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OBJECTIVE: To describe the demographic characteristics of patients undergoing orthognathic surgery at the University of Otago over a nine-year period. METHODS: The case notes of patients who underwent orthognathic surgery procedures at the University of Otago from 2001 to 2009 were reviewed retrospectively. This was augmented with a brief literature review of surgical considerations and complications in orthognathic surgery among older patients. RESULTS: The 92 patients included in the study were aged 15 to 56 years. The mean patient age increased over the nine-year observation period, from 22.1 years (sd, 9.4) during 2001-2003, 25.0 years (sd, 12.7) during 2004-2006, to 27.7 years (sd, 11.4) during 2007-2009. Most patients were from New Zealand European or European backgrounds, with only 5.5% identifying as Maori, and 3.3% as Asian. A female preponderance was observed (with a female:male ratio of 1.6:1). Complications were encountered with 24 patients (26.1%). Ten patients had long-term (lasting for one year or more) sensory nerve disturbance; all of those had undergone a mandibular bilateral sagittal split osteotomy (BSSO) procedure (they comprised 12.7% of all BSSO patients treated); half of those patients were over 35 years old, and four were over 40 years old. CONCLUSIONS: There has been an increase in the proportion of older patients undergoing orthognathic surgery at the University of Otago. Observations from this case series support findings from other studies demonstrating a higher rate of sensory nerve disturbance among older BSSO patients. [ABSTRACT FROM AUTHOR]

Objective: Excess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D).Research Design and Methods: The effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE-fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium.Results: β-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and β-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors.Conclusions: These findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D. [ABSTRACT FROM AUTHOR]

An 18-month-old boy with partial and full thickness burns to his upper face and scalp was treated by an interdisciplinary team at the Role 3 Multinational Medical Unit in Kandahar. A novel approach to his burn management is presented, highlighting some of the issues and constraints that military surgeons are faced with while on operational deployment in a theater of conflict. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate New Zealand GDPs' awareness of maxillofacial trauma and to identify their associated referral patterns. DESIGN: Cross-sectional survey of a random sample of GDPs. METHOD: A nationwide postal questionnaire survey was sent to GDPs on the New Zealand Dental Register, maintained by the Dental Council of New Zealand. The questionnaire requested socio-demographic details, together with information on the availability of specialist services and their need for continuing professional development in oral and maxillofacial surgery (OMS). The questionnaire also asked the GDPs to indicate which specialty (plastic surgery, ear nose and throat (ENT) surgery, OMS and Other) they expected to manage--and to which specialty they would refer-seven types of maxillofacial injury. RESULTS: Some 377 GDPs responded (76.6%). The majority of GDPs expected OMS to manage maxillofacial trauma, except for facial lacerations and isolated nasal fractures which were expected to be managed by plastic surgery (83.0%) and ENT surgery (79.7%), respectively. Most GDPs (48.0% to 87.9%) referred maxillofacial trauma to OMS, except for isolated nasal fractures, for which there were similar proportions referred to ENT surgery and OMS (45.8% and 41.4%, respectively). Differences in awareness of and referral patterns for maxillofacial trauma were identified by dentist characteristics. Most GDPs (96.0%) felt there was a need for continuing professional development in OMS, and most (84.1%) preferred this to be in the form of lectures and seminars. CONCLUSION: The first-ever study of GDP referral patterns for maxillofacial trauma in New Zealand has revealed that most GDPs in New Zealand referred maxillofacial trauma appropriately to OMS. [ABSTRACT FROM AUTHOR]

