Search

The role of genetic testing within maternal medicine is expanding. Advancing technology and the increasing availability of genetic testing have seen more patients receiving a genetic diagnosis than ever before. Improved healthcare and understanding of these rare diseases means that many patients are living well into their reproductive years and starting families. Individual diseases are considered by their patterns of inheritance i.e. autosomal recessive, autosomal dominant and chromosomal diseases. This chapter specifically addresses the following examples and outlines an approach to pre-conceptual and pregnancy management; autosomal recessive (cystic fibrosis, phenylketonuria), autosomal dominant (osteogenesis imperfecta, vascular Ehlers-Danlos syndrome) and chromosomal (Turner syndrome). For many rare and ultrarare genetic diseases, there may be no clear guidelines or consensus on the correct management in pregnancy. This chapter seeks to provide a framework for the clinician to use to address the unique needs and risk profile of these patients in pregnancy and pre-conceptually and plan accordingly. The role of pharmacogenetics in maternal medicine, the future of education in genetics for patients and clinicians and the important role of genetic counselling are all considered in this chapter. This overview highlights the important role of genetics in maternal medicine and how this can inform management and planning for the safe care of mother and baby., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone., Methods: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants., Findings: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group., Interpretation: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone., Funding: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895)., Competing Interests: Declaration of interests EL reports grants from Boehringer Ingelheim, Medela, Johnson & Johnson/Ethicon, Covidien/Medtronic, Guardant Health, Takeda, Lilly Oncology, and Bayer, paid to his institution, his company, or personally; consulting fees from BeiGene, Roche, and BMS; honoraria from Medela; two patents (P52435GB and P57988GB) issued to Imperial Innovations; and being founder of My Cancer Companion, Healthcare Companion. SP reports consulting fees from AnHeart Therapeutics, Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Ellipses, EQRx, Daiichi Sankyo, GSK, Guardant Health, IO Biotech, Janssen, Lilly, Merck Serono, Mirati, MSD, Novocure, Novartis, PharmaMar, Roche, Takeda, Pfizer, Pierre Fabre, and Turning Point Therapeutics; honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, and Takeda; fees for expert testimony from Roche and Merck Serono; support for meeting attendance from Janssen, Roche, and Gilead; and being a member of the British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board. NT reports honoraria from BMS. DF reports grants from Astex Therapeutics, Boehringer Ingelheim, Bayer Oncology, Bergen Bio, GSK, MSD, Owkin, Roche, and RS Oncology paid to his institution; consulting fees from MSD, Cambridge Clinical Laboratories, and RS Oncology; honoraria from BMS, BI, MSD, Ikena, and Owkin; and meeting support from RS Oncology and MSD, all paid to Thoracic Oncology Services where he is director. RCR reports research funding from Cancer Research UK, Asthma and Lung UK, June Hancock Mesothelioma Research Fund, Mick Knighton Mesothelioma Research Fund, and Mesobank; and participation on an advisory board for the UK Lung Cancer Coalition. PT reports honoraria from AstraZeneca. LC-S reports support for meeting attendance from Lilly. RC reports honoraria from AstraZeneca, MSD, Takeda, Janssen, Roche, and GSK; support for meeting attendance from Takeda and Janssen; participation on advisory boards for GSK, Takeda, Janssen, Pharmamar, and Amgen; and stock options with TCC and Supportive Care UK. YS reports honoraria from Amgen, AstraZeneca, AbbVie, BMS, MSD, Lilly, Roche, and Takeda; and support for meeting attendance from Takeda and Roche. ZT reports honoraria from AstraZeneca. RS reports honoraria and support for meeting attendance from Lilly and BMS. EF reports membership of the National Lung Cancer and Mesothelioma Clinical Experts Group and Northern Cancer Alliance Targeted Lung Health Check Clinical Lead. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Cardiotoxicity is a common and under-reported side effect of tyrosine-kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI). Baseline risk factors may help in risk-stratifying patients at increased risk of cardiotoxicity. This real-world study investigated the effects of baseline risk factors in cardiotoxicity on patients with non-small-cell lung cancer (NSCLC) treated with TKIs and ICIs., Methods: This is a retrospective study carried out at The Royal Marsden Hospital, UK. Newly diagnosed patients with localized or metastatic NSCLC who received anticancer therapy with TKIs and/or ICIs were eligible. Patients who received only chemotherapy were excluded. Patients were followed up from the time of diagnosis until death or discharge. The relationship between cardiotoxicity and risk factors were tested by logistic regression., Results: Of 88/451 (19.5%) patients developed cardiotoxicity. Risk factors hypothesized to have a causal relationship with anticancer treatment-induced cardiotoxicity were analyzed. Cardiotoxicity risk was increased with prior diabetes mellitus (OR = 1.93, 95% CI, 1.04-3.61, P = .038), history of smoking (OR = 1.91, 95% CI, 1.13-3.22, P = .016) and presence of baseline cardiovascular disease (OR = 2.03, 95% CI, 1.13-3.64, P = .018). The risk of developing cardiotoxicity increased in patients for smokers with diabetes mellitus (OR = 3.03, 95% CI, 1.40-6.55, P < .01) and for smokers with previous cardiovascular disease (OR = 1.99, 95% CI, 1.03-3.84, P = .041)., Conclusion: Diabetes mellitus, smoking and baseline cardiovascular disease may synergistically contribute to cardiotoxicity when a patient is exposed to potentially cardiotoxic anticancer agents. Risk stratification at baseline may improve cardio-oncology care., Competing Interests: Disclosure Hasan Kobat, Praveena Idaikkadar and Michael Davidson declared no conflict of interest. Islam Elkonaissi is licensed clinical pharmacist in the UK and UAE, received honoraria from Roche, AZ, BMS, Novartis, J&J, MSD for educational events/presentations and received support from Roche, AZ, J&J for attending meetings and/or travel. Emma Foreman is licenced clinical pharmacist in the UK and received honoraria from AZ, BMS and Ipsen for speaking at educational events. Mary O'Brien declares royalties or licenses: Fast Fact of non–small-cell lung cancer, edition 1 and 2. Sparger publisher, consulting fees: advisory boards for MSD, Amgen, Puma, Pierre Fabra, Iteos, AstraZeneca, Sanofi, received payment/honoraria for the lecture to Chinese oncologist sponsored by Lilly and by Roche, received support for attending ASCO 2022 supported by MSD and ESMO 2022 and she is PHarmamar Lurbinectinib IDMC for the Lagoon trial. Shereen Nabhani-Gebara received EU H2020 grant for AI in Oncology, received speaking fee from Pfizer in September 2021, received support for attending meetings and/or travel from British Oncology Pharmacy Association, and have a leadership or fiduciary role at British Oncology Pharmacy Association., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Study Objective: To study the incidence of intrauterine adhesions (IUAs) after hysteroscopic myomectomy. Previous studies report a range of incidence for IUAs after hysteroscopic myomectomy., Design: A retrospective review study., Setting: An academic community hospital in the Boston metropolitan area., Patients: Patients undergoing hysteroscopic myomectomy at our institution from January 2019 to February 2022. Patients were excluded if they did not have plans for future fertility or had a new diagnosis of cancer., Interventions: All patients underwent hysteroscopic myomectomy using bipolar resectoscope without postoperative medical or barrier treatment. All procedures were performed by 1 of 4 fellowship-trained high-volume gynecologic surgeons with resident and fellow assistance. Incidence of postoperative IUAs was assessed and treated using second-look office hysteroscopy., Measurements and Main Results: A total of 44 patients without preoperative IUAs underwent hysteroscopic myomectomy during our study period, and 4 patients (9.1%) developed new IUAs. Among 9 patients who were found to have preoperative IUAs and underwent concurrent hysteroscopic myomectomy and lysis of adhesions, we found a recurrence of IUAs in 5 patients (55.6%). We found the number, size, and deepest type of myoma removed were not correlated to an increased risk of new IUA formation. In addition, removing myomas on opposing walls during the same operation did not increase the incidence of new IUAs., Conclusion: Formation of IUAs after hysteroscopic myomectomy is a well-documented consequence. Our reported incidence of 9.1% of new IUAs that are not affected by the number, size, deepest type of myoma resected, and resection of myomas on opposing uterine walls contributes to the current literature. In addition, our finding of 55.6% of recurrent IUAs in patients undergoing both hysteroscopic myomectomy and lysis of adhesions highlights a high-risk population requiring additional study., (Copyright © 2023 AAGL. Published by Elsevier Inc. All rights reserved.)

