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Stephen A Stewart,1,2 Richard N McNeely,1 Wing C Chan,1 Jonathan E Moore1,3,4 1Cathedral Eye Clinic, Belfast, Northern Ireland, UK; 2School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, Northern Ireland, UK; 3Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, UK; 4Department of Ophthalmology, Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Stephen A Stewart, Cathedral Eye Clinic, Belfast, Northern Ireland, UK, Tel +44 28 9032 2020, Email stephen.stewart@doctors.org.ukPurpose: To assess the visual and refractive outcomes following exchange of an opacified multifocal intraocular lens (IOL).Patients and Methods: A consecutive series of 37 eyes (31 patients) that underwent IOL exchange between November 2015 and May 2021 were included in this study. The indication for surgery in all cases was opacification of a multifocal IOL. Outcome measures included design and anatomical location of the secondary IOL, intraoperative and postoperative complications, visual acuity and refractive accuracy.Results: An opacified Lentis Mplus multifocal IOL was explanted from all eyes and replaced with a monofocal IOL in 21 eyes (57%) and multifocal IOL in 16 eyes (43%). Secondary IOLs were implanted in the capsular bag or sulcus or were iris-fixated. IOL exchange was performed at a mean interval of 7 years after the primary surgery. Anterior vitrectomy was required for vitreous prolapse in 9 eyes (24%). Mean corrected distance visual acuity (CDVA) postoperatively was − 0.02 ± 0.08 logMAR for eyes with a monofocal secondary IOL and 0.02 ± 0.08 logMAR for eyes with a multifocal secondary IOL. Mean refractive prediction error was − 0.57 ± 0.67 D in the multifocal-monofocal group and − 0.33 ± 0.59 D in the multifocal–multifocal group.Conclusion: An opacified multifocal IOL can be exchanged for a monofocal or multifocal IOL, depending on available capsular support and the patient’s desired refractive outcome. Vitreous prolapse requiring anterior vitrectomy is the most common intraoperative complication. An improvement in visual acuity and a low postoperative complication rate were achieved in this cohort of patients.Keywords: cataract surgery, multifocal IOL, opacified IOL, IOL exchange

Critical responses to Peter Manson’s work often refer to him as a Scottish or Glasgow-based poet. In a review of Manson’s 2017 pamphlet Factitious Airs, Alice Tarbuck proposes that one of the key things differentiating Manson from his avant-garde contemporaries is his attentiveness to place and particularly “to Scottish speech rhythms and cultural ideas.” Nonetheless, most critical writing on Manson has sought to read his work primarily in terms of international movements in experimental poetics. This article therefore considers Manson’s relationship with and place within contemporary Scottish poetry, asking what connections can be made between his writing and that of his geographical peers. Manson has, notably, written very sympathetically about Tom Leonard’s work. Another potential point of contact would be Object Permanence, which, like Poor. Old. Tired. Horse thirty years before, brought writers from Scotland into contact with new currents in international poetry (and vice versa). In Manson’s work as a translator of Mallarmé there is also a connection with the modern(ist) Scottish tradition of poetic translation exemplified by Edwin Morgan. Situating Manson’s work in the landscape of contemporary Scottish poetry, this article asks to what extent this offers a potentially fruitful context within which to read his work – going on to explore what the implications of such a reading might be.

This work aims at addressing two issues simultaneously: data compression at input space and semantic segmentation. Semantic segmentation of remotely sensed multi- or hyperspectral images through deep learning (DL) artificial neural networks (ANN) delivers as output the corresponding matrix of pixels classified elementwise, achieving competitive performance metrics. With technological progress, current remote sensing (RS) sensors have more spectral bands and higher spatial resolution than before, which means a greater number of pixels in the same area. Nevertheless, the more spectral bands and the greater number of pixels, the higher the computational complexity and the longer the processing times. Therefore, without dimensionality reduction, the classification task is challenging, particularly if large areas have to be processed. To solve this problem, our approach maps an RS-image or third-order tensor into a core tensor, representative of our input image, with the same spatial domain but with a lower number of new tensor bands using a Tucker decomposition (TKD). Then, a new input space with reduced dimensionality is built. To find the core tensor, the higher-order orthogonal iteration (HOOI) algorithm is used. A fully convolutional network (FCN) is employed afterwards to classify at the pixel domain, each core tensor. The whole framework, called here HOOI-FCN, achieves high performance metrics competitive with some RS-multispectral images (MSI) semantic segmentation state-of-the-art methods, while significantly reducing computational complexity, and thereby, processing time. We used a Sentinel-2 image data set from Central Europe as a case study, for which our framework outperformed other methods (included the FCN itself) with average pixel accuracy (PA) of 90% (computational time ∼90s) and nine spectral bands, achieving a higher average PA of 91.97% (computational time ∼36.5s), and average PA of 91.56% (computational time ∼9.5s) for seven and five new tensor bands, respectively.

We consider a problem of high-resolution array radar/SAR imaging formalized in terms of a nonlinear ill-posed inverse problem of nonparametric estimation of the power spatial spectrum pattern (SSP) of the random wavefield scattered from a remotely sensed scene observed through a kernel signal formation operator and contaminated with random Gaussian noise. First, the Sobolev-type solution space is constructed to specify the class of consistent kernel SSP estimators with the reproducing kernel structures adapted to the metrics in such the solution space. Next, the “model-free” variational analysis (VA)-based image enhancement approach and the “model-based” descriptive experiment design (DEED) regularization paradigm are unified into a new dynamic experiment design (DYED) regularization framework. Application of the proposed DYED framework to the adaptive array radar/SAR imaging problem leads to a class of two-level (DEED-VA) regularized SSP reconstruction techniques that aggregate the kernel adaptive anisotropic windowing with the projections onto convex sets to enforce the consistency and robustness of the overall iterative SSP estimators. We also show how the proposed DYED regularization method may be considered as a generalization of the MVDR, APES and other high-resolution nonparametric adaptive radar sensing techniques. A family of the DYED-related algorithms is constructed and their effectiveness is finally illustrated via numerical simulations.