Background: Postoperative pain and swelling following third molar (M3) removal can be debilitating, and there is interest in using advanced platelet-rich fibrin (A-PRF) to reduce their severity., Purpose: This study compared postoperative pain and swelling between A-PRF and gelatin dressing in extraction sockets following mandibular M3 removal., Methods, Setting, Sample: This split-mouth, single-blinded, randomized controlled trial was completed at the Oral Surgery clinic of University of Otago between November 2020 and July 2021. Patients aged between 16 and 40 years with bilaterally impacted mandibular M3 of similar Pederson index difficulty and deemed to be American Society of Anesthesiologists (ASA) I or II comprised the study sample., Predictor/exposure/independent Variable: The exposure variable was M3 socket management. One socket received A-PRF and 1 gelatin dressing, while the other received 2 gelatin dressings., Main Outcome Variable(s): The outcome variables were postoperative pain and swelling over 7 days. Pain was measured using the visual analog scale (VAS), and swelling using stereophotogrammetry., Covariates: Demographic characteristics (gender, ethnicity, and age), dental anxiety, smoking status, Pederson index, and intraoperative surgical time were the covariates., Analyses: The two sides were compared using cross-tabulations and the McNemar test for categorical and paired t-tests for continuous variables. Statistical analysis used IBM SPSS Statistics for Windows (version 28).The Alpha level was 0.05., Results: 76 (87.3%) of 87 patients who met the eligibility criteria participated in the study, and 70 patients (65.7% female; age range 16-30 years) were included in the analysis. Mean visual analog scale scores showed no statistically significant difference between the A-PRF and control sides, being 29.6 (95% CI 23.9, 35.3) and 29.5 (95% CI 23.5, 35.5) on day 2, and falling to 12.6 (95% CI 8.7, 16.5) and 14.2 (95% CI 10.0, 18.4) by day 7. Likewise, mean peak facial swelling on day 2 was recorded as 6.3 cm 3 (95% CI 4.9, 7.7) and 6.6 cm 3 (95% CI 5.5, 7.7), and by day 7 they were 1.1 cm 3 (95% CI 0.5, 1.7) and 1.0 cm 3 (95% CI 0.3, 0.7) on the A-PRF and control sides, respectively., Conclusions: A-PRF placement in M3 sockets did not reduce postoperative pain and swelling over gelatin dressing alone., (Copyright © 2024 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Craniofacial bone defects result from various disorders such as trauma, congenital malformations and infections. Cleft lip and palate are the most prevalent congenital craniofacial birth defect in humans. Growth factors (GFs) are soluble proteins secreted by cells that regulate various cellular processes and tissue regeneration. At present, developing three-dimensional scaffolds for delivering GFs to the site of injury has become an important aspect in craniofacial bone regeneration. This study aims to develop a novel 3D bone substitute using lyophilized-platelet-rich fibrin (LyPRF) biocomposite scaffolds for potential application for CLP repair. Collagen (C), bioglass (BG), and LyPRF were used to fabricate a biocomposite (C-BG-LyPRF) scaffold. The physical, chemical, and biocompatibility properties of the scaffold were evaluated. The C-BG-LyPRF scaffold demonstrated a mean pore diameter of 146 µm within a porosity of 87.26%. The FTIR spectra verified the presence of am-ide I, II, and III functional groups. The inorganic phase of the C-BG-LyPRF scaffold was composed of sodium, calcium, silicon, and phosphorus, as determined by EDX analysis. Furthermore, C-BG-LyPRF scaffold was biocompatible with MC3T3-E1 cells in both the Live/Dead and prolif-eration assays. Data demonstrate the developed C-BG-LyPRF scaffold exhibits biomimetic and biocompatibility properties, establishing it as a promising biomaterial for craniofacial regeneration., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The demands of operational deployment mean that defense force personnel must be dentally fit. Although medical evacuation for dental causes should be avoided, dental emergencies are a major non-combat-related contributor to withdrawal from deployment. Information on the oral health status of recruits and officer cadets entering the New Zealand Defence Force (NZDF) is scarce, yet it is useful for service and workforce planning. We investigated oral health status and its associations in new recruits and officer cadets entering the NZDF over a 13-month period., Materials and Methods: This study used data from recruits' initial dental examination (including baseline forensic charting), posterior bitewing radiographs, orthopantomograph radiograph, and a socio-dental questionnaire. The impaction status of third molar teeth was evaluated. Ethical approval was obtained from the University of Otago Ethics Committee (reference number D18/200) and the NZDF Organisational Research Committee., Results: Of the 874 (83%) of the 1,053 recruits (age range 17-59 years) who participated, one in five were Māori. Nearly two-thirds were Army recruits. Caries prevalence was almost 70%. Mean Decayed, Missing, and Filled Teeth (DMFT) (3.0 overall) was higher among females and Māori. Few teeth were missing due to caries. Third molars were common, seen in 745 (88.3%). One in four maxillary third molars (but only one in six mandibular ones) had fully erupted. The most common type of impaction among mandibular third molars was the mesioangular type, followed by vertical, horizontal, and distoangular. Almost 60% of recruits had one or more potentially problematic third molars. The prevalence was highest in the youngest age groups, those of medium or low socioeconomic status and in Army or Navy recruits., Conclusions: Recruits' oral health was acceptable, but potentially problematic third molars were common, indicating a need for careful assessment (and their possible removal) before operational deployment., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study seeks to evaluate the impact of breast cancer (BRCA) gene status on tumor dissemination pattern, surgical outcome and survival in a multicenter cohort of paired primary ovarian cancer (pOC) and recurrent ovarian cancer (rOC)., Patients and Methods: Medical records and follow-up data from 190 patients were gathered retrospectively. All patients had surgery at pOC and at least one further rOC surgery at four European high-volume centers. Patients were divided into one cohort with confirmed mutation for BRCA1 and/or BRCA2 (BRCAmut) and a second cohort with BRCA wild type or unknown (BRCAwt). Patterns of tumor presentation, surgical outcome and survival data were analyzed between the two groups., Results: Patients with BRCAmut disease were on average 4 years younger and had significantly more tumor involvement upon diagnosis. Patients with BRCAmut disease showed higher debulking rates at all stages. Multivariate analysis showed that only patient age had significant predictive value for complete tumor resection in pOC. At rOC, however, only BRCAmut status significantly correlated with optimal debulking. Patients with BRCAmut disease showed significantly prolonged overall survival (OS) by 24.3 months. Progression-free survival (PFS) was prolonged in the BRCAmut group at all stages as well, reaching statistical significance during recurrence., Conclusions: Patients with BRCAmut disease showed a more aggressive course of disease with earlier onset and more extensive tumor dissemination at pOC. However, surgical outcome and OS were significantly better in patients with BRCAmut disease compared with patients with BRCAwt disease. We therefore propose to consider BRCAmut status in regard to patient selection for cytoreductive surgery, especially in rOC., (© 2022. The Author(s).)

Aims: Fractures to the maxillofacial region can have a serious impact on quality of life. The over-representation of males in the occurrence of almost all types and mechanisms of these injuries has tended to divert attention away from maxillofacial fractures in females. This study aimed to describe trends in maxillofacial trauma in a New Zealand tertiary trauma centre over a 12 year period, with a particular focus on gender differences., Method: A retrospective audit was undertaken of records for maxillofacial fracture cases referred to Dunedin Hospital and Southland Hospital Maxillofacial Units during the period January 2009 to December 2020. Information on age, gender and ethnicity, aetiology, alcohol and/or drug involvement, fracture type, and management was obtained from the Southern District Health Board - Health Connect South Network., Results: Over the observation period, 1,561 patients presented for a total of 2,480 fractures. There was an increase in the proportion of fractures arising from falls and involving the orbit, while those due to interpersonal violence (IPV) or involving the mandible fell. Additionally, the proportion of cases treated conservatively rose, while the use of surgical fixation fell. While overall just over one in five patients were female, that proportion increased from one in six in 2009-2011 to one in four in 2018-2020. Fractures among females were due mainly to falls (55.6%) and road traffic accidents (23.2%), and frequently involved the orbit (46.3%). The proportion of presentations involving people aged 50 or older also increased over time., Conclusions: A greater proportion of women are suffering from facial fractures in the past decade than they have previously. Public health interventions for those at risk and their families are necessary. Interventions should have a focus on preventing falls and domestic violence, with a particular focus on older people and Māori/Pasifika populations. Improved and continued monitoring of these changing patterns is important for addressing the issues they present to New Zealand., Competing Interests: Nil.

