (P < 0.001) and resection (P = 0.007). No survival differences were reported between surgery and biopsy (P = 0.912) or between complete and partial resection (P = 0.220). Overall survival was neither influenced by surgical approach (P = 0.157) nor by shunting strategy (P = 0.822). Mean follow-up was 8 months and median overall survival 3 months. Only 2 cases (4.8%) of pineal metastasis showed recurrence., Conclusions: Pineal region metastases carry significant morbidity. Biopsy or surgical resection, combined with adjuvant chemotherapy/radiotherapy and/or shunting, may significantly improve performance status., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Z scores are the method of choice to report dimensions in pediatric echocardiography. Z scores based on body surface area (BSA) have been shown to cause systematic biases in overweight and obese children. Using aortic valve (AoV) diameters as a paradigm, the aims of this study were to assess the magnitude of z score underestimation in children with increased body mass index z score (BMI-z) and to determine if a predicting model with height and weight as independent predictors would minimise this bias., Methods: In this multicentre, retrospective, cross-sectional study, 15,006 normal echocardiograms in healthy children 1-18 years old were analyzed. Residual associations with body size were assessed for previously published z score. BSA-based and alternate prediction models based on height and weight were developed and validated in separate training and validation samples., Results: Existing BSA-based z scores incompletely adjusted for weight, BSA, and BMI-z and led to an underestimation of > 0.8 z score units in subjects with higher BMI-z compared with lean subjects. BSA-based models led to overestimation of predicted AoV diameters with increasing weight or BMI-z. Models using height and weight as independent predictors improved adjustment with body size, including in children with higher BMI-z., Conclusions: BSA-based models result in underestimation of z scores in patients with high BMI-z. Prediction models using height and weight as independent predictors minimise residual associations with body size and generate well fitted predicted values that could apply to all children, including those with low or high BMI-z., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Platelet derived growth factor beta and its receptor, Pdgfrb, play essential roles in the development of vascular mural cells, including pericytes and vascular smooth muscle cells. To determine if this role was conserved in zebrafish, we analyzed pdgfb and pdgfrb mutant lines. Similar to mouse, pdgfb and pdgfrb mutant zebrafish lack brain pericytes and exhibit anatomically selective loss of vascular smooth muscle coverage. Despite these defects, pdgfrb mutant zebrafish did not otherwise exhibit circulatory defects at larval stages. However, beginning at juvenile stages, we observed severe cranial hemorrhage and vessel dilation associated with loss of pericytes and vascular smooth muscle cells in pdgfrb mutants. Similar to mouse, pdgfrb mutant zebrafish also displayed structural defects in the glomerulus, but normal development of hepatic stellate cells. We also noted defective mural cell investment on coronary vessels with concomitant defects in their development. Together, our studies support a conserved requirement for Pdgfrb signaling in mural cells. In addition, these zebrafish mutants provide an important model for definitive investigation of mural cells during early embryonic stages without confounding secondary effects from circulatory defects., Competing Interests: Declaration of competing interest The authors declare no competing or financial interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic continues to highlight both global interconnectedness and schisms across place, context and peoples. While countries such as Australia have securitised their borders in response to the global spread of disease, flows of information and collective affect continue to permeate these boundaries. Drawing on interviews with Australian healthcare workers, we examine how their experiences of the pandemic are shaped by affect and evidence 'traveling' across time and space. Our analysis points to the limitations of global health crisis responses that focus solely on material risk and spatial separation. Institutional responses must, we suggest, also consider the affective and discursive dimensions of health-related risk environments., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Time series were compiled of terrestrial nitrogen, phosphorus, carbon, iron, and silica fluxes to the Southern California Bight (SCB), a U.S. West Coast embayment (Sutula et al., 2021). Monitoring data and model output were used to construct a baseline of inputs from direct point source (PS) discharges of wastewater treatment (WWT) effluent (via ocean outfalls) and PS, non-point and natural sources from coastal rivers. The baseline covers 1971-2017 for large WWT plants discharging >50 million gallons per day (MGD) and 1997-2017 for small WWT plants and rivers. PS are the dominant nitrogen source, with contributions of 70% of the total annual freshwater discharge and 95% of nitrogen loads. WWT upgrades have reduced organic nitrogen loads by 73% since 1971. Inorganic nitrogen loads have generally held constant (35-40 Gg y -1 ) for the large WWT plants. This baseline represents a period prior to extensive wastewater and stormwater recycling that is increasing in the region., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. The term, "long COVID-19" is used to define any patient with persistent symptoms after acute COVID-19 infection (ie, after 4 weeks). It is postulated that cardiac injury might be linked to symptoms that persist after resolution of acute infection, as part of this syndrome. The Canadian Cardiovascular Society Rapid Response Team has generated this document to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of long COVID-19., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort., Research Question: The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis., Study Design and Methods: In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses., Results: The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24)., Interpretation: Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Hospitals