Abstract Background The aim of the study was to investigate the abductor hallucis muscle characteristics, defined as dorso-plantar (DP) thickness, medio-lateral (ML) width, and cross-sectional area (CSA) in relation to the severity of hallux valgus using musculoskeletal ultrasound. One hundred and two feet, mean (SD) age of 60.3 (20.54) years old, displaying varying severities of hallux valgus were stratified into four groups representing the four grades of the Manchester Scale (grade 0: no deformity, grade 1: mild deformity, grade 2: moderate deformity and grade 3: severe deformity). Methods The abductor hallucis muscle was imaged in each foot using a portable ultrasound system. The mean (SD) DP thickness, ML width, and CSA measurements were compared across the four Manchester Scale grades using a one-way ANOVA. Results Significant differences in DP thickness were found between feet with no hallux valgus (grade 0) and feet with hallux valgus grade 2 (p = 0.001) and 3 (p 0.0125). Conclusions We speculate that morphological changes to the abductor hallucis muscle occur early in the development of the deformity.

Abstract Background The cause of the high HIV prevalence in sub-Saharan Africa is incompletely understood, with heterosexual penile-vaginal transmission proposed as the main mechanism. Heterosexual HIV transmission has been estimated to have a very low probability; but effects of cofactors that vary in space and time may substantially alter this pattern. Methods To test the effect of individual variation in the HIV infectiousness generated by co-infection, we developed and analyzed a mathematical sexual network model that simulates the behavioral components of a population from Malawi, as well as the dynamics of HIV and the co-infection effect caused by other infectious diseases, including herpes simplex virus type-2, gonorrhea, syphilis and malaria. Results The analysis shows that without the amplification effect caused by co-infection, no epidemic is generated, and HIV prevalence decreases to extinction. But the model indicates that an epidemic can be generated by the amplification effect on HIV transmission caused by co-infection. Conclusion The simulated sexual network demonstrated that a single value for HIV infectivity fails to describe the dynamics of the epidemic. Regardless of the low probability of heterosexual transmission per sexual contact, the inclusion of individual variation generated by transient but repeated increases in HIV viral load associated with co-infections may provide a biological basis for the accelerated spread of HIV in sub-Saharan Africa. Moreover, our work raises the possibility that the natural history of HIV in sub-Saharan Africa cannot be fully understood if individual variation in infectiousness is neglected.

Purpose: To document the change of clinical (wrist motion and grip strength) measurements and Patient-Rated Wrist Evaluation (PRWE) scores at 9 weeks and 3, 6, and 12 months after distal radius fracture (DRF) in women 50 years and older with exclusively isolated, displaced, and low-energy DRFs treated by either closed and/or open reduction and to relate these outcomes to their radiographic results., Methods: In this retrospective single-institution cohort study, patients' post-DRF clinical measurements and PRWE scores were prospectively collected from December 2007 through September 2018 and stratified according to their final radiographic values of volar/dorsal tilt, ulnar variance, and radial inclination., Results: Of the 1,319 women identified, 1,126 (85%) were treated nonsurgically, and 193 (15%) were treated operatively. At 12 months, patients averaged restoration (ratio of injured and uninjured sides' values) of 96% pronation, 95% extension, 91% supination, 81% flexion, and 80% (77% nondominant, 85% dominant) grip strength. The mean PRWE score was 39.5 at week 9 and 14.4 at 12 months with 54% of patients scoring <10 and 13% scoring zero. The mean volar/dorsal tilt, ulnar variance, and radial inclination values in those treated nonsurgically were 1.4° dorsal, +3.9 mm, and 18.0°, respectively. Analogous values in patients treated surgically were 6° volar, +2.6 mm, and 22°, respectively. Volar tilt ≥25°, dorsal tilt >10°, ulnar variance >+7.5 mm, and radial inclination ≤13° were thresholds beyond which motion and grip strength were reduced and/or PRWE scores increased. In general, older patients experienced more residual deformity and were less likely to have undergone surgery., Conclusions: Generally, outcomes were satisfactory for patients with radiographic results within identified thresholds for acceptable fracture reduction. Outcomes were significantly less favorable for patients with radiographic results beyond these thresholds; for these patients, early surgical intervention should be considered. Low-energy DRFs should prompt bone density investigation., Type of Study/level of Evidence: Therapeutic 2b., 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.)

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8 + T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8 + T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy., (© 2024. The Author(s).)

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression. See related article by Belle et al., p. 1324., (©2024 American Association for Cancer Research.)

Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy. See related article by Ye et al., p. 1302., (©2024 American Association for Cancer Research.)

The 21st Century Cures Act is designed to make healthcare information more accessible and transparent to patients and the healthcare team. The provisions to address information blocking dictate that health information such as.

Purpose: To assess the 3-month and 12-month postoperative visual performance and subjective quality of vision (QoV) after combined implantation of complementary continuous phase multifocal intraocular lenses (IOLs)., Setting: Private practice, United Kingdom., Design: Case series., Methods: The study enrolled 44 patients undergoing phacoemulsification with implantation of an Artis Symbiose Mid in the dominant eye and an Artis Symbiose Plus in the nondominant eye. Refraction, uncorrected distance visual acuity (UDVA), corrected distance visual acuity, uncorrected intermediate visual acuity (UIVA), uncorrected near visual acuity (UNVA), electronic reading desk, and a QoV questionnaire were evaluated at 3 months and 12 months postoperatively., Results: The mean binocular UDVA was -0.06 ± 0.08 logMAR and -0.07 ± 0.06 logMAR at 3 months and 12 months ( P = .097), respectively. The mean binocular UIVA was 0.03 ± 0.13 logMAR and 0.03 ± 0.10 logMAR ( P = 1.0), respectively. The mean binocular UNVA was 0.07 ± 0.10 logMAR and 0.07 ± 0.08 logMAR ( P = .875), respectively. There was a significant improvement in QoV for both day and night between 3 and 12 months, with a significant reduction in halos at 12 months. Spectacle independence was reported in 93.2% of cases at 12 months., Conclusions: The Artis Symbiose Mid and Plus IOL combined implantation provided an excellent range of uncorrected vision at 3 and 12 months. There was a significant improvement in QoV and less halos at 12 months. This IOL combination provided very high rates of complete spectacle independence., (Copyright © 2023 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Healthy eating reduces risk for chronic disease, but can be out of reach for many Americans experiencing food insecurity. Produce Prescription Programs (PPPs) have emerged as an intervention to address barriers related to fruit and vegetable consumption. Using a social prescribing model, PPPs connect patients with referrals to community resources to reduce barriers to healthy eating. There is evidence of success of PPPs at improving dietary intake, yet little discussion within the literature of practical aspects of implementation. As interest grows around establishing PPPs within communities, increased attention to strategic planning and implementation remains necessary to develop robust and effective programming. We describe implementing the Pontiac Prescription for Health pilot program, highlighting the participatory planning process with partners. Development and implementation included a program model, recruitment methods and materials, a voucher contract and tracking system with produce vendors, physical activity opportunities, culturally competent health education sessions, and evaluation tools. We offer insight into lessons learned and practical implications for future "on-the-ground" planning and implementation. Engaging in a rigorous participatory planning process with all community partners, allowing adequate time to establish service agreements and a voucher system with vendors, and engaging program participants in different ways and spaces throughout the community can enhance program success.