Background: In traditional Chinese medicine (TCM), frankincense and myrrh are the main components of the antitumor drug Xihuang Pill. These compounds show anticancer activity in other biological systems. However, whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma (HCC) is unknown, and the potential molecular mechanism(s) has not yet been determined., Aim: To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo ., Methods: In the present study, which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (http://tcmspw.com/tcmsp.php), Universal Protein database (http://www.uniprot.org), GeneCards: The Human Gene Database (http://www.genecards.org/) and Comparative Toxicogenomics Database (http://www.ctdbase.org/), the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted. The core prediction targets were screened by molecular docking. In vivo , SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model, and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d. The tumors were collected and evaluated: the tumor volume and growth rate were gauged to evaluate tumor growth; hematoxylin-eosin staining was performed to estimate histopathological changes; immunofluorescence (IF) was performed to detect the expression of CD31, α-SMA and collagen IV; transmission electron microscopy (TEM) was conducted to observe the morphological structure of vascular cells; enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of secreted HIF-1α and TNF-α; reverse transcription-polymerase chain reaction (RT-qPCR) was performed to measure the mRNA expression of HIF-1α, TNF-α, VEGF and MMP-9; and Western blot (WB) was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways., Results: The results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets. The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets, with the greatest affinity for EGFR. Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes, such as cytokine-receptor binding, and pathways, such as those involving serine/threonine protein kinase complexes and MAPK, HIF-1 and ErbB signaling cascades. The animal experiment results were verified. First, we found that, through frankincense and/or myrrh treatment, the volume of subcutaneously transplanted HCC tumors was significantly reduced, and the pathological morphology was attenuated. Then, IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression, increased the coverage of perivascular cells, tightened the connection between cells, and improved the shape of blood vessels. In addition, ELISA, RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors, inflammatory factors and angiogenesis-related factors, namely, HIF-1α, TNF-α, VEGF and MMP-9. Furthermore, mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation, thereby inhibiting the phosphorylation activity of its downstream targets: the PI3K/Akt and MAPK (ERK, p38 and JNK) pathways., Conclusion: In summary, frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways, highlighting the potential of this dual TCM compound as an anti-HCC candidate., Competing Interests: Conflict-of-interest statement: All authors declare no financial or commercial conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Platelet-rich fibrin (PRF) has gained popularity in craniofacial surgery, as it provides an excellent reservoir of autologous growth factors (GFs) that are essential for bone regeneration. However, the low elastic modulus, short-term clinical application, poor storage potential and limitations in emergency therapy use restrict its more widespread clinical application. This study fabricates lyophilised PRF (Ly-PRF), evaluates its physical and biological properties, and explores its application for craniofacial tissue engineering purposes., Material and Methods: A lyophilisation method was applied, and the outcome was evaluated and compared with traditionally prepared PRF. We investigated how lyophilisation affected PRF's physical characteristics and biological properties by determining: (1) the physical and morphological architecture of Ly-PRF using SEM, and (2) the kinetic release of PDGF-AB using ELISA., Results: Ly-PRF exhibited a dense and homogeneous interconnected 3D fibrin network. Moreover, clusters of morphologically consistent cells of platelets and leukocytes were apparent within Ly-PRF, along with evidence of PDGF-AB release in accordance with previously reports., Conclusions: The protocol established in this study for Ly-PRF preparation demonstrated versatility, and provides a biomaterial with growth factor release for potential use as a craniofacial bioscaffold.

