Staphylococcus aureus (S. aureus), most frequently detected in DFI, recently was suggested as an intracellular pathogen that can invade and survive within mammalian host cells. Autophagy in macrophages plays a vital immune role in combating intracellular pathogens through bacterial destruction, but there is a lack of empirical research about the infection characteristics and autophagy in diabetic skin infection.Diabetic foot ulcer infection (DFI) is an infectious disease of the skin and soft tissue in diabetics notorious for making rapid progress and being hard to cure. S. aureus clearance ability and wound healing in vitro. Western blot and immunofluorescence staining were used to evaluate the autophagic flux of the macrophages in diabetic rats dermis, even with S. aureus infection.Here, we used streptozotocin‐induced Sprague Dawley rats as a diabetic skin wound model to examine the We demonstrated that infections in diabetic rats appeared more severe and more invasive with weakened pathogen clearance ability of the host immune system, which coincided with the suppressed autophagic flux in dermal macrophages, featured by a significant increase in endogenous LC3II/I and in p62.S. aureus, which weakens the intracellular killing of S. aureus, potentially worsens the infections, and accelerates the infection spread in the diabetic rat model. Further understanding of the special immune crosstalk between diabetes host and S. aureus infection through autophagic factors will help to explain the complex clinical phenomenon and guarantee the development of effective therapies for diabetic foot infections.Our results first provided convincing evidence that autophagy of macrophages was dysfunctional in diabetes, especially after being infected by  Staphylococcus aureus (S. aureus), which weakens the intracellular killing of S. aureus, potentially worsen the infections, and accelerates the infection spread in the diabetic rat model.Infections in diabetic rats appeared more severe and more invasive with weakened pathogen clearance ability of the host immune system, which coincided with the suppressed autophagic flux in dermal macrophages, featured by a significant increase in endogenous LC3II/I and in p62. Our results provided convincing evidence that autophagy of macrophages was dysfunctional in diabetes, especially after being infected by  Recently, a new contribution in immune response for several populations of cells residing in different layers of the skin has emerged. The immune system within the skin is located in both major structural compartments, the epidermis and dermis, and consists of several important types of immune‐competent cells.Xenophagy plays an essential role in host defense against invading pathogens,S. aureus in DFI,S. aureus in diabetic rat skin infection to investigate DFU infection characteristics, and examined the autophagic flux in diabetic rats' infected wound skin and dermis macrophages, tried to investigate the potential relationship between the autophagy and the unique infection characteristic in diabetics. And we showed that the diabetic rats appeared to have similar features as the diabetic patients in the clinic after wound infection, including defective bacteria clearance ability, more invasive infection, and more chronic wounds. Besides this, the overall situation (weight and blood glucose) of the diabetic rats obviously worsened after infection with S. aureus, while there were no differences in the normal rats. Furthermore, we found that S. aureus infection can trigger the autophagy of skin macrophages in both the normal and diabetic rats, however, the autophagic flux was blocked in the diabetic rats, which could play an important role in the bacterial internalization. Ongoing analysis of autophagy in the intracellular bacterium infection in diabetes will increase our knowledge about the inner immune response to the infection of DFU.Our in vitro study found that advanced glycation end products (AGEs), a set of adducts formed on proteins by glycation with reducing sugars such as glucose in diabetics, impaired autophagic flux of the host macrophages by inducing autophagosome formation but blocking the autophagosome‐lysosome fusion, which diminished intracellular bactericidal capability of macrophages, and is likely to increase the invasiveness of 22.1S. aureus strain NCTC8325 was kindly provided by Dr. Wenjiao Chang (USTC). Bacteria were grown overnight at 37°C in Luria‐Bertani broth (Huankai). The optical density at 600 nm of bacterial cultures was measured to determine growth curves.Monoclonal rabbit anti‐beta‐actin (ab8227), anti‐CD68 (ab125212), and monoclonal mouse anti‐LC3B (ab63817) were obtained from Abcam. Monoclonal mouse anti‐P62 (AF5384), goat antimouse immunoglobulin G (IgG) (H+L) horseradish peroxidase (HRP) (S0002), goat antirabbit IgG (H+L) HRP (S0001) were obtained from Affinity Biosciences. Cy3‐AffiniPure Goat antimouse IgG (H+L) (33208ES60), FITC‐AffiniPure Goat antimouse IgG (H+L) (33208EA33), and 4′,6‐diamidino‐2‐phenylindole  were obtained from Yeasen. 2.2n = 18), normal + infection (n = 18), diabetic (n = 18), or diabetic + infection (n = 18) groups by body weight. Diabetic groups were given streptozotocin  injections and infection groups were inoculated with NCTC8325. After STZ injection, the blood glucose of tail vein was monitored with a blood glucose meter (Omron) once a week. STZ‐treated rats were considered to be diabetic when the concentration of blood glucose was equal to or higher than 16.7 mmol/L. The dorsal skin was shaved, treated with depilatory cream to remove hair, and then cleaned with a povidone‐iodine solution followed by an alcohol wipe. One circular, full‐thickness wound was created on the dorsal skin of each rat using a 10 mm biopsy punch. S. aureus NCTC8325 (5 × 108 colony‐forming units [CFUs]) was applied to wounds of infected group animals, which were then covered with sterile gauzes and fixed with the sterile band. Rats were placed on a warming pad (37°C) until they fully recovered from surgery and were then re‐caged. On postoperative day (POD) 0, 4, 7, and 10 images of wounds with a ruler (six rats per time point per group) were collected by the camera , and the wound area was analyzed by ImageJ. Wound healing rates were calculated according to the formula (wound area [POD 0] − wound area [POD N])/wound area (POD 0). Skin wound granulation tissue, liver, kidney, lung, and serum were isolated from rats as previously described. All the tissues were divided into three parts, then were frozen in liquid nitrogen or fixed in 4% formaldehyde, used to extract total protein or tissue stain respectively. White blood cell counts (WBC) were determined in whole blood. Finally, rats were anesthetized.Animal experimental procedures were undertaken according to the protocols of the Guangdong Academy of Medical Sciences. Seventy‐two Sprague Dawley rats were allocated randomly into normal . After 48 h culture at 37°C and 5% CO2, two operators used ImageJ (version 1.36b) to count the colonies on the TSA plate under the premise of double‐blind, and the results were taken as the average. For tissue culture, fresh tissue soaked in sterile PBS was dried with the sterile filter paper, then were weighed and recorded. The tissue was homogenized with a hand‐held electric homogenizer (Kimble), and then resuspended with 1 ml sterile PBS for homogenization, following by continuous dilution with sterile PBS in turn to make a series of diluted bacterial solutions of 10−2, 10−3, and 10−4. Within 20 min, 1 ml of tissue homogenate was incubated to the TSA and cultured as the swab culture. Populations of different bacterial species were differentiated by colony color, shape, and size and then confirmed by biochemical methods.At specific postinfection time points, bacteria were collected by rolling sterile swabs on the whole wound surface five times and then eluting in 1 ml of sterile phosphate‐buffered saline (PBS). Equal weights of wound tissue, the muscle under the wound, liver, kidney, and lung tissue were isolated and homogenized in 1 ml of sterile PBS. The swab elutions and tissue homogenates were then serially diluted in PBS and plated on tryptose soya agar (TSA) to determine the tissue bacterial burden.2.4Tissue fixed by 4% formaldehyde was loaded by paraffin and sectioned with a thickness of 4 μm perpendicular to the head and tail axis and the skin surface, and baked at 60°C for 2 h to prevent paraffin flakes from falling off. After dewaxing by xylene, gradient alcohol dehydration , hematoxylin staining for 5–6 min, following by adequate washing, eosin staining for 2–3 min, washing with 70% alcohol until the color is moderate under the microscope. Go through radiant alcohol dehydration, xylene transparent, neutral resin after drying, finally cover the histological slides of tissue samples with slide seal, and observe with an optical microscope.2.5Tissue samples were treated with lysis buffer contained phenylmethylsulfonyl fluoride after PBS washing. For Western blot, the tissue lysates were resolved by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes probed with anti‐LC3 (1:1000) and p62 (1:1000) monoclonal antibodies. After combination with the secondary antibodies (1:5000), the primary antibody's immunoreactive bands were detected by enhanced chemiluminescence, and signal values were normalized to the internal control (β‐actin).2.6Immunofluorescence staining was performed to analyze the colocalization of LC3, p62, and CD68. Paraffin sections of skin tissue were stained with primary antibodies recognizing LC3 (1:1000), p62 (1:1000), or CD68 (1:500). After washing