and ambulatory facilities significantly reduced cardiac care delivery in response to the first wave of the COVID-19 pandemic. The deferral of elective cardiovascular procedures led to a marked reduction in health care delivery with a significant impact on optimal cardiovascular care. International and Canadian data have reported dramatically increased wait times for diagnostic tests and cardiovascular procedures, as well as associated increased cardiovascular morbidity and mortality. In the wake of the demonstrated ability to rapidly create critical care and hospital ward capacity, we advocate a different approach during the second and possible subsequent COVID-19 pandemic waves. We suggest an approach, informed by local data and experience, that balances the need for an expected rise in demand for health care resources to ensure appropriate COVID-19 surge capacity with continued delivery of essential cardiovascular care. Incorporating cardiovascular care leaders into pandemic planning and operations will help health care systems minimise cardiac care delivery disruptions while maintaining critical care and hospital ward surge capacity and continuing measures to reduce transmission risk in health care settings. Specific recommendations targeting the main pillars of cardiovascular care are presented: ambulatory, inpatient, procedural, diagnostic, surgical, and rehabilitation., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The idea that natural language is shaped by biases in learning plays a key role in our understanding of how human language is structured, but its corollary that there should be a correspondence between typological generalisations and ease of acquisition is not always supported. For example, natural languages tend to avoid close repetitions of consonants within a word, but developmental evidence suggests that, if anything, words containing sound repetitions are more, not less, likely to be acquired than those without. In this study, we use word-internal repetition as a test case to provide a cultural evolutionary explanation of when and how learning biases impact on language design. Two artificial language experiments showed that adult speakers possess a bias for both consonant and vowel repetitions when learning novel words, but the effects of this bias were observable in language transmission only when there was a relatively high learning pressure on the lexicon. Based on these results, we argue that whether the design of a language reflects biases in learning depends on the relative strength of pressures from learnability and communication efficiency exerted on the linguistic system during cultural transmission., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the association between the CT rim sign and gangrenous cholecystitis (GC) and increased surgical difficulty., Method: Patients who had a contrast enhanced CT of the abdomen and pelvis, followed by non-elective cholecystectomy were analyzed. The scans were reviewed for the CT rim sign by radiologists blinded to the pathologic and clinical outcomes. Demographic and clinical characteristics were compared between patients with and without GC using t-tests or Wilcoxon ranked sum test for continuous variables, and Fishers' exact test for categorical variables, when appropriate. A logistic regression model was fitted with multiple risk factors. Odds ratios as well as 95% confidence intervals were then calculated for the risk factors. A secondary analysis predicting increased surgical difficulty, defined as an operative time of greater than 2 h or increased conversion rate to open surgery, was also examined., Results: A total of 100 patients were included; 20 of which had GC. On imaging, patients with GC were more likely to have a CT rim sign (65% vs 32.5%, OR = 3.80, 95% CI: 1.24-12.7, p = 0.011). The presence of the CT rim sign did not reach a statistically significant association with an operative time >2 h or conversion to open case (56.52% vs 33.77%, OR = 2.55, p = 0.056)., Conclusion: The CT rim sign can be utilized to raise the possibility of GC, however the presence of the CT rim sign does not demonstrate an association with increased surgical difficulty., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The triple code model of numerical cognition (TCM) details the neurocognitive mechanisms associated with perceiving and manipulating numerical information in exact symbolic (Arabic digits and number words) and approximate nonsymbolic numerical magnitude (e.g., dot arrays) representation codes. The current study provides a first empirical fMRI-based investigation into neurodevelopmental differences in 30 healthy children's and 44 healthy adults' recruitment of neural correlates associated with the Arabic digit, number word, and nonsymbolic magnitude codes. Differences between the two groups were found in cingulate regions commonly associated with domain-general aspects of cognitive control, as opposed to neural correlates of number processing per se. A primary developmental difference was identified in verbal number discrimination, where only adults recruited left-lateralized perisylvian language areas in accordance with the TCM. We therefore call for a revision of the verbal code and a formulation of separate child and adult-specific neurocognitive mechanisms associated with the discrimination of number words. Although further research is necessary, results indicate that numerical discrimination abilities in middle-school-aged children operate close to adult-level maturity. Neurodevelopmental differences may be more apparent in younger children, or on the level of functional network dynamics as opposed to a shift in recruited neural substrates., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In this study, a natural surfactant, saponin was isolated from soapnut ( Sapindus Mukorossi ). The extracted surfactant was characterized by Fourier-transform infrared spectroscopy (FTIR) analysis. The effectiveness of the isolated surfactant as EOR agent was evaluated from foam generation/stabilization properties, wettability alteration of the rock surfaces, as well as oil-water interfacial tension (IFT) reduction characteristics. The performance of the extracted saponin was compared with that of a commercial