Characteristics of urinary tract infections in children with positive urine culture for Aerococcusurinae.

Urinary tract infections caused by Aerococcus urinae have rarely been reported in children, and the clinical characteristics remain unclear. We reviewed medical records of children whose urine cultures grew A. urinae (≥104 CFU/mL) at a tertiary children's hospital in Tokyo, Japan. We found 17 pediatric patients in a review of 22,769 urine cultures between June 2006 and May 2022. The median age of 17 patients was 10.7 years (IQR 8-13 years), and males represented 76.5 % of the patients. Sixteen patients (94.1 %) had underlying urological conditions (neurogenic bladder, vesicoureteral reflux, urethral stenosis, bladder exstrophy, or urinary catheterization). The chief symptoms were fever (35.3 %), malodorous urine (23.5 %), nausea (11.8 %), and back pain (5.9 %). Ten patients were asymptomatic. Pyelonephritis was diagnosed in five male patients. All of them had underlying abnormal conditions of the bladder, and two had malodorous urine. All patients had favorable outcomes after 10-14 days of ampicillin/amoxicillin-based antimicrobial therapy.

Induction of acute silkworm hemolymph melanization by Staphylococcus aureus treated with peptidoglycan-degrading enzymes.

Staphylococcus aureus, a Gram-positive bacterium, causes inflammatory skin diseases, such as atopic dermatitis, and serious systemic diseases, such as sepsis. In the skin and nasal environment, peptidoglycan (PGN)-degrading enzymes, including lysozyme and lysostaphin, affects S. aureus PGN. However, the effects of PGN-degrading enzymes on the acute innate immune-inducing activity of S. aureus have not yet been investigated. In this study, we demonstrated that PGN-degrading enzymes induce acute silkworm hemolymph melanization by S. aureus. Insoluble fractions of S. aureus treated with lysozyme, lysostaphin, or both enzymes, were prepared. Melanization of the silkworm hemolymph caused by the injection of these insoluble fractions was higher than that of S. aureus without enzyme treatment. These results suggest that structural changes in S. aureus PGN caused by PGN-degrading enzymes affect the acute innate immune response in silkworms.

Acid-treated Staphylococcus aureus induces acute silkworm hemolymph melanization.

The skin microbiome maintains healthy human skin, and disruption of the microbiome balance leads to inflammatory skin diseases such as folliculitis and atopic dermatitis. Staphylococcus aureus and Cutibacterium acnes are pathogenic bacteria that simultaneously inhabit the skin and cause inflammatory diseases of the skin through the activation of innate immune responses. Silkworms are useful invertebrate animal models for evaluating innate immune responses. In silkworms, phenoloxidase generates melanin as an indicator of innate immune activation upon the recognition of bacterial or fungal components. We hypothesized that S. aureus and C. acnes interact to increase the innate immunity-activating properties of S. aureus. In the present study, we showed that acidification is involved in the activation of silkworm hemolymph melanization by S. aureus. Autoclaved-killed S. aureus (S. aureus [AC]) alone does not greatly activate silkworm hemolymph melanization. On the other hand, applying S. aureus [AC] treated with C. acnes culture supernatant increased the silkworm hemolymph melanization. Adding C. acnes culture supernatant to the medium decreased the pH. S. aureus [AC] treated with propionic acid, acetic acid, or lactic acid induced higher silkworm hemolymph melanization activity than untreated S. aureus [AC]. S. aureus [AC] treated with hydrochloric acid also induced silkworm hemolymph melanization. The silkworm hemolymph melanization activity of S. aureus [AC] treated with hydrochloric acid was inhibited by protease treatment of S. aureus [AC]. These results suggest that acid treatment of S. aureus induces innate immune activation in silkworms and that S. aureus proteins are involved in the induction of innate immunity in silkworms.

Role of tenascin C in lesion formation in early peritoneal endometriosis.