with PBS, the binding of the primary antibodies was revealed by Cy3‐AffiniPure Goat antimouse IgG (H+L) and FITC‐AffiniPure Goat antimouse IgG (H+L) and confocal laser scanning microscopy. CD68‐positive staining emitted bright green fluorescence, and LC3‐ or p62‐positive staining emitted red fluorescence. Nuclei were stained with DAPI. Controls for antibody specificity were included in all experiments; the primary antibody was replaced with PBS.2.7SD). All experiments were repeated at least three times. Statistical analysis was performed with SPSS v20.0 (IBM). Student's t‐test and one‐way analysis of variance were used to analyze the differences in between‐group comparisons and multiple comparisons, especially. A two‐tailed p < .05 was considered significant.Results are presented as the mean ± standard deviation  and POD 10  after infection. Compared with the noninfected group, bodyweight of infected diabetic rats was decreased significantly on POD 10 .Bodyweight and blood sugar were the main indexes to evaluate the overall situation of diabetic rats. As Figure p > .05) between normal rats and diabetic rats in WBC when there was no infection. However, the WBC change trends appeared different between the two groups after S. aureus infection. For the normal rats, WBC showed a significant increase at the earlier stage (POD 4) . But for the diabetic rats, the WBC peak appeared later, (10.78 ± 3.13) × 109/L for infection versus (7.63 ± 2.09) × 109/L for noninfection on POD10 (p < .05). Additionally, WBC of the rats with deep invasion and distant organ spread infection was significantly higher than that of the ones without spread  but significantly delayed the wound healing of diabetic rats.As per expectation, the skin wounds of diabetic rats were more difficult to heal compared with normal ones，with or without infection. After n Figure . S. aurep > .05); but at the late stages (POD 7 and POD 10), S. aureus infection significantly reduced the wound healing rates of diabetic rats, respectively 64.50 ± 9.00% for noninfection versus 36.00 ± 6.46% for infection (p < .05) on POD 7 and 81.20 ± 1.06% for noninfection versus 47.55 ± 2.41% for infection (p < .05) on POD 10. In normal rats, S. aureus infection had no significant impact on wound healing (p > .05). With infection, 83.33% (5/6) of the wound area was closed at the end of observation in the normal rats, while none (0/6) was closed in the diabetic rats . Further on POD 10, the increasing multiple rose to 138.66 times (p < .01). Wound tissue culture showed similar results. On POD 4, 7, and 10, the tissue bacteria burden of diabetic rats was significantly higher, respectively 2.35, 2.63, and 645.50 folds of the normal ones (p < .01). In addition, the changing trend of bacteria load in diabetic and normal rats appeared obviously different. The bacterial burden in the wound of normal rats decreased gradually with infection time, while the diabetic rats showed the opposite trend. The bacterial load of diabetic rats on POD 10 was 1.87 times (for wound surface) and 2.85 times (for wound tissue) higher than that on POD4, respectively.The results of swab culture showed that the wound surface bacteria burden of diabetic rats on POD 7 was 73.54 times of the normal ones ([2.89 ± 0.06] × 10S. aureus infections (8.00 ± 0.67 CFU/100 mg tissue), five kidney S. aureus infections (8.33 ± 4.06 CFU/100 mg tissue) and two lung S. aureus infections  and one was normal (1/18). Five rats suffered from hematogenous spread infection to distant organs, all of which were diabetic rats, including two liver 3.4As autophagy is the predominant way to clear intracellular pathogens, we examined LC3‐II and P62 expression to evaluate autophagy levels in the infected rat skin. In contrast to normal rats, the significant accumulation of LC3‐II and decreased P62 in wounded, noninfected diabetic rat skin on POD 4 and POD 7 indicated autophagy was triggered, and the autophagic flux was continuous , and meant that infection can trigger autophagy of dermis macrophages in diabetic rats  secondary to skin infection occurred in diabetic rats, and the kidney is the most susceptible organ. These results indicated that the immune cell of diabetic rats could not kill or limit S. aureus effectively like the normal rats, causing infection to become more aggressive.Diabetic rats showed delayed wound healing, worsened overall situation, defective pathogen clearance, with increased invasiveness of the infections, which coincided with the DFI patients in the clinic.Besides this, some interesting change trends after infection were found in this model. To the normal rats, WBC in peripheral blood rose at a very early stage and reached the peak rapidly, which ensured fighting the pathogens in time. On the other hand, the bacteria burden in the wound decreased with the infection time, without antibacterial therapy, and the infection did not delay wound healing. Unfortunately, the diabetic rats showed a WBC increase at a very late stage, consequently the continuously increasing bacterial burden and significantly delayed healing. The results indicated that delayed inflammatory response and deficiency of professional immune cells could cause the impaired bacteria killing in DFI.Macrophages are the predominant resident professional immune cells in the dermis,Wound healing is a complex process that depends on multiple factors, such as extracellular matrix, cytokines, inflammatory cells, and repair cells, highly coordinated in space and time. Autophagy affects wound healing over the whole procedure. In the early inflammatory phase, autophagy of the skin cells helps to eliminate pathogens in the wound by the xenophagy pathway, meanwhile, downregulates the inflammatory response to prevent tissue damage caused by excessive inflammation. In the following process of wound angiogenesis, autophagy can affect angiogenesis through multiple hypoxia signal pathways; however, excessive autophagy can lead to autophagic death of constituent cells in this procedure.Some researchers found that the autophagic flux in diabetic animal models were abnormal. Wang et al.The deficiency of host professional immune cells' intracellular bacteria‐killing ability promotes pathogen intracellularity, which plays a crucial role in the infection spreading and invasion. Selective autophagy of macrophages acts as an innate immune defense mechanism and a direct antimicrobial mechanism.The autophagy process can be divided into three steps: autophagosomes formation, autolysosomes formation, and degradation. Briefly, when autophagy was triggered, the LC3‐II wound is raised to structure the biomembrane vesicles “autophagosomes” to enclose the pathogens first; second, after the autophagosomes fused with lysosomes to form autolysosome and finally the contents were degraded in the autolysosome, and meanwhile, p62 wound decrease. This whole process was called autophagic flux.S. aureus infection further triggered the autophagy, but the p62 did not decline like that in an intact autophagic flux, instead of an obvious increase. That indicated some mistake existed in the fusion or degradation step. That would not only cause the S. aureus in the autophagosomes to avoid being killed but also be protected by this biomembrane vesicle to reproduce, invade, and disseminate. This can be explained by our published research results in vitro, which revealed that AGEs impaired the host macrophages' autophagic flux via elevating lysosomal Arl8 level in macrophage, a key negative regulator in perinuclear positioning of lysosomes when autophagosome‐lysosome fuse, finally inducing autophagosome formation but inhibiting the autolysosome formation.In this study, we observed that autophagy activation already existed in diabetic rats' skin, especially with wounds, coincident with the previous study. The S. aureus was an extracellular infection, but recent research suggested that S. aureus is a facultative intracellular pathogen, which can survive in host cells that make the infection more invasive.S. aureus strains were shown to subvert host autophagy by triggering autophagosome formation while inhibiting the fusion of phagosomes with lysosomes, creating a protective niche for intracellular bacteria to grow and escape from the infected cells.S. aureus, their growth phase at the time of infection, as well as MOI during the infection.It was once believed that S. aureus impaired autophagic flux in the diabetic host macrophages by inducing autophagosome formation but blocking the subsequent course. The exact relationship and underlying mechanisms of impairment of autophagy and infection characteristics of DFI are still unclear.S. aureus infection through autophagic factors will help to explain the complex clinical phenomenon and guarantee the development of effective therapies for DFIs.In conclusion, our data showed that it is featured by delayed wound healing, defective pathogen clearance, increased invasiveness of the infections in the STZ rat skin wound infection model, and Chaohui Duan, Li Yan, and Xiaoying Xie contributed to the design of the study and the writing of the manuscript. Rihui Zhong, Ling Luo, and Xianghua Lin performed animal experiments. Lisi Huang, Songyin Huang, Lijia Ni, Baiji Chen, and Rui Shen assisted with molecular experiments, image processing, and quantitative data collection. All authors read and approved the final version of the manuscript.The author declares that there are no conflict of interests.Animal experimental procedures were undertaken according to the protocols of the Guangdong Academy of Medical Sciences.Supporting information.Click here for additional data file.