saponin and sodium dodecyl sulfate (SDS). The foaming properties of the saponin with carbon dioxide (CO 2 ) was characterized using Teclis Foamscan instrument at room condition and 60 °C. The IFT and contact angles at room conditions and reservoir conditions were measured using KRŰSS Drop Shape Analyzer (DSA 25 and DSA 100) via pendant drop and sessile drop techniques respectively. The foamability of the saponin-stabilized foam was good at ambient condition and 60 °C. Moreover, the time taken for almost 100% liquid drainage was higher in saponin-stabilized foam than the SDS-stabilized foam. The optimum concentration for attaining maximum foam stability decreased from 0.4 wt% at room temperature to 0.1 wt% at 60 °C. Signifying that the quantity of the surfactant to be used in foam generation could reduce at high temperature. The isolated saponin exhibited relatively good interfacial activities individually and in synergistic interaction with silicon dioxide (SiO 2 ) nanoparticles at reservoir conditions. Precisely, at 8 MPa and 80 °C, the crude-oil water IFT was reduced from 23.24 mN/m to 1.59 mN/m (about 93.2%) by 0.2 wt% saponin concentration. The IFT was further reduced to 0.87 mN/m (about 96.3%) by a mixed system of 0.5 wt% saponin and 0.05 wt% SiO 2 nanoparticles concentration. Increasing IFT with increasing temperature were observed at very high temperature due to phase separation resulting from clouding phenomenon. However, the clouding temperature increased with 0.1 wt% saponin concentration, and in presence of SiO 2 nanoparticles (0.05 wt% and 0.1 wt%). The study suggests that the extracted saponin could be considered as supplementary alternative to conventional EOR surfactants., Competing Interests: The authors would like to state that this manuscript titled “Oil-water interfacial tension reduction, wettability modification and foaming properties of saponin extracted from soapnut (Sapindus Mukorossi)” has not been published and is not under consideration for publication elsewhere. Also, there is no conflicts of interest to disclose concerning this manuscript., (© 2020 Elsevier B.V. All rights reserved.)

European Union guidelines indiscriminately discuss a permitted daily exposure (PDE) for pyrrolizidine alkaloids (PA) of up to 0.007 μg/kg body weight for oral and for topical exposure to herbal medicinal products. In this study, lycopsamine served as a model substance for measuring the extent of skin permeation of PAs following the application of a spiked comfrey cream (Symphytum officinale s.l.) to abdominal skin from human donors in Franz diffusion cells. PAs could be excluded in the non-spiked cream with a limit of detection of 8 μg/kg. Only small amounts of the applied quantity of lycopsamine had migrated through the skin sample into the receptor cell side of the diffusion cell after 24 h. In five of six diffusion cells, there was no detectable lycopsamine within the skin and only 0.6 ± 0.4% of the applied dose in the receptor fluid. The theoretical skin penetration of 4.9% of the applied quantity of lycopsamine largely resulted from the worst case approach of assuming the presence of at least a quantity corresponding to the limit of detection - the true penetration is probably considerably lower. Even with the worst-case calculation, the currently discussed guidelines on PA overestimate the risk related to topical preparations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Addressing the lack of sanitation globally is a major global challenge with 700 million people still practicing open defecation. Circular Economy (CE) in the context of sanitation focuses on the whole sanitation chain which includes the provision of toilets, the collection of waste, treatment and transformation into sanitation-derived products including fertiliser, fuel and clean water. After a qualitative study from five case studies across India, covering different treatment technologies, waste-derived products, markets and contexts; this research identifies the main barriers and enablers for circular sanitation business models to succeed. A framework assessing the technical and social system changes required to enable circular sanitation models was derived from the case studies. Some of these changes can be achieved with increased enforcement, policies and subsidies for fertilisers, and integration of sanitation with other waste streams to increase its viability. Major changes such as the cultural norms around re-use, demographic shifts and soil depletion would be outside the scope of a single project, policy or planning initiative. The move to CE sanitation may still be desirable from a policy perspective but we argue that shifting to CE models should not be seen as a panacea that can solve the global sanitation crisis. Delivering the public good of safe sanitation services for all, whether circular or not, will continue to be a difficult task., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Recent research has shown that semantic category systems, such as color and kinship terms, find an optimal balance between simplicity and informativeness. We argue that this situation arises through pressure for simplicity from learning and pressure for informativeness from communicative interaction, two distinct pressures that often (but not always) pull in opposite directions. Another account argues that learning might also act as a pressure for informativeness, that learners might be biased toward inferring informative systems. This results in two competing hypotheses about the human inductive bias. We formalize these competing hypotheses in a Bayesian iterated learning model in order to simulate what kinds of languages are expected to emerge under each. We then test this model experimentally to investigate whether learners' biases, isolated from any communicative task, are better characterized as favoring simplicity or informativeness. We find strong evidence to support the simplicity account. Furthermore, we show how the application of a simplicity principle in learning can give the impression of a bias for informativeness, even when no such bias is present. Our findings suggest that semantic categories are learned through domain-general principles, negating the need to posit a domain-specific mechanism., (Copyright © 2020 Elsevier B.V. All rights reserved.)