OBJECTIVE: To identify cytokines or extracellular matrix components that contribute to adhesion to, and invasion of, the peritoneum, proximal to lesions in the early phase of endometriosis. DESIGN: Laboratory-based study. SETTING: University Hospital and Laboratory of Animal Science. PATIENTS AND ANIMALS: Five women with ovarian endometrioma, 138 wild-type (WT) C57BL/6N mice, and 48 Tenascin C (Tnc) knockout (TncKO) mice. INTERVENTIONS: To establish a murine endometriosis model, 20 pieces of minced uterine tissue fragments from each horn were administered intraperitoneally to syngeneic mice. Three days later, endometriotic lesions and peritoneal tissues were collected. Separately, we transfected human peritoneal mesothelial cells (HMrSV5) or human endometrial stromal cells (hESCs) with Tnc small interfering ribonucleic acid. MAIN OUTCOME MEASURES: We employed a polymerase chain reaction array to profile gene expression in the murine peritoneum, in both peritoneum distal to lesions and peritoneum surrounding lesions (PSL). The expression of upregulated genes in the PSL was verified in the peritoneal samples by real-time reverse transcription-polymerase chain reaction. TncKO mice were used to investigate the role of Tnc in the development of endometriosis. We evaluated the proliferative activity or inflammatory state of lesions by Ki67 or CD3 immunostaining. Intraperitoneal distribution of macrophages was assessed by fluorescence-activated cell sorting. Using Tnc small interfering ribonucleic acid, we examined the invasive capacity of hESCs in a coculture system with HMrSV5. RESULTS: Tnc gene expression was significantly higher in PSL than in peritoneum distal to lesions. The weight and number of TncKO lesions in TncKO hosts were lower than those of WT lesions in WT hosts. In contrast, the weight and number of nonattached TncKO lesions in TncKO hosts were higher than those of nonattached WT lesions in WT hosts. We observed decreased Ki67-positive cells or H-scores for CD3, a lower proportion of M1 macrophages, and a higher proportion of M2 macrophages in TncKO lesions in TncKO recipients. Silencing of Tnc expression in hESCs and HMrSV5 diminished the invasivity of hESCs. CONCLUSION: Tnc may be a crucial factor in the development of early peritoneal endometriosis.

A scoping review of remote facilitation during simulation-based healthcare education.

BACKGROUND: Remote facilitation is a synchronous distance education method where instructors facilitate a lesson, in real-time, in physically separate conditions. In this scoping review, we aimed to describe types of remote facilitation used in a healthcare simulation, the influences on learner outcomes, and related factors. METHODS: We accessed PubMed, EMBASE, CINAHL, ERIC, and Web of Science using our search strategies. Five reviewers performed the review using the Preferred Reporting Items for Systematic Reviews and Meta Analysis extension for Scoping Reviews (PRISMA-ScR) framework, and the Johanna Briggs Institute (JBI) guidelines. RESULTS: We included a total of 29 articles presenting 28 simulation studies. The most common tool was videoconferencing (n = 26, 89.7%). Knowledge improvement was the most frequently measured outcome. There was no significant difference in learning outcomes between the two teaching modes. There were differences in learners' preferences and satisfaction with remote facilitators before and after COVID-19. CONCLUSIONS: Our scoping review indicates that remote facilitation has been widely accepted in many healthcare professions using various types of simulation modalities. Remote facilitation can be used to overcome logistical problems of synchronous multi-location education, and to improve learner knowledge, skills, and confidence measured by instructor evaluation or self-assessment.

Do clinical interview transcripts generated by speech recognition software improve clinical reasoning performance in mock patient encounters? A prospective observational study.

BACKGROUND: To investigate whether speech recognition software for generating interview transcripts can provide more specific and precise feedback for evaluating medical interviews. METHODS: The effects of the two feedback methods on student performance in medical interviews were compared using a prospective observational trial. Seventy-nine medical students in a clinical clerkship were assigned to receive either speech-recognition feedback (n = 39; SRS feedback group) or voice-recording feedback (n = 40; IC recorder feedback group). All students' medical interviewing skills during mock patient encounters were assessed twice, first using a mini-clinical evaluation exercise (mini-CEX) and then a checklist. Medical students then made the most appropriate diagnoses based on medical interviews. The diagnostic accuracy, mini-CEX, and checklist scores of the two groups were compared. RESULTS: According to the study results, the mean diagnostic accuracy rate (SRS feedback group:1st mock 51.3%, 2nd mock 89.7%; IC recorder feedback group, 57.5%-67.5%; F(1, 77) = 4.0; p = 0.049), mini-CEX scores for overall clinical competence (SRS feedback group: 1st mock 5.2 ± 1.1, 2nd mock 7.4 ± 0.9; IC recorder feedback group: 1st mock 5.6 ± 1.4, 2nd mock 6.1 ± 1.2; F(1, 77) = 35.7; p < 0.001), and checklist scores for clinical performance (SRS feedback group: 1st mock 12.2 ± 2.4, 2nd mock 16.1 ± 1.7; IC recorder feedback group: 1st mock 13.1 ± 2.5, 2nd mock 13.8 ± 2.6; F(1, 77) = 26.1; p < 0.001) were higher with speech recognition-based feedback. CONCLUSIONS: Speech-recognition-based feedback leads to higher diagnostic accuracy rates and higher mini-CEX and checklist scores. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials on June 14, 2022. Due to our misunderstanding of the trial registration requirements, we registered the trial retrospectively. This study was registered in the Japan Registry of Clinical Trials on 7/7/2022 (Clinical trial registration number: jRCT1030220188).