Oncologists are at an increased risk of developing burnout, leading to negative consequences in patient care and in professional satisfaction and quality of life. This study was designed to investigate exhaustion and disengagement among German oncologists and assess the prevalence of burnout among oncologists within different professional settings. Furthermore, we wanted to examine possible relations between sociodemographic factors, the oncological setting, professional experience and different aspects of burnout.Arbeitsgemeinschaft Internistische Onkologie) within the German Cancer Society.In a cross-sectional study design, an Internet-based survey was conducted with 121 oncologists between April and July 2020 using the Oldenburg Burnout Inventory, which contains items on exhaustion, disengagement, and burnout. Furthermore, sociodemographic data of the participants were assessed. The participants were members of the Working Group Medical Oncology (The survey showed a burnout prevalence of 43.8%, which correlated with age and professional experience; that is, the prevalence is particularly high among younger oncologists. Exhaustion is closely related to employment status; that is, it was significantly higher among employed oncologists. There were remarkably low levels of disengagement among oncologists, highlighting the own demand to fulfil job requirements despite imminent or actual overburdening in daily work.More support is necessary to mitigate the professional stressors in the healthcare system. To ensure quality medical care, employees should be offered preventive mental health services early in their careers. Since the second half of the last century, burnout among healthcare workers in hospitals has been becoming the focus of health psychology and occupational medicine research. Compared with the general population, health care professionals are at an increased risk of developing symptoms of burnout ) within the German Cancer Society were asked via email to participate in an Internet-based survey. The inclusion criteria were a minimum age of 18 years and a medical practice with patients with cancer. This cross-sectional study, platform provided by SoSci Survey, was open for 3 months from April to July in 2020. The access was only possible using a hyperlink sent in an email circular sent to all AIO members. Participation in the survey was voluntary and anonymous. The manuscript was prepared according to the Strengthening the Reporting of Observational Studies in Epidemiology statement criteria —on a 5-point Likert scale (1 = “strongly disagree” to 5 = “strongly agree”). Four items of each subscale were inverted. The exhaustion dimension (OLBIexh) refers to the “general feelings of emptiness, overtaxing from work, a strong need for rest and a state of physical exhaustion” (Demerouti and Bakker EE) surveys only affective aspects. Depersonalization (MBIDP) refers to distancing from a beneficiary and is only one aspect of the disengagement scale (OLBIdis). OLBIdis refers to “distancing oneself from one’s work and the associated attitudes and attitudes toward work, to negative cynical attitudes and behaviors toward one’s work in general” . The last issue in particular seemed crucial, as work-related attitudes are predictors of job performance (Hettiararchchi and Jayarathna The 16-item Oldenburg Burnout Inventory (OLBI) (Demerouti and Bakker p < 0.01) for healthcare workers with mean levels of exhaustion (M = 2.53) and disengagement (M = 2.38) ) were assessed, including the estimated proportion of total working time, proportion of inpatient work, working hours with tumor patients and the estimated proportion of working time with palliative patients.Furthermore, sociodemographic data, profession, medical field, professional experience, workplace, and employment status, board certification, work on inpatient palliative care unit (PCU) and participation in an outpatient palliative care team  was used to determine the risk of burnout. For all tests, p-values of less than 0.05 were used to indicate statistical significance. Analyses were done using Statistical Package for the Social Sciences, version 27 .To evaluate exhaustion, disengagement, and burnout among German oncologists, absolute and relative frequencies for categorical data, mean values, standard deviation, and range for continuous variables were calculated. Participants whose data were incomplete were nevertheless included, as the missing data only included some sociodemographic data. First, we used one-way analysis of variance (ANOVA) as an alternative to Informed consent was obtained from all participants. Ethical Approval was received on September 2019 from the Ethical Committee of the Medical Faculty in Heidelberg (S-615/2019). The study was registered to the German Clinical Trials Register (DRKS500018851).n = 80, 66%), reflecting the majority of AIO members  as well as the majority of German oncologists . Professional experience varied widely between 2 and 49 years  = 15–29 years). Moreover, 113 (94.9%) physicians had a board certification in hemato-oncology. The participants worked on average 82.40% ± 17.13%  of their time with patients with tumor. Twenty-one (17.4%) physicians worked within a PCU, spending 27.81% ± 24.11% (range 6–81%) of their working time, whereas 11 (9.1%) physicians participated in an outpatient palliative care team (SAPV), accounting for 11.64% ± 8.51% (range 2–34%) of their working time. Absolute and relative frequencies are shown in Table Approximately 1400 physicians were contacted, among whom 121 participated, which corresponds to a response rate of 8.64%. The mean age was 50.28 ± 9.32 years . This corresponds to the distribution of all age groups of AIO members  and represents the biggest age cohort of physicians, board certified in internal medicine in Germany   and hospital employees  . To evaluate the disengagement scale, the range of values was divided into three parts and designated as low (< 1.63), medium (1.63–2.24) and high (> 2.24). Moreover, 60 (49.59%) physicians showed low disengagement , 46 (38.02%) showed medium disengagement  and 15 (12.40%) showed high disengagement . High disengagement was mainly related to men  of the total sample had burnout. Focusing on the more specific exhaustion scale with a cutoff of MExh > 2.5, 53 (43.8%) physicians showed increased values in the exhaustion scale as a hint for suffering from burnout.Based on a cutoff of Mr =  − 0.183, p < 0.01); that is, the older the physician, the less exhaustion. Using a cutoff at the highest quartile (P75), physicians older than 57 years (n = 31) have significantly lower values (mean = 2.09 ± 0.94) on the exhaustion scale than physicians younger than 57 years  (t(119) =  − 2,581; p < 0.05).Pearson’s correlation coefficients showed a significant negative correlation between age and exhaustion . Kendall’s Tau showed a significant negative correlation between professional experience and exhaustion ; that is, the less work experience, the greater the exhaustion. Pearson’s chi-square test confirmed an association between professional experience of less than 20 years with burnout (MExh ≥ 2.5): χ2(1) = 5.176; p < 0.05, φ = 0.209. The risk of burnout among physicians with a professional experience of less than 25 years  was thrice higher than that among physicians with a professional experience of at least 25 years   . The difference in exhaustion between employed (mean = 2.415 ± 0.582) and self-employed (mean = 2.08 ± 0.60) physicians was significant (t(119) = 2.576; p < 0.05), suggesting that employed physicians describe themselves as more exhausted than self-employed colleagues. The comparison of the mean values of exhaustion showed a significant difference (t(114) = 2.115; p < 0.05) between physicians treating less than 30% of inpatients  and physicians treating more than 30% of inpatients (mean = 2.45 ± 0.609). Moreover, 35 (32.4%) employed and seven (9.6%) self-employed physicians showed signs of burnout; the relative risk was insignificant.Pearson’s correlation coefficients showed a slightly positive correlation between employment status and exhaustion  with a mean age of 52.82 ± 5.741 years (range 41–60 years) and a professional experience between 5 and 34 years . They were predominantly hemato-oncology specialists , self-employed in oncological joint practice  or employed in a hospital  and predominantly did not work in an inpatient PCU . Physicians additionally working in inpatient palliative care settings (n = 4) on average worked 48.25% ± 34.40% (range 4–81%) of their time on PCUs.Physicians participating in an outpatient palliative care team (SAPV) were predominantly male ; that is, the higher the percentage of working time in SAPV was, the higher the level of exhaustion was.Pearson’s correlation coefficients were calculated to evaluate the correlation between exhaustion and the percentage of engagement in an outpatient palliative care team (SAPV). The results showed a strongly positive correlation   among oncologists than in other medical disciplines  KV . This isHowever, this survey has several limitations. First, the number of physicians that responded was limited; physicians with a higher symptom load might have reported at a higher frequency, leading to an overestimation of the prevalence of burnout, though the prevalence of burnout reported here is in line with data published.Second, since the participants were members of a professional society, the work demands, and job characteristics might not reflect clinical routine in Germany. Third, since this survey was conducted in summer 2020 after the first peak of the coronavirus disease 2019 (COVID-19) pandemic, additional stressors associated with this might have influenced the results of this survey. In contrast, during the survey running, the incidence rates of COVID-19 were low in Germany with only few major structural issues occurring in hospitals. The main limitation of this study is related to its cross-sectional design, which does not allow either temporal or causal inferences. Further investigations with consecutive measurements are required to obtain a more detailed understanding of burnout among oncologists.This survey highlights a high rate of exhaustion among German oncologists, with a focus on professional burden during the early years of career. More support is necessary to mitigate potential stressors for medical personnel within the healthcare system. To ensure high-quality medical care, physicians should be offered preventive mental healthcare services early in their careers.