Aims: Recent randomized trials demonstrated a benefit of low-dose colchicine added to guideline-based treatment in patients with recent myocardial infarction or chronic coronary disease. We performed a systematic review and meta-analysis to obtain best estimates of the effects of colchicine on major adverse cardiovascular events (MACE)., Methods and Results: We searched the literature for randomized clinical trials of long-term colchicine in patients with atherosclerosis published up to 1 September 2020. The primary efficacy endpoint was MACE, the composite of myocardial infarction, stroke, or cardiovascular death. We combined the results of five trials that included 11 816 patients. The primary endpoint occurred in 578 patients. Colchicine reduced the risk for the primary endpoint by 25% [relative risk (RR) 0.75, 95% confidence interval (CI) 0.61-0.92; P = 0.005], myocardial infarction by 22% (RR 0.78, 95% CI 0.64-0.94; P = 0.010), stroke by 46% (RR 0.54, 95% CI 0.34-0.86; P = 0.009), and coronary revascularization by 23% (RR 0.77, 95% CI 0.66-0.90; P < 0.001). We observed no difference in all-cause death (RR 1.08, 95% CI 0.71-1.62; P = 0.73), with a lower incidence of cardiovascular death (RR 0.82, 95% CI 0.55-1.23; P = 0.34) counterbalanced by a higher incidence of non-cardiovascular death (RR 1.38, 95% CI 0.99-1.92; P = 0.060)., Conclusion: Our meta-analysis indicates that low-dose colchicine reduced the risk of MACE as well as that of myocardial infarction, stroke, and the need for coronary revascularization in a broad spectrum of patients with coronary disease. There was no difference in all-cause mortality and fewer cardiovascular deaths were counterbalanced by more non-cardiovascular deaths., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Risk assessment of patients with acute COVID-19 in a telemedicine context is not well described. In settings of large numbers of patients, a risk assessment tool may guide resource allocation not only for patient care but also for maximum health care and public health benefit., Objective: The goal of this study was to determine whether a COVID-19 telemedicine risk assessment tool accurately predicts hospitalizations., Methods: We conducted a retrospective study of a COVID-19 telemedicine home monitoring program serving health care workers and the community in Atlanta, Georgia, with enrollment from March 24 to May 26, 2020; the final call range was from March 27 to June 19, 2020. All patients were assessed by medical providers using an institutional COVID-19 risk assessment tool designating patients as Tier 1 (low risk for hospitalization), Tier 2 (intermediate risk for hospitalization), or Tier 3 (high risk for hospitalization). Patients were followed with regular telephone calls to an endpoint of improvement or hospitalization. Using survival analysis by Cox regression with days to hospitalization as the metric, we analyzed the performance of the risk tiers and explored individual patient factors associated with risk of hospitalization., Results: Providers using the risk assessment rubric assigned 496 outpatients to tiers: Tier 1, 237 out of 496 (47.8%); Tier 2, 185 out of 496 (37.3%); and Tier 3, 74 out of 496 (14.9%). Subsequent hospitalizations numbered 3 out of 237 (1.3%) for Tier 1, 15 out of 185 (8.1%) for Tier 2, and 17 out of 74 (23%) for Tier 3. From a Cox regression model with age of 60 years or older, gender, and reported obesity as covariates, the adjusted hazard ratios for hospitalization using Tier 1 as reference were 3.74 (95% CI 1.06-13.27; P=.04) for Tier 2 and 10.87 (95% CI 3.09-38.27; P<.001) for Tier 3., Conclusions: A telemedicine risk assessment tool prospectively applied to an outpatient population with COVID-19 identified populations with low, intermediate, and high risk of hospitalization., (©James B O'Keefe, Elizabeth J Tong, Thomas H Taylor Jr, Ghazala A Datoo O’Keefe, David C Tong. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 30.04.2021.)

Background: Despite emerging evidence suggesting that selected patients presenting with ST-segment elevation myocardial infarction (STEMI) treated successfully with primary percutaneous coronary intervention (PPCI) may be considered for early discharge, STEMI patients are typically hospitalised longer to monitor for serious complications., Methods: We assessed the feasibility of identifying low-risk STEMI patients in our institution for early discharge using the Zwolle risk score (ZRS). We evaluated consecutive STEMI patients who underwent successful PPCI within the period 1 January 2016 to 31 December 2017. Low-risk was defined as ZRS≤3. Demographic, angiographic characteristics, length of stay (LOS), and 30-day major adverse cardiovascular events (MACE) defined as cardiac death, stroke, congestive cardiac failure, and non-fatal myocardial infarction, were recorded., Results: There were 183 STEMI patients in our study cohort (mean age 62.0±12.2 years, 77.0% male). The median ZRS was 2 (interquartile range 1-4) with 132 (72.1%) patients classified as low-risk. The overall 30-day MACE and mortality rates were 10.4% and 3.3% respectively. None of the 35 (26.5%) low-risk patients who were discharged within 72 hours experienced MACE at 30 days. Low-risk STEMI patients had significantly shorter median LOS (86.3 vs. 93.2 hours, p=0.002), lower 30-day MACE (4.5% vs. 25.5%, p<0.0001) and mortality (0% vs. 11.8%, p<0.0001) compared to high-risk group (ZRS>3). Receiver operating characteristic (ROC) curve analyses for ZRS in predicting 30-day MACE and mortality yielded C-statistics of 0.79 (95%CI 0.68-0.90, p<0.0001) and 0.98 (95%CI 0.95-1.00, p<0.0001) respectively., Conclusion: Low-risk STEMI patients stratified by Zwolle risk score, who were treated successfully with PPCI, experienced low 30-day MACE and mortality rates, indicating that early discharge may be safe in these patients. Larger studies are warranted to evaluate the safety of ZRS-guided early discharge of STEMI patients, as well as the economic and psychological impacts., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Objective: Describe the disease course in a cohort of outpatients with COVID-19 and evaluate factors predicting duration of symptoms., Design: Retrospective cohort study., Setting: Telemedicine clinic at a large medical system in Atlanta, Georgia., Participants: 337 patients with acute COVID-19. Exclusion criteria included intake visit more than 10 days after symptom onset and hospitalisation prior to intake visit., Main Outcome Measures: Symptom duration in days., Results: Common symptoms at intake visit are upper respiratory (73% cough, 55% loss of smell or taste, 57% sinus congestion, 32% sore throat) and systemic (66% headache, 64% body aches, 53% chills, 30% dizziness, 36% fever). Day of symptom onset was earliest for systemic and upper respiratory symptoms (median onset day 1 for both), followed by lower respiratory symptoms (day 3, 95% CI 2 to 4), with later onset of gastrointestinal symptoms (day 4, 95% CI 3 to 5), when present. Cough had the longest duration when present with median 17 days (95% CI 15 to 21), with 42% not resolved at final visit. Loss of smell or taste had the second longest duration with 14 days (95% CI 12 to 17), with 38% not resolved at final visit. Initial symptom severity is a significant predictor of symptom duration (p<0.01 for multiple symptoms)., Conclusions: COVID-19 illness in outpatients follows a pattern of progression from systemic symptoms to lower respiratory symptoms and persistent symptoms are common across categories. Initial symptom severity is a significant predictor of disease duration for most considered symptoms., Competing Interests: Competing interests: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years, no other relationships or activities that could appear to have influenced the submitted work. GDO served on an advisory board of Eyepoint Pharmaceuticals in 2019. It is unrelated to the current work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The use of platelet concentrates (PCs) in oral and maxillofacial surgery, periodontology, and craniofacial surgery has been reported. While PCs provide a rich reservoir of autologous bioactive growth factors for tissue regeneration, their drawbacks include lack of utility for long-term application, low elastic modulus and strength, and limited storage capability. These issues restrict their broader application. This review focuses on the lyophilization of PCs (LPCs) and how this processing approach affects their biological and mechanical properties for application as a bioactive scaffold for craniofacial tissue regeneration., Materials and Methods: A comprehensive search of five electronic databases, including Medline, PubMed, EMBASE, Web of Science, and Scopus, was conducted from 1946 until 2019 using a combination of search terms relating to this topic., Results: Ten manuscripts were identified as being relevant. The use of LPCs was mostly studied in in vitro and in vivo craniofacial bone regeneration models. Notably, one clinical study reported the utility of LPCs for guided bone regeneration prior to dental implant placement., Conclusions: Lyophilization can enhance the inherent characteristics of PCs and extends shelf-life, enable their use in emergency surgery, and improve storage and transportation capabilities. In light of this, further preclinical studies and clinical trials are required, as LPCs offer a potential approach for clinical application in craniofacial tissue regeneration.