Background: Evidenced-based interventions have been developed to prevent venous thromboembolism (VTE) in ambulatory patients with cancer, including VTE-risk assessment for all patients and targeted primary thromboprophylaxis for high-risk patients. Despite supportive evidence and recommendations, oncologists rarely assess VTE risk or provide primary prophylaxis. Our previous work identified barriers and facilitators to using VTE prevention interventions in oncology practice., Objectives: To identify potential strategies that address the identified barriers and leverage facilitators to achieve successful implementation of evidence-based interventions for VTE prevention in oncology practice., Methods: We used the Implementation Research Logic Model, an implementation science framework, to map the relationships among barriers and facilitators, feasible and effective implementation strategies, and implementation and clinical outcomes that will be used to evaluate the implementation strategies., Results: We identified 12 discrete implementation strategies (eg, conducting clinician education and training and staged implementation scale-up) that address barriers and leverage facilitators through their mechanisms of action (eg, increased clinician awareness of evidence and targeting the highest effectiveness). We identified key implementation (eg, penetration, adoption, acceptability, fidelity, appropriateness, and sustainability), system (eg, integration of VTE-risk assessment into clinical workflow), and clinical (eg, lower VTE rates) outcomes targeted by the selected strategies., Conclusion: Using the Implementation Research Logic Model framework and building on our knowledge of barriers and facilitators, we identified implementation strategies and important outcomes to evaluate these strategies. We will use these results to test and measure the strategies to improve the uptake of evidence-based recommendations for VTE prevention in oncology practice., (© 2023 The Authors. Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Despite general interest in the concept, there is a lack of formal education systems that foster ocean literacy. Informal marine education programs may be filling this gap; where students undertake unique, immersive learning experiences connected to the marine environment. This paper consolidates information about marine education programs within Australia's temperate region - the Great Southern Reef - and evaluates the extent to which ocean literacy is being delivered through these programs under the banner of Australia's national curriculum. Using the mixed methods approach of a survey and semi-structured interviews, we found that participants are familiar with ocean literacy principles (89.4 %), and half of the informal providers (51 %) reported incorporating these principles into their education programs. We discuss the barriers to teaching and learning about ocean concepts reported by respondents, and argue that formal and informal education programs, working in tandem, can improve school curricula and promote greater ocean literacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Type 2 diabetes mellitus (T2DM) and comorbid conditions require patients to take complex medication regimens. Greater regimen complexity has been associated with poorer T2DM management; however, the relationship between overall regimen complexity and glycemic control is unclear., Objectives: Our objectives were: (1) to examine associations between regimen complexity (with the Medication Regimen Complexity Index [MRCI]) and glycemic control (A1C), and (2) to compare overall MRCI with other measures of regimen complexity (overall and diabetes-specific medication count) and diabetes-specific MRCI., Methods: This was a secondary data analysis of cross-sectional data from a parent trial. Participants were patients with T2DM taking at least 3 chronic medications followed in safety net clinics in the Chicago area. The MRCI measures complexity based on dosing frequency, route of administration, and special instructions for prescribed medications. MRCI scores were created for overall regimens and diabetes-specific medications. Sociodemographics and outpatient visit utilization were included in models as covariates. Linear regression was used to examine the associations between variables of interest and hemoglobin A1C., Results: Participants (N = 432) had a mean age of 56.9 years, most were female (66.0%), and Hispanic or Latino (73.3%). Regimen complexity was high based on overall medications (mean = 6.6 medications, SD: 3.09) and MRCI (mean = 21.4, SD: 11.3). Higher diabetes-specific MRCI was associated with higher A1C in bivariate and multivariable models. In multivariable models, overall MRCI greater than 14, fewer outpatient health care visits, male gender, and absence of health insurance were independently associated with higher A1C. The variance in A1C explained by MRCI was higher compared to medication count for overall and diabetes-specific regimen complexity., Conclusions: More complex regimens are associated with worse A1C and measuring complexity with MRCI may have advantages. Deprescribing, increasing insurance coverage, and promoting engagement in health care may improve A1C among underserved populations with complex regimens., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objective: Spinal cord stimulation is an effective treatment modality for chronic pain. Although percutaneous leads are commonly placed in the outpatient setting, paddle leads are typically implanted in the inpatient setting. Given the substantial cost savings associated with the ambulatory setting, we aimed to demonstrate the feasibility and safety of thoracic paddle lead implantation in a freestanding ambulatory surgery center (ASC)., Methods: Consecutive patients undergoing thoracic paddle lead implantation at a single freestanding ASC from January 2015 to December 2020 were queried. Demographic, perioperative, and outcome data were collected. Primary outcomes were incidence of intraoperative or immediate postoperative complications and need for inpatient transfer. Secondary outcomes included readmission at 30 and 90 days and reoperation at 30 days, 90 days, and 1 year., Results: A total of 46 patients underwent ambulatory thoracic paddle lead implantation over the study period. Two patients (4.3%) suffered an immediate postoperative complication requiring return to surgery at the ASC-one for an epidural hematoma, and one for a flank hematoma. All but one patient (97.8%) were discharged home on the day of surgery. The overall 30- and 90-day readmission rates were 4.3% and 6.5%, respectively. One patient (2.2%) required reoperation for a mechanical complication. No device-related infections were noted during the follow-up period., Conclusions: Thoracic laminotomy for paddle lead spinal cord stimulator implantation can be performed in a freestanding ASC with complication rates comparable to the hospital setting. Future comparative studies that assess clinical outcomes and cost are necessary to determine the cost-effectiveness of the ambulatory setting., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Incidental adrenal masses (IAMs) are common but rarely evaluated. To improve this, we developed a standardized radiology report recommendation template and investigated its implementation and effectiveness., Methods: We prospectively studied implementation of a standardized IAM reporting template as part of an ongoing quality improvement initiative, which also included primary care provider (PCP) notifications and a straightforward clinical algorithm. Data were obtained via medical record review and a survey of radiologists. Outcomes included template adoption rates and acceptability (implementation measures), as well as the proportion of patients evaluated and time to follow-up (effectiveness outcomes)., Results: Of 4,995 imaging studies, 200 (4.0%) detected a new IAM. The standardized template was used in 54 reports (27.0%). All radiologists surveyed were aware of the template, and 91% affirmed that standardized recommendations are useful. Patients whose reports included the template were more likely to have PCP follow-up after IAM discovery compared with those with no template (53.7% versus 36.3%, P = .03). After adjusting for sex, current or prior malignancy, and provider ordering the initial imaging (PCP, other outpatient provider, or emergency department or inpatient provider), odds of PCP follow-up remained 2.0 times higher (95% confidence interval 1.02-3.9). Patients whose reports included the template had a shorter time to PCP follow-up (log-rank P = .018). PCPs ultimately placed orders for biochemical testing (35.2% versus 18.5%, P = .01), follow-up imaging (40.7% versus 23.3%, P = .02), and specialist referral (22.2% versus 4.8%, P < .01) for a higher proportion of patients who received the template compared with those who did not., Conclusions: Use of a standardized template to communicate IAM recommendations was associated with improved IAM evaluation. Our template demonstrated high acceptability, but additional strategies are necessary to optimize adoption., (Copyright © 2022 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Introduction: Computed tomography (CT) of the chest (CTC), abdomen, and pelvis (CTAP) is common when assessing trauma patients in the emergency department. However, unnecessary imaging can expose patients to unneeded radiation and increase healthcare costs. Here, we characterize the use of torso CT imaging for the evaluation of ground level falls (GLF) at a single level 1 trauma center., Patients and Methods: We conducted a retrospective review of all patients ≥18 years old presenting to a single level 1 trauma center with a GLF (1m or less) in 2015-2019. Data were obtained through chart review. Descriptive statistics were used to summarize patient characteristics. Multivariable logistic regression was used to assess factors leading to patients obtaining torso CT imaging. The utility of CT imaging in identifying injuries that changed management was also