Here, we report a case of a patient who presented to Strong Memorial Hospital with new-onset renal failure and anemia and was found to have multiple myeloma with lambda light-chain cast nephropathy secondary to a very large (14 cm × 14 cm × 12 cm) plasmacytoma without bone marrow involvement. This case is notable as solitary plasmacytomas are almost never seen with concomitant myeloma-defining CRAB criteria or significantly elevated serum free light-chain ratios. Although solitary plasmacytomas are typically definitively treated with radiation, this case highlights that systemic treatment may be helpful in certain clinical scenarios. Multiple myeloma is a plasma cell dyscrasia characterized by clonal plasma cells >10% on bone marrow biopsy or the presence of a plasmacytoma in the setting of clinical features known as “CRAB criteria,” which include hypercalcemia, renal insufficiency, anemia, or the presence of lytic bone lesions –8. A sinth rib. The patient denied any pulmonary symptoms.A 57-year-old male with a past medical history significant for papillary thyroid cancer treated definitively with thyroidectomy presented to his primary care physician with progressive fatigue, headache, and abdominal cramping. He reported dramatically decreased urine output starting two days prior to presentation, despite aggressive hydration. Initial workup revealed a markedly elevated creatinine level at 4.68 mg/dL. The patient had no prior history of kidney disease. His last known creatinine level, obtained 8 months prior, was 1.04 mg/dL. Initial laboratory studies also revealed new mild anemia with a hemoglobin level of 11.1 g/dL. He was sent to the emergency department for further evaluation. Additional lab studies on presentation revealed worsening renal function with a creatinine level of 7.72 mg/dL and hyponatremia with sodium of 127 mmol/L and normal serum osmolality of 285 mOsm. The 24-hour urine protein level was 750 mg. Renal ultrasound showed no evidence of hydronephrosis and normal-sized kidneys (11.4 cm for the R kidney and 12.3 cm for the L kidney). A chest X-ray was obtained due to decreased right-sided breath sounds on exam, which showed a large right hemithorax opacification. Follow-up CT chest revealed a 14.0 × 14.0 × 12.0 cm mass in the lower lobe of the right lung  as well 2 orally on days 1, 8, and 15), bortezomib , and dexamethasone  (CyBorD) chemotherapy as well as plasmapheresis. Biopsy of the lung mass was performed, and the pathology was consistent with plasmacytoma, with lambda-restricted clonal plasma cells  daratumumab 1800 mg weekly was added, which resulted in a marked decrease in his lambda FLC level to 5 mg/dL. He was referred to radiation oncology for treatment of the plasmacytoma and underwent external beam radiation therapy (EBRT) with 52.2 Gy delivered in 29 fractions. Following radiation, his lambda FLC completely normalized. His therapy was de-escalated to dexamethasone 40 mg PO monthly and daratumumab 1800 mg SC monthly. He has remained stable on this regimen with no biochemical evidence of recurrence at the time of this report. A repeat PET/CT showed a further decrease in the size of the mass, measuring approximately 8.8 cm × 6.7 cm without significant SUV uptake, consistent with treatment response.In the outpatient setting, the patient achieved at least a very good partial response (VGPR) with continued chemotherapy. The patient's kidney function continued to improve, and he was able to discontinue dialysis within one month of initiation, although his kidney function did not recover to his previous baseline. Positron emission tomography/computed tomography (PET/CT) scan performed after one cycle of chemotherapy did not show any evidence of osseous disease or additional plasmacytomas. A repeat chest CT after 4 cycles of treatment demonstrated an interval decrease in the size of the plasmacytoma to 13.0 × 11.0 × 10.0 cm. Due to the development of mild neuropathy and a relative plateau in levels of FLC, his chemotherapy was switched to lenalidomide 10 mg orally (PO) for 21–28 days, bortezomib 1.3 mg/mth rib lytic lesion and invaded the lung. The rib lesion was not hypermetabolic on PET/CT, which has high sensitivity and specificity in this setting [In this report, we describe a patient who presented to our institution with new-onset renal failure due to biopsy-proven light-chain cast nephropathy from multiple myeloma secondary to a very large plasmacytoma. It is not clear whether this plasmacytoma was extramedullary or whether it initially arose from the patient's right 11 setting , and it Regardless of the plasmacytoma's origin, this appears to be the first case reported of a large plasmacytoma without marrow involvement, fulfilling the International Myeloma Working Group definition of multiple myeloma  by the cSolitary plasmacytomas with little or no bone marrow involvement do not normally result in light-chain cast nephropathy. While many patients with solitary plasmacytoma have a detectable serum monoclonal protein, the median M spike was 0 g/dL and 0.5 g/dL in two case series , 18. AppTypically, solitary plasmacytomas, with or without the presence of bone marrow involvement, can be treated definitively with radiotherapy , 23. ThiIt is possible that the patient's disease could have been controlled with radiotherapy alone. However, recent studies have found a significant benefit to systemic therapy for solitary plasmacytoma, with significantly lower rates of progression to multiple myeloma , 27. Fur


There are few reports regarding the influence of varying illumination on the compensation effect before and after corneal refractive surgery. We aimed to evaluate the changes in refraction, higher-order aberrations, and aberration compensation between mesopic and photopic illumination before and after small incision lenticule extraction.In this prospective cohort study, only the right eyes of patients who underwent small incision lenticule extraction for the correction of myopia and myopic astigmatism at the Tianjin Eye Hospital were included. Wavefront refraction and higher-order aberrations were measured preoperatively and 3 months postoperatively under mesopic and photopic illumination. Compensation factors were calculated as 1 − .t = − 4.589, p < .001) spherical refractive error under mesopic vs. photopic illumination , whereas postoperatively, the eyes also exhibited statistically significantly higher  astigmatism (− 0.608 [0.414] vs. − 0.382 [0.319] D). Differences in spherical refraction between the two illuminations were the highest in postoperative eyes (Δ > 0.5 D). Only postoperative eyes exhibited statistically significant elevations  in higher-order aberrations under mesopic illumination, and only preoperative eyes exhibited statistically significantly enhanced  and decreased  compensation factors under mesopic illumination.Forty patients undergoing small incision lenticule extraction were enrolled. All surgeries were completed without postoperative complications. Preoperatively, the eyes only had a statistically significantly higher (Exaggerations in higher-order aberrations and myopic shift after small incision lenticule extraction became apparent under mesopic illumination. Slight undercorrection may have an enhanced effect under low illumination and may reduce night vision. The specific changes in compensation effects in preoperative eyes may improve optical quality under mesopic illumination. Postoperative eyes have reduced compensation ability, specifically for spherical aberrations, under mesopic illumination, which may diminish night vision. Further studies that include the measurement of subjective night vision parameters should be conducted. Corneal refractive surgery is performed worldwide . SatisfaChanges in refraction (lower-order aberrations) and HOAs cause degradation in retinal image quality –8. ThereFurthermore, a compensation effect between the anterior corneal surface and internal ocular optics assists in maintaining stability for optimal optical quality. There is ample evidence for a compensation effect for HOAs in natural eyes , 10. HowThe objective of our current study was to investigate the differences in refraction, HOAs, and compensation for aberrations between mesopic and photopic illumination before and after small incision lenticule extraction (SMILE). To the best of our knowledge, no similar study has been reported to date, and this study may contribute to a better understanding of postoperative night vision after SMILE.The objective of our current study was to investigate the differences in refraction, HOAs, and compensation for aberrations between mesopic and photopic illumination before and after SMILE.This prospective study involved 40 consecutive participants (the right eye of each patient was selected) who underwent SMILE at Tianjin Eye Hospital, Tianjin Medical University, China, for the correction of myopia and myopic astigmatism between June and November 2016. The inclusion criteria were as follows: age ≥ 18 years, stable refraction (a change ≤0.50 diopters [D]) in the past 2 years, discontinuation of soft contact lens use ≥2 weeks and of rigid gas permeable lens use ≥4 weeks, a clear cornea without opacities, central corneal thickness > 500 μm, residual stromal bed thickness > 250 μm, intraocular pressure < 21 mmHg, and no other ocular conditions. The exclusion criteria were keratoconus (verified or suspected) and systemic diseases such as diabetes or connective tissue disease.The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Tianjin Eye Hospital, Tianjin, China (No. 202056). Informed consent was obtained from all participants after thorough explanation of the nature and possible consequences of the procedures were provided.All participants underwent a thorough preoperative eye examination. Routine examinations included uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) examinations, slit lamp microscopy, manifest and cycloplegic refraction, indirect fundoscopy, and tonometry. In addition, wavefront refraction and HOAs were measured both preoperatively and 3 months postoperatively using a wavefront analyzer . UDVA examination, tonometry, and slit lamp microscopy were also examined postoperatively.Regarding surgical planning, as the refractive accuracy achieved using manifest refraction is better than that predicted using wavefront refraction , the forOcular aberrations included corneal and internal aberrations. Corneal topography was performed, and ocular aberrations measured, using the wavefront analyzer. The device was first used to measure corneal and ocular wavefront aberrations along the same axis; using these measurements as reference points, internal aberrations could be calculated accurately in a relatively short amount of time.All measurements were performed in a dark room after 10 min of rest, immediately after the participant blinked to reduce tear film-related HOA deterioration. Measurements were conducted for the right eye only, with an undilated pupil, under quiet conditions. Pupil diameter (mm) was used as a reference for defining mesopic and photopic illumination, as there is an empirical relationship between pupil diameter and illuminance (lx) , 15. MesAll procedures were performed by the same experienced surgeon (Y.W.). Three drops of oxybuprocaine hydrochloride (Benoxil) were applied 3 min before surgery for topical anesthesia. Thereafter, participants were instructed to fixate on a target light to allow the initiation of suction. The surgeon confirmed the alignment of the center of the ablation zone with the center of the pupil. Thereafter, surgery was performed using a 500 kHz VisuMax femtosecond laser , with a laser energy of approximately 170 nJ. The details of the surgical procedure have been previously described . BrieflyPostoperatively, 0.3% ofloxacin (Tarivid) eye drops were instilled four times daily for 3 days, and 0.1% fluorometholone (Flumetholon) eye drops were instilled four times daily for 2 weeks; the dosages were tapered over 2 months (one drop less every 2 weeks).w/c), where w was the aberration of the whole eye, and c the aberration of the anterior corneal surface. The aberration of the whole eye was equal to the aberration of the anterior corneal surface when CF = 0, i.e., when there was no compensation effect by the internal optics. A compensation effect was present when CF > 0. Typically, the aberration of the anterior corneal surface is partially compensated by that of the internal ocular optics (CF ranging from 0 to 1). Additionally, a negative value (CF < 0) indicates augmentation, indicating that the aberration of the whole eye is larger than that of the anterior corneal surface.The compensation factor (CF), as defined by Artal and Guirao , was calK) between the internal ocular optics and the anterior corneal surface appeared as a compensation effect in x eyes and as an augmentation effect in y eyes (x + y = 40). The proportion of eyes that demonstrated a compensation effect for K was calculated as x/40 × 100 (ranging from 0 to 100%). A higher value indicates that K of the internal ocular optics tends to compensate for K of the anterior corneal surface.In the current study, which included 40 eyes, the relationship of a certain HOA , and statistical analysis was performed using IBM SPSS Statistics for Windows . Data normality was examined using the Kolmogorov–Smirnov test. Normally distributed data were described as means ± standard deviations, while non-normally distributed data were described as medians [interquartile ranges]. A two-sample paired Table All surgeries were completed without postoperative complications. At 3 months postoperatively, all 40 (100%) eyes had a UDVA of 20/25 or better. The mean efficacy index at 3 months postoperatively was 0.99 ± 0.11. The CDVA 3 months postoperatively was the same as the preoperative CDVA in 11 (28%) eyes; 16 (40%) eyes gained one line; 10 (25%) gained two or more lines; 3 (8%) lost one line; and none lost two or more lines. The correlation between attempted and achieved refraction was high . All forty (100%) eyes were within 0.5 D of the attempted refraction, and the astigmatism of all 40 (100%) eyes was within 0.5 D at postoperative month 3.t = 27.392, p < .001). As indicated in Table t = − 4.589, p < .001)—natural eyes exhibited a higher spherical refractive error under mesopic illumination than under photopic illumination.The mean preoperative pupil diameter under mesopic and photopic illuminations was 6.90 ± 0.78 and 4.34 ± 0.92 mm, respectively . As indicated in Table t = − 5.853, p < .001; and t = − 3.013, p = .005; respectively). Postoperative eyes exhibited a higher spherical refractive error and astigmatism under mesopic illumination than under photopic illumination.The mean postoperative pupil diameter under mesopic and photopic illumination was 7.01 ± 0.78 and 4.38 ± 0.88 mm, respectively (The pre- and postoperative differences in refraction between mesopic and photopic illuminations are indicated in Table p > .05)—natural eyes did not exhibit more HOAs under mesopic vs. photopic illumination.As indicated in Table p < .001). Postoperative eyes exhibited more HOAs under mesopic illumination than under photopic illumination.As indicated in Table 40, Z3− 1, Z31, Z3− 3, and Z33 between mesopic and photopic illumination were not significant . The preoperative Z40 and Z31 under mesopic and photopic illumination are illustrated in Fig. The preoperative differences in Z3− 1, Z3− 3, and Z33 were not significant . However, as depicted in Fig. 40 and Z31 were observed between mesopic and photopic illumination . Thus, a higher proportion of postoperative eyes exhibited primary spherical aberrations and horizontal coma under mesopic illumination relative to photopic illumination.The postoperative differences in Zχ2 = 6.373, p = .01)—natural eyes exhibited a higher compensation effect for fourth-order aberrations under mesopic illumination than under photopic illumination  , coma (Z3− 1 and Z31), and trefoil (Z3− 3 and Z33). Differences were observed in the preoperative CF distributions for Z40 and Z33 between mesopic and photopic illumination . The preoperative compensation effect for primary spherical aberration was enhanced, whereas that for horizontal trefoil was reduced under mesopic illumination relative to photopic illumination   and subjective night vision parameters need to be investigated, which may help surgeons identify the most important factors affecting postoperative visual quality, as well as determine suitable methods to improve surgical outcomes.The results of the current study illustrate that augmentations in both HOAs and myopic shift become apparent under mesopic illumination after SMILE. Therefore, a slight undercorrection, which is easy to ignore in clinical practice, may have an enhanced effect under low illumination and reduce night vision. Finally, postoperative eyes seem to have a low compensation ability, specifically for spherical aberrations, under mesopic illumination, which may be another reason for the deterioration of night vision. These findings may contribute to the improvement of surgical outcomes.


With the rapid influx of novel anti‐cancer agents, phase I clinical trials in oncology are evolving. Historically, response rates on early phase trials have been modest with the clinical benefit and ethics of enrolment debated. However, there is a paucity of real‐world data in this setting.To better understand the changing landscape of phase I oncology trials, we performed a retrospective review at our institution to examine patient and trial characteristics, screening outcomes, and treatment outcomes.We analyzed all consecutive adult patients with advanced solid organ malignancies who were screened across phase I trials from January 2013 to December 2018 at a single institution. During this period, 242 patients were assessed for 28 different trials. Median age was 64 years (range 30–89) with an equal sex distribution. Among 257 screening visits, the overall screen failure rate was 18%, resulting in 212 patients being enrolled onto a study. Twenty‐six trials (93%) involved immunotherapeutic agents or molecular targeted agents either alone or in combination, with only two trials of cytotoxic agents (7%). Twenty‐two (13.4%) of the 209 treated patients experienced a total of 33 grade 3 or higher treatment‐related adverse events. There was one treatment‐related death (0.5%). Of 190 response‐evaluable patients, 7 (4%) had a complete response, 34 (18%) a partial response, and 59 (31%) experienced stable disease for a disease control rate of 53%. The median overall survival for our cohort was 8.0 (95% CI: 6.8–9.2) months.The profile of phase I trials at our institution are consistent with the changing early drug development landscape. Response rates and overall survival in our cohort are superior to historically reported rates and comparable to contemporaneous studies. Severe treatment‐related toxicity was relatively uncommon, and treatment‐related mortality was rare. A meta‐analysis of phase I trials conducted between 2014 and 2015 demonstrated encouraging response rates of 20%.The American Society of Clinical Oncology recently released a position statement on phase I trials, reiterating that, while remaining an integral part of clinical cancer research, these trials do indeed have therapeutic intent.Much of the published literature reporting on the trends and outcomes of phase I trials have taken place in the era of cytotoxic agents. Few reviews have included molecular targeted agents (MTAs) and immuno‐oncology (IO) agents, with even fewer addressing combination trials, thus failing to shed light on the most recent trends. Additionally, large systematic reviews of early phase trials rely on published results of trials and are therefore inherently prone to publication bias. The rate of unpublished trials is reported to be as high as 30%2Following approval from the Monash Health Human Research Ethics Committee, all adults with a solid organ malignancy screened for a phase I trial from January 1, 2013 to December 31, 2018 at Monash Health, Melbourne, Australia were identified from the medical oncology research database. Data collection from the hospital electronic medical records included baseline demographics, previous lines of treatment, type of investigational agent(s) (drug class), screening outcome, treatment response, and toxicity and survival outcomes. Investigational agents were classified as IO, MTAs, cytotoxic agents, antibody drug conjugates (ADCs), and other. For statistical analysis of clinical outcomes, trials were broadly grouped into two types—IO (if the study involved at least one immuno‐oncologic agent) and non‐IO. Trials were also categorized as single agent or combination treatments .An early referral was defined as a patient referred in either the first‐ or second‐line setting for advanced disease. A late referral was defined as a patient referred after receiving more than two prior lines of systemic therapy. Screening visits refer to consultations at which patients signed the Patient Informed Consent Form for trial participation. Screen failure was defined as the inability of a consented patient to receive any study drug administration due to ineligibility, patient withdrawal of consent, decline in clinical status, or trial suspension (sponsor decision).χ2) testing was performed to detect any differences between ORR based on trial type and trial category. OS was defined as the time from consent to death from any cause. Kaplan–Meier estimates of survival were calculated separately for patients grouped by trial type and referral type (early vs late). Ninety‐day mortality (90DM) rates were calculated from the date of trial enrolment for the entire cohort. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 25.0. Armonk, New York.Treatment responses were collected from clinic notes and correlated with radiology reports. All trials utilized the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria for response assessments. Prostate cancer trials additionally utilized the Prostate Cancer Working Group 2 response criteria. The response‐evaluable population was all patients who had at least one treatment response assessment. Toxicity grading was performed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4 or 4.1 scale. Rates of clinically significant grade 2  or grade 3–5 treatment‐related adverse events (TRAEs) were recorded. Toxicity data were determined for the population of patients that received at least one dose of study drug. Chi‐square  and deterioration in performance status prior to dosing despite fulfilling performance status criteria at screening . Other causes of ineligibility were secondary to protocol‐defined exclusions including comorbid illness , concurrent second malignancy , brain metastases , absence of measurable disease , absence of requisite biomarker(s) , prohibited concomitant medications , and prolonged corrected QT interval on baseline electrocardiogram . Three patients were enrolled but did not commence treatment. Therefore, the toxicity‐evaluable safety cohort of subjects who received a minimum of one dose of study drug consisted of 209 patients (86%). The response‐evaluable cohort consisted of 190 (79%) patients who had at least one response assessment.Twenty‐eight phase I trials in solid tumors were conducted at our center over the 6‐year study period and 242 patients were screened Figure . Thirteen = 121) of patients were male. The European Cooperative Oncology Group (ECOG) performance status of all patients was either 0  or 1 . Patients referred to the unit had a median of two lines of treatment in both time periods (range 0–12). The most frequently seen tumor types are also listed in Table Table 3.1Of the 21 trials, eight (29%) were first‐in‐human (FIH). Most studies were histology‐agnostic while four were specific to tumor type . Of the 28 trials, only 1 (4%) was investigator‐initiated, with the remaining 27 being industry‐sponsored. Four (14%) trials required the presence of a tissue‐based biomarker for study eligibility, which was confirmed by central laboratory assessment during a “pre‐screening” process; these included a BRAF V600E mutation (1), BRAF V600/KRAS/NRAS mutation (1), mesothelin positivity in the dose expansion phase (1) and HER2 positivity (1). Only one trial (4%), a study involving the combination of an oncolytic virus (administered via intrahepatic injection) and an immune checkpoint inhibitor mandated serial tumor biopsies at various time points. Fourteen trials investigated single agents only, nine were combination studies, and five studies had a monotherapy arm followed by combination treatment. The majority of IO agents investigated were immune checkpoint inhibitors; PD‐1/programmed death‐ligand 1 (PD‐L1) inhibitors as single agents or in combination were studied in 14 trials and one trial involved a bispecific antibody targeting PD‐1 and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4). Other drugs classified as IO included an adenosine receptor antagonist, an indoleamine‐pyrrole 2,3‐dioxygenase inhibitor, two oncolytic viruses and a bispecific antibody targeting CD3ε on T‐cells and prostate‐specific membrane antigen in refractory prostate cancer. MTAs included both small molecules and monoclonal antibodies with specific cancer‐relevant targets. Two trials featured ADCs, one targeting mesothelin in select solid tumors and the other targeting the HER2/ErbB2 receptor in tumors with HER2 overexpression and/or amplification. Two trials involved cytotoxic agents and one trial, classified as ‘other,’ investigated a novel iron chelator. The breakdown of recruitment based on trial type and category is described in Table 3.2n = 209) who received at least one dose of trial‐specified treatment, 190 (91%) had a disease response assessment. Nineteen (9%) patients came off trial prior to the first scheduled response assessment scan due to the following reasons—early clinical progression (n = 10), cancer‐related death (n = 4), toxicity (n = 4) and unrelated medical illness (n = 1). Forty‐one (22%) patients had a confirmed response as defined by RECIST v1.1. Of these, 7 (4%) patients had a complete response, and 34 (18%) patients had a partial response. In addition, 59 (31%) subjects had stable disease producing a DCR of 53%. When grouped according to trial type, ORR in IO trials was 28% compared to 14% in non‐IO trials (p = .022). Patients in combination trials experienced a superior ORR than those treated in single‐agent studies . Patients referred early had an ORR (24%) compared with those referred late (18%) (p = .257).Of all patients (p = .003). Furthermore, there was no difference in OS when comparing trial category . The median OS in patients referred earlier was superior to those referred late  , 166 (78%) of all patients enrolled had died. After a median follow‐up of 23.2 months (range: 1.0–84.2), the median OS for the entire cohort was 8.0 months (95% CI: 6.8–9.1). Median OS calculated according to trial type was identical at 8 months in IO and non‐IO trials (3.3p = .07) or category (p = .83). Dose‐limiting toxicities (DLTs) at our center occurred in 3 (1%) patients, 2 of whom were on single agent MTA trials and 1 on a single agent ADC trial.Clinically significant grade 2 and all ≥ grade 3 TRAEs and the corresponding trials by drug class are detailed in Table 4The principal objectives of phase I trials have conventionally been to characterize the safety profile of the agent(s) under investigation, and to establish the recommended phase II dose (RP2D) for further evaluation.Efficacy endpoints such as ORR, progression‐free survival (PFS) and OS are often secondary endpoints due to relatively small numbers of patients recruited to early phase trials.In our study, ORR was 22% and DCR was 53%, independent of drug class, comparable to that of recently published data.The growing success of phase I trials has encouraged referral for earlier participation as a therapeutic option as opposed to a last resort; the early referral rate at our institution may reflect this trend, where almost half of all patients (47%) were referred either untreated for advanced disease or after only one line of systemic therapy. We can speculate that trials investigating IO and MTAs were attractive to referrers, and such studies were already starting to feature by 2013, when our study period commenced. Additionally, phase I trials in our unit provided an opportunity for patients to access anti‐PD‐1/PD‐L1 drugs in the absence of drug approval and government reimbursement, likely contributing to earlier referral patterns. We found that patients referred early also had an improved OS compared with those referred later. Although OS is typically longer in earlier lines of therapy for approved agents or combinations in many tumor types, the longer OS seen in the phase I setting from our cohort is potentially a reflection that agents from drug classes with proven activity were being employed.A screen failure rate of 18% compared favorably to the previously reported rate of 25% in phase I trials.The issue of risk and potential harm associated with phase I trials in oncology has long been debated.This study has clear limitations including its retrospective nature and single center focus. Our relatively small cohort makes it difficult to draw conclusions relating to safety and anti‐tumor activity. Additionally, the trials in our portfolio were heterogenous involving a variety of trial designs and investigational agents with distinct mechanisms of action. There were only four basket trials that is, investigating a biomarker‐directed therapy across different tumor histologies, and no umbrella trials—perhaps reflecting the time period of the study. These master protocols have lately emerged as critical tools in investigating targeted therapies and data pertaining to their influence on early phase clinical research would ideally feature in a study of this kind. Nevertheless, the major strength of our study is its real‐world representation of individual patient data. There is certainly a recognized need to share and access patient‐level phase I trial data in order to optimize trial design, identify important safety issues and ultimately improve patient care.In conclusion, our study adds to the growing body of evidence supporting phase I oncology trials as valid treatment options. It highlights the complexities surrounding design, endpoints, biomarker use, and clinical outcome reporting. Notably, there is a paucity of such data in an Australian context and hence the findings of this study are unique and valuable when considering the evolving phase I trial landscape in oncology. The 90DM rate of 20% in a good performance status group highlights the poor prognosis for most patients with advanced solid organ cancer and hence it is incumbent on clinicians to exercise caution while conducting early phase trials by carefully consenting patients and offering reasonable expectations based on pre‐clinical and clinical evidence. Finally, as next generation sequencing and other forms of biomarker identification become more prevalent, the role of optimal patient selection when conducting early phase oncology trials will become increasingly relevant.Dr Ben Markman—Novartis advisory board member, Amgen advisory board member. Prof Eva Segelov—MSD advisory board member, IPSEN advisory board member, speaker fees from SHIRE, fees from MERCK SERONO. The other authors do not have any conflicts of interest or funding sources to disclose.Conceptualization: B.M, D.D, S.M.; Data curation: S.M., A.D.; Methodology: B.M, D.D, S.M.; Investigation: S.M, A.D, B.M, D.D.; Resources: S.M, A.D, C.H.; Writing—Original Draft: S.M, A.D, D.D, B.M.; Writing—Review and Editing: all authors; Visualization: S.M, B.M, D.D.; Supervision: B.M, D.D.; Funding acquisition, project administration, software, validation: Not applicable.All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The study was conducted following approval from the Monash Health Human Research Ethics Committee (Ref: RES‐19‐0000‐953Q). Requirement for patient consent: Not applicable.


Atrial fibrillation (AF) and stable coronary artery disease (SCAD) frequently coexist.To investigate the prognosis of catheter ablation versus drug therapy in patients with AF and SCAD.In total, 25 512 patients with AF in the Chinese AF Registry between 2011 and 2019 were screened for SCAD. 815 patients with AF and SCAD underwent catheter ablation therapy were matched with patients by drug therapy in a 1:1 ratio. Primary end point was composite of thromboembolism, coronary events, major bleeding, and all‐cause death. The secondary endpoints were each component of the primary endpoint and AF recurrence.p < .01). In multivariate analysis, there was no significant difference between the strategy of catheter ablation and drug therapy in primary composite end point . However, catheter ablation was associated with fewer all‐cause death independently . In subgroup analysis, catheter ablation was an independent risk factor for all‐cause death in the high‐stroke risk group , not in the low‐medium risk group .Over a median follow‐up of 45 ± 23 months, the patients in the catheter ablation group had a higher AF recurrence‐free rate (53.50% vs. 18.41%, In the patients with AF and SCAD, catheter ablation was not independently associated with the primary composite endpoint compared with drug therapy. However, catheter ablation was an independent protective factor of all‐cause death Over 20 percent of patients with AF suffered from CAD,In recent years, catheter ablation has become an important choice for AF treatment. EAST‐AFNET 4 trial reported that early rhythm‐control therapy was associated with a lower risk of a composite of death from cardiovascular causes, stroke, or hospitalization than usual care among patients with early AF and cardiovascular conditions.22.1All the patients were screened from the Chinese Atrial Fibrillation Registry (CAFR) study between August 2011 and December 