Background: We hypothesized that routine cholangiography during laparoscopic cholecystectomy may increase use of postoperative imaging and invasive testing., Methods: A retrospective review was performed of laparoscopic cholecystectomy cases at 6 community hospitals from 2017 through 2020. For surgeons performing routine vs selective cholangiography, we compared primary outcomes of operative time, 30-day complications, and postoperative imaging or procedures., Results: In total, 2359 laparoscopic cholecystectomy procedures were performed. Eighteen surgeons performed routine cholangiography (1125 cases), and 13 performed selective (1234 cases). Mean operative time was longer in the routine group (125.3 vs 98.7 min, P < .001). Between groups, 30-day complications were similar. Two common bile duct injuries were identified in the routine group. Postoperatively, the routine group underwent 2.5 times more imaging and invasive testing (P < .001)., Conclusions: In community hospitals, laparoscopic cholecystectomy can be performed safely by surgeons using cholangiography routinely or selectively. Routine cholangiography resulted in more postoperative imaging and invasive testing., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKα inhibition (p38i) limits tumor growth by reprogramming the metastatic tumor microenvironment in a CD4+ T cell-, IFNγ-, and macrophage-dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single-cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies., Significance: Immunotherapy is rarely effective in breast cancer. We dissected the metastatic tumor stroma, which revealed a novel therapeutic approach that targets the stromal p38MAPK pathway and creates an opportunity to unleash an immunologic response. Our work underscores the importance of understanding the tumor stromal compartment in therapeutic design. This article is highlighted in the In This Issue feature, p. 1275., (©2023 American Association for Cancer Research.)

As the coronavirus disease (COVID-19) pandemic prolongs, documenting trajectories of the socioeconomic gradient of mental health is important. We describe changes in the prevalence and absolute and relative income-related inequalities of mental health between April and December 2020 in Canada. We used data from the Canadian Longitudinal Study on Aging (CLSA) COVID-19 Questionnaire Study and the pre-pandemic CLSA Follow-up 1. We estimated the prevalence proportion, the concentration index (relative inequality), and the generalized concentration index (absolute inequality) for anxiety and self-reported feeling generally unwell at multiple points in April-December 2020, overall, by sex and age group, by region, and among those who reported poor or fair overall health and mental health pre-pandemic. Overall, the prevalence of anxiety remained unchanged (22.45 to 22.10%, p = 0.231), but self-reported feeling generally unwell decreased (9.83 to 5.94%, p = 0.004). Relative and absolute income-related inequalities were unchanged for both anxiety and self-reported feeling generally unwell, with exceptions of an increased concentration of self-reported feeling generally unwell among the poor, measured by the concentration index, overall (-0.054 to -0.115, p = 0.004) and in Ontario (-0.035 to -0.123, p = 0.047) and British Columbia (-0.055 to -0.141, p = 0.044). The COVID-19 pandemic appeared to neither exacerbate nor ameliorate existing income-related inequalities in mental health among older adults in Canada between April and December 2020. Continued monitoring of inequalities is necessary., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to determine the demographics and perceptions of diversity, equity, and inclusion (DEI) in the field of dermatopathology to provide a measurable baseline for future efforts to enhance equity measures within our subspecialty., Methods: A questionnaire based on a previously validated instrument by Association of American Medical Colleges (AAMC) was sent to American Society of Dermatopathology (ASDP) members to collect the demographic information (gender, race, sexual orientation, disability, experience and practice setting, etc.) and evaluate eight diversity, engagement, and inclusivity statements on a 1-5 Likert scale., Results: The demographics of 207 of 1331 (15%) respondents showed slight male predominance. Eleven percent of respondents identified as LGBTQI. The major racial distribution was comprised of 62% White, 18% Asian (including Middle Eastern/Indian), 10% Hispanic, and 4% Black respondents. New-in-practice respondents (those in practice-5 years or less) were more likely to have a pathology background (71% vs. 56%, p = 0.047) than their more-established peers with more than 5 years of service. This trend also contributed to increased diversity in terms of gender (66% females) and race (48% non-White) among the newer generation. Dermatology-trained dermatopathologists were mostly White (70%) and male (53%). Analysis of respondent demographics with perception statements showed that White and US graduate respondents (compared to other groups) were more likely to have a positive perception about DEI within the field of dermatopathology., Conclusions: The results provide a snapshot of the current state of diversity within the field of dermatopathology. Moreover, these results highlight opportunities for further increasing diversity in general and leadership in particular within dermatopathology., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Substance use is a perennial public health concern with associated health risks and economic impacts on society. In this article, we present a selective review of the epidemiological and clinical literatures on alcohol and substance use from a lifespan developmental perspective. We compare and contrast risk factors for the initiation of use and the development of a substance use disorder in adolescence, young adulthood, middle-age and later life. During adolescence, alcohol use experimentation is at its peak. Specific risk factors have been identified including trauma and parenting style that can increase the risk of substance use for teenagers. Emerging adults and college students are likely to experiment with other substances in addition to alcohol such as nicotine, marijuana, cocaine, and prescription medication such as Adderall. Middle-age and older adults with alcohol and substance use in their developmental histories may have an undiagnosed alcohol use disorder. Others will develop a late-onset substance use disorder in older age, possibly due to a dearth of social support, coping with bereavement, and medical complication. Based on Social Cognitive Theory, the roles of expectancies and self-efficacy are hypothesized to impact substance use and the risk of substance use disorder across the lifespan. Implications of the present review for future research on age-specific risk factors in alcohol use in relation to underlying developmental processes are considered.