Selection of highly responsive T cell receptors by an analysis combining the expression of multiple markers.

The clinical success of T cell receptor (TCR) gene-transduced T (TCR-T) cell therapy is expected as one of the next-generation immunotherapies for cancer, in which the selection of TCRs with high functional avidity (high-functional TCRs) is important. One widely used approach to select high-functional TCRs is a comparison of the EC50 values of TCRs, which involves laborious experiments. Therefore, the establishment of a simpler method to select high-functional TCRs is desired. We herein attempted to establish a simple method to select high-functional TCRs based on the expression of T cell activation markers using the mouse T cell line BW5147.3 (BW). We examined relationships between the EC50 values of TCRs in interleukin-2 production and the expression levels of TCR activation markers on BW cells. In TCR-expressing BW cells stimulated with antigenic peptides, the CD69, CD137, and PD-1 expression was differentially induced by various doses of peptides. An analysis of TCRs derived from the tumor-infiltrating lymphocytes of murine melanoma and peripheral blood T cells of hepatocellular carcinoma patients treated with a peptide vaccination revealed that an analysis combining CD69, CD137, and PD-1 expression levels in BW cells stimulated with a single dose of an antigenic peptide selected high-functional TCRs with functional avidity assessed by EC50 values. Our method facilitates the section of high-functional TCRs among tumor-reacting TCRs, which will promote TCR-T cell therapy. The stimulation of BW cells expressing objective TCRs with a single dose of antigenic peptides and analysis combining the expression of CD69, CD137, and PD-1 allows us to select highly responsive TCRs.

Risk factors indicating immune-related adverse events with combination chemotherapy with immune checkpoint inhibitors and platinum agents in patients with non-small cell lung cancer: a multicenter retrospective study.

PURPOSE: Immune checkpoint inhibitors (ICI) ushered in a new era for the treatment of non-small cell lung cancer (NSCLC). However, they carry the risk of immune-related adverse events (irAEs). Recently, various studies have been conducted on the predictive factors for irAEs, but there are no reports focusing only on ICI plus platinum agents. The present study aimed to identify the risk factors for irAEs due to ICI combined with platinum-based induction immunochemotherapy in NSCLC patients, focusing only on the period of combined therapy and excluding the period of ICI maintenance therapy. METHODS: This retrospective study included 315 NSCLC patients who started ICI combined with platinum-based chemotherapy treatment at 14 hospitals between December 2018 and March 2021. A logistic regression analysis was used to explore the predictive factors. RESULTS: Fifty patients (15.9%) experienced irAEs. A multivariate analysis revealed that squamous cell carcinoma (P = 0.021; odds ratio [OR]: 2.30; 95% confidence interval [Cl]: 1.14-4.65), anti-programmed death 1 antibody (anti-PD-1) plus anti-cytotoxic T-lymphocyte antigen-4 antibody (anti-CTLA-4) regimens (P < 0.01; OR: 22.10; 95% Cl: 5.60-87.20), and neutrophil-to-lymphocyte rate (NLR) < 3 (P < 0.01; OR: 2.91; 95% Cl: 1.35-6.27) were independent predictive factors for irAEs occurrence. CONCLUSION: Squamous cell carcinoma, anti-PD-1 plus anti-CTLA-4 regimens, and NLR < 3 may be predictive factors for the occurrence of irAEs due to induction immunochemotherapy in patients with NSCLC. By focusing on the potential risk of irAEs in patients with these factors, irAEs can be appropriately managed from an early stage.