evaluated., Results: Of the 1,195 patients captured during the study period, 492 patients had a positive torso physical exam (PE), and 703 had a negative torso PE. Of patients with a negative torso PE, 127 CTC and 142 CTAP were obtained, with only 5.5% CTC identifying traumatic injuries not previously diagnosed on chest radiograph (CXR), and only 0.7% CTAP identifying new injuries not identified on pelvic radiograph (PXR). Multivariable logistic regression demonstrated that only a positive PE was significantly associated with the identification of abnormal imaging findings on torso CT. A negative PE, CXR, and PXR have a negative predictive value of 98%., Discussion: These data suggest that patients with a negative PE, even if intoxicated, intubated, or with a decreased GCS, are highly unlikely to have new, clinically relevant findings on torso CT imaging., Conclusion: Using PE, CXR, and PXR as a screening tool in patients sustaining GLF, which if negative close to obviates the need for torso CT, may reduce healthcare costs and radiation exposure without compromising patient care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cannabis sativa L. has been known for at least 2000 years as a source of important, medically significant specialised metabolites and several bio-active molecules have been enriched from multiple chemotypes. However, due to the many levels of complexity in both the commercial cultivation of cannabis and extraction of its specialised metabolites, several heterologous production approaches are being pursued in parallel. In this review, we outline the recent achievements in engineering strategies used for heterologous production of cannabinoids, terpenes and flavonoids along with their strength and weakness. We provide an overview of the specialised metabolism pathway in C. sativa and a comprehensive list of the specialised metabolites produced along with their medicinal significance. We highlight cannabinoid-like molecules produced by other species. We discuss the key biosynthetic enzymes and their heterologous production using various hosts such as microbial and eukaryotic systems. A brief discussion on complementary production strategies using co-culturing and cell-free systems is described. Various approaches to optimise specialised metabolite production through co-expression, enzyme engineering and pathway engineering are discussed. We derive insights from recent advances in metabolic engineering of hosts with improved precursor supply and suggest their application for the production of C. sativa speciality metabolites. We present a collation of non-conventional hosts with speciality traits that can improve the feasibility of commercial heterologous production of cannabis-based specialised metabolites. We provide a perspective of emerging research in synthetic biology, allied analytical techniques and plant heterologous platforms as focus areas for heterologous production of cannabis specialised metabolites in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Localized wastewater surveillance has allowed for public health officials to gain a broader understanding of SARS-CoV-2 viral prevalence in the community allowing public health officials time to prepare for impending outbreaks. Given variable levels of virus in the population through public health interventions, proper concentration and extraction of viral RNA is a key step in ensuring accurate detections. With many commercial RNA extraction kits and methodologies available, the performance of 4 different kits were evaluated for SARS-CoV-2 RNA detection in wastewater, specifically focusing on their applicability to lower population densities such as those at university campus dorms. Raw wastewater samples were collected at 4 sites on a college campus over a 24 hour period as a composite sample. Included in these sites was an isolation site that housed students that tested positive for Covid-19 via nasopharyngeal swabs. These samples were analyzed using the following kits: Qiagen All Prep PowerViral DNA/RNA kit, New England BioLabs Monarch RNA MiniPrep Kit, and Zymo Quick RNA-Viral Kit, and the Zymo Quick-RNA Fecal/Soil Microbe MicroPrep Kit. All four sites were processed according to the manufacturer's guidelines. Extractions were then quantified with RT-qPCR one-step reactions using an N2 primer and a linearized plasmid standard. While the Zymo Quick-RNA Fecal/Soil Microbe MicroPrep Kit (also known as the Zymo Environ Water RNA Kit) only recovered approximately 73% (±38%) SARS-CoV-2 RNA compared to the Zymo Quick-RNA Viral kit, it was the most time efficient kit to yield comparable results. This extraction kit had a cumulative processing time of approximately 5 h compared, while the other three kits had processing times between approximately 9 and 9.5 h. Based on the current research, the most effective kits for smaller population densities are pellet based and include a homogenization, inhibitor removal, and RNA preservation step., 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.)

Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD- patients treated with HD-AraC on AAML0431 (P = .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P = .0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P = .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD., (© 2021 by The American Society of Hematology.)

Some bulls with apparently normal semen quality yield unacceptably low pregnancy rates. We hypothesised that a differential uterine immunological response to sperm from high and low fertility bulls may contribute to these differences. The experimental model used was heifer follicular phase uterine explants incubated with frozen-thawed sperm from high and low fertility bulls (3-5 replicates per experiment). Inflammatory gene expression of IL1A, IL1B, IL6, TNFA and CXCL8 were assessed by qPCR and IL1-β and IL-8 were quantified in explant supernatants by ELISA. Neutrophil binding affinity to sperm from high and low fertility bulls was also assessed. There was a significant up-regulation of IL1A, IL1B and TNFA from frozen-thawed sperm, irrespective of fertility status, compared to the unstimulated control. This response was confirmed at the protein level, with an increase of IL-1β and IL-8 protein concentrations by 5 and 2.7 fold, respectively (P < 0.05). Although no significant differences in the inflammatory response at the gene or protein level were evident between high and low fertility bulls, more sperm from low compared to high fertility bulls bound to neutrophils (P < 0.05). Using bulls of unknown fertility, cauda epididymal sperm (CES) plus seminal plasma (SP) upregulated IL6 (P < 0.05) but there was no upregulation of any inflammatory gene expression for CES alone. Overall, this ex vivo study demonstrated an upregulation of inflammatory gene expression in the uterus in response to frozen-thawed bull sperm. While there was no difference between sperm from high and low fertility bulls, there was a greater binding affinity of low fertility sperm by neutrophils., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Self-assembling peptide hydrogels (SAPH) are a popular biomaterial due to their biocompatibility with a wide range of cell types, synthetic design, structural properties that provide a more accurate 3D microenvironment, and potential for cell- and/or drug-delivery system. Mimicking solid tumors in vitro using hydrogels is one method of testing anti-cancer drug efficacy and observing cancerous cell-ECM interactions within a 3D system. In this study, a SAPH, PeptiGel®Alpha1, was used to model in vitro the 3D breast tumor microenvironment. PeptiGel®Alpha1 is composed of entangled nanofibers with consistent diameter and mechanical properties similar to breast cancer that more accurately mimic the stiffness of breast tumor tissue than Matrigel® or collagen type I. PeptiGel®Alpha1 supported the viability and growth of the breast cancer cell lines MCF-7 and MDA-MB-231 and recapitulated key features of solid tumors such as hypoxia and invasion. MCF-7 cells in the hydrogels formed large spheroids resembling acini, while MDA-MB-231 remained dispersed. When treated with tamoxifen, PeptiGel®Alpha1 acted as a barrier, providing drug penetration geometry similar to that in vivo, providing better prediction of the drug effect. Finally, it was observed that MCF-7 cells engulfed the peptide matrix after 14 days, highlighting a potential use in drug delivery. PeptiGel®Alpha1 is a suitable platform for in vitro modeling of breast cancer., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Pathogenic variants in SCN2A cause a wide range of neurodevelopmental phenotypes. Reports of genotype-phenotype correlations are often anecdotal, and the available phenotypic data have not been systematically analyzed., Methods: We extracted phenotypic information from primary descriptions of SCN2A-related disorders in the literature between 2001 and 2019, which we coded in Human Phenotype Ontology (HPO) terms. With higher-level phenotype terms inferred by the HPO structure, we assessed the frequencies of clinical features and investigated the association of these features with variant classes and locations within the Na V 1.2 protein., Results: We identified 413 unrelated individuals and derived a total of 10,860 HPO terms with 562 unique terms. Protein-truncating variants were associated with autism and behavioral abnormalities. Missense variants were associated with neonatal onset, epileptic spasms, and seizures, regardless of type. Phenotypic similarity was identified in 8/62 recurrent SCN2A variants. Three independent principal components accounted for 33% of the phenotypic variance, allowing for separation of gain-of-function versus loss-of-function variants with good performance., Conclusion: Our work shows that translating clinical features into a computable format using a standardized language allows for quantitative phenotype analysis, mapping the phenotypic landscape of SCN2A-related disorders in unprecedented detail and revealing genotype-phenotype correlations along a multidimensional spectrum.