Background: End-stage kidney disease patients on dialysis are particularly susceptible to COVID-19 infection due to comorbidities, age, and logistic constraints of dialysis making social distancing difficult. We describe our experience with hospitalized dialysis patients with COVID-19 and factors associated with mortality., Methods: From March 1, 2020, to May 31, 2020, all dialysis patients admitted to 4 Emory Hospitals and tested for COVID-19 were identified. Sociodemographic information and clinical and laboratory data were obtained from the medical record. Death was defined as an in-hospital death or transfer to hospice for end-of-life care. Patients were followed until discharge or death., Results: Sixty-four dialysis patients with COVID-19 were identified. Eighty-four percent were African-American. The median age was 64 years, and 59% were males. Four patients were on peritoneal dialysis, and 60 were on hemodialysis for a median time of 3.8 years, while 31% were obese. Fever (72%), cough (61%), and diarrhea (22%) were the most common symptoms at presentation. Thirty-three percent required admission to intensive care unit, and 23% required mechanical ventilation. The median length of stay was 10 days, while 11 patients (17%) died during hospitalization and 17% were discharged to a temporary rehabilitation facility. Age >65 years (RR 13.7, CI: 1.9-100.7), C-reactive protein >100 mg/dL (RR 8.3, CI: 1.1-60.4), peak D-dimer >3,000 ng/mL (RR 4.3, CI: 1.03-18.2), bilirubin >1 mg/dL (RR 3.9, CI: 1.5-10.4), and history of peripheral vascular disease (RR 3.2, CI: 1.2-9.1) were associated with mortality. Dialysis COVID-19-infected patients were more likely to develop thromboembolic complications than those without COVID-19 (RR 3.7, CI: 1.3-10.1)., Conclusion: In a predominantly African-American population, the mortality of end-stage kidney disease patients admitted with COVID-19 infection was 17%. Age, C-reactive protein, D-dimer, bilirubin, and history of peripheral vascular disease were associated with worse survival., (© 2021 S. Karger AG, Basel.)

Anti-PD1/PDL1 therapy has proven efficacious against many cancers but only reached modest objective response rates against recurrent ovarian cancer. A deeper understanding of the tumor microenvironment (TME) may reveal other immunosuppressive mechanisms that warrant investigation as immunotherapeutic targets for this challenging disease. Matched primary and recurrent tumors from patients with high-grade serous ovarian carcinoma (HGSC) were analyzed by multicolor immunohistochemistry/immunofluorescence for the presence of T cells, B cells, macrophages, and for the expression of immunosuppressive and HLA molecules. Cancer- and immune-related gene expression was assessed by NanoString analysis. Recurrent tumors showed increased infiltration by immune cells, displayed higher expression of PDL1, IDO, and HLA molecules, and contained more stromal tissue. NanoString analysis demonstrated increased expression of gene signatures related to chemokines and T cell functions in recurrent tumors. The ovarian tumors showed high gene expression of LAG3 and HAVCR2 (TIM3) and enhanced levels of TIGIT and CTLA4 in recurrent tumors compared to primary tumors. The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.

Background: Inflammation plays a crucial role in clinical manifestations and complications of acute coronary syndromes (ACS). Colchicine, a commonly used treatment for gout, has recently emerged as a novel therapeutic option in cardiovascular medicine owing to its anti-inflammatory properties. We sought to determine the potential usefulness of colchicine treatment in patients with ACS., Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial involving 17 hospitals in Australia that provide acute cardiac care service. Eligible participants were adults (18-85 years) who presented with ACS and had evidence of coronary artery disease on coronary angiography managed with either percutaneous coronary intervention or medical therapy. Patients were assigned to receive either colchicine (0.5 mg twice daily for the first month, then 0.5 mg daily for 11 months) or placebo, in addition to standard secondary prevention pharmacotherapy, and were followed up for a minimum of 12 months. The primary outcome was a composite of all-cause mortality, ACS, ischemia-driven (unplanned) urgent revascularization, and noncardioembolic ischemic stroke in a time to event analysis., Results: A total of 795 patients were recruited between December 2015 and September 2018 (mean age, 59.8±10.3 years; 21% female), with 396 assigned to the colchicine group and 399 to the placebo group. Over the 12-month follow-up, there were 24 events in the colchicine group compared with 38 events in the placebo group ( P =0.09, log-rank). There was a higher rate of total death (8 versus 1; P =0.017, log-rank) and, in particular, noncardiovascular death in the colchicine group (5 versus 0; P =0.024, log-rank). The rates of reported adverse effects were not different (colchicine 23.0% versus placebo 24.3%), and they were predominantly gastrointestinal symptoms (colchicine, 23.0% versus placebo, 20.8%)., Conclusions: The addition of colchicine to standard medical therapy did not significantly affect cardiovascular outcomes at 12 months in patients with ACS and was associated with a higher rate of mortality. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12615000861550.