Association between equol producers and type 2 diabetes mellitus among Japanese older adults.

AIMS/INTRODUCTION: Equol, which is produced by enteric bacteria from soybean isoflavones, has a chemical structure similar to estrogen. Both in vivo and in vitro studies have shown the beneficial metabolic effects of equol. However, its effects on type 2 diabetes remain unclear. We investigated the association between the equol producers/non-producers and type 2 diabetes. MATERIALS AND METHODS: The participants included 147 patients with type diabetes mellitus aged 70-89 years, and 147 age- and sex-matched controls. To ascertain the equol producers or non-producers, we used the comparative logarithm between the urinary equol and daidzein concentrations (cut-off value -1.75). RESULTS: The urinary equol concentration was significantly lower in the diabetes group compared with the non-diabetes group (P = 0.01). A significant difference in the proportion of equol producers was observed among all participants (38.8% in the diabetes group and 53.1% in the non-diabetes group; P = 0.01). The proportion of equol producers among women was significantly lower in the diabetes group (31.4%) than in the non-diabetes group (52.8%; P < 0.01). Additionally, the frequency of dyslipidemia in female equol producers was significantly lower than that in female non-equol producers (P < 0.01). Among men, no such differences were observed. We found a significant positive correlation between the urinary equol and daidzein concentrations among equol producers (r = 0.55, P < 0.01). CONCLUSIONS: Our study findings showed that postmenopausal women had a low proportion of equol producers with diabetes and dyslipidemia.

Hybrid PBL and Pure PBL: Which one is more effective in developing clinical reasoning skills for general medicine clerkship?-A mixed-method study.

This study aims to compare the effectiveness of Hybrid and Pure problem-based learning (PBL) in teaching clinical reasoning skills to medical students. The study sample consisted of 99 medical students participating in a clerkship rotation at the Department of General Medicine, Chiba University Hospital. They were randomly assigned to Hybrid PBL (intervention group, n = 52) or Pure PBL group (control group, n = 47). The quantitative outcomes were measured with the students' perceived competence in PBL, satisfaction with sessions, and self-evaluation of competency in clinical reasoning. The qualitative component consisted of a content analysis on the benefits of learning clinical reasoning using Hybrid PBL. There was no significant difference between intervention and control groups in the five students' perceived competence and satisfaction with sessions. In two-way repeated measure analysis of variance, self-evaluation of competency in clinical reasoning was significantly improved in the intervention group in "recalling appropriate differential diagnosis from patient's chief complaint" (F(1,97) = 5.295, p = 0.024) and "practicing the appropriate clinical reasoning process" (F(1,97) = 4.016, p = 0.038). According to multiple comparisons, the scores of "recalling appropriate history, physical examination, and tests on clinical hypothesis generation" (F(1,97) = 6.796, p = 0.011), "verbalizing and reflecting appropriately on own mistakes," (F(1,97) = 4.352, p = 0.040) "selecting keywords from the whole aspect of the patient," (F(1,97) = 5.607, p = 0.020) and "examining the patient while visualizing his/her daily life" (F(1,97) = 7.120, p = 0.009) were significantly higher in the control group. In the content analysis, 13 advantage categories of Hybrid PBL were extracted. In the subcategories, "acquisition of knowledge" was the most frequent subcategory, followed by "leading the discussion," "smooth discussion," "getting feedback," "timely feedback," and "supporting the clinical reasoning process." Hybrid PBL can help acquire practical knowledge and deepen understanding of clinical reasoning, whereas Pure PBL can improve several important skills such as verbalizing and reflecting on one's own errors and selecting appropriate keywords from the whole aspect of the patient.

Frequency of Difficult Patient Encounters in a Japanese University Hospital and Community Hospitals: A Cross-sectional Study.