Intervertebral disc (IVD) degeneration is a process that starts in the central nucleus pulposus (NP) and leads to inflammation, extracellular matrix (ECM) degradation, and progressive loss of disc height. Early treatment of IVD degeneration is critical to the reduction of low back pain and related disability. As such, minimally invasive therapeutic approaches that can halt and reverse NP degeneration at the early stages of the disease are needed. Recently, we developed an injectable graphene oxide (GO) - self-assembling peptide FEFKFEFK (F: phenylalanine; K: lysine; E: glutamic acid) hybrid hydrogels as potential delivery platform for cells and/or drugs in the NP. In this current study, we explored the possibility of using the GO present in these hybrid hydrogels as a vehicle for the sequestration and controlled delivery of transforming growth factor beta-3 (TGF-β3), an anabolic growth factor (GF) known to direct NP cell fate and function. For this purpose, we first investigated the potential of GO to bind and sequestrate TGF-β3. We then cultured bovine NP cells in the new functional scaffolds and investigated their response to the presence of GO and TGF-β3. Our results clearly showed that GO flakes can sequestrate TGF-β3 through strong binding interactions resulting in a slow and prolonged release, with the GF remaining active even when bound to the GO flakes. The adsorption of the GF on the GO flakes to create TGF-β3-loaded GO flakes and their subsequent incorporation in the hydrogels through mixing, [(GO/TGF-β3 Ads )-F8] hydrogel, led to the upregulation of NP-specific genes, accompanied by the production and deposition of an NP-like ECM, rich in aggrecan and collagen II. NP cells actively interacted with TGF-β3-loaded GO flakes and remodeled the scaffolds through endocytosis. This work highlights the potential of using GO as a nanocarrier for the design of functional hybrid peptide-based hydrogels. STATEMENT OF SIGNIFICANCE: Intervertebral disc (IVD) degeneration is a process that starts in the central nucleus pulposus (NP) and leads to inflammation, extracellular matrix (ECM) degradation, and progressive loss of disc height. As such, minimally invasive therapeutic approaches that can halt and reverse NP degeneration at the early stages of the disease are needed. In this current study, we explored the possibility of using peptide - GO hybrid hydrogels as a vehicle for the sequestration and controlled delivery of transforming growth factor beta-3 (TGF-β3), an anabolic growth factor (GF) known to direct NP cell fate and function., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The repair of tendon injuries is often compromised by post-operative peritendinous adhesions. Placing a physical barrier at the interface between the tendon and the surrounding tissue could potentially solve this problem by reducing adhesion formation. At present, no such system is available for routine use in clinical practice. Here, we propose the development of a bilayer membrane combining a nanofibrous poly(ε-caprolactone) (PCL) electrospun mesh with a layer of self-assembling peptide hydrogel (SAPH) laden with type-B synoviocytes. This bilayer membrane would act as an anti-adhesion system capable of restoring tendon lubrication, while assisting with synovial sheath regeneration. The PCL mesh showed adequate mechanical properties (Young's modulus=19±4 MPa, ultimate tensile stress=9.6±1.7 MPa, failure load=0.5±0.1 N), indicating that the membrane is easy to handle and capable to withstand the frictional forces generated on the tendon's surface during movement (~0.3 N). Morphological analysis confirmed the generation of a mesh with nanosized PCL fibres and small pores (< 3 μm), which prevented fibroblast infiltration to impede extrinsic healing but still allowing diffusion of nutrients and waste. Rheological tests showed that incorporation of SAPH layer allows good lubrication properties when the membrane is articulated against porcine tendon or hypodermis, suggesting that restoration of tendon gliding is possible upon implantation. Moreover, viability and metabolic activity tests indicated that the SAPH was conducive to rabbit synoviocyte growth and proliferation over 28 days of 3D culture, sustaining cell production of specific matrix components, particularly hyaluronic acid. Synoviocyte-laden peptide hydrogel promoted a sustained endogenous production of hyaluronic acid, providing an anti-friction layer that potentially restores the tendon gliding environment., 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 © 2020. Published by Elsevier Ltd.)

Purpose: Childhood epilepsies have a strong genetic contribution, but the disease trajectory for many genetic etiologies remains unknown. Electronic medical record (EMR) data potentially allow for the analysis of longitudinal clinical information but this has not yet been explored., Methods: We analyzed provider-entered neurological diagnoses made at 62,104 patient encounters from 658 individuals with known or presumed genetic epilepsies. To harmonize clinical terminology, we mapped clinical descriptors to Human Phenotype Ontology (HPO) terms and inferred higher-level phenotypic concepts. We then binned the resulting 286,085 HPO terms to 100 3-month time intervals and assessed gene-phenotype associations at each interval., Results: We analyzed a median follow-up of 6.9 years per patient and a cumulative 3251 patient years. Correcting for multiple testing, we identified significant associations between "Status epilepticus" with SCN1A at 1.0 years, "Severe intellectual disability" with PURA at 9.75 years, and "Infantile spasms" and "Epileptic spasms" with STXBP1 at 0.5 years. The identified associations reflect known clinical features of these conditions, and manual chart review excluded provider bias., Conclusion: Some aspects of the longitudinal disease histories can be reconstructed through EMR data and reveal significant gene-phenotype associations, even within closely related conditions. Gene-specific EMR footprints may enable outcome studies and clinical decision support.

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterised by limited treatment options and a poor prognosis. At relapse after platinum-based chemotherapy, single-agent chemotherapy is commonly used and single-arm trials of immune-checkpoint inhibitors have demonstrated encouraging activity., Patients and Methods: PROMISE-meso is an open-label 1:1 randomised phase III trial investigating the efficacy of pembrolizumab (200 mg/Q3W) versus institutional choice single-agent chemotherapy (gemcitabine or vinorelbine) in relapsed MPM patients with progression after/on previous platinum-based chemotherapy. Patients were performance status 0-1 and unselected for programmed cell death ligand 1 (PD-L1) status. At progression, patients randomly assigned to receive chemotherapy were allowed to crossover to pembrolizumab. The primary end point was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary end points were overall survival (OS), investigator-assessed PFS, objective response rate (ORR), and safety. Efficacy by PD-L1 status was investigated in exploratory analyses., Results: Between September 2017 and August 2018, 144 patients were randomly allocated (pembrolizumab: 73; chemotherapy: 71). At data cut-off [20 February 2019, median follow-up of 11.8 months (interquartile range: 9.9-14.5)], 118 BICR-PFS events were observed. No difference in BICR-PFS was detected [hazard ratio = 1.06, 95% confidence interval (CI): 0.73-1.53; P = 0.76], and median BICR-PFS (95% CI) for pembrolizumab was 2.5 (2.1-4.2), compared with 3.4 (2.2-4.3) months for chemotherapy. A difference in ORR for pembrolizumab was identified (22%, 95% CI: 13% to 33%), over chemotherapy (6%, 95% CI: 2% to 14%; P = 0.004). Forty-five patients (63%) assigned to chemotherapy received pembrolizumab at progression. With follow-up to 21 August 2019 [17.5 months: (14.8-19.7)], no difference in OS was detected between groups (HR = 1.12, 95% CI: 0.74-1.69; P = 0.59), even after adjusting for crossover. Pembrolizumab safety was consistent with previous observations. Exploratory efficacy analyses by PD-L1 status demonstrated no improvements in ORR/PFS/OS., Conclusion: This is the first randomised trial evaluating the efficacy of pembrolizumab in MPM patients progressing after/on previous platinum-based chemotherapy. In biologically unselected patients, although associated with an improved ORR, pembrolizumab improves neither PFS nor OS over single-agent chemotherapy., Competing Interests: Disclosure SP reports personal fees from Bristol-Myers Squibb, personal fees from Roche, personal fees from Takeda, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Merck Sharp & Dohme, personal fees from EMD Serono, personal fees from Guardant Health, personal fees from Abbvie, personal fees from Boehringer Ingelheim, personal fees from OncLive, personal fees from Medscape, personal fees from Incyte, personal fees from Paradox Pharmaceuticals, personal fees from Eli Lilly, outside the submitted work. AC-F reports the receipt of honoraria or consultation fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp & Dohme, and Takeda, and honoraria for talks in a company's organised public event from F. Hoffmann-La Roche and Merck Sharp & Dohme. UD reports consultancy services for Roche Tumour Agnostic Evidence Working Group 2020. RS has attended advisory boards for Merck Sharp & Dohme. MO'B is a co-investigator in the Merck Sharp & Dohme Pearls study (Keynote 091) and has attended advisory boards for Merck Sharp & Dohme. DG received honoraria from Merck Sharp & Dohme for chairing a meeting. EN participated in advisory boards from Bristol-Myers Squibb, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim, Amgen, and AstraZeneca. WDJ reports honoraria and travel grants from Roche, Merck Sharp & Dohme, Pfizer, Takeda, and Novartis. RLC received honoraria or travel expenses from Takeda, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Roche, Merck Serono, Pfizer, had consulting or advisory role from Roche, Boehringer Ingelheim, Aristo