Artificial intelligence-assisted ultrasound imaging in hemophilia: research, development, and evaluation of hemarthrosis and synovitis detection.

Background: Joint bleeding can lead to synovitis and arthropathy in people with hemophilia, reducing quality of life. Although early diagnosis is associated with improved therapeutic outcomes, diagnostic ultrasonography requires specialist experience. Artificial intelligence (AI) algorithms may support ultrasonography diagnoses. Objectives: This study will research, develop, and evaluate the diagnostic precision of an AI algorithm for detecting the presence or absence of hemarthrosis and synovitis in people with hemophilia. Methods: Elbow, knee, and ankle ultrasound images were obtained from people with hemophilia from January 2010 to March 2022. The images were used to train and test the AI models to estimate the presence/absence of hemarthrosis and synovitis. The primary endpoint was the area under the curve for the diagnostic precision to diagnose hemarthrosis and synovitis. Other endpoints were the rate of accuracy, precision, sensitivity, and specificity. Results: Out of 5649 images collected, 3435 were used for analysis. The area under the curve for hemarthrosis detection for the elbow, knee, and ankle joints was ≥0.87 and for synovitis, it was ≥0.90. The accuracy and precision for hemarthrosis detection were ≥0.74 and ≥0.67, respectively, and those for synovitis were ≥0.83 and ≥0.74, respectively. Analysis across people with hemophilia aged 10 to 60 years showed consistent results. Conclusion: AI models have the potential to aid diagnosis and enable earlier therapeutic interventions, helping people with hemophilia achieve healthy and active lives. Although AI models show potential in diagnosis, evidence is unclear on required control for abnormal findings. Long-term observation is crucial for assessing impact on joint health.

Factors Associated with Neutralizing Antibody Responses following 2-Dose and 3rd Booster Monovalent COVID-19 Vaccination in Japanese People Living with HIV.

People living with HIV (PLWH) could be at risk of blunted immune responses to COVID-19 vaccination. We investigated factors associated with neutralizing antibody (NAb) responses against SARS-CoV-2 and variants of concern (VOCs), following two-dose and third booster monovalent COVID-19 mRNA vaccination in Japanese PLWH. NAb titers were assessed in polyclonal IgG fractions by lentiviral-based pseudovirus assays. Overall, NAb titers against Wuhan, following two-dose vaccination, were assessed in 82 PLWH on treatment, whereby 17/82 (20.73%) were classified as low-NAb participants. Within the low-NAb participants, the third booster vaccination enhanced NAb titers against Wuhan and VOCs, albeit to a significantly lower magnitude than the rest. In the multivariate analysis, NAb titers against Wuhan after two-dose vaccination correlated with age and days since vaccination, but not with CD4+ count, CD4+/CD8+ ratio, and plasma high-sensitivity C-Reactive protein (hsCRP). Interestingly, an extended analysis within age subgroups revealed NAb titers to correlate positively with the CD4+ count and negatively with plasma hsCRP in younger, but not older, participants. In conclusion, a third booster vaccination substantially enhances NAb titers, but the benefit may be suboptimal in subpopulations of PLWH exhibiting low titers at baseline. Considering clinical and immune parameters could provide a nuanced understanding of factors associated with vaccine responses in PLWH.

Lifetime Follow-Up of a Patient with Metastatic Prostate Cancer Undergoing Multiple Surgical Resections: A Case Report.