Objective Difficult patient encounters (DPEs) are defined as encounters with patients causing strong negative feelings in physicians. In primary care settings, DPEs account for approximately 15% of visits among outpatients. To our knowledge, this is the first epidemiological study of DPEs in Japan. Methods We conducted a survey of 8 physicians (5.0±2 years of clinical experience) who examined first-visit patients ≥15 years old with clinical symptoms at the Department of General Medicine in Chiba University Hospital and 4 community hospitals over a 2-month period since December 2015. Materials We evaluated 10-Item Difficult Doctor-Patient Relationship Questionnaire (DDPRQ-10) scores (DPE ≥31 points; non-DPE ≤30 points) and patient age, sex, and presence of psychological or social problems. Results The valid response rate was 98.9% (94/95) and 98.4% (189/192) in the university and community hospitals, respectively. The percentage of DPEs was 39.8% (37/93) and 15.0% (26/173) in the university and community hospitals, respectively; the percentage of DPEs was significantly higher at the university hospital than at the community hospitals (p<0.001). The proportion of patients with psychosocial problems was significantly higher in the DPE group than in the non-DPE group (93.7% vs. 40.4%, p<0.001). Conclusion Our findings were similar to those reported in primary care settings in other countries in community hospital outpatient and general internal medicine departments, where patients are mostly non-referrals, although the values were higher in university hospital general medicine departments, where patients were mostly referrals. Patients involved in DPEs have a high rate of psychological and social problems.

Peutz-Jeghers Syndrome.

This case report describes multiple dark-brown 1- to 2-mm hyperpigmented macules on the lips, nose, and conjunctivae.

Acute melanization of silkworm hemolymph by peptidoglycans of the human commensal bacterium Cutibacterium acnes.

Cutibacterium acnes is a pathogenic bacterium that cause inflammatory diseases of the skin and intervertebral discs. The immune activation induced by C. acnes requires multiple cellular responses in the host. Silkworm, an invertebrate, generates melanin by phenoloxidase upon recognizing bacterial or fungal components. Therefore, the melanization reaction can be used as an indicator of innate immune activation. A silkworm infection model was developed for evaluating the virulence of C. acnes, but a system for evaluating the induction of innate immunity by C. acnes using melanization as an indicator has not yet been established. Here we demonstrated that C. acnes rapidly causes melanization of the silkworm hemolymph. On the other hand, Staphylococcus aureus, a gram-positive bacterium identical to C. acnes, does not cause immediate melanization. Even injection of heat-killed C. acnes cells caused melanization of the silkworm hemolymph. DNase, RNase, and protease treatment of the heat-treated C. acnes cells did not decrease the silkworm hemolymph melanization. Treatment with peptidoglycan-degrading enzymes, such as lysostaphin and lysozyme, however, decreased the induction of melanization by the heat-treated C. acnes cells. These findings suggest that silkworm hemolymph melanization may be a useful indicator to evaluate innate immune activation by C. acnes and that C. acnes peptidoglycans are involved in the induction of innate immunity in silkworms.

A Case of Post-cataract Surgery Endophthalmitis Successfully Treated with Conservative Therapy.

BACKGROUND: Postoperative endophthalmitis after cataract surgery often requires emergency surgery if caused by an infection. However, early reoperation after the surgery put a heavy mental burden on the patient. Here we report a relatively mild case of postoperative endophthalmitis in which emergency surgery was avoided through careful observation including gram stain and culture test. CASE: 87-year-old male. The patient had a sudden decrease in visual acuity on the 4th day after cataract surgery of the left eye performed at another hospital and visited his previous doctor on the following day. Postoperative endophthalmitis was suspected, so he was referred to our department on the same day. The inflammation was observed in the anterior segment of the left eye. The gram staining results for collected anterior aqueous humor were negative. The patient was followed up with continued medication and careful observation without undergoing emergency surgery. The inflammation of the anterior segment subsequently improved. The patient underwent a left vitrectomy three months later to remove residual vitreous opacity. CONCLUSION: Postoperative endophthalmitis after cataract surgery is often indicated for emergency surgery, but there can be cases in which conservative therapy with thorough observation succeeds in retaining visual function.

Behavior-based medical diagnosis-Applying perspectives of behavioral science to clinical reasoning.

Behavioral science, the scientific study of human behavior and the elucidation of its laws, is also applied to medicine, and is included in pre-graduate education.Understanding patient behaviors that correspond to behavior-based medical diagnosis and interpreting the clinical information suggested by these patient behaviors can be useful in avoiding diagnostic errors in clinical practice.

A controlled clinical trial comparing potent progestins, LNG-IUS and dienogest, for the treatment of women with adenomyosis.