Background/aim: This study analyzed the gene expression of the "classic" KLK1 and "new" kallikreins KLK4-KLK15, in relation to the molecular characteristics and in vitro invasiveness of 21 breast cancer (BC) and three normal breast-derived cell lines (CLs)., Materials and Methods: Gene expression of KLKs was determined by using real-time polymerase chain reaction (PCR). The invasiveness of the CLs was examined using a fibroblast-collagen-based in vitro cell culture assay., Results: KLK5 and KLK7-KLK11 were down-regulated in several BCCLs. In contrast, KLK4, KLK8, KLK12 and KLK15 demonstrated strikingly high expression in two BCCLs, UACC 812 and MDA-MB 330. The KLK expression differed frequently according to the presence of androgen receptor (KLK1 and KLK5-KLK9), and occasionally according to estrogen receptor (KLK9) and EGFR (KLK7). Two KLK clusters were detected (first: KLK1, 4, 12, 15; second: all other KLKs), with two subclasses within the second cluster (KLK5-9 and KLK10, 11, 13, and 14). The CLs that expressed at least six KLKs belonged predominantly to basal or HER2 intrinsic subtypes. No KLK predicted the in vitro invasiveness of CLs., Conclusion: Gene expression of KLKs was altered in BCCLs. This change was mostly down-regulation and often related to the presence of androgen receptor. The observed clusters point to a possible functional interplay of selected KLKs in BCCLs., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Elevated triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been utilised as a predictor of outcomes in patients with adverse cardiometabolic risk profiles. In this study, we examined the prognostic value of elevated TG/HDL-C level in an Australian population of patients with high clinical suspicion of coronary artery disease (CAD) presenting for coronary angiography., Methods: Follow-up data was collected for 482 patients who underwent coronary angiography in a prospective cohort study. The primary endpoint was all-cause mortality and the secondary endpoint was a major adverse cardiac event (MACE). Patients were stratified into two groups according to their baseline TG/HDL-C ratio, using a TG/HDL-C ratio cut point of 2.5., Results: The mean follow-up period was 5.1 ± 1.2 years, with 49 all-cause deaths. Coronary artery disease on coronary angiography was more prevalent in patients with TG/HDL-C ratio ≥2.5 (83.6% vs. 69.4%, p = 0.03). On the Kaplan-Meier analysis, patients with TG/HDL-C ratio ≥2.5 had worse long-term prognosis (p = 0.04). On multivariate Cox regression adjusting for established cardiovascular risk factors and CAD on coronary angiography, TG/HDL-C ratio ≥2.5 was an independent predictor of long-term all-cause mortality (hazard ratio [HR] 2.10, 95% confidence interval [CI] 1.04-4.20, p = 0.04). On multivariate logistic regression adjusting for known cardiovascular risk factors and CAD on coronary angiography, TG/HDL-C ratio ≥2.5 was strongly associated with an increased risk of long-term MACE (odds ratio [OR] 2.72, 95% CI 1.42-5.20, p = 0.002)., Conclusions: Elevated TG/HDL-C ratio is an independent predictor of long-term all-cause mortality and is strongly associated with an increased risk of MACE., (Copyright © 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to "platinum-sensitive", exhibiting a decreased IC 50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions., Competing Interests: maximum reaction velocity

With increasingly detailed imaging and mechanical analysis, modalities need arises to update methodology and assessment criteria for skull bone analysis to understand how bone microarchitecture and the presence of attached tissues may affect the response to mechanical load. The main aim was to analyze the effect of macroscopic and microstructural features, as well as periosteal attachment, on the mechanical properties of human skull bone. Fifty-six skull specimens from ethanol-phenoxyethanol-embalmed cadavers were prepared from two human cadavers. Assuming symmetry of the skull, all samples from one-half each were stripped of periosteum and dura mater, while the soft tissues were kept intact on the remaining samples on the contralateral side. The specimens were analyzed using microcomputed tomography to assess trabecular connectivity density, total surface area, and volume ratio. The specimens were loaded under three-point bend tests until fracture with optical co-registration. The bone fragments were then lyophilized to measure their water content. With increasingly detailed imaging and mechanical analysis modalities, there is a need to update methodology and assessment criteria for skull bone analysis to understand how the bone microarchitecture and the presence of attached tissues may affect the response to mechanical load. The mechanical properties were negatively correlated to bone thickness and water content. Conversely, most microarchitectural features did not influence either mechanical parameter. The correlation between mechanical response data and morphologic properties remains similar between the results of embalmed tissues presented here and fresh osseous tissue from literature data. The findings presented here add to the existing methodology to assess human skull for research purposes. The interaction between most microarchitectural features in ethanol-phenoxyethanol-embalmed embalmed skull samples and bending stress appear to be minute.

Resistance to platinum-based chemotherapy is a common event in patients with cancer, generally associated with tumor dissemination and metastasis. Whether platinum treatment per se activates molecular pathways linked to tumor spreading is not known. Here, we report that the ubiquitin-specific protease 1 (USP1) mediates ovarian cancer cell resistance to platinum, by regulating the stability of Snail, which, in turn, promotes tumor dissemination. At the molecular level, we observed that upon platinum treatment, USP1 is phosphorylated by ATM and ATR and binds to Snail. Then, USP1 de-ubiquitinates and stabilizes Snail expression, conferring resistance to platinum, increased stem cell-like features, and metastatic ability. Consistently, knockout or pharmacological inhibition of USP1 increased platinum sensitivity and decreased metastatic dissemination in a Snail-dependent manner. Our findings identify Snail as a USP1 target and open the way to a novel strategy to overcome platinum resistance and more successfully treat patients with ovarian cancer.

Objective: To explore brain activations associated with electroacupuncture simulation at Tongli (HT 5) and its comparison with brain activations during picture-naming task., Methods: Twenty healthy subjects were enrolled in this study. Half of them received electroacupuncture stimulation at HT 5 (ACUP group) and the other half of them received stimulation at a nonmeridian sham acupoint (SHAM group). All subjects performed picture-naming task. Each subject finished two runs of functional magnetic resonance imaging examinations in one session and picture-naming task was performed before electroacupuncture stimulation. Subjective brain activations were obtained using generalized linear model and inter-group analyses were performed after that., Results: The electroacupuncture stimulation at HT 5 induced significant brain activations in both the anterior and posterior language regions, including the left inferior frontal gyrus, which was in consistent with activations induced during picture-naming task. Group analysis showed a tendency of increased activation of ACUP group in left inferior frontal gyrus compared with SHAM group (P<0.05 FDR corrected)., Conclusions: Electroacupuncture treatment at the acupoint HT 5 has modulation effect on typical language-implicated brain regions in healthy subjects, which provides supporting evidence for beneficial effects of needling at HT 5 for recovery of language function in aphasia.

Mechanical properties of the human scalp have not been investigated to a great extent with limited information available. The purpose of this study was to provide new baseline material data for human scalp tissue of various ages, which can be applied to experimental and constitutive models, such as in the area of impact biomechanics. This study used specimens from the left and right temporal, fronto-parietal and occipital regions of the human scalp. It investigated the tensile behavior of scalp tissue using tissues harvested from unfixed, fresh cadavers. These samples were subjected to an osmotic stress analysis and upon testing, cyclic loading followed by stretching until failure in a universal testing machine. Strain evaluation was conducted using digital image correlation in a highly standardized approach. Elastic modulus, tensile strength, strain at maximum load and strain to failure were evaluated computationally. No significant differences were observed comparing the tensile strength between males and females. In contrast to that, a sex-dependent difference was found for the elastic modulus of the occipital scalp region and for the elongation properties. Additionally, regional differences within the male group, as well as an age dependent correlation for females were found in the elastic modulus and tensile strength. Scanning electron microscope analyses have shown the ultrastructural failure patterns, indicated by damaged keratin plates, as well as partially disrupted and retraced collagens at the failure site. The novel data obtained in this study could add valuable information to be used for modeling purposes, as well as provide baseline data for simulant materials and comparisons of tissue properties following head injury or forensic investigations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Reducing time to reperfusion for ST-segment elevation myocardial infarction (STEMI) is essential in improving outcomes. Consequently, numerous strategies have been employed to reduce median door-to-balloon time (DTBT)., Methods: CODE STEMI is an ED physician-activated STEMI notification system. On activation, an announcement is made over the hospital's public announcement (PA) system. We prospectively analysed all in-hours STEMI patients who had primary percutaneous coronary intervention (PPCI) Pre-CODE STEMI (2014) and after CODE STEMI was implemented (2015). The primary end-points were median DTBT and the proportion of STEMI patients achieving a DTBT ≤90 min. The secondary end-points were in-hospital outcomes, and a composite of major adverse cardiac events (MACE) and hospital readmission rates at 30 days and 12 months., Results: There were 41 and 42 patients in Pre-CODE STEMI and CODE STEMI groups respectively. Baseline characteristics were similar. DTBT was significantly reduced by 22.1 min from 67.1 ± 34.9 min Pre-CODE STEMI to 45.0 ± 22.7 min (P = 0.001) in the CODE STEMI group. Door-to-door time (DTDT) was also reduced from 46.3 ± 30.9 min to 29.4 ± 23.3 min (P = 0.006). A greater proportion of CODE STEMI patients achieved the target DTBT ≤90 min (95.2% vs 73.2%, P = 0.007). CODE STEMI patients had less systolic dysfunction measured by a left ventricle ejection fraction of ≤40% (10.0% vs 27.8%, P = 0.07). There were trends to lower in-hospital mortality rates (4.8% vs 9.8%, P = 0.43), MACE at 30 days and 12 months (4.8% vs 9.8%, P = 0.43; 11.9% vs 22.0%, P = 0.25)., Conclusion: The novel in-hospital in-hours CODE STEMI notification system significantly reduced DTBT in patients undergoing PPCI., (© 2017 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.)

Purpose: Tumor-infiltrating lymphocytes (TILs) have an established impact on the prognosis of high-grade serous ovarian carcinoma (HGSOC), however, their role in recurrent ovarian cancer is largely unknown. We therefore systematically investigated TIL densities and MHC class I and II (MHC1, 2) expression in the progression of HGSOC., Experimental Design: CD3+, CD4+, CD8+ TILs and MHC1, 2 expression were evaluated by immunohistochemistry on tissue microarrays in 113 paired primary and recurrent HGSOC. TILs were quantified by image analysis. All patients had been included to the EU-funded OCTIPS FP7 project., Results: CD3+, CD4+, CD8+ TILs and MHC1 and MHC2 expression showed significant correlations between primary and recurrent tumor levels (Spearman rho 0.427, 0.533, 0.361, 0.456, 0.526 respectively; P<.0001 each). Paired testing revealed higher CD4+ densities and MHC1 expression in recurrent tumors (Wilcoxon P=.034 and P=.018). There was also a shift towards higher CD3+ TILs levels in recurrent carcinomas when analyzing platinum-sensitive tumors only (Wilcoxon P=.026) and in pairs with recurrent tumor tissue from first relapse only (Wilcoxon P=.031). High MHC2 expression was the only parameter to be significantly linked to prolonged progression-free survival after first relapse (PFS2, log-rank P=.012)., Conclusions: This is the first study that analyzed the development of TILs density and MHC expression in paired primary and recurrent HGSOC. The level of the antitumoral immune response in recurrent tumors was clearly dependent on the one in the primary tumor. Our data contribute to the understanding of temporal heterogeneity of HGSOC immune microenvironment and have implications for selection of samples for biomarker testing in the setting of immune-targeting therapeutics., (Copyright © 2018. Published by Elsevier Inc.)

Background: Inflammation and microvascular dysfunction (MVD) are independently associated with adverse cardiovascular outcomes in patients with ischemic heart disease. This study aimed to assess the relationship between inflammation, MVD, and myocardial injury., Methods: Coronary microvascular function was assessed in 74 patients undergoing percutaneous coronary intervention (PCI) using the index of microvascular resistance (IMR) by a pressure-temperature sensor-tipped wire. Serum high-sensitivity C-reactive protein (hsCRP) level was quantified by rate turbidimetry. Severe MVD was defined as IMR ≥ 30. Pearson correlation was computed to assess the relationships between hsCRP, troponin, and IMR of culprit vessel. Predictors of severe MVD were assessed by regression analysis., Results: Acute coronary syndromes (ACSs) represented 49% of the total cohort. Study cohort was divided into low C-reactive protein (CRP) (hsCRP < 3 mg/L) and high CRP (hsCRP ≥ 3 mg/L) groups. There was higher representation of smokers (78 vs. 52%), diabetics (39 vs. 18%), and ACS (61 vs. 33%), as well as higher body mass index (29.4 ± 4.6 vs. 27.2 ± 4.1) in the high CRP group. Pre-PCI and post-PCI IMR were significantly elevated in the high CRP group compared to the low CRP group (pre-PCI IMR: 29.0 ± 13.9 vs. 17.4 ± 11.1, p  < 0.0001; post-PCI IMR: 23.0 ± 16.8 vs. 15.5 ± 8.4, p  = 0.02). Peak troponin levels were significantly raised in the high CRP group (9.96 ± 17.19 vs. 1.17 ± 3.00 μg/L, p  = 0.002). There was a strong positive correlation between hsCRP and pre-PCI IMR ( r  = 0.85, p  < 0.0001). Pre- and post-PCI IMR levels were correlated with peak troponin level ( r  = 0.45, p  < 0.0001; r  = 0.33, p  = 0.005, respectively). Predictors of severe MVD include male gender (OR 3.0), diabetes (OR 3.7), smoking history (OR 4.0), ACS presentation (OR 8.5), and hsCRP ≥ 3 mg/L (OR 5.6)., Conclusion: hsCRP is a significant predictor of MVD while MVD is associated with myocardial injury, supporting the central role of inflammation and MVD in the pathophysiology and complications of coronary artery disease., Clinical Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN): 12617000648325. Universal Trial Number (UTN): U1111-1196-2246.

Blunt force impacts to the head and the resulting internal force transmission to the brain and other cranial tissue are difficult to measure. To model blunt force impact scenarios, the compressive properties resembling tissue elasticity are of importance. Therefore, this study investigated and compared the elastic behavior of gelatin, alginate, agar/glycerol and agar/glycerol/water simulant materials to that of porcine brain in a fresh and unfixed condition. Specimens, 10 × 10 × 10mm 3 , were fabricated and tested at 22°C, apart from gelatin which was conditioned to 4°C prior to testing. For comparison, fresh porcine brains were sourced and prepared to the same dimensions as the simulants. Specimens underwent compression tests at crosshead displacement rates of 2.5, 10 and 16mms -1 (equivalent to strain rates of 0.25, 1 and 1.6s -1 ), obtaining apparent elastic moduli values at different strain rate intervals (0-0.2, 0.2-0.4 and 0.4-0.5). The results of this study indicate that overall all simulant materials had an apparent elastic moduli similar in magnitude across all strain ranges compared to brain, even though comparatively higher, especially the apparent elastic moduli values of alginate. In conclusion, while agar/glycerol/water and agar/glycerol had similar apparent elastic moduli in magnitude and the closest apparent elastic moduli in the initial strain range (E 1 ), gelatin showed the most similar values to fresh porcine brain at the transitional (E 2 ) and higher strain range (E 3 ). The simulant materials and the fresh porcine brain exhibited strain rate dependent behavior, with increasing elastic moduli upon increasing loading velocities., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: In 75% of ovarian cancer patients the tumor mass is completely eradicated by established surgical and cytotoxic treatment; however, the majority of the tumors recur within 24 months. Here we investigated the role of circulating tumor cells (CTCs) indicating occult tumor load, which remains inaccessible by established diagnostics., Experimental Design: Blood was taken at diagnosis (baseline samples, n = 102) and six months after completion of adjuvant first-line chemotherapy (follow-up samples; n = 78). CTCs were enriched by density gradient centrifugation. A multi-marker immunostaining was established and further complemented by FISH on CTCs and tumor/metastasis tissues using probes for stem-cell like fusion genes MECOM and HHLA1., Results: CTCs were observed in 26.5% baseline and 7.7% follow-up blood samples at a mean number of 12.4 and 2.8 CTCs per ml blood, respectively. Baseline CTCs indicated a higher risk of death in R0 patients with complete gross resection (univariate: HR 2.158, 95% CI 1.111-4.191, p = 0.023; multivariate: HR 2.720, 95% CI 1.340-5.522, p = 0.006). At follow-up, the presence of CTCs was associated with response to primary treatment as assessed using RECIST criteria. Chromosomal gains at MECOM and HHLA1 loci suggest that the observed cells were cancer cells and reflect pathophysiological decisive chromosomal aberrations of the primary and metastatic tumors., Conclusions: Our data suggest that CTCs detected by the multi-marker protein panel and/or MECOM/HHLA1 FISH represent minimal residual disease in optimally debulked ovarian cancer patients. The role of CTCs cells especially for clinical therapy stratification of the patients has to be validated in consecutive larger studies applying standardized treatment schemes., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.