and received research funding from Roche, Bristol-Myers Squibb, Boehringer Ingelheim. RGC reports advisory board and speaker invitations from Merck Sharp & Dohme. SP received honoraria from Abbvie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, and Takeda. RS received grants for ETOP during the conduct of the study, personal fees from: Abbvie, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche, Takeda and grants from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech, Merck Sharp & Dohme, Roche, and Pfizer outside the submitted work. All other authors declare no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction/objectives: Severe subaortic stenosis (SAS) is a congenital heart defect in dogs that often results in clinical signs and reduced survival. The objective of this study was to describe characteristics of dogs with severe, symptomatic SAS who underwent combined cutting and high-pressure balloon valvuloplasty (CB/HPBV)., Animals, Materials, and Methods: Retrospective description of the clinical characteristics, CB/HPBV procedural deviations from reported methodology and outcomes in a series of six client-owned dogs with severe, symptomatic SAS., Results: Breeds included two each of Newfoundland, Golden retriever, and German shepherd. Median age was 10.1 months (range: 5-72.3 months), and median weight was 25.5 kg (range: 21.8-36.4 kg). Before CB/HPBV, clinical signs were present in all dogs; four were managed for congestive heart failure (CHF). Three dogs had concurrent congenital heart disease. Median Doppler-estimated left ventricular outflow tract pressure gradient was pre-operatively 149.7 mmHg (range: 89.9-254.7 mmHg) and post-operatively 134.1 mmHg (range: 83.9-181.2 mmHg). Median aortoseptal angle was steep at 136° (range: 109-143°). Clinical improvement was documented in all dogs, based on temporary discontinuation of diuretics and/or owner-perceived reduction in clinical signs. At the time of writing, three dogs had died suddenly, one was euthanized because of recurrence of clinical signs, and one died in CHF. Median survival time was 26.4 months after procedure (range: 6.3-45.8 months). One dog remained alive at 44 months after procedure., Conclusions: Palliative CB/HPBV is a potential therapeutic option for dogs with severe, symptomatic SAS complicated by concurrent congenital heart disease, arrhythmias, or CHF., Competing Interests: Conflicts of Interest Statement The authors do not have any conflicts of interest to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Medial ulnar collateral ligament (MUCL) insufficiency is becoming common in younger, nonprofessional athletes. In contrast to elite athletes who develop valgus extension overload syndrome and associated chronic pathologic changes in the MUCL, younger patients present with sprains and partial tears that can often be managed non-operatively with successful outcome and rapid return to play. In the younger throwing athlete with medial-sided elbow pain, a hinged elbow brace and rehabilitation of dysfunctional muscles often lead to successful recovery and return to play within 1-2 months. In more severe injuries, direct repair of the partial tear with or without added internal bracing supplementation allows restoration of stability with a return to play with 4 to 6 months., Competing Interests: Disclosure The authors have nothing to disclose., (Published by Elsevier Inc.)

Background: Previous studies suggest isolated distal deep vein thrombosis (IDDVT) has a self-limited clinical course. However, these studies excluded cancer patients, who remain a high-risk population. In addition, studies to evaluate the long-term clinical outcomes of IDDVT in cancer patients have been limited. Here, we report outcomes from our experience in treating cancer-associated IDDVT versus proximal venous thromboembolism (VTE)., Methods: We prospectively evaluated a cohort of patients referred to our cancer-associated thrombosis clinic from August 2014 through May 2018. We compared clinical characteristics, anticoagulation prescription, VTE recurrence, overall survival, major bleeding, and subsequent hospital admission between cancer patients with IDDVT and proximal VTE. A propensity score matching method was used to reduce bias from confounding variables., Results: Of 1100 patients referred to the clinic, 124 IDDVT and 178 proximal VTE events were analyzed. After propensity score matching, 96 patients were included in each cohort. There was no difference in the rate of recurrent VTE between cancer patients with proximal VTE vs IDDVT, with or without matching (matched: hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.31-1.92; P = .58). There was no difference in overall survival between cancer patients with proximal VTE vs. IDDVT with or without matching (matched: HR, 1.18; 95% CI, 0.77-1.82; P = .45). Furthermore, subsequent hospital admissions and major bleeding events were similar between patients with proximal VTE events versus IDDVT., Conclusions: Cancer patients with IDDVT have similar outcomes as their proximal counterparts, including rate of recurrence and overall survival. These findings suggest treatment of cancer-associated IDDVT should mirror treatment of proximal events., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: UK COVID-19 mortality rates are amongst the highest globally. Controversy exists on the vulnerability of thoracic cancer patients. We describe the characteristics and sequelae of patients with thoracic cancer treated at a UK cancer centre infected with COVID-19., Methods: Patients undergoing care for thoracic cancer diagnosed with COVID-19 (RT-PCR/radiology/clinically) between March-June 2020 were included. Data were extracted from patient records., Results: Thirty-two patients were included: 14 (43%) diagnosed by RT-PCR, 18 (57%) by radiology and/or convincing symptoms. 88% had advanced thoracic malignancies. Eleven of 14 (79%) patients diagnosed by RT-PCR and 12 of 18 (56%) patients diagnosed by radiology/clinically were hospitalised, of which four (29%) and 2 (11%) patients required high-dependency/intensive care respectively. Three (21%) patients diagnosed by RT-PCR and 2 (11%) patients diagnosed by radiology/clinically required non-invasive ventilation; none were intubated. Complications included pneumonia and sepsis (43% and 14% respectively in patients diagnosed by RT-PCR; 17% and 11% respectively in patients diagnosed by radiology/clinically). In patients receiving active cancer treatment, therapy was delayed/ceased in 10/12 (83%) and 7/11 (64%) patients diagnosed by RT-PCR and radiology/clinically respectively. Nine (28%) patients died; all were smokers. Median time from symptom onset to death was 7 days (range 3-37)., Conclusions: The immediate morbidity from COVID-19 is high in thoracic cancer patients. Hospitalisation and treatment interruption rates were high. Improved risk-stratification models for UK cancer patients are urgently needed to guide safe cancer-care delivery without compromising efficacy., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Childhood lead exposure impairs future decision-making and may influence criminal behavior, but its role in future firearm violence is unclear. Using public health, education, and criminal justice datasets linked at the individual level, we studied a population-based cohort of all persons born between June 1, 1986 and December 31, 2003 with a valid blood lead test before age 6 years and stable Milwaukee residency (n = 89,129). We estimated associations with firearm violence perpetration (n = 553) and victimization (n = 983) using logistic regression, adjusting for temporal trends, child sex, race, and neighborhood socioeconomic status. Increasing risks for firearm violence perpetration and victimization were found in each higher category of blood lead compared to the lowest, after adjusting for confounding. For perpetration, risk ratios (RR) for increasing comparisons of mean blood lead in categories of ≥5 < 10, ≥10 < 20, and ≥20 μg/dL compared to persons with mean blood lead < 5 μg/dL, were: RR 2.3 (95% CI 1.6, 3.3), RR 2.5 (95% CI 1.7, 3.9), and RR 2.8 (95% CI 1.8, 4.4). For victimization, the same increasing categoric comparisons were: RR 1.8 (95% CI 1.4, 2.3), RR 2.4 (95% CI 1.8, 3.2), RR 3.3 (95% CI 2.4, 4.5). The proportion of firearm violence attributable to blood lead ≥5 μg/dL was 56% for perpetration and 51% for victimization. In Milwaukee, during a period of high lead exposures, childhood levels may have substantially contributed to adult firearm violence. While we cannot definitively conclude causality, the possibility that over half of firearm violence among this sample might be due to lead exposure suggests the potential importance of lead exposure reduction in firearm violence prevention efforts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process., Methods: A pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting., Results: It was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography-computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography-computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits., Conclusion: A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Unprotected exposure to handheld lasers can cause temporary or permanent vision loss depending on the laser classification., Objective: To evaluate the occurrence of, and details associated with, reported eye injuries resulting from handheld lasers., Methods: A 14-item questionnaire developed by Health Canada was distributed by the Canadian Ophthalmological Society and the Canadian Association of Optometrists to their respective members., Results: Questionnaire data were available from 909 respondents (263 ophthalmologists; 646 optometrists). Response rates were 23.1% and 12.7%, respectively. Validated data were available from 903 respondents, where 157 (17.4%) reported encountering at least 1 eye injury from a handheld laser. A total of 318 eye injuries were reported with an annual increase of 34.4% (95% CI 21.6%-48.7%, p < 0.0001) between 2013 and 2017. When respondents