BACKGROUND Prostate cancer (PC) often metastasizes after primary resection, and long-term survival following surgical removal of multiple pulmonary metastases is rare. We present a case of a surgeon who demonstrated long-term survival after overcoming repeated surgical challenges for multiple pulmonary metastases from PC. CASE REPORT Twenty-six years ago, a 62-year-old man initially reported discomfort during urination. A prostate examination revealed mildly elevated prostate-specific antigen (PSA) levels. Six months later, PC was diagnosed, and a radical prostatectomy was performed, revealing moderately differentiated adenocarcinoma but no vessel infiltration. At 9 years after the operation, three 10-mm nodules were detected in the right lung. Then, surgical biopsy by wedge pulmonary resection revealed metastatic PC, and therefore, right lower lobectomy including all nodules was planned. Although postoperative maintenance with luteinizing hormone-releasing hormone agonists kept the low PSA levels for 3 years, other newly limited metastases were observed in the opposite left lung, necessitating more surgeries of partial left lung resection. Six years later, a third lung metastasis was detected, as well as mild increases in the tumor size and PSA level, and the patient died 26 years after the initial PC intervention because of malnutrition for 1 year after sustaining bone compression fractures due to a fall, and not due to PC progression. CONCLUSIONS Repeated surgical resections for slow-growing metastatic pulmonary PC was an alternative treatment that facilitated favorable survival and a good quality of life for 26 years in the present case.

Haemophilia and cardiovascular disease in Japan: Low incidence rates from ADVANCE Japan baseline data.

INTRODUCTION: With the increasing life expectancy of people with haemophilia, the risk of cardiovascular disease (CVD) and thrombotic events has become a growing concern. Longitudinal studies on the incidence and risk factors of CVD in this population are limited, and optimal prevention and treatment strategies are yet to be established. AIM: This study aimed to present the baseline data of a prospective longitudinal study focusing on a subset of Japanese patients with haemophilia, specifically investigated the incidence, risk factors and treatment modalities for CVD and thrombotic diseases in people aged 40 years in Japan over 10 years through the ADVANCE Japan study. METHODS: The ADVANCE Japan study is a prospective multicentre cohort study involving 600 adult individuals with haemophilia A/B aged 40 years in Japan. The primary endpoint was the incidence of CVD, with secondary endpoints encompassing anticoagulant use, mortality rates, and comparison with the general population. RESULTS: Baseline data from the 600 participants revealed that thrombotic events occurred in 13 individuals (2.2%), mostly in those with haemophilia A. Atrial fibrillation was observed in 11 participants (1.8%). Hypertension and dyslipidaemia were identified as the prevalent risk factors. Various prophylactic treatments were employed, and no severe bleeding events were observed during the study period. CONCLUSION: This study provides vital baseline data for a 10-year prospective investigation of CVD and thrombotic disease risk in people with haemophilia. These findings will contribute to refining prevention and treatment approaches and improving patients' quality of life.

Relationship between CD4+ T-cell counts at baseline and initial periodontal treatment efficacy in patients undergoing treatment for HIV infection: A retrospective observational study.

AIM: To retrospectively investigate the relationship between the CD4+ T-cell counts at baseline and the efficacy of the initial periodontal treatment of patients undergoing treatment for human immunodeficiency virus (HIV) infection using the periodontal inflamed surface area (PISA). MATERIALS AND METHODS: Thirty-three patients with chronic periodontitis who had undergone periodontal examination at baseline and after the initial periodontal treatment were enrolled. PISA was calculated from the periodontal probing depth and bleeding on probing, and the ratio of PISA after treatment to that at baseline (PISA response ratio) was calculated. Groups with a response ratio of <1 and ≥1 were defined as the improvement and the non-improvement groups, respectively. RESULTS: PISA after the initial periodontal treatment significantly decreased compared with that at baseline (p < .05). A weak negative correlation was found between the PISA response ratio and CD4+ T-cell counts at baseline (p < .05). The CD4+ T-cell counts at baseline were significantly higher in the improvement group than in the non-improvement group (p < .05). Multivariate analysis revealed that the CD4+ T-cell counts at baseline was an independent factor that affects the PISA (p < .05). CONCLUSIONS: The higher the CD4+ T-cell counts at baseline in patients undergoing treatment for HIV infection, the more effective the initial periodontal treatment.

The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs.