2019. CAFR has been described in details previously.Patients would be enrolled in this study if meeting all the following inclusion criteria: (1) age ≥ 18 years; (2) diagnosis of AF; (3) suffered from SCAD. AF was diagnosed by 12‐lead electrocardiogram or 24 hours‐Holter with a record lasting ≥30 seconds. SCAD was defined as a clinical condition with at least one of the following inclusion criteria: myocardial infarction (MI) ≥3 months ago; coronary artery bypass grafting (CABG) or PCI ≥3 months; stable chest pain with proven myocardial ischemia; or previous coronary angiography showing ≥1 coronary stenosis >50% and not require revascularization.Patients should be excluded if meeting any of the exclusion criteria as the followings: (1) valvular AF; (2) a history of catheter ablation or surgery for AF. In the CAFR, there were 12 104 patients underwent catheter ablation and 13 408 patients underwent drug therapy. Totally, 2665 patients were selected according to the inclusion criteria and exclusion criteria, including 1921 patients with catheter ablation and 844 patients with drug therapy. After propensity‐score matching, 815 pairs of patients in each group were enrolled in the study. The patient selection flow diagram was shown in Figure 2.2In the Catheter Ablation Group, all antiarrhythmic drugs (AAD) except amiodarone were stopped for at least five half‐lives before catheter ablation. The procedure was performed by experienced physicians. AF ablation strategy of our study has been described previously.Patients underwent catheter ablation were treated with anticoagulant drugs  and AADs  for 3 months after the procedure. AADs were withdrawn in the patients without recurrence 3 months after the catheter ablation. The patients with high risk for stroke were encouraged to continue taking anticoagulation. Antithrombotic strategy was determined by the discussion between physicians and the patients according to the patients' thromboembolism and bleeding risk and the patients' intention. The long‐term antithrombotic and AAD therapy in the ablation group were adopted the data after 3‐month follow‐up.In the drug therapy group, the long‐term plan of drug therapy was determined by the professional physicians at the first visit. According to the patients' thromboembolism and bleeding risk, antiplatelet drugs  or/and anticoagulant drugs  would be prescribed by the physicians. According to the patients' symptom and rhythm, the physicians would prescribe AADs  or/and rate control drugs .2.3Scheduled follow‐up was implemented at 3, 6, and 12 months after the initiation and every 6 months thereafter. Three strategies were applied to monitor heart rhythm: (i) regular reexamination: 24 hours‐Holter was performed monthly in the first 3 months, which was followed by an ECG and/or 24 hours‐Holter every 6 months thenceforth; (ii) symptom triggered reexamination: patients would record ECGs whenever experienced AF symptoms; and (iii) opportunistic screenings: ECGs recorded for routine examinations or other diseases were involved.2.4The primary endpoint was the composite of thromboembolism, coronary events, major bleeding, and all‐cause death. The thromboembolism included ischemic stroke (IS), transient ischemic attack (TIA), and systemic embolism (SE). The coronary events included MI and coronary revascularization. The major bleeding was defined according to the International Society on Thrombosis and Hemostasis (ISTH).2.5Propensity‐score matching was used to reduce the selection bias. To generate the propensity score, we made a multiple regression model enrolling 12 baseline variables, including the age, gender, type of AF, MI, heart failure, hypertension, diabetes, history of bleeding, history of thromboembolism, hyperlipidemia, renal insufficiency, liver insufficiency, and chronic obstructive pulmonary disorder. Patients from the catheter ablation group were matched with patients from the drug therapy group by one‐to‐one greedy nearest neighbor matching with a caliper of 0.2.t‐test or Wilcoxon test if not in normal distribution. The Chi‐square tests were used to compare categorical variables. Kaplan–Meier was used to calculate AF recurrence‐free survival. The incidence rates of outcome events were calculated by dividing the numbers of events by person‐years. Cox regression analysis was used to find the independent predictors of primary endpoint. The multivariate analysis model included variables with a p‐value < .05 in univariate analysis, including ablation, age, type of AF, diabetes, heart failure, history of bleeding, history of thromboembolism, estimated glomerular filtration rate (EGFR), left atrial diameter, left ventricular end‐diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), digoxin, statins, antithrombotic drugs. A p‐value < .05 was considered statistically significant. All statistical analyses were performed using SAS software, version 9.4 .Continuous variables were presented as means ± SD or medians and quartiles. Categorical variables were presented as numbers and proportions. Continuous variables in normal distribution were compared with Student's 33.1Totally, 815 pairs of patients with AF and SCAD were enrolled with a mean duration of 45 ± 23 months follow‐up. The baseline characteristics of the patients were shown in Table 3.2All the patients in the catheter ablation group achieved pulmonary vein isolation. 118 (21%) of the 575 patients with paroxysmal AF and 208 (87%) of the 240 patients with non‐paroxysmal AF underwent additional linear ablation, fractionated potentials ablation or superior vena cava isolation. Complications occurred in 13 patients (1.60%), including six pericardial tamponade, 1 pericardial effusion, 1 acute heart failure, 2 stroke, 1 puncture hematoma, 1 great saphenous venous thrombosis, and 1 femoral arteriovenous fistula.p < .01; Figure With a mean duration of 54.5 ± 24.0 months follow‐up, after a single ablation, the AF recurrence‐free rate was higher in the catheter ablation group than the drug therapy group  and all‐cause mortality  were significantly lower in the catheter ablation group. There were no significant differences of other secondary endpoints including thromboembolism, coronary events, and major bleeding between the two groups. With regard to the component of thromboembolism, 62 patients in the drug therapy group experienced thromboembolism events  and 60 patients in the catheter ablation group experienced thromboembolism events . There was no significant difference in the type of thromboembolism events between the two groups (p = .42).Clinical adverse events were shown in Table p < .01), diabetes , previous bleeding , previous embolism , eGFR , LVEF , and digoxin  were independently associated with the primary endpoint. In multivariate analysis, catheter ablation therapy was not an independent risk factor for the primary endpoint . Catheter ablation therapy was an independent protective factor for all‐cause death  in the multivariate model.The univariate and multivariate analyses of risk factors for primary endpoint were shown in Table 3.4p < .01). However, catheter ablation was not an independent risk factor for all‐cause death in the low‐medium risk group .The patients were divided into two different stroke risk subgroups based on the CHA2DS2‐VASc score. The patients with CHA2DS2‐VASc score ≤ 1 in men or ≤ 2 in women were grouped into the low‐medium risk group, and the patients with CHA2DS2‐VASc score ≥ 2 in men or ≥ 3 in women were grouped into the high‐risk group. As it was shown in Table 44.1To the best of our knowledge, this study was the largest study that exploring catheter ablation therapy versus drug therapy on the outcomes in the patients with AF and SCAD based on the real‐world data. The main findings of this study are: (1) Compared with drugs therapy, catheter ablation was more effective at maintaining sinus rhythm for the patients with AF and SCAD. (2) In multivariate analysis, catheter ablation was not independently associated with fewer primary composite endpoints of thromboembolism, coronary events, major bleeding, or all‐cause death. (3) For a secondary endpoint, after adjustment for the confounders in multivariate analysis, catheter ablation was an independent protective factor of all‐cause death after adjusting for other potential risk factors.4.2AF and CAD were closely related, and they shared some same risk factors, such as hypertension, diabetes, sleep apnea syndrome, obesity, smoking, and inflammation. CAD could affect the blood supply of atria, and coronary artery revascularization could reduce the recurrence of AF.4.3In the recently published CABANA study, catheter ablation was not superior to drug therapy on the primary endpoint, which was a composite of death, disabling stroke, serious bleeding, and cardiac arrest.A small observational trial of catheter ablation therapy vs. medical therapy in the patients with AF and prior coronary intervention provided evidence that catheter ablation may reduce adverse events, including acute coronary syndrome requiring hospitalization, stroke, pulmonary embolism and mortality.4.4According to recent guidelines, patients with AF and CAD were suggested to take an anticoagulant or at last an antiplatelet drug.4.5The incidence of coronary events was relatively low in this study. In a similar study by Chong et al., after catheter ablation of AF, 2.3% of patients who had undergone PCI experienced MI, and 15.8% of patients experienced unstable angina.4.6In most registries on AF, stroke was much less common than bleeding. However, the incidence of thromboembolism events was higher than that of major bleeding in this study. Compared with bleeding, Chinese were more likely to suffer from thromboembolism events. It was reported in an observational study enrolling 9806 AF patients with anticoagulation therapy, the incidence of IS and SE was 6.5%, and the incidence of intracranial hemorrhage and gastrointestinal bleeding was 4.9%.4.7Some main limitations existed in this study. (1) Our research was a prospective cohort study rather than a randomized controlled trial. Selection bias could exist for the inherent deficiency of observational study. For balancing patients' characteristics, propensity‐score matching was used to reduce the bias. There were also some slight differences of the baseline characteristics between the two groups. Multivariate analysis was used to adjust for potential confounding factors. (2) A gap of drugs therapy between the clinical practice in the real world and the guidelines appeared in this study. However, the application of drugs in our study was in accordance with other Chinese studies. This study emphasized the effects of catheter ablation versus drug therapy on the prognosis in the patients with AF and SCAD in the real world. (3) The time span of our study's enrollment was long, from 2011 to 2019. The standard of drug treatment and the catheter ablation technology has partly changed. However, the enrollment and follow‐up were consistent and ongoing in the CAFR.5In conclusion, in the patients with AF and SCAD, compared with drug therapy, after adjusted the cofounders, catheter ablation was not significantly associated with fewer primary composite endpoints of thromboembolism, coronary events, major bleeding, and all‐cause death. However, catheter ablation could lead to fewer all‐cause death.


The annual incidence of new hip fractures increased from 2005 to 2014 in Nagasaki and females were much more affected. High-risk factors were identified as age ≥ 80 years, winter, indoors, living room, Monday, and early morning. Seven days after admission, most patients remained hospitalized and had been treated surgically.Hip fractures are major osteoporotic fractures that reduce quality of life. In Japan, the incidence of hip fractures increased steadily from 1986 to 2014 and the number of hip fractures could be 7.3–21.3 million by 2050. This study aimed to determine the incidence of hip fractures from 2005 to 2014 in Nagasaki Prefecture and to analyze the characteristics of and risk factors for hip fracture.Hip fractures that occurred in Nagasaki Prefecture between 2005 and 2014 were analyzed using emergency transportation records. Fracture type, age, sex, location in which fracture occurred, and risk factors for hip fracture were clarified.The total number of new hip fractures among individuals ≥ 35 years old was 17,395  and the annual incidence per 100,000 population increased from 147.9 in 2005 to 235.0 in 2014. Females (79.6%) were much more commonly affected than males (20.4%) and cervical fractures were more common than trochanteric fractures in all age groups. Hip fracture tended to be associated with age ≥ 80 years, winter rather than summer, indoors rather than outdoors, and living room rather than the bathroom or toilet. Other high-risk factors were Monday as day of the week, and early morning as the time of day. Seven days after admission, 97.3% of patients were hospitalized and 78.1% of hip fractures had been treated surgically.Information on actual situations and valid preventive measures relevant to hip fracture are urgently needed. Hip fracture is a serious complication of osteoporosis and represents a major problem worldwide. The burden of osteoporosis in patients with hip fracture is now well recognized, involving economic costs as well as morbidity and premature mortality. The incidence of hip fracture increases along with the population of elderly individuals, since hip fracture incidence increases exponentially with age. Numbers of hip fractures worldwide for males and females in 1990 were estimated as 338,000 and 917,000, respectively, with totals expected to approximately double from 1.26 to 2.6 million by 2025, and to increase to 7.3–21.3 million by 2050 . The JapIn Japan, all ambulance services are required by law to record prehospital transport data, such as age, sex, address, and times of emergency call and hospital arrival. In particular, Nagasaki Prefecture has maintained original emergency transportation records since 2004, including additional information such as diagnostic codes, definitive diagnosis, and outcome at 1 week after ambulance transport. Thirteen main diagnostic codes are used by the treating physicians. Coding of injuries due to external causes is divided into the following: traumatic intracranial hemorrhage; cardiovascular and lung injury; abdominal organ injury; pelvic fracture; other fractures; severe multiple trauma; spinal cord injury; asphyxia; burn; drowning; poisoning; minor injuries; and proximal femoral fracture (hip fracture). In Nagasaki Prefecture, all ambulance attendants must submit half of an emergency transportation record with prehospital data, then hospitals (attending physicians) are encouraged to submit the other half of the record with the definitive diagnosis and outcome at 1 week after ambulance transport. The participation rate of ambulance attendants is 100% and the average collection rate from hospitals after 1 week has been reported as 91.6% . This hin = 486,852). Inclusion criteria for this study were as follows: fracture of the femoral neck  as a definitive diagnosis; and age ≥ 35 years. The definitive diagnosis was made by the attending physician at 1 week after ambulance. We excluded cases with no definitive diagnosis, no description of outcome, or unknown type of accident in the emergency transportation records. Patients transferred from another hospital and those with unknown transport type were also excluded.We conducted a retrospective study using standardized regional data from emergency transportation records collected in the Nagasaki Medical Control Council. From April 2004 to March 2015, a total of 522,912 patients were transported by ambulance in Nagasaki Prefecture and the mean collection rate of emergency transportation records was 93.1% , age (5-year strata), transport time, street address, destination hospital, affected side, fracture type , area in which the fracture occurred (indoors vs. outdoors), and outcomes at 1 week after ambulance transport, including status, transferred hospital, and treatment method. The incidence of hip fractures in each study year was calculated as the number of fractures per 100,000 population per year. The initials and date of birth were omitted from database information to ensure protection of personal information. Duplication of cases was therefore checked based on ambulance number, date, and time of ambulation. Area in which the injury occurred was categorized as “house,” “outdoors,” “hospital,” “facilities for the elderly,” and “public.” Status at 1 week after ambulance transport was divided into five categories: “hospitalization”; “transfer to a different hospital”; “discharge from the hospital in an ambulatory state”; “mortality”; and “unknown.” The present study was approved by the research ethics committee at Nagasaki University Graduate School of Biomedical Sciences .P < 0.01.Significant differences between two groups were tested with Mann–Whitney U tests for unpaired values . The categories/ratios of variables such as outcomes and treatment history at 1 week after ambulance transportation were compared using Pearson’s chi-squared test. Continuous variables such as age strata, seasonal, and daily variations were tested with one-way analysis of variance multiple comparison tests followed by post hoc Tukey–Kramer and Bonferroni-Dunn multiple comparison tests. All data were analyzed using SPSS version 22.0 . Values are expressed as mean ± standard deviation. Statistical significance was defined for values of The total number of new hip fractures among individuals ≥ 35 years old was 17,395 and the mean age was 82.6 ± 9.4 years. The total number of patients and population ≥ 35 years old in Nagasaki Prefecture in each year are summarized in Table P < 0.01), the cervical/trochanteric ratio decreased over time, meaning that the growth rate of trochanteric fractures was higher than that of cervical fractures. There were almost 3.9 times more females with hip fractures (79.6%) than males (20.4%), and the ratios of females with cervical and trochanteric fractures were 79.4%  and 80.5% , respectively. The affected side in total was 7,853 cases (49.4%) on the right side and 8,034 cases (50.6%) on the left side, and ratios of the affected side remained almost unchanged during the observation period (P > 0.01).A total of 9,270 cervical fractures , 6,593 trochanteric fractures , and 1,532 unclassified fractures were detected and changes over time in the prevalences of both fracture types are shown in Table P < 0.01). The transition of age-specific patients from 2005 to 2014 revealed a gentle increase in the number of patients ≥ 80 years old, and a more prominent increase for patients ≥ 90 years old.Total age- and sex-specific numbers of patients were divided into 12 strata in 5-year intervals, as shown in Fig. P < 0.01). Daily variations are shown in Fig. P < 0.01).The total number of patients per month was highest in December and lowest in July in every year from 2005 to 2014 Fig. . Mean nuThe number and percentage of areas and places in which hip fractures occurred are summarized in Table P < 0.01).Recognition time  was divided into 24 timeframes and the mean number of patients per year was distributed as shown in Fig. At 1 week after ambulance transport, 83.7% of patients with hip fracture remained at the hospital where they had first been brought, much more than the proportions of transfers (13.6%), mortality (0.43%), or discharge from the hospital in an ambulatory state (0.06%) , and include additional information at 1 week after ambulance transport. This methodology can supply reliable, objective data, and enable high-quality analysis within a specific region. As a result, the annual number (1392–2222 cases) and incidence  of new hip fractures among the population ≥ 35 years old increased gradually from 2005 to 2014. Numbers in males and females have been increasing in a similar manner, mainly ascribed to the increase in the elder population. Life expectancy over the age of 50 years has increased, but elderly individuals experience increased fragility of bone and decreased motor function . The maiFracture type- and affected side-specific analyses revealed that cervical fractures (58.4%) occurred more frequently than trochanteric fractures (41.6%) among patients > 35 years old, while the affected side was similar between right and left. In Japan, trochanteric fractures have been reported to be more common than cervical fractures , 10. AltAge- and sex-specific data indicated that almost 3.9 times more females (79.6%) were affected than males 20.4%), and most hip fractures occurred in patients ≥ 80 years old (70.9%) of the total. The 80- to 85-year-old age stratum in males and 70- to 90-year-old age stratum in females contained more cases than 35- to 65-year-old age groups. Orimo et al. %, and mo reportedSeveral studies have demonstrated characteristic seasonality in hip fractures , 15–17. Focusing on the area and location of injury, 88.1% of patients with hip fracture were injured indoors, in the house, hospital, or nursing home. Furthermore, 76.4% of fractures occurring indoors were in the living room rather than the bathroom or toilet. Rates of injuries resulting from simple falls indoors are reportedly higher in older age groups –11. ConsThis study appears to be the first to report variations in hip fracture by time of day. A certain proportion of cases are likely to have involved family members or other caregivers calling the ambulance after finding the patient with hip fracture, especially for elderly individuals living alone. However, most hip fractures occur by falls from a standing or sitting position, and injury rates in bed reportedly comprise only 1.0–2.2% of cases –10. RecoGenerally, hip fractures are treated surgically, except in special cases where surgical treatment is not needed or cannot be performed. In addition, early surgery (within 2 days after injury) is recommended to minimize postoperative hospitalization time and complications , 20. AccThe mortality rate of 0.43% in this study was extraordinarily low compared to previous epidemiological research. Stenqvist et al.  and OgawSeveral limitations to this study must be considered. First, we investigated data from emergency transportation records in this study, so patients injured within the same institution or admitted to the hospital by other means could not be counted. Second, even though a definitive diagnosis was written in the records as hip fracture, 10 cases (0.06%) were in the category of “discharge from the hospital in an ambulatory state” 1 week after ambulance transport. The exact reasons for this were unknown. Although these limitations could cause some bias, the relatively large number of patients collected in this study spanning one decade may compensate for such deficits.The present study investigated a total of 17,395 cases of hip fracture among individuals ≥ 35 years old from 1986 to 2014 in Nagasaki Prefecture using emergency transportation records and analyzed the current incidence, trends, characteristics, and risk factors for such fractures. The mean age at injury was 82.6 years and the annual incidence per 100,000 population increased from 147.9 in 2005 to 235.0 in 2014. Females (79.6%) were much more commonly affected than males (20.4%) and cervical fractures were more common in all age groups. Risk factors identified included age ≥ 80 years, winter season, indoor areas, living room as location in the house, Monday as the day of the week, and early morning as the timeframe. At 7 days after admission, 97.3% of patients remained hospitalized, and 78.1% of hip fractures had been treated surgically.