PURPOSE: To evaluate the efficacy of two progestins, levonorgestrel intrauterine system (LNG-IUS) and dienogest (DNG), for adenomyosis. METHODS: This study enrolled 157 women with adenomyosis, randomized to either LNG-IUS (n = 76) or DNG (n = 81) groups as a controlled clinical trial for 72 months. Participants were classified by three different localizations of adenomyosis: diffuse, focal, and extrinsic. VAS (Visual analog scale) score, days, and amount of uterine bleeding were assessed. Uterine volume or bone mineral density (BMD) were measured by three-dimensional ultrasonography or dual-energy X-ray absorptiometry. RESULTS: LNG-IUS and DNG comparably reduced pain scores in patients with adenomyosis. With regard to pain control, DNG offered greater efficacy than LNG-IUS in 3 months of treatment. In all types of adenomyosis, the days of bleeding after 12 months with DNG were significantly decreased compared to those with LNG-IUS. The decrease of whole uterine body was transient in any subtypes. A comparable decrease in BMD due to age-related changes in both groups was observed. CONCLUSIONS: LNG-IUS and DNG could be useful for long-term management of adenomyosis. In terms of durations of uterine bleeding, DNG was superior to LNG-IUS for 6 years.

Effect of Baffle Clearance on Scale Deposition in an Agitated Vessel.

The material deposition in a mixing tank agitated by the MAXBLEND impeller in a turbulent state was quantified and compared between cases with and without baffle clearance. Magnesium hydroxide formed from the chemical reaction between calcium hydroxide and magnesium chloride was used as a model of scale formation. Flow velocity in the tank was investigated by employing computational fluid dynamics simulation and experimentally validated by an ultrasonic velocity profiler method. Results showed that the amount of scale decreased with the increase in the rotational speed of the impeller due to the erosion effect on the tank wall. In the case without baffle clearance, the smaller weight of the scale was deposited on the front of the baffle plate due to the flow impingement, which enhanced the removal of the scale deposition. However, the lower-velocity magnitude behind the baffles resulted in an enhancement in the formation of scale. Installation of baffle clearance caused a contraction flow in between the tank wall and baffles, and consequently, the higher flow velocity reduced the amount and thickness of the scale. Measurement of the torque showed that the baffle clearance did not affect the power consumption, so the installation of baffle clearance can be a promising approach to reduce scale deposition in terms of saving operational costs and increasing process efficiency and safety.

Physical findings and tests useful for differentiating lymphedema.

Stemmer's sign is useful in diagnosing lymphedema as it is present in 92% of the cases. Indocyanine green (ICG) lymphography is also useful for diagnosing lymphedema, and it allows them to see all the anatomy of the lymphatic vessels, leaking pumping capacity, and dermal reflux. The diagnostic ability of ICG lymphography and its evaluation capability for disease severity is similar to lymphoscintigraphy which is the gold-standard examination for extremity lymphoedema but with less invasiveness and a lower cost.

Successful discontinuation of biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis in real-world settings.

OBJECTIVES: To analyze the proportion of successful biological disease-modifying antirheumatic drugs (bDMARDs) discontinuation and related factors in patients with rheumatoid arthritis (RA) in clinical settings. METHODS: Among 1775 RA patients who started bDMARDs between 2003 and 2012, 43 patients with DAS28-ESR <3.2 at the time of bDMARD discontinuation were extracted. Patients were divided into two groups (bio-free success: BS and bio-free failure: BF groups) based on bDMARD usage and disease activity 1 year after discontinuation. We evaluated the proportion of bio-free success and assessed factors related to bio-free success. RESULTS: Twenty-five patients (58.1%: BS group) maintained discontinuation of bDMARDs and DAS28-ESR <3.2 at 1 year after discontinuation. The median DAS28-ESR at bDMARD initiation was lower in the BS group than in the BF group (3.95 vs 5.04; p = .04). The BS group experienced a larger decrease in average glucocorticoid (GC) dose during bDMARD use than the BF group (-3.0 mg/day vs 0 mg/day; p = .01). CONCLUSION: bDMARDs were discontinued without flare up of RA in 58.1% of patients with RA in clinical settings. A lower DAS28-ESR at initiation and reduction of GC dose before discontinuation of bDMARD were important factors associated with bio-free success.