Objectives: To describe dispensing patterns of antipsychotic medications to long-term care (LTC) residents and assess factors associated with continuation of an antipsychotic after a fall-related hospitalization., Design: A retrospective cohort study., Setting and Participants: Nova Scotia Seniors Pharmacare Program (NSSPP) beneficiaries age 66 years and older who resided in LTC and received at least 1 dispensation of an antipsychotic within the study period of April 1, 2009, to March 31, 2017., Methods: Linkage of administrative claims data from the NSSPP and the Canadian Institute of Health Information Discharge Abstract Database identified LTC residents with an antipsychotic dispensation and from the subgroup of those dispensed antipsychotic medications who experienced a fall-related hospitalization. Antipsychotic dispensing patterns were reported with counts and means. Predictors of continuation of an antipsychotic after a fall-related hospitalization (sex, length of stay, days supplied, age, year of admission, rural/urban) were reported and analyzed with multiple logistic regression., Results: There were 19,164 unique NSSPP beneficiaries who were dispensed at least 1 prescription for an antipsychotic medication. Of those who received at least 1 antipsychotic dispensation 90% (n = 17,201) resided in LTC. A mean of 40% (n = 2637) of LTC residents received at least 1 antipsychotic dispensation in each year. Risperidone and quetiapine were dispensed most frequently. Of the 544 beneficiaries residing in LTC who survived a fall-related hospitalization, 439 (80.7%) continued an antipsychotic after hospital discharge. Female sex [OR 1.7, 95% CI (1.013‒2.943)], age 66‒69 [OR 4.587, 95% CI (1.4‒20.8)], 75-79 [OR 2.8, 95% CI (1.3‒6.3)], and 80‒84 years [OR 3.1, 95% CI (1.6‒6.4)] (compared with age 90+ years) were associated with increased risk of antipsychotic continuation., Conclusions and Implications: With 90% of antipsychotic dispensations in Nova Scotia being to LTC residents and 40% of LTC residents being dispensed antipsychotics in any year there is a need to address this level of antipsychotic dispensation to older adults., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Carcinoma dissemination can occur when heterogeneous tumor and tumor-stromal cell clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system mimicking native breast tumor microenvironment, we developed 3D computational models, which hypothesize that leader cells need to generate high protrusive forces and overcome extracellular matrix (ECM) resistance at the leading edge. From single-cell sequencing analyses, we find that leader cells are heterogeneous and identify and isolate a keratin 14- and cadherin-3-positive subpopulation sufficient to lead collective migration. Cdh3 controls leader cell protrusion dynamics through local production of laminin, which is required for integrin/focal adhesion function. Our findings highlight how a subset of leader cells interact with the microenvironment to direct collective migration., Competing Interests: Declaration of interests The Longmore laboratory receives funding from Pfizer-CTI, San Diego CA and Centene Corporation, St. Louis, MO, USA., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disorder that is typified by motor signs and symptoms but can also lead to significant cognitive impairment and dementia Parkinson's Disease Dementia (PDD). While dementia is considered a nonmotor feature of PD that typically occurs later, individuals with PD may experience mild cognitive impairment (PD-MCI) earlier in the disease course. Olfactory deficit (OD) is considered another nonmotor symptom of PD and often presents even before the motor signs and diagnosis of PD. We examined potential links among cognitive impairment, olfactory functioning, and white matter integrity of olfactory brain regions in persons with early-stage PD. Cognitive tests were used to establish groups with PD-MCI and with normal cognition (PD-NC). Olfactory functioning was examined using the University of Pennsylvania Smell Identification Test (UPSIT) while the white matter integrity of the anterior olfactory structures (AOS) was examined using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) analysis. Those with PD-MCI demonstrated poorer olfactory functioning and abnormalities based on all DTI parameters in the AOS, relative to PD-NC individuals. OD and microstructural changes in the AOS of individuals with PD may serve as additional biological markers of PD-MCI.

In this work the preparation and characterisation of intranasal implants for the delivery of risperidone (RIS) is described. The aim of this work is to develop better therapies to treat chronic conditions affecting the brain such as schizophrenia. This type of systems combines the advantages of intranasal drug delivery with sustained drug release. The resulting implants were prepared using biodegradable materials, including poly(caprolactone) (PCL) and poly(lactic-co-glycolic acid) (PLGA). These polymers were combined with water-soluble compounds, such as poly(ethylene glycol) (PEG) 600, PEG 3000, and Tween® 80 using a solvent-casting method. The resulting implants contained RIS loadings ranging between 25 and 50 %. The obtained implants were characterised using a range of techniques including thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared (ATR-FTIR), X-ray diffraction (XRD), and Scanning Electron Microscopy (SEM). Moreover, in vitro RIS release was evaluated showing that the addition of water-soluble compounds exhibited significant faster release profiles compared to pristine PCL and PLGA-based implants. Interestingly, PCL-based implants containing 25 % of RIS and PLGA-based implants loaded with 50 % of RIS showed sustained drug release profiles up to 90 days. The former showed faster release rates over the first 28 days but after this period PLGA implants presented higher release rates. The permeability of RIS released from the implants through a model membrane simulating nasal mucosa was subsequently evaluated showing desirable permeation rate of around 2 mg/day. Finally, following in vitro biocompatibility studies, PCL and PLGA-based implants showed acceptable biocompatibility. These results suggested that the resulting implants displayed potential of providing prolonged drug release for brain-targeting drugs., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in wildtype and transformed murine astrocytes, as well as patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned during early development by gonadal sex. These data provide a rationale for the further study of sex differences in radiation response and how senescence might be enhanced for radiation sensitization. The determination that p21 and gonadal sex are required for sex differences in radiation response will serve as a foundation for these future mechanistic studies., (© 2022. The Author(s).)

Exogenous and endogenous female hormones influence nicotine use and cessation, potentially through mechanisms such as anxiety and negative affect. In the present study, college females using all types of hormonal contraceptives (HC) were compared to those not using HC to determine the potential influence on current smoking, negative affect, and current and past cessation attempts. Differences between progestin-only and combination HC were also examined. Of the 1,431 participants, 53.2% ( n  = 761) reported current HC use, and 12.3% ( n  = 176) of participants endorsed current smoking. Women currently using HC were significantly more likely to smoke (13.5%; n  = 103) compared to women not using HC (10.9%; n  = 73), p  = .04. There was a significant main effect of HC use being associated with lower anxiety levels ( p  = .005), as well as a significant HC use by smoking status interaction, such that women who smoke using HC reported the lowest levels of anxiety among participants ( p  = .01). Participants using HC were more likely to be making a current attempt to quit smoking than those not using HC ( p  = .04) and were more likely to have made past quit attempts ( p  = .04). No significant differences were observed across women using progestin-only, combined estrogen and progestin, and women not using HC. These findings provide evidence that exogenous hormones may be an advantageous treatment target and that they warrant additional study., Competing Interests: The authors have no conflicts to declare., (© 2022 The Authors. Published by Elsevier B.V.)

Background: Ongoing developments in the medical field have improved survival rates and long-term management of children with complex chronic health conditions. While the number of children with medical complexity is small, they use a significant amount of health resources across various health settings and sectors. Research to date exploring this pediatric population has relied primarily on quantitative or qualitative data alone, leaving significant gaps in our understanding of this population., Objective: The objective of this research is to use health administrative and family-reported data to gain an in-depth understanding of patterns of health resource use and health care needs of children with medical complexity and their families in the Canadian Maritimes., Methods: An explanatory sequential mixed methods design will be used to achieve our research objective. Phase 1 of this research will leverage the use of health administrative data to examine the prevalence and health service use of children with medical complexity. Phase 2 will use case study methods to collect multiple sources of family-reported data to generate a greater understanding of their experiences, health resource use, and health care needs. Two cases will be developed in each of the 3 provinces. Cases will be developed through semistructured interviews with families and their health care providers and health resource journaling. Findings will be triangulated from phase 1 and 2 using a joint display table to visually depict the convergence and divergence between the quantitative and qualitative findings. This triangulation will result in a comprehensive and in-depth understanding into the population of children with medical complexity., Results: This study will be completed in May 2022. Findings from each phase of the research and integration of the two will be reported in full in 2022., Conclusions: There is a current disconnect between the Canadian health care system and the needs of children with medical complexity and their families. By combining health administrative and family-reported data, this study will unveil critical information about children with medical complexity and their families to more efficiently and effectively meet their health care needs. Results from this research will be the first step in designing patient-oriented health policies and programs to improve the health care experiences, health system use, and health outcomes of children with medical complexity and their families., International Registered Report Identifier (irrid): DERR1-10.2196/33426., (©Sydney Breneol, Janet A Curran, Marilyn Macdonald, William Montelpare, Samuel A Stewart, Ruth Martin-Misener, Jocelyn Vine. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 06.04.2022.)

Goals of care discussions typically focus on decision maker preference and underemphasize prognosis and outcomes related to frailty, resulting in poorly informed decisions. Our objective was to determine whether navigated care planning with nursing home residents or their decision makers changed care plans during the first wave of the COVID-19 pandemic. The MED-LTC virtual consultation service, led by internal medicine specialists, conducted care planning conversations that balanced information-giving/physician guidance with resident autonomy. Consultation included (1) the assessment of co-morbidities, frailty, health trajectory, and capacity; (2) in-depth discussion with decision makers about health status and expected outcomes; and (3) co-development of a care plan. Non-parametric tests and logistic regression determined the significance and factors associated with a change in care plan. Sixty-three residents received virtual consultations to review care goals. Consultation resulted in less aggressive care decisions for 52 residents (83%), while 10 (16%) remained the same. One resident escalated their care plan after a mistaken diagnosis of dementia was corrected. Pre-consultation, 50 residents would have accepted intubation compared to 9 post-consultation. The de-escalation of care plans was associated with dementia, COVID-19 positive status, and advanced frailty. We conclude that during the COVID-19 pandemic, a specialist-led consultation service for frail nursing home residents significantly influenced decisions towards less aggressive care.

Introduction: Children with medical complexity and their families are an important population of interest within the Canadian healthcare system. Despite representing less than 1% of the paediatric population, children with medical complexity require extensive care and account for one third of paediatric healthcare expenditures. Opportunities to conduct research to assess disparities in care and appropriate allocation of health resources relies on the ability to accurately identify this heterogeneous group of children. This study aims to better understand the population of children with medical complexity in the Canadian Maritimes, including Nova Scotia (NS), New Brunswick (NB) and Prince Edward Island (PEI). This will be achieved through three objectives: (1) Evaluate the performance of three algorithms to identify children with medical complexity in the Canadian Maritimes in administrative data; then using the 'best fit' algorithm (2) Estimate the prevalence of children with medical complexity in the Canadian Maritimes from 2003 to 2017 and (3) Describe patterns of healthcare utilisation for this cohort of children across the Canadian Maritimes., Methods and Analysis: The research will be conducted in three phases. In Phase 1, an expert panel will codevelop a gold-standard definition of paediatric medical complexity relevant to the Canadian Maritime population. A two-gate validation process will then be conducted using NS data and the gold-standard definition to determine the 'best fit' algorithm. During phase 2 the 'best fit' algorithm will be applied to estimate the prevalence of children with medical complexity in NS, NB and PEI. Finally, in phase 3 will describe patterns of healthcare utilisation across the Canadian Maritimes., Ethics and Dissemination: Ethics approval for this protocol was granted by the institutional research ethics board at the IWK Health Centre (REB # 1026245). A waiver of consent was approved. This study will use an integrated knowledge translation approach, where end users are involved in each stage of the project, which could increase uptake of the research into policy and practice. The findings of this research study will be submitted for publication and dissemination through conference presentations and with our end users., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Breast cancer can recur months to decades after an initial diagnosis and treatment. The mechanisms that control tumor cell dormancy remain poorly understood, making it difficult to predict which patients will recur and thus benefit from more rigorous screening and treatments. Unfortunately, the extreme rarity of dormant DTCs has been a major obstacle to their study., Methods: To overcome this challenge, we developed an efficient system to isolate and study rare dormant breast cancer cells from metastatic organs including bones, which represent a major site of metastasis. After isolation of cells from the long bones, we used single cell RNA-sequencing (scRNA-seq) to profile proliferative and dormant PyMT-Bo1 breast cancer cells. We also compared this signature to dormant versus proliferative tumor cells isolated from the lungs. Finally, we compared our dormant signature to human datasets., Results: We identified a group of genes including Cfh, Gas6, Mme and Ogn that were highly expressed in dormant breast cancer cells present in the bone and lung. Expression of these genes had no impact on dormancy in murine models, but their expression correlated with disease-free survival in primary human breast cancer tumors, suggesting that these genes have predictive value in determining which patients are likely to recur., Conclusions: Dormant breast cancer cells exhibit a distinct gene expression signature regardless of metastatic site. Genes enriched in dormant breast cancer cells correlate with recurrence-free survival in breast cancer patients., (© 2022. The Author(s).)

Purpose: The Canadian Network for Observational Drug Effect Studies (CNODES) studies the benefits and risks of post-market drugs and evaluates its research mobilization efforts for accountability, demonstrating value, and learning. As part of these evaluation efforts, and acknowledging gender disparity in authorship across many academic disciplines, CNODES examined the relationship between gender and authorship in its own journal articles and the literature citing them., Methods: CNODES articles (published 2012-2017) and all citing articles were identified and extracted using Scopus. Scopus author IDs were used to extract full names and a web service (www.genderapi.com) was used to estimate gender, converting all probabilities <80% to "indeterminate." T-tests and visualizations were used to compare the proportion of females between CNODES and the citing literature., Results: Twenty-eight CNODES articles and 463 citing articles were identified. The mean number of authors per article was 9.5 in CNODES articles and 5.7 in the citing literature. CNODES articles had a female authorship rate of 36%, compared to 29% in the citing literature (7% difference, 95% CI: [1%, 13%]). There were no female authors in 14% of CNODES articles versus 36% of the citing literature. Women were first authors in 25% and corresponding authors in 14% of CNODES articles., Conclusions: This analysis provides a benchmark and method to monitor progress in female parity in pharmacoepidemiology authorship. Further work is needed to determine and address barriers and facilitators to women's recruitment and advancement in the field of pharmacoepidemiology., (© 2021 John Wiley & Sons Ltd.)

Levothyroxine (LEVO) sodium is an FDA-approved drug that is used to treat underactive thyroid (hypothyroidism) and other conditions. It is generally used as a thyroid-stimulating hormone administered orally. However, this approach has some drawbacks such as this drug should be taken every day 30 min to 1 h prior to breakfast with an empty stomach, moreover, some food interactions must be monitored. Thus, alternative innovative approaches capable of providing sustained LEVO release should be developed. Our research was designed to establish a simple quantitative determination method for LEVO in rat plasma for pre-clinical evaluation of long acting formulations using a high-performance liquid chromatography method, to validate the analytical method according to ICH guidelines and to characterise its pharmacokinetic behavior in rats. After simple protein precipitation with acetonitrile, LEVO was eluted on a Xselect CSH™ C18 column (Waters, 3.0 × 150 mm) with a particle size of 3.5 μm using a mobile phase of water and acetonitrile at a ratio of 65 : 35% v/v, including 0.1% v/v of trifluoracetic acid. The calibration standards used for plasma ranged between 0.5-1000 ng mL -1 with a correlation coefficient ( r 2 ) of ≥0.998. The limit of detection was 0.44 ng mL -1 and the lower limit of quantitation was 1.33 ng mL -1 . The extraction recovery of LEVO in rat plasma samples by this method was between 80 and 85%. The method was selective, sensitive, accurate and precise for detecting and quantifying LEVO in a pharmacokinetic study carried out in rats for pre-clinical evaluation of long acting formulations. The validated HPLC method meets the ICH established requirements and therefore offers a wide range of potential applications in pre-clinical therapeutic drug monitoring, pharmacokinetics and toxicology.

Objective: In the present study, we sought to establish a link between suicidal ideation (SI) and smoking in college students, determine whether psychopathology accounted for the association, and determine whether smoking expectancies were moderators. Participants: Participants ( N  = 607) were identified as nonsmokers, exsmokers, infrequent smokers, or daily smokers. Methods: Participants were assessed for smoking patterns, smoking expectancies, psychopathology, SI, and past suicide attempts. Results: Daily smokers had the highest level of SI. There was a dose-response relationship between smoking and SI, such that the higher the daily smoking rate, the greater the SI, even when controlling for depression, alcohol use, and drug use. Trend-level results indicated that at lower smoking rates, elevated smoking-related negative affect reduction (NAR) expectancies were associated with lower SI, while elevated NAR expectancies in combination with higher smoking rates were associated with greater SI. Conclusion: Smoking cessation programs for college students should screen for SI.

Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell-produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.

Abstract: Retrospective cohort studyTo characterize the learning curve of a spine surgeon during the first 2 years of independent practice by comparing to an experienced colleague. To stratify learning curves based on procedure to evaluate the effect of experience on surgical complexity.The learning curve for spine surgery is difficult to quantify, but is useful information for hospital administrators/surgical programs/new graduates, so appropriate expectations and accommodations are considered.Data from a retrospective cohort (2014-2016) were analyzed at a quaternary academic institution servicing a geographically-isolated, mostly rural area. Procedures included anterior cervical discectomy and fusion, posterior cervical decompression and stabilization, single and 2-level posterior lumbar interbody fusion, lumbar discectomy, and laminectomy. Data related to patient demographics, after-hours surgery, and revision surgery were collected. Operative time was the primary outcome measure, with secondary measures including cerebrospinal fluid leak and early re-operation. Time periods were stratified into 6 month quarters (quarter [Q] 1-Q4), with STATA software used for statistical analysis.There were 626 patients meeting inclusion criteria. The senior surgeon had similar operative times throughout the study. The new surgeon demonstrated a decrease in operative time from Q1 to Q4 (158 minutes-119 minutes, P < .05); however, the mean operative time was shorter for the senior surgeon at 2 years (91 minutes, P < .05). The senior surgeon performed more revision surgeries (odds ratio [OR] 2.5 [95% confidence interval [CI] 1.7-3.6]; P < .001). Posterior interbody fusion times remained longer for the new surgeon, while laminectomy surgery was similar to the senior surgeon by 2 years. There were no differences in rates of cerebrospinal fluid leak (OR 1.2 [95% CI 0.6-2.5]; P > .05), nor reoperation (OR 1.16 [95% CI 0.7-1.9]; P > .05) between surgeons.A significant learning curve exists starting spine practice and likely extends beyond the first 2 years for elective operations., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Question: What are the effects of specific types of exercise treatments on pain intensity and functional limitation outcomes for adults with chronic low back pain?, Design: Systematic review with network meta-analysis of randomised controlled trials., Participants: Adults with non-specific low back pain for ≥ 12 weeks., Intervention: Exercise treatments prescribed or planned by a health professional that involved conducting specific activities, postures and/or movements with a goal to improve low back pain outcomes., Outcome Measures: Pain intensity (eg, visual analogue scale or numerical rating scale) and back-related functional limitations (eg, Roland Morris Disability Questionnaire or Oswestry Disability Index), each standardised to range from 0 to 100., Results: This review included 217 randomised controlled trials with 20,969 participants and 507 treatment groups. Most exercise types were more effective than minimal treatment for pain and functional limitation outcomes. Network meta-analysis results were compatible with moderate to clinically important treatment effects for Pilates, McKenzie therapy, and functional restoration (pain only) and flexibility exercises (function only) compared with minimal treatment, other effective treatments and other exercise types. The estimated mean differences for these exercise types compared with minimal treatment ranged from -15 to -19 for pain and from -10 to -12 for functional limitation., Conclusion: This review found evidence that Pilates, McKenzie therapy and functional restoration were more effective than other types of exercise treatment for reducing pain intensity and functional limitations. Nevertheless, people with chronic low back pain should be encouraged to perform the exercise that they enjoy to promote adherence., Registration: DOI:10.1002/14651858.CD009790., (Copyright © 2021 Australian Physiotherapy Association. Published by Elsevier B.V. All rights reserved.)

This work aimed to develop a subcutaneous implant for prolonged delivery of LEVO to treat hypothyroidism. This could overcome challenges with patient compliance and co-administration and could improve treatment of this condition. For this purpose, implants were produced by solvent casting mixtures of poly(caprolactone) (PCL), poly(ethylene glycol) (PEG) and LEVO sodium. These implants contained mixtures of PCL of differing molecular weight, PEG and different LEVO sodium loadings (20% or 40% w/w). SEM images confirmed that the drug was evenly dispersed throughout the implant. In vitro release rates ranging from 28.37 ± 1.19 - 78.21 ± 19.93 µg/day and 47.39 ± 8.76 - 98.92 ± 4.27 µg/day were achieved for formulations containing 20% and 40% w/w drug loading, respectively. Implants containing higher amounts of low molecular weight PCL and 40% w/w of LEVO showed release profiles governed by zero order kinetics. On the other hand, implants containing higher amounts of high molecular weight PCL showed a release mechanism governed by Fickian diffusion. Finally, two representative formulations were tested in vivo. These implants were capable of providing detectable LEVO levels in plasma during the entire duration of the experiments (4 weeks) with LEVO plasma levels ranging between 5 and 20 ng/mL., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Deficiency of thyroid hormones (hypothyroidism) is treated with oral levothyroxine (LEVO). However, the effectiveness of oral administration is highly dependent on the co-administration of food and other drugs. This factor, in combination with the chronic nature of this condition, mean that there are concerns with patient compliance. Development of long acting formulations to treat hypothyroidism could potentially solve this problem. However, LEVO instability in solution could be problematic. In order to develop long acting LEVO delivery systems in vitro drug release experiments should be carried out. However, short term LEVO stability in aqueous solution will prevent this. BSA was used as a stabiliser for LEVO; extending the stability of the drug in aqueous solutions from a few hours to 2 weeks. In order to achieve this, the required concentration of the protein was 0.1% w/v. Subsequently, an HPLC method capable of separating LEVO from the protein was developed and validated following ICH guidelines. The analysis was carried out using a reverse phase HPLC method on an Agilent 1220 Infinity II LC system. The column used to achieve separation was a Zorbax Eclipse plus C18 (95 Å pore size, 250 mm length x 4.6 mm internal diameter; 5 μm particle size). The mobile phase used was composed of acetonitrile and 0.1% trifluoroacetic acid at a ratio of 50:50% v/v. UV detection of LEVO sodium was carried out at 225 nm. The retention time for the drug was 6.6 minutes. The method showed a limit of detection of 0.03 μg/mL and a limit of quantification of 0.09 μg/mL. Finally, this method was used to evaluate the release from implants containing 20% w/w of LEVO. These devices were prepared using a solvent casting method with poly(caprolactone) and LEVO. These devices showed an initial burst release over the first 3 days. Subsequently, they were capable of providing a linear release rate over the following 25 days., 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 © 2021 Elsevier B.V. All rights reserved.)

Background: Children, caregivers, and clinicians often prefer midstream clean catch technique to urethral catheterization for obtaining urine cultures. However, contamination is common, potentially resulting in unnecessary medical intervention and cost. With this resident-led initiative, we aimed to reduce pediatric midstream clean catch urine culture contamination over 6 months., Methods: A bundled intervention was implemented in the emergency department, inpatient units, and outpatient clinics at our institution. Baseline contamination rates were collected April 2016 to September 2017; the intervention was introduced October 2017 to March 2018 and evaluated April 2018 to September 2018. Sustainability was measured October 2018 to September 2020. Balancing measures included rates of repeat urine cultures, positive cultures, and contaminated cultures by urethral catheterization., Results: Rates of midstream clean catch urine culture contamination were 45.3% preintervention and 30.9% postintervention, a 14.7% (95% confidence interval: 8.0% to 21.5%) absolute decrease. Before and after intervention, girls and patients 16 to 17 years old had the highest rates of midstream clean catch contamination. Six months postintervention, the rate of repeat urine culture decreased from 4.9% to 0.9% with no change in positive culture results or contaminated cultures by urethral catheterization. Over the subsequent 2 years, the impact of the intervention decreased (rate of contamination over 30 months postintervention: 38.4%, a 7.3% [95% confidence interval: 2.9% to 11.6%] absolute decrease; rate of repeat urine culture: 3.2%)., Conclusions: An intervention to improve midstream clean catch urine culture collection was associated with a clinically meaningful decrease in contamination. Impact of the resident-led intervention decreased over time., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Increasing numbers of patients are using cannabis before procedures that require anesthesia. This study set out to examine the impact of cannabis use on anesthetic agent requirements, associated cardiac and respiratory morbidity, and overall satisfaction levels in patients undergoing esophagogastroduodenoscopy (EGD). This involved a retrospective review of patients undergoing EGD at a single center. Fortyseven, self-reported cannabis users were identified and 23 were successfully cross-matched with control participants for comparison purposes. The Wilcoxon signed rank test was used to evaluate differences in propofol administration between the 2 groups, and the McNemar test was used to test for differences in fentanyl and ketamine administration. No statistically significant differences were observed in propofol, fentanyl, or ketamine administration in the cannabis group compared with the control group. No adverse cardiac or respiratory events were reported within 30 days for either group. This study was specific to EGD procedures of short duration, and larger studies are needed to confirm results of no consequence in cannabis users undergoing anesthesia. Future studies should consider cannabis users who undergo anesthesia for diverse procedure types of various durations., Competing Interests: This work was supported by the Tufts Clinical and Translational Science Institute, funded through National Institutes of Health Award Number UL1TR002544. The authors did not discuss off-label use within the article. Disclosure statements are available for viewing upon request., (Copyright © by the American Association of Nurse Anesthetists.)

Breast cancer bone metastases are common and incurable. Tumoral integrin β3 (β3) expression is induced through interaction with the bone microenvironment. Although β3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of β3 + tumor cells in murine bone metastases after docetaxel chemotherapy. β3 + tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples ( n = 38). High tumoral β3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral β3 had minimal effect in vitro , but significantly enhanced in vivo docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact β3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in β3-expressing cells characterized by enhanced oxygen consumption, reactive oxygen species generation, and protein production. We identified mTORC1 as a candidate for therapeutic targeting of this β3-mediated, chemotherapy-induced metabolic response. mTORC1 inhibition in combination with docetaxel synergistically attenuated murine bone metastases. Furthermore, micelle nanoparticle delivery of mTORC1 inhibitor to cells expressing activated αvβ3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that β3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with αvβ3-targeted mTORC1 inhibitor nanotherapy. Our work demonstrates the importance of the metastatic microenvironment when designing treatments and presents new, bone-specific strategies for enhancing chemotherapeutic efficacy., (©2021 American Association for Cancer Research.)

Study Design: Retrospective cohort study., Objective: To examine the relationship between preoperative Modic change (MC) and postoperative clinical assessment scores for patients receiving lumbar discectomy or transforaminal lumbar interbody fusion for lumbar disk herniation., Summary of Background Data: Lumbar disk herniation is a risk factor for MC development. MC on spinal magnetic resonance imaging (MRI) has been associated with worse preoperative and postoperative clinical assessment scores., Materials and Methods: We reviewed data for 285 primary single-level surgeries. Preoperative and 12-month postoperative assessment scores were recorded using the visual analog scale leg pain, Oswestry Disability Index, and Short Form-36 Physical Component Summary. MC subgroup on preoperative MRI was recorded by a single neuroradiologist., Results: One hundred seventy-nine patients (female, 56%; age-53±13 y) with preoperative MRI were included. Age and sex were similar across MC subgroups. The sample prevalence of MC on preoperative MRI was 62%, and MC2 was the most common subgroup (35%). No differences in preoperative assessment scores were identified, regardless of presence or absence of MC. For the overall cohort, improvement in assessment scores were observed: Short Form-36 improved an average of 8.2 points [95% CI (95% CI), 5.8-10.7], Oswestry Disability Index by 11.3 points (95% CI, 8.7-14.0), and visual analog scale by 2.8 points (95% CI, 2.1-3.5). In nearly all cases, MCID values were met, even when stratifying by MC subgroup. Few differences in postoperative assessment scores were identified when comparing across MC1, MC2, or no MC groups., Conclusions: Statistically and clinically significant improvement in postoperative clinical assessment scores was observed for both lumbar discectomy and transforaminal lumbar interbody fusion groups. MC on preoperative MRI was not associated with worse preoperative or postoperative clinical assessment scores., Level of Evidence: Level III., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Low back pain is a leading cause of disability globally. It is a common reason for presentation to the emergency department where opioids are commonly prescribed. This is a retrospective cohort study of opioid-naive adults with low back pain presenting to 1 of 4 emergency departments in Nova Scotia. We use routinely collected administrative clinical and drug-use data (July 2010-November 2017) to investigate the prevalence of prolonged opioid use and associated individual and prescription characteristics. In total, 23,559 eligible individuals presented with nonspecific low back pain, with 84.4% being opioid-naive. Our study population included 4023 opioid-naive individuals who filled a new opioid prescription within 7 days after their index emergency department visit (24.4%). The prevalence of prolonged opioid use after a new opioid prescription for low back pain (filling an opioid prescription 8-90 days after the emergency department visit and filling a subsequent prescription ±30 days of 6 months) was 4.6% (185 individuals). Older age and female sex were associated with clinically important increased odds of prolonged opioid use. First prescription average >90 morphine milligram equivalents/day (odds ratio 1.6, 95% confidence interval 1.0-2.6) and greater than 7-day supply (1.9, 1.1-3.1) were associated with prolonged opioid use in adjusted models. We found evidence of declining opioid prescriptions over the study period, but that 24.3% of first opioid prescriptions in 2016 would not have aligned with current guideline recommendations. Our study provides evidence to support a cautious approach to prescribing in opioid-naive populations., (Copyright © 2020 International Association for the Study of Pain.)

Background: Walking is an easily prescribed physical activity for people with low back pain (LBP). However, the evidence for its effectiveness to improve pain and disability levels for people with chronic low back pain (CLBP) within a community setting has not been evaluated. This study evaluates the effectiveness of a clinician guided, pedometer-driven, walking intervention for increasing physical activity and improving clinical outcomes compared to education and advice., Methods: Randomized controlled trial recruiting N = 174 adults with CLBP. Participants were randomly allocated into either a standardized care group (SG) or pedometer based walking group (WG) using minimization allocation with a 2:1 ratio to the WG. Prior to randomization all participants were given a standard package of education and advice regarding self-management and the benefits of staying active. Following randomization the WG undertook a physiotherapist guided pedometer-driven walking program for 12 weeks. This was individually tailored by weekly negotiation of daily step targets. Main outcome was the Oswestry Disability Index (ODI) recorded at baseline, 12 weeks, 6 and 12 months. Other outcomes included, numeric pain rating, International Physical Activity Questionnaire (IPAQ), Fear-Avoidance Beliefs Questionnaire (FABQ), Back Beliefs questionnaire (BBQ), Physical Activity Self-efficacy Scale, and EQ-5D-5L quality of life estimate., Results: N = 138 (79%) participants completed all outcome measures at 12 weeks reducing to N = 96 (55%) at 12 months. Both observed and intention to treat analysis did not show any statistically significant difference in ODI change score between the WG and the SG at all post-intervention time points. There were also no significant between group differences for change scores in all secondary outcome measures. Post hoc sensitivity analyses revealed moderately disabled participants (baseline ODI ≥ 21.0) demonstrated a greater reduction in mean ODI scores at 12 months in the WG compared to SG, while WG participants with a daily baseline step count < 7500 steps demonstrated a greater reduction in mean ODI scores at 12 weeks., Conclusions: Overall, we found no significant difference in change of levels of (ODI) disability between the SG and WG following the walking intervention. However, ODI responses to a walking program for those with moderate levels of baseline disability and those with low baseline step count offer a potential future focus for continued research into the benefit of walking as a management strategy for chronic LBP., Trial Registration: United States National Institutes of Health Clinical Trails registry (http://ClinicalTrials.gov/) No. NCT02284958 (27/10/2014).