reported on only their most severe case, 77 (53.5%) reported vision loss that ranged from minor to severe, which persisted for more than 6 months in 42.9% of the cases. Another 59 (41.3%) noted the presence of retinal damage. The prevalence of eye injuries from handheld lasers was higher for males (82.5%) than females (14.0%), more frequent among those under the age of 50 years, and occurred predominately as a result of exposure from another person (67.6%) versus self-induced (26.1%) (p < 0.0001)., Conclusions: Although this pilot study permits insight into the potential prevalence of injuries resulting from exposure to handheld laser devices in Canada, the results are not nationally representative. These findings support additional surveillance activities that may inform risk assessment and potential risk management strategies., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: There is widespread recognition that creating a safety culture supports high-quality health care. However, the complex factors affecting cultural change interventions are not well understood. This study examines factors influencing the implementation of an intervention to promote professionalism and build a safety culture at an Australian hospital., Methods: The study was completed midway into the three-year intervention and involved collecting qualitative data from two sources. First, face-to-face interviews were conducted pre- and mid-intervention with a purposely selected sample. Second, a survey with three open-ended questions was completed one year into the intervention by clinical and patient support staff. Data from interviews and survey questions were analyzed using a combination of inductive and deductive approaches., Results: A total of 25 participants completed preintervention interviews, and 24 took part mid-intervention. Of the 2,047 staff who completed the survey (61% response rate), 59.1% of respondents answered at least one open-ended question. Multiple interrelated factors were identified as enhancing intervention implementation. These include sustaining a favorable implementation climate, leaders consistently demonstrating behaviors that support a safety culture, increasing compatibility of working conditions with intervention aims, building confidence in systems to address unprofessional behaviors, and responding to evolving needs., Conclusion: Strengthening safety culture remains an enduring challenge, but this study yields valuable insights into factors influencing implementation of a multifaceted behavior change intervention. The findings provide a basis for practical strategies that health care leaders seeking cultural improvements can employ to enhance the delivery of similar interventions and address potential impediments to success., (Copyright © 2019 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Understanding the cracking behaviour of biological composite materials is of practical importance. This paper presents the first study to track the interplay between crack initiation, microfracture and plastic deformation in three dimensions (3D) as a function of tubule and collagen fibril arrangement in elephant dentin using in situ X-ray nano-computed tomography (nano-CT). A nano-indenter with a conical tip has been used to incrementally indent three test-pieces oriented at 0°, 45° and 70° to the long axis of the tubules (i.e. radial to the tusk). For the 0° sample two significant cracks formed, one of which linked up with microcracks in the axial-radial plane of the tusk originating from the tubules and the other one occurred as a consequence of shear deformation at the tubules. The 70° test-piece was able to bear the greatest loads despite many small cracks forming around the indenter. These were diverted by the microstructure and did not propagate significantly. The 45° test-piece showed intermediate behaviour. In all cases strains obtained by digital volume correlation were well in excess of the yield strain (0.9%), indeed some plastic deformation could even be seen through bending of the tubules. The hoop strains around the conical indenter were anisotropic with the smallest strains correlating with the primary collagen orientation (axial to the tusk) and the largest strains aligned with the hoop direction of the tusk. STATEMENT OF SIGNIFICANCE: This paper presents the first comprehensive study of the anisotropic nature of microfracture, crack propagation and deformation in elephant dentin using time-lapse X-ray nano-computed tomography. To unravel the interplay of collagen fibrils and local deformation, digital volume correlation (DVC) has been applied to map the local strain field while the crack initiation and propagation is tracked in real time. Our results highlight the intrinsic and extrinsic shielding mechanisms and correlate the crack growth behavior in nature to the service requirement of dentin to resist catastrophic fracture. This is of wide interest not just in terms of understanding dentin fracture but also can extend beyond dentin to other anisotropic structural composite biomaterials such as bone, antler and chitin., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The combined use of the Manchester Triage System (MTS) with the Early Warning Score (EWS) may be useful in ensuring both appropriate prioritisation and continued monitoring in the Emergency Department (ED) leading to early intervention for deteriorating patients thus improving patient outcomes especially in overcrowded EDs., Purpose: Determine the effect of the EWS and MTS on accuracy of the MTS and ED waiting times., Methods: A retrospective cohort chart review of all adult patients who presented to the ED in one large hospital in Ireland (n = 10,048) at three time points between 1st September 2015-30th September 2016; 3 months prior to EWS introduction, implementation month and 9 months post-implementation., Results: Patients were significantly more likely to be categorised as an MTS category 2 (rather than 3-5) after the EWS was introduced (p < 0.001). Waiting times between triage and clinician review (p < 0.05) increased as did total time in the ED (p > 0.001). A similar finding was observed for patients with an MTS of 3-5., Conclusion: Although positive in terms of patient outcomes, the effective and sustained combined use of the MTS and EWS requires increased bed capacity and experienced clinical staff to ensure that the ED journey time reduced rather than increased., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Neuraxial block-related hypotension and maternal obesity contribute to uterine hypoperfusion and decreased umbilical arterial pH at cesarean delivery. Between the time of anesthesia placement and delivery, the fetus may be exposed to a hypoperfused uterine environment without surgeon awareness of fetal compromise., Objective: We sought to evaluate neonatal umbilical arterial pH according to predelivery time intervals at scheduled term cesarean., Study Design: We performed a retrospective cohort study of cesarean deliveries between September 2014 and February 2017. Singleton gestations undergoing scheduled cesarean delivery under spinal anesthesia between 37 and 41 weeks with a reassuring preoperative nonstress test were included. Time intervals between operative room entry, spinal anesthesia placement, skin incision, uterine incision, and delivery were calculated. The primary outcome was umbilical arterial pH. Demographic data, maternal blood pressures, predelivery time intervals, and delivery outcomes were analyzed according to umbilical arterial pH intervals of <7.0, 7.01-7.10, 7.11-7.20, 7.21-7.30, and >7.30. Umbilical cord gas analytes and neonatal outcomes were analyzed by spinal to delivery time. Stepwise linear regression was performed to identify predictors of decreasing umbilical arterial pH. Receiver-operator characteristic curves were calculated for spinal to delivery time and umbilical arterial pH <7.0 and 7.1., Results: Among 527 included participants, median umbilical arterial pH was 7.27 [interquartile range, 7.23-7.29] and body mass index was 35 kg/m 2 [interquartile range, 30-41]. Both maternal body mass index and hypotensive episodes increased with decreasing umbilical arterial pH (P <.001, P ≤ .02). All predelivery time intervals (operative room to delivery, spinal to skin, spinal to delivery, and uterine incision to delivery) increased as umbilical arterial pH interval decreased (P < .05 for all). In a stepwise linear regression, maternal body mass index, noncephalic presentation, spinal start to delivery interval, uterine incision to delivery interval, and maximum reduction in blood pressure from baseline were predictive of decreasing umbilical arterial pH after controlling for confounding variables (F [5,442] = 17.7, P = .0001], adjusted R 2 of 0.157. When evaluated by spinal to delivery time, both umbilical arterial and venous pH and partial pressure of carbon dioxide decreased (P < .001 for all), but base deficit and neonatal outcomes were similar (P ≥ .7 for all). There were 2 cases of hypoxic-ischemic encephalopathy (0.38%). A receiver-operating characteristic curve demonstrated that a spinal start to delivery time greater than 27 minutes was associated with an umbilical arterial pH <7.1 (area under the curve, 0.74, 100% sensitivity, 21% specificity), and an interval greater than 30 minutes was associated with an umbilical arterial pH <7.0 (area under the curve, 0.80, 100% sensitivity, 33% specificity)., Conclusion: Longer spinal-to-delivery and uterine incision-to-delivery time intervals were associated with decreasing umbilical arterial pH at scheduled term cesarean delivery. Efforts to minimize predelivery time following spinal placement could reduce the frequency of unanticipated neonatal acidemia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Currently, cystic fibrosis patients require daily nebulized treatments to achieve optimal lung health. Growth of pathogenic bacteria in patient nebulizers is well known, and disinfection guidelines have been established. In this short communication, we sought to discover what effect, if any, repeated nebulization/disinfection cycles had on nebulizer output. We nebulized saline repeatedly after exposure to boiling water, steam, and alcohol disinfection methods. While alcohol disinfection did not affect nebulizer output, boiling water and steam significantly decreased nebulizer output from baseline, 74.1 ± 5.9% (p = 0.022) and steam 63.6 ± 6.5% (p = 0.0048) after 60 cycles respectively. This decrease in nebulizer output could significantly increase the duration of nebulizer treatment time and negatively impact the burden of care on patients with cystic fibrosis., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: There is an urgent need to develop a convenient and less invasive technique to monitor the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). We proposed folate receptor-based assay to count circulating tumor cells (CTCs) to predict and dynamically monitor the therapeutic response to first-line EGFR-TKIs in patients with EGFR-mutated NSCLC., Patients and Methods: Eligible patients were enrolled, and 3 mL of blood was obtained before initial treatment, 1 month after treatment, and every 2 months thereafter. CTCs were isolated on the basis of negative enrichment by immunomagnetic beads and detected by a ligand-targeted PCR method., Results: A total of 232 patients with EGFR-mutated NSCLC and treated with first-line EGFR-TKIs were included. Patients with low baseline CTC count had a markedly longer progression-free survival (hazard ratio = 0.48; P < .001) and overall survival (hazard ratio = 0.52; P = .002) than those with high count. This difference remained significant in multivariate analysis. Dynamic change of CTC count was significantly associated with partial response (P = .042) and stable disease/progressive disease (P = .032). Notably, dynamic monitoring of CTC provided evidence of resistance to EGFR-TKIs before computed tomographic scanning with a median lead time of 113 days (range, 45-169 days)., Conclusion: The current evidence suggests that folate receptor-positive CTC counts can be used for both the dynamic monitoring and prediction of outcome in EGFR-mutated NSCLC patients treated with EGFR-TKIs, which could serve as an alternative or supplement to computed tomographic scanning., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Human cytomegalovirus (HCMV) can cause severe disease in patients with compromised or immature immune systems. Currently approved pharmacotherapies for the treatment of systemic HCMV infections [ganciclovir (GCV), cidofovir (CDV), foscarnet] are limited by a high incidence of adverse effects and/or the development of drug resistance. Given that many of these drugs have the same viral target (HCMV-encoded DNA polymerase), cross-resistance is relatively common. The primary means to combat drug resistance is combination pharmacotherapy using therapeutics with different molecular mechanisms of action with the expectation that those combinations result in an additive or synergistic enhancement of effect; combinations that result in antagonism can, in many cases, be detrimental to the outcome of the patient. We therefore tested select combinations of approved (GCV, CDV, letermovir (LMV)) and experimental (brincidofovir (BCV), cyclopropavir (CPV), maribavir (MBV), BDCRB) drugs with the hypothesis that combinations of drugs with different and distinct molecular mechanisms of action will produce an additive and/or synergistic enhancement of antiviral effect against HCMV in vitro. Using MacSynergy II (a statistical package that measures enhancement or lessening of effect relative to zero/additive), select drug combination studies demonstrated combination indices ranging from 160 to 372 with 95% confidence intervals greater than zero indicating that these combinations elicit a synergistic enhancement of effect against HCMV in vitro. These data suggest that administration of a viral DNA polymerase inhibitor, MBV, and/or a viral terminase inhibitor in combination has the potential to address the resistance/cross-resistance problems associated with currently available therapeutics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: To reduce long-term morbidity (adhesions-related complications and impaired quality of life due to scars), laparoscopy has been used as an alternative to open surgery in Wilms tumours (WTs). However, concerns have been raised on the risk of local recurrence after this type of resection., Objective: The aim was to determine the incidence of local recurrence after laparoscopic transperitoneal radical nephrectomy (LTRN)., Study Design: We analysed 18 local cases and conducted a review of the English literature in Pubmed from 2004 to 2017 with the following keywords: (Wilms OR nephroblastoma) AND (laparoscopy OR minimally invasive surgery) AND 2004:3000. The review was conducted according to PRISMA guidelines. Data were collected independently in duplicate in a preformed Excel database. Review articles and duplicated case reports were excluded. Patients with retroperitoneoscopic or nephron-sparing surgery were also excluded., Results: One hundred and four LTRNs have been performed for WT with neoadjuvant chemotherapy in 93 cases. Tumour was ruptured preoperatively in three cases but never intraoperatively. The median volume of the tumour was 229.4 mL (3.8-776 mL). Local stage was specified in 86 cases: 49 stage I, 28 stage II, and nine stage III. Lymph nodes were sampled in 48 patients (median 2.3 [0-14] nodes). Histology was reported in 90 cases: 27 favourable and two unfavourable histology (COG); and six low, 50 intermediate, and five high-risk tumours (International Society of Paediatric Oncology). With a median follow-up of 20.5 months (1-114 months), there were four local recurrences (3.8%) at a median of 8.5 (7-9) months after surgery. Three tumours were initial local stage I (2 intermediate and 1 high risk) and one stage III. The results are presented in the Figure., Discussion: The incidence of local recurrence after LTRN is 3.8%. This is lower than previously reported after open resection. However, tumours amenable to minimally invasive surgery are smaller, with higher numbers of low stage and standard histology. Additionally, the quality of the reports is suboptimal and follow-up is relatively short., Conclusion: LTRN does not seem to increase the incidence of local recurrence in WT but inclusion of patients in international protocols with prolonged and systematic follow-up is of utmost importance to carefully evaluate this risk., (Copyright © 2018 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: Overall complication rates for adult spinal deformity (ASD) surgery have been reported; however, little data exist on the peak timing associated with specific complications. This study quantifies the peak timing for multiple complication types in an ASD cohort at minimum 2-year follow-up., Methods: Multicenter, prospective analysis of all complications after ASD surgery in a consecutively enrolled cohort was performed. Inclusion criteria were ASD, age ≥18 years, spinal fusion ≥4 levels, and minimum 2-year follow-up. Complications included major and minor and specific complication types. Peak timing of specific complications was identified and described. Regression analysis was performed to assess correlation between patient/surgical factors and complication timing., Results: There were 280 patients who met the inclusion criteria. Mean follow-up time was 2.9 years (range, 2-5 years). Of the patients, 209 (74.6%) had at least 1 complication, accounting for 529 total complications (258 minor and 271 major). Both major and minor complications peaked at <3 months. Infection and neurologic complications peaked at <3 months. Proximal junctional kyphosis had bimodal peaks at <3 and >24 months. Implant failure peaked at 12-24 and >24 months. There was a significant positive correlation between preoperative sagittal vertical axis and total complications at 6-12 months, major complications at 24 months, and reoperation. Body mass index was associated with total complications and implant failure at 12-24 and >24 months., Conclusions: The peak timing of specific complications after ASD surgery is identifiable. Understanding when these complications are likely to occur may improve patient counseling, early diagnosis, and prophylactic interventions and may help inform future reimbursement models., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Tranexamic acid (TXA) is an antifibrinolytic that has been shown to decrease blood loss and transfusion rates after hip and knee arthroplasty, with only limited evidence to support its use in shoulder arthroplasty. This study was conducted to determine whether intravenous (IV) TXA is more effective than placebo in reducing blood loss after primary total shoulder arthroplasty (TSA)., Methods: In this prospective, double-blind, placebo-controlled, randomized clinical trial, patients undergoing primary anatomic and reverse TSA were randomized to receive 1 g of intravenous TXA or a placebo of an equivalent volume of intravenous normal saline administered 10 minutes before the incision. The primary outcome measurement was calculated postoperative blood loss. Secondary outcomes included transfusion rates, weight of hemoglobin loss, hospital length of stay, and thromboembolic events., Results: The study enrolled 110 patients, 2 of whom were excluded because they did not have a postoperative hemoglobin measurement, and the remaining 108 patients (52 for TXA, 56 for placebo) were analyzed. There were no significant differences between TXA and placebo groups in preoperative characteristics. For the primary outcome, the TXA group had significantly lower postoperative blood loss of 1100.9 ± 367.4 mL compared with 1274.5 ± 460.0 mL for the placebo group ( P  = .03). For secondary outcomes, TXA had lower weight of hemoglobin loss compared with placebo (152.2 ± 57.3 g vs. 178.0 ± 65.8 g; P  = .03). No patients in the TXA or placebo groups required a transfusion., Conclusions: Intravenous TXA reduced blood loss after primary TSA compared with placebo.

Context: Globally, low- and middle-income countries are home to 70% of cancer deaths and 99% of HIV deaths, but they consume just 7% of opioid analgesics., Objective: The American Cancer Society's Treat the Pain program partners with governments in low- and middle-income countries to improve access to high-quality essential pain medicines., Method: Treat the Pain has developed the MORPHINE Framework to provide a structure to describe challenges to access to pain relief and to group and sequence interventions to address these challenges., Results: Treat the Pain has used the framework to improve access to oral morphine in partner countries in Sub-Saharan Africa, including Nigeria, Ethiopia, Uganda, Kenya, and Swaziland, addressing both supply- and demand-side challenges., Conclusion: Treat the Pain is supporting governments in Sub-Saharan Africa to reduce needless suffering and improve access to essential pain medicines for patients in pain by supporting the expansion of locally produced, affordable oral morphine solution and expanding basic training in pain assessment and management., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Prader-Willi syndrome (PWS) is a rare (1:20.000) genetic condition affecting both males and females. Among other features, in boys, the syndrome is characterized by cryptorchidism in 86-100% of cases, hypogonadism, delayed puberty and infertility. The aim of the present study is to appraise the results of orchidopexy in this selected population of children., Study Design: A follow-up study of children with PWS treated for undescended testes at a single institution over a 20-year period was performed. Patients were identified from a National PWS registry and reviewed at a special follow-up clinic. Data were collected from electronic and hard copies records and reported as median (range)., Results: Thirty-three children (1-17 years) were identified. Co-morbidities were present in 22 (66%) and 15 (45%) were on growth-hormone therapy. Six patients (19%) had normal testes palpable in the scrotum; twenty-seven (81%) had undescended testes and required orchidopexy. Thirteen (48%) underwent a bilateral procedure for a total of 40 procedures. A 2-stage Fowler-Stephens orchidopexy was required in 2 (7%) testes. At surgery hypotrophic testes were documented in 6 (22%) patients. Age at orchidopexy was 1.4 years (0.5-5.5). Age at FU was 7.2 years (1.7-17). Length of follow-up is 3.5 years (0.4-14). At follow-up 16 (40%) testes were of normal size and palpable in the scrotum; 7 (17.5%) testes required redo-orchidopexy. All patients (6/33) over 16 years of age that had testosterone levels tested had values below normal limits after successful orchidopexy., Conclusions: This study evaluates the results of orchidopexy in a large population of children with PWS. At follow-up, only 40% of testes were of normal size and in the scrotum. This information should be taken into consideration for patients' management and pre-operative parents' counseling., (Copyright © 2017 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Introduction: In the era of biomarker-driven systemic therapy for advanced NSCLC, the role of routine repeated biopsies for decision making outside EGFR-mutant disease remains unproven. We report our center's experience of safety and adequacy for molecular retesting of tumor material obtained from image-guided lung rebiopsies in NSCLC., Methods: We performed a retrospective case note analysis of patients undergoing image-guided lung rebiopsies at a single cancer center between 2011 and 2014. The primary objective was to determine the pathological success rate. Secondary and exploratory objectives were to determine technical success rate, histological concordance, molecular adequacy, genotypes identified, and complication rate., Results: In all, 103 patients underwent transthoracic image-guided procedures. A total of 66 rebiopsies in NSCLC were identified and analyzed. The pathological success rate was 87.1%. A high histological discordance rate was observed (12 of 52 evaluable cases [23.1%]). Pretest molecular adequacy as determined by the lung pathologist was 78.8% (52 of 66). Of 52 adequate samples 51 were sent for molecular analysis, with a total of 209 genes analyzed (including EGFR, ALK receptor tyrosine kinase gene [ALK], KRAS, BRAF, dicoidin domain receptor tyrosine kinase 2 gene [DDR2], NRAS, ROS1, and rearranged during transfection proto-oncogene gene [RET]). The rate of postgenotyping molecular adequacy was 87.1% (182 of 209). Overall, 20 new potentially actionable mutations were identified, with 13 of 66 patients (19.7%) starting to receive new targeted treatment as a result. Overall, rebiopsies informed clinical decision making in 63.6% of cases. The rates of complications were 15% for pneumothorax, 3% for pneumothorax requiring chest drain, and 8% for hemoptysis., Conclusions: We have validated the pathological and molecular adequacy rates of rebiopsies and demonstrated clinical utility in routine decision making., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Peritoneal dialysis (PD) is the modality of choice for children with end-stage renal disease (ESRD) awaiting renal transplant; however, this option is sometimes avoided for those with previous laparotomy. The goal of this study was to compare the outcomes of PD in patients with and without previous laparotomy., Patients and Methods: Twenty-four patients who had been started on peritoneal dialysis were retrospectively analysed. Group LAP consisted of six patients with previous laparotomy, and Group NO-LAP of 18 controls with either retroperitoneal or no abdominal surgery. The percentage of theoretical maximum volume of infusion, time to reach it, complications (infection and drainage difficulties), and number of catheters needed to finish therapy were analysed., Results: The characteristics of patients and technique of insertion are presented in Table. The percentage of maximum theoretical volume of infusion was similar in both groups. Median of catheter survival was similar in both groups. Complications were divided into malfunction (slow drainage, obstruction or leak) and infection. Incidence of complications per catheter and per month of dialysis was ten times lower in Group NO-LAP. Peritoneal dialysis failed in one patient with recurrent intraperitoneal adhesions after adhesiolysis in Group LAP., Conclusion: Despite a higher incidence of complications (malfunction and infections), PD remains an acceptable option after laparotomy. In this series, it was sufficient in achieving adequate filtration in five patients., (Copyright © 2017 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Purpose: Leptomeningeal disease (LMD) is an uncommon complication of advanced breast cancer. The prognosis is poor, and although radiotherapy (RT), systemic and intra-thecal (IT) chemotherapy are accepted treatment modalities, efficacy data are limited. This study was designed to evaluate potential predictors of survival in this patient group., Methods: Breast cancer patients with LMD diagnosed by MRI in a 10-year period (2004-2014) were identified from electronic patient records. PFS and OS estimates were calculated using Kaplan-Meier method, with planned sub-group analysis by treatment modality. Cox regression was employed to identify significant prognostic variables., Results: We identified 182 eligible patients; all female, median age at LMD diagnosis 52.5 years (range 23-80). Ninety patients (49.5%) were ER positive/HER2 negative; 48 (26.4%) were HER2 positive, and 27 (14.8%) were triple negative. HER2 status was unknown in 17 (9.3%). Initial management of LMD was most commonly whole or partial brain RT in 62 (34.1%), systemic therapy in 45 (24.7%) or supportive care alone in 37 (20.3%). Fourteen patients (7.7%) underwent IT chemotherapy, of whom two also received IT trastuzumab. From diagnosis of LMD, the median PFS was 3.9 months (95%CI 3.2-5.0) and median OS was 5.4 months (95%CI 4.2-6.6). Patients treated with systemic therapy had the longest OS (median 8.8 months, 95%CI 5.5-11.1), compared to RT; 6.1 months (95%CI 4.2-7.9 months), IT therapy; 2.9 months (95%CI 1.2-5.8) and supportive care; 1.7 months (95%CI 0.9-3.0). On multivariable analysis, triple negative histology, concomitant brain metastases, and LMD involving both the brain and spinal cord were associated with poor OS., Conclusions: Breast cancer patients with triple negative LMD, concomitant brain metastases or LMD affecting both the spine and brain have the poorest prognosis. Clinical trials to identify more effective treatments for these patients are urgently needed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)