Adeno-associated virus (AAV) vectors are promising modalities of gene therapy to address unmet medical needs. However, anti-AAV neutralizing antibodies (NAbs) hamper the vector-mediated therapeutic effect. Therefore, NAb prevalence in the target population is vital in designing clinical trials with AAV vectors. Hence, updating the seroprevalence of anti-AAV NAbs, herein we analyzed sera from 100 healthy individuals and 216 hemophiliacs in Japan. In both groups, the overall seroprevalence against various AAV serotypes was 20%-30%, and the ratio of the NAb-positive population increased with age. The seroprevalence did not differ between healthy participants and hemophiliacs and was not biased by the concomitant blood-borne viral infections. The high neutralizing activity, which strongly inhibits the transduction with all serotypes in vitro, was mostly found in people in their 60s or of older age. The multivariate analysis suggested that "60s or older age" was the only independent factor related to the high titer of NAbs. Conversely, a large proportion of younger hemophiliacs was seronegative, rendering them eligible for AAV-mediated gene therapy in Japan. Compared with our previous study, the peak of seroprevalences has shifted to older populations, indicating that natural AAV exposure in the elderly occurred in their youth but not during the last decade.

Discrepancies in preferences regarding the care of terminal-phase pneumonia in elderly patients among patients, families, and doctors: A multicenter questionnaire survey in nagasaki, Japan.

BACKGROUND: Before advance care planning, it is essential to understand the differences in preferences for medical care of terminal-phase pneumonia in elderly patients among the patients, their families, and their doctors. This study aimed to clarify these differences and investigate the actual care provided to elderly patients with pneumonia in nursing hospitals. METHODS: Multicenter questionnaire surveys of 179 patients admitted to nursing homes and long-term care beds in hospitals of three healthcare corporations, their families, and their physicians were conducted between January and August 2018. The questionnaires mainly assessed preferences for life-prolonging medical care procedures, including antibiotic treatments, in terminal-phase pneumonia. A follow-up survey regarding the prognosis and the actual care provided by the physicians was conducted 1 year after the first survey. RESULTS: Only 16.2% of the patients had sufficient prior discussions with their families about their care. More families preferred cardiac massage, intubation, and tracheostomy, while fewer families preferred peripheral intravenous fluids or antibiotics than physicians. A total of 30 patients' families (16.7%) answered to withhold antibiotic treatment, while all physicians supported antibiotic administration. The only significant factor related to withholding antibiotics was high age (P = 0.0057). The follow-up survey administered to the doctors revealed that 49 patients (35.7%) had died within one year. Of the 137 patients, 54 patients (39.4%) had developed pneumonia during this observation period and all were treated with antibiotics. CONCLUSIONS: This study revealed large discrepancies between patients/families and physicians regarding preferences for care. Medical staff should make efforts to fill the gap by ensuring advance care planning.

Factors Influencing Functional Exercise Capacity After Lung Resection for Non-Small Cell Lung Cancer.

Purpose: We investigated, in patients who underwent lung resection for non-small cell lung cancer (NSCLC), the magnitude of early limitation in functional exercise capacity and the associations with pre- and postoperative factors. Methods: Consecutive patients with preoperative clinical stage I to IIIA NSCLC who underwent lung resection were prospectively enrolled. We measured functional exercise capacity (6-minute walk distance [6MWD]) and skeletal muscle strength (handgrip [HF] and quadriceps force [QF]) within 2 days prior to surgery and on day 7 postoperatively. Results: Two hundred eighteen participants were recruited (median age 69 years) of whom 49 developed postoperative complications (POCs). 6MWD was markedly decreased (514 m vs 469 m, P < .001); HF and QF were slightly decreased following surgery. Multiple linear regression showed that preoperative vital capacity (P < .01), QF (P < .05), the duration of chest tube drainage (P < .001), and presence of POCs (P < .05) were significant predictors. However, intraoperative factors were not significantly associated with the decