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Abstract Objectives Dasatinib 100 mg daily and nilotinib 600/800 mg daily have been compared to imatinib as first line treatments for CML in two recent randomised studies. However, no head to head evidence exists of the relative efficacy of dasatinib and nilotinib. Methods We conducted a systematic literature review and used the data extracted to perform an indirect comparison meta-analysis of the three interventions. Results Data from eight clinical studies (3,520 individuals) were included, all of which were of good quality (low risk of bias). At six months, the odds of complete cytogenetic response (CCyR) for dasatinib and nilotinib were approximately three times those for imatinib (range 2.77 to 3.06, all values not significant). At twelve months datatinib and nilotinib were significantly better than imatinib for both CCyR and major molecular response (MMR) (CCyR odds range 2.06 to 2.41, MMR odds range 2.09 to 2.87). At eighteen months dasatinib and nilotinib were again significantly better in terms of CCyR than imatinib (response odds 1.55 to 2.01). When dasatinib and nilotinib were compared to each other, for both clinical endpoints at all time points the response odds were not significantly different. Conclusions On the basis of a systematic review of the current literature base, dasatinib 100 mg, nilotinib 600 mg and nilotinib 800 mg should be viewed as equivalent in terms of complete cytogenetic and major molecular response.

Purpose: This study aims to evaluate how various demographic factors impact the stage at diagnosis and, therefore, prognosis of laryngeal cancer., Materials and Methods: Using the National Cancer Database, 96,409 patients were diagnosed with laryngeal squamous cell carcinoma between 2004 and 2020. Early (stage 0 or I) vs. late-stage (stage IV) cancers were compared based on demographic variables utilizing Chi-square and multivariate analysis with a significance of p < 0.05., Results: Female, Black, and generally older patients were more likely to have late-stage cancer than their counterparts. When compared with a community cancer program, patients treated at other facility types were more likely to be diagnosed late. Patients with private insurance, Medicare, or other government insurance were all less likely to have late-stage cancer compared to patients without insurance. Compared to patients in the lowest median household income quartile, patients in the third quartile and fourth quartile were diagnosed earlier. Patients living in an area with the lowest level of high school degree attainment were most likely to be diagnosed late. Living in a more populous area was associated with a lower chance of being diagnosed late. Increasing Charlson-Deyo Score was associated with a stronger likelihood of being diagnosed at a later stage., Conclusion: Patients who are female, Black, uninsured, have a low household income, live in less populated and less educated areas, are treated at non-community cancer programs, and have more comorbid conditions have later stage diagnoses. This data contributes to understanding inequities in healthcare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Sophisticated scientific methods have facilitated dose individualisation with substantial advancements in therapeutic drug monitoring (TDM) practice. It is unclear whether these methods have translated to the clinical setting. This study aimed to determine current TDM practice for tobramycin monitoring in cystic fibrosis (CF) centres in the USA and Canada, UK and Ireland, and Australia and New Zealand due to a high prevalence of CF., Methods: A web-based survey was developed and circulated via CF specialist groups within the targeted geographical regions. Themes included centre demographics, tobramycin usage, dosing and infusion practices, TDM practices, and blood sampling methods., Results: In total 77 responses were received from 75 different CF centres over the 3-month evaluation period (October 2019-January 2020). Respondents were from the USA and Canada (60%), Australia and New Zealand (25%), and the UK and Ireland (15%). Tobramycin was used in 97% of sites, with an international variation in practice across all survey aspects including dosing and infusion practice. TDM-based dose adjustment in the UK and Ireland was most commonly based only on trough sample collection for avoidance of toxicity, where use of computer programs for targeting both efficacy and toxicity endpoints were most common in Australia and New Zealand. The underlying pharmacokinetic basis of that program was not known by 33% of sites who utilised a computer program for tobramycin dose individualisation., Conclusion: There remains substantial heterogeneity in tobramycin management worldwide. Despite two decades of research into TDM of tobramycin, there has been a slow uptake of new technologies and evolution of practice. An improved understanding of TDM processes is required for translation of evidence-based research into clinical practice. International guidelines require updating due to the advances in research to support confidence in the changes in clinical practice., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background. Local health services make limited use of economic evaluation to inform decisions to fund new health service interventions. One barrier is the relevance of published intervention effects to the local setting, given these effects can strongly reflect the original evaluation context. Expert elicitation methods provide a structured approach to explicitly and transparently adjust published effect estimates, which can then be used in local-level economic evaluations to increase their local relevance. Expert elicitation was used to adjust published effect estimates for 2 interventions targeting the prevention of inpatient hypoglycemia. Methods. Elicitation was undertaken with 6 clinical experts. They were systematically presented with information regarding potential differences in patient characteristics and quality of care between the published study and local contexts, and regarding the design and application of the published study. The experts then assessed the intervention effects and provided estimates of the most realistic, most pessimistic, and most optimistic intervention effect sizes in the local context. Results. The experts estimated both interventions would be less effective in the local setting compared with the published effect estimates. For one intervention, the experts expected the lower complexity of admitted patients in the local setting would reduce the intervention's effectiveness. For the other intervention, the reduced effect was largely driven by differences in the scope of implementation (hospital-wide in the local setting compared with targeted implementation in the evaluation). Conclusions. The pragmatic elicitation methods reported in this article provide a feasible and acceptable approach to assess and adjust published intervention effects to better reflect expected effects in the local context. Further development and application of these methods is proposed to facilitate the use of local-level economic evaluation., Highlights: Local health services make limited use of economic evaluation to inform their decisions on the funding of new health service interventions. One barrier to use is the relevance of published intervention evaluations to the local setting.Expert elicitation methods provide a structured way to consider differences between the evaluation and local settings and to explicitly and transparently adjust published effect estimates for use in local economic evaluations.The pragmatic elicitation methods reported in this article offer a feasible and acceptable approach to adjusting published intervention effects to better reflect the effects expected in the local context. This increases the relevance of economic evaluations for local decision makers., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was conducted at Flinders University for the NHMRC Partnership Centre for Health System Sustainability (grant 9100002) administered by the Australian Institute of Health Innovation, Macquarie University. Along with the NHMRC, the funding partners in this research collaboration are the Bupa Health Foundation; NSW Ministry of Health; Department of Health, WA; and the University of Notre Dame Australia. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report. The authors hold all data for the project., (© The Author(s) 2024.)

Background: Osteogenesis Imperfecta (OI) usually causes an increased fracture burden and bone deformity, with subsequent operations common. In addition to skeletal manifestations, there is a potential increase in bleeding susceptibility due to the increased frequency of orthopedic procedures, warranting investigation into methods to mitigate this risk. This study aims to evaluate the safety and efficacy of tranexamic acid (TXA) usage to reduce intraoperative blood loss in children with OI. We want to assess the potential benefits, risks, and complications involved with TXA use in this patient population., Methods: TXA-receiving patients (cases) were matched 1:1 with non-TXA-receiving controls on the following criteria: age within 2 years, bone category, and OI Type. Descriptive statistics were used to summarize the data. Fisher Exact Test was performed to compare transfusion status between groups. A Wilcoxon Rank Sum test was performed to assess differences between the groups in days of stay, length of surgery, and estimated blood loss (EBL). All analyses were conducted using SAS version 9.4. P <0.05 was considered statistically significant., Results: Our TXA-receiving population of 30 patients consisted of 11 females and 19 males. One patient was OI type I, 13 were OI type III, 14 were OI type IV, and 2 were categorized as Other (not Type I through Type IV). We found a significant difference in transfusion status ( P =0.02), with zero TXA patients requiring a transfusion compared with 20% of the control cases. There is also a significant difference in median EBL ( P =0.0004) between groups, with TXA patients having decreased intraoperative EBL (20 vs. 62.5 mL). There was also a difference in median days of postoperative stay between TXA-receiving and non-TXA-receiving patients ( P =0.001; 2.6 vs. 4 d)., Conclusions: Our study concluded that TXA use in OI patients is associated with lower perioperative transfusions and intraoperative blood loss rates. These results support the standard usage of TXA in these patients to reduce intraoperative blood loss., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Published evidence on health service interventions should inform decision-making in local health services, but primary effectiveness studies and cost-effectiveness analyses are unlikely to reflect contexts other than those in which the evaluations were undertaken. A ten-step framework was developed and applied to use published evidence as the basis for local-level economic evaluations that estimate the expected costs and effects of new service intervention options in specific local contexts., Methods: Working with a multidisciplinary group of local clinicians, the framework was applied to evaluate intervention options for preventing hospital-acquired hypoglycemia. The framework included: clinical audit and analyses of local health systems data to understand the local context and estimate baseline event rates; pragmatic literature review to identify evidence on relevant intervention options; expert elicitation to adjust published intervention effect estimates to reflect the local context; and modeling to synthesize and calibrate data derived from the disparate data sources., Results: From forty-seven studies identified in the literature review, the working group selected three interventions for evaluation. The local-level economic evaluation generated estimates of intervention costs and a range of cost, capacity and patient outcome-related consequences, which informed working group recommendations to implement two of the interventions., Conclusions: The applied framework for modeled local-level economic evaluation was valued by local stakeholders, in particular the structured, formal approach to identifying and interpreting published evidence alongside local data. Key methodological issues included the handling of alternative reported outcomes and the elicitation of the expected intervention effects in the local context.

Background: There are significant differences in prognosis for osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordomas based on the stage at diagnosis. The five-year survival of these bone cancers varies from 75-87% at an early stage of diagnosis and falls to 27-55% at a late stage of diagnosis., Patients and Methods: This study retrospectively evaluated the odds of stage I vs stage IV cancer at the time of diagnosis in patients with primary malignant bone tumors (osteosarcoma, chondrosarcoma, Ewing sarcoma and chordoma) diagnosed in the National Cancer Database (NCDB) between 2004 and 2018. Cross tabulations with Chi-square analysis were performed to evaluate frequencies of different socioeconomic and geographical characteristics between patients with stage I vs stage IV cancer. Multivariable binary logistic regression was performed to evaluate relationships between socioeconomic and geographical factors and the odds of stage IV cancer at the time of diagnosis. Statistical significance was set at α = 0.05., Results: 8882 patients with stage I and 3063 with stage IV primary malignant bone tumors were identified. The odds of stage IV bone cancer at diagnosis are increased for patients on Medicaid (odds ratio [OR] = 1.298, 95% confidence interval [CI]: 1.043-1.616) or Medicare (OR = 1.795, 1.411-2.284). Odds of stage IV bone cancer at diagnosis were decreased with female sex (OR = 0.733, 0.671-0.800), private insurance (OR = 0.738, 0.601-0.905), and those treated at community cancer programs (OR = 0.542, 0.369-0.797), comprehensive cancer program (OR = 0.312, 0.215-0.452), or academic/research facilities (OR = 0.370, 0.249-0.550). No significant relationship was identified between the stage at diagnosis and race, ethnicity, Charlson-Deyo score, or education level. Stage IV cancer at diagnosis showed was proportionally lower in chondrosarcomas (17.1%) and chordomas (2.1%) than osteosarcomas (45.0%) and Ewing sarcomas (35.8%)., Conclusion: Odds of stage IV bone cancer at diagnosis are greater with male sex, Medicaid or Medicare insurance status, or treatment at community cancer programs. Providers should have a low suspicion for additional evaluation when treating patients with symptoms of bone cancer and should be aware of these disparities when treating people in these groups. This is to the authors' knowledge the first such study conducted through the NCDB., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, McMahon et al.)

Purpose: The demand for high-quality and more comprehensive oncology care will continue to rise globally. Effective leadership is particularly important., Methods: The evolving endeavor of ASCO to reach out globally has covered the development of the next-generation leaders from Asia Pacific. Through the Leadership Development Program, the untapped talent of the region and the future leaders in oncology will gain the knowledge and skill sets, which prepares them to navigate the complex dynamics of oncology health care., Results: The region is the largest and the most populous with more than 60% of the world's population. It has 50% of cancer cases and is estimated to account for 58% of cancer deaths worldwide. The demand for high-quality and more comprehensive oncology care will continue to rise in the years to come. This growth will intensify the need for capable leaders. Leadership styles and behaviors are different. These are shaped within the context of cultural and philosophical views and beliefs. The pan-Asian interdisciplinary group of young leaders are expected to gain knowledge and skillsets through the Leadership Development Program. They will learn to work on strategic projects within a team and gain knowledge about advocacy. Communication and presentation skills and conflict management are also important components of the program. Through learning culturally relevant skills, participants can effectively collaborate with others, build relationships, and lead within their own institutions and societies and within ASCO., Conclusion: Institutions and organizations need to have a deeper and more sustained focus on leadership development. Successfully addressing the challenges on leadership development in Asia Pacific is important.

Purpose: Palliative care in Sarawak is mainly provided by health care professionals with limited formal training in palliative care. Therefore, in 2020, collaborative work between Sarawak General Hospital, University Malaysia Sarawak, and ASCO began. This study reports on the outcome of this collaboration., Methods: The collaboration was initiated with the first ASCO Palliative Care e-course, Train the Trainer program, International Development and Education Award-Palliative Care and translation of ASCO Palliative Care Interdisciplinary Curriculum resources., Results: This collaboration has resulted in the change of practice of palliative care among the oncology team of Sarawak General Hospital., Conclusion: It encourages more timely palliative care referrals to ensure that patients with complex physical, psychosocial, and spiritual needs have the necessary input and support from the palliative care team throughout the course of patients' illnesses.

Background: Physician review websites (PRWs) are increasing in usage and popularity. Our purpose is to characterize one-star reviews of orthopedic oncology surgeons to understand factors in healthcare that contribute to patient satisfaction., Methods: Orthopedic oncology surgeons were randomly selected from the Musculoskeletal Tumor Society. A search for one-star reviews was performed on Google Reviews, Healthgrades, and Vitals.com. Reviews were classified as clinical or nonclinical. Statistical analyses were performed regarding the frequency of reviews and complaints for each category., Results: Of the 7,733 reviews discovered, 908 (11.7%) were identified as one-star reviews. Of 907 usable complaints, 362 (40.8%) were clinical and 545 (59.2%) were nonclinical. The most common nonclinical complaints included bedside manner (65%) and limited time with providers (19%). The most common clinical complaints included complications (26%) and disagreements with the treatment plan (26%). There were 120 surgical and 221 nonsurgical reviews. Surgical patients had a higher rate of clinical complaints. Nonsurgical patients had a higher rate of total complaints., Conclusion: To the best of our knowledge, this is the first study examining PRWs regarding orthopedic oncology surgeons. Most one-star reviews were due to nonclinical complaints from nonsurgical patients. The most common factors are bedside manner, limited time with provider, phone communication issues, and rude/unprofessional conduct., Competing Interests: All authors declare that they have no conflicts of interest., (Copyright © 2022 Leeann Qubain et al.)

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na + /K + ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG 35-55 -induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG 35-55 (PLG-MOG 35-55 ) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Purpose: Delivering high-quality cancer care to patients through a multidisciplinary team (MDT) care approach remains a challenge, particularly in low- and middle-income countries characterized by fragmented health systems and limited human resources for cancer care. City Cancer Challenge (C/Can) is supporting cities in low- and middle-income countries as they work to improve access to equitable quality cancer care. C/Can has developed an innovative methodology to address the MDT gap, piloted in four cities-Asunciòn, Cali, Kumasi, and Yangon., Methods: Collaborating with a network of partners, C/Can and ASCO have developed a package of technical cooperation support focusing on two priority areas that have emerged as core needs: first developing consensus-based, city-wide patient management guidelines for the most common cancers and second, building capacity for the implementation of MDTs in institutions providing cancer care in the city., Results: The real-time application of C/Can's MDT approach in Cali and Asuncion underlined the importance of engaging the right stakeholders early on and embedding MDT guidelines in local and national regulatory frameworks to achieve their sustainable uptake. The results in Cali and Asuncion were essential for informing the process in Yangon, asserting the clear benefits of city-to-city knowledge exchange. Finally, the global COVID-19 pandemic prompted a rapid adaptation of the methodology from an in-person to virtual format; the unexpected success of the virtual program in Kumasi has led to its application in subsequent C/Can cities., Conclusion: The application of C/Can's methodology in this first set of cities has reinforced not only the importance of both resource appropriate guidelines and a highly trained health workforce but also the need for commitment to work across institutions and disciplines.

Cancer treatment utilizing infusion therapies to enhance the patient's own immune response against the tumor have shown significant functionality in a small subpopulation of patients. Additionally, advances have been made in the utilization of nanotechnology for the treatment of disease. We have previously reported the potent effects of 3-4 daily intravenous infusions of immune modifying poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IMPs; named ONP-302) for the amelioration of acute inflammatory diseases by targeting myeloid cells. The present studies describe a novel use for ONP-302, employing an altered dosing scheme to reprogram myeloid cells resulting in significant enhancement of tumor immunity. ONP-302 infusion decreased tumor growth via the activation of the cGAS/STING pathway within myeloid cells, and subsequently increased NK cell activation via an IL-15-dependent mechanism. Additionally, ONP-302 treatment increased PD-1/PD-L1 expression in the tumor microenvironment, thereby allowing for functionality of anti-PD-1 for treatment in the B16.F10 melanoma tumor model which is normally unresponsive to monotherapy with anti-PD-1. These findings indicate that ONP-302 allows for tumor control via reprogramming myeloid cells via activation of the STING/IL-15/NK cell mechanism, as well as increasing anti-PD-1 response rates., Competing Interests: Authors JP, TM, AE, and MB are employed by Cour Pharmaceutical Development Company. SM and LS are co-founders of, members of the Scientific Advisory Board, grantees of, and hold stock options in Cour Pharmaceutical Development Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from onCOUR Pharm., Inc. The funder had the following involvement with the study formed the hypotheses, designed experiments, performed experiments, analyzed results, and prepared the manuscript. onCOUR Pharma, Inc. holds the patent for this technology. All authors declare no other competing interests., (Copyright © 2022 Podojil, Cogswell, Chiang, Eaton, Ifergan, Neef, Xu, Meghani, Yu, Orbach, Murthy, Boyne, Elhofy, Shea, Meeks and Miller.)

Purpose: Ewing sarcoma is a primary malignant bone tumor that manifests predominantly in the proximal long bones and pelvis and traditionally presents with nonspecific symptoms. This tumor preferentially affects children and young adults, occurring most often in patients of European descent. The most important established prognostic factor is the presence of metastasis at the time of diagnosis followed by primary site, size of the primary neoplasm, patient age, and lactate dehydrogenase (LDH) levels. To the authors' knowledge, this is the first study focused on the effects of socioeconomic and geographic factors on overall survival in Ewings sarcoma., Methods: A total of 3,920 patients diagnosed with Ewing sarcoma were identified in the National Cancer Database (NCDB) using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) code 9260. Of these, 3,238 met the inclusion criteria and were analyzed. Descriptive statistics, Kaplan-Meier survival curves, and Cox regression tables were all performed using IBM SPSS Statistics for Windows, Version 27.0 (Released 2020; IBM Corp., Armonk, New York, United States)., Results: Univariate analysis showed greater mortality for patients of increasing age at the time of diagnosis, at two, five, and 10 years of follow-up, Black race patients at two years, Medicare insurance status at two years, urban or rural residence at two and 10 years, more advanced tumor stage at two and five years, and patients with a comorbidity score of ≥2 at two years. Multivariate analysis showed greater mortality at two years with increasing age, Black race, uninsured status, urban or rural residence, and increasing tumor stage. Mortality also increased for patients at five years of follow-up in patients with increasing age or more advanced tumor stage.  Conclusion: Patient mortality in the first two years after diagnosis is increased for patients of the Black race, those living in urban or rural areas, and for patients that are uninsured or using Medicare as their primary payor at the time of diagnosis. To improve patient outcomes, clinicians should recognize and address not only the unique biology of patients but also their unique challenges in access to healthcare. Patients and providers should work to elicit changes on an individual and community level to improve their personal health and the health of those around them., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, McMahon et al.)

Purpose: To evaluate the educational content, quality, and reliability of YouTube videos regarding the Achilles tendon and Achilles tendon injuries., Methods: The first 50 videos found on YouTube after searching "Achilles tendon" were evaluated and classified by content type and uploader source. Reliability and accuracy were assessed using the Journal of the American Medical Association (JAMA) benchmark criteria, nonspecific educational content was assessed via the Global Quality Score (GQS), and specific educational content was assessed using the Achilles Tendon Specific Score (ATSS). ANOVA was performed to determine differences in video reliability and educational content quality by video content type and source. Multivariate stepwise regressions were used to evaluate the effects of specific video characteristics on JAMA benchmark criteria, GQS, and ATSS., Results: The 50 videos evaluated had a cumulative view total of 53,323,307, a mean of 1,066,466, and a range of 1,009 to 42,663,665 views per video. Most videos focused on disease-specific information (38%) and exercise training (22%). Most videos were uploaded by non-physicians (34%) or medical sources (health websites) (32%). A higher view ratio was an independent predictor of lower JAMA scores (lower reliability and accuracy) (standardized beta = -0.281, P = 0.048) and increased video duration was an independent predictor of greater GQS (standardized beta = 0.380, P = 0.007) and ATSS scores (standardized beta = 0.364, P = 0.009) (increased quality of nonspecific and specific educational content)., Conclusion: Videos on YouTube regarding the Achilles tendon were viewed numerous times, but their educational content and reliability were poor. Providers treating patients for Achilles tendon-related pathologies should initiate a dialogue with patients about their use of internet sources and should educate them on their optimal usage. They should warn them of the low quality of YouTube-derived information and provide them with reliable sources that may better give them control over their own care., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, McMahon et al.)

Background: Repeat Rapid Response Team (RRT) calls are associated with increased in-hospital mortality risk and pose an organisation-level resource burden. Use of Non-Technical Skills (NTS) at calls has the potential to reduce potentially preventable repeat calling. NTS are usually improved through training, although this consumes time and financial resources. Re-designing the Rapid Response System (RRS) to promote use of NTS may provide a feasible alternative., Methods: A pre-post observational study was undertaken to assess the effect of an RRS re-design that aimed to promote use of NTS during RRT calls. The primary outcome was the proportion of admissions each month subject to repeat RRT calling, and the average number of repeat calls per admission each month was the secondary outcome of interest. Univariate and multivariable interrupted time series analyses compared outcomes between the two study phases., Results: The proportion of admissions with repeat calls each month increased across both phases of the study period, but the increase was lower in the post re-design phase (change in regression slope -0.12 (standard error 0.07) post versus pre re-design). The multivariable model predicted a 6% reduction (95% confidence interval -15.1-3.1; P = 0.19) in the proportion of admissions having repeat calls at the end of the post redesign phase study compared to the predicted proportion in the absence of the re-design. The average number of calls per admission was also predicted to decrease in the post re-design phase, with an estimated difference of -0.07 calls per admission (equivalent to one fewer repeat call per 14 patients who had RRT calls) at the end of the post re-design phase (95% confidence interval -0.23-0.08, P = 0.35)., Conclusion: This study of an RRS re-design showed modest, but not statistically significant, reductions in the proportion of admissions with repeat calls and the mean number of repeat calls per admission. Given the economic and workforce capacity issues that all health care systems now face, even small improvements in the RRS may have lasting impact across the organisation. For the potential interest of RRS managers, this paper presents a pragmatic, low-cost initiative intended to enhance communication and cooperation at RRT calls., Competing Interests: The authors have declared that no competing interests exist.

Abstract: Exercise is the most common treatment recommended by healthcare providers for the treatment of musculoskeletal pain. We examined whether voluntary running wheel exercise improves pain and bone remodeling in rats with monosodium iodoacetate-induced unilateral knee joint pain. During acquisition of wheel running before osteoarthritis (OA) treatment, rats separated into 2 groups characterized by either high or low levels of voluntary wheel running as indicated by distance and peak speed. After the induction of knee joint OA, all rats showed diminished voluntary wheel running throughout the study. Voluntary wheel running failed to alter evoked nociceptive responses evaluated as weight asymmetry or hind paw tactile thresholds at any timepoint of the study. By contrast, relief of ongoing pain was demonstrated by conditioned place preference produced by lidocaine injection into the monosodium iodoacetate-treated knee in high but not low-running rats. Both high and low voluntary runners showed diminished trabecular bone loss compared with sedentary controls. These observations indicate that both high-intensity and low-intensity exercise is beneficial in protecting against bone remodeling in advanced OA. The data suggest that similar to clinical observation, bone remodeling does not correlate with pain. In addition, these results suggest that higher intensity exercise may relieve persistent ongoing OA pain while maintaining movement-evoked nociception. The relief of ongoing pain can potentially offer significant improvement in quality of life, whereas preservation of responses to movement-evoked pain may be especially important in protecting the joint from damage because of overuse., (Copyright © 2021 International Association for the Study of Pain.)

Cervical cancer is the leading cause of death among women in Nepal. The American Society of Clinical Oncology (ASCO) and The University of Texas MD Anderson Cancer Center collaborated with international and local experts to hold a cervical cancer prevention course in Nepal in November 2019. The course included didactic lectures and a hands-on workshop. The didactic lectures included the epidemiology of cervical cancer globally and locally, cervical cancer screening guidelines, human papillomavirus vaccination, colposcopy and visual inspection with acetic acid (VIA), cervical dysplasia, and cervical cancer treatment. The hands-on workshop consisted of four stations: (1) VIA; (2) colposcopy, cervical biopsy, and endocervical curettage; (3) thermal ablation; and (4) loop electrosurgical excision procedure (LEEP). A train-the-trainer model short course was held by the international faculty to assist six local faculty to become familiar with the instruments, procedures, and models used in the hands-on training stations. Forty-two people (84% gynecologist, 8% radiation oncologist, and 8% other) attended the course. Following the course, the international faculty visited the regional hospitals for additional educational activities. Increased knowledge in cervical cancer screening guidelines and ability in performing VIA, colposcopy and cervical biopsy, thermal ablation, and LEEP were reported by 89%, 84%, 84%, 87%, and 84% of participants, respectively, from the postcourse on-site evaluations. From the 6-month follow-up survey, all respondents reported that they had made practice changes based on what they learned in the course and had implemented or tried to implement the cervical cancer screening guidelines presented at the course. In conclusion, the course evaluations suggested an improvement in participants' ability to perform cervical cancer screening and diagnostic procedures and reported the changes in practices after training.

Purpose: In response to the COVID-19 pandemic, the ASCO launched a Global Webinar Series to address various aspects of cancer care during the pandemic. Here we present the lessons learned and recommendations that have emerged from these webinars., Methods: Fifteen international health care experts from different global regions and oncology disciplines participated in one of the six 1-hour webinars to discuss the latest data, share their experiences, and provide recommendations to manage cancer care during the COVID-19 pandemic. These sessions include didactic presentations followed by a moderated discussion and questions from the audience. All recommendations have been transcribed, categorized, and reviewed by the experts, who have also approved the consensus recommendations., Results: The summary recommendations are divided into different categories, including risk minimization; care prioritization of patients; health care team management; virtual care; management of patients with cancer undergoing surgical, radiation, and systemic therapy; clinical research; and recovery plans. The recommendations emphasize the protection of patients and health care teams from infections, delivery of timely and appropriate care, reduction of harm from the interruption of care, and preparation to handle a surge of new COVID-19 cases, complications, or comorbidities thereof., Conclusion: The recommendations from the ASCO Global Webinar Series may guide practicing oncologists to manage their patients during the ongoing pandemic and help organizations recover from the crisis. Implementation of these recommendations may improve understanding of how COVID-19 has affected cancer care and increase readiness to manage the current and any future outbreaks effectively.

Bacteria belonging to the Lachnospiraceae family are abundant, obligate anaerobic members of the microbiota in healthy humans. Lachnospiraceae impact their hosts by producing short-chain fatty acids, converting primary to secondary bile acids, and facilitating colonization resistance against intestinal pathogens. To increase our understanding of genomic and functional diversity between members of this family, we cultured 273 Lachnospiraceae isolates representing 11 genera and 27 species from human donors and performed whole-genome sequencing assembly and annotation. This analysis revealed substantial inter- and intra-species diversity in pathways that likely influence an isolate's ability to impact host health. These differences are likely to impact colonization resistance through lantibiotic expression or intestinal acidification, influence host mucosal immune cells and enterocytes via butyrate production, or contribute to synergism within a consortium by heterogenous polysaccharide metabolism. Identification of these specific functions could facilitate development of probiotic bacterial consortia that drive and/or restore in vivo microbiome functions., Competing Interests: Declaration of Interests E.G.P. has received speaker honoraria from Bristol-Myer Squibb, Celgene, Seres Therapeutics, MedImmune, Novartis, and Ferring Pharmaceuticals; is an inventor on patent application no. WPO2015179437A1, entitled “Methods and compositions for reducing Clostridium difficile infection” and no. WPO2017091753A1, entitled “Methods and compositions for reducing vancomycin-resistant Enterococci infection or colonization”; and holds patents that receive royalties from Seres Therapeutics. The remaining authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aim of the study was to evaluate clinical outcomes and adverse events (AEs) experienced by patients treated within the Hospital in the Home (HITH) service of a major metropolitan hospital in South Australia., Methods: A retrospective case note audit of 100 HITH episodes among adults who received continuous intravenous antimicrobial therapy via an elastomeric or electronic infusion device was undertaken. Age- and sex-adjusted binomial logistic regression analyses were undertaken to identify factors associated with major and minor AEs., Results: Of the 100 patients included, 71 were male and the mean (SD) patient age was 62.8 (17.19) years. Elastomeric infusion devices were used for 98 patients. The mean (SD) HITH treatment duration was 20.1 (11.9) days. Overall, 130 AEs were documented for 72 patients (72%), of whom 12 patients experienced a major AE and 68 patients experienced a minor AE. There were 45 occasions among 23 patients where an infusion administered through an elastomeric device did not run to completion. Fifteen patients were readmitted to hospital. Minor AEs were more likely among people with more vascular line days (adjusted odds ratio [aOR] = 1.05; 95% confidence interval (CI) = 1.01-1.10 per day increase) and females (aOR = 4.43; 95% CI = 1.14-17.17). An increased number of vascular line days was associated with an increased likelihood of an incomplete infusion (aOR = 1.05; 95% CI = 1.01-1.09). Hospital readmission was more likely with increasing age (aOR = 1.06; 95% CI = 1.01-1.11 per year increase)., Conclusions: Adverse events need to be monitored carefully when HITH treatment is provided for extended periods.

Patients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1-17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatures during murine cancer development using the BBN carcinogen and identified an increase in the expression of the T cell inhibitory protein B7-H4 (VTCN1, B7S1, B7X). B7-H4 expression temporally correlated with decreased lymphocyte infiltration. While the increase in B7-H4 expression within the bladder by CD11b + monocytes is shared with human cancers, B7-H4 expression has not been previously identified in other murine cancer models. Higher expression of B7-H4 was associated with worse survival in muscle-invasive bladder cancer in humans, and increased B7-H4 expression was identified in luminal and luminal-papillary subtypes of bladder cancer. Evaluation of B7-H4 by single-cell RNA-Seq and immune mass cytometry of human bladder tumors found that B7-H4 is expressed in both the epithelium of urothelial carcinoma and CD68+ macrophages within the tumor. To investigate the function of B7-H4, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4 + and CD8 + T cells. Additionally, anti-B7-H4 antibody treatment of BBN-carcinogen bladder cancers resulted in decreased tumor size, increased CD8 + T cell infiltration within the bladder, and a complimentary decrease in tumor-infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage, a reduction in tumor size, and an increased level of tumor necrosis. These findings suggest that antibodies targeting B7-H4 may be a viable strategy for bladder cancers unresponsive to PD-1 checkpoint inhibitors., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Temporomandibular joint osteoarthritis (TMJOA) is a prevalent source of temporomandibular joint disorder (TMD). Women are more commonly diagnosed with TMD and are more likely to seek care at tertiary orofacial pain clinics. Limited knowledge regarding mechanisms underlying temporomandibular joint (TMJ) pain impairs development of improved pain management strategies. In a rat model of unilateral TMJOA, monosodium iodoacetate (MIA) produces joint pathology in a concentration-dependent manner. Unilateral MIA produces alterations in meal patterns in males and females without altering overnight time spent eating or weight across 2 weeks. Monosodium iodoacetate (80 mg/mL)-treated males develop ongoing pain within 2 weeks after MIA injection. Females develop ongoing pain at a 5-fold lower MIA concentration (16.6 mg/m). Monosodium iodoacetate (80 mg/mL)-treated males show spread of tactile hypersensitivity across the face during the first week after injection and then to the fore paws and hind paws during the second week after injection, indicating development of central sensitization. At the lower dose, female rats demonstrate a similar spread of tactile hypersensitivity, whereas male rats do not develop ongoing pain or spread of tactile hypersensitivity outside the area of the ipsilateral temporomandibular joint. These observations indicate that females have a higher susceptibility to development of ongoing pain and central sensitization compared with male rats that is not due to differences in MIA-induced joint pathology. This model of TMJOA pain can be used to explore sex differences in pain processes implicated in development of neuropathic pain, ongoing pain, and central sensitization, allowing for development of individualized strategies for prevention and treatment of TMD joint pain.

Intestinal commensal bacteria can inhibit dense colonization of the gut by vancomycin-resistant Enterococcus faecium (VRE), a leading cause of hospital-acquired infections 1,2 . A four-strained consortium of commensal bacteria that contains Blautia producta BP SCSK can reverse antibiotic-induced susceptibility to VRE infection 3 . Here we show that BP SCSK reduces growth of VRE by secreting a lantibiotic that is similar to the nisin-A produced by Lactococcus lactis. Although the growth of VRE is inhibited by BP SCSK and L. lactis in vitro, only BP SCSK colonizes the colon and reduces VRE density in vivo. In comparison to nisin-A, the BP SCSK lantibiotic has reduced activity against intestinal commensal bacteria. In patients at high risk of VRE infection, high abundance of the lantibiotic gene is associated with reduced density of E. faecium. In germ-free mice transplanted with patient-derived faeces, resistance to VRE colonization correlates with abundance of the lantibiotic gene. Lantibiotic-producing commensal strains of the gastrointestinal tract reduce colonization by VRE and represent potential probiotic agents to re-establish resistance to VRE.

JunD, a member of the AP-1 family, is essential for cell proliferation in prostate cancer (PCa) cells. We recently demonstrated that JunD knock-down (KD) in PCa cells results in cell cycle arrest in G 1 -phase concomitant with a decrease in cyclin D1, Ki67, and c-MYC, but an increase in p21 levels. Furthermore, the over-expression of JunD significantly increased proliferation suggesting JunD regulation of genes required for cell cycle progression. Here, employing gene expression profiling, quantitative proteomics, and validation approaches, we demonstrate that JunD KD is associated with distinct gene and protein expression patterns. Comparative integrative analysis by Ingenuity Pathway Analysis (IPA) identified 1) cell cycle control/regulation as the top canonical pathway whose members exhibited a significant decrease in their expression following JunD KD including PRDX3, PEA15, KIF2C, and CDK2, and 2) JunD dependent genes are associated with cell proliferation, with MYC as the critical downstream regulator. Conversely, JunD over-expression induced the expression of the above genes including c-MYC. We conclude that JunD is a crucial regulator of cell cycle progression and inhibiting its target genes may be an effective approach to block prostate carcinogenesis., (Copyright © 2019 Elsevier B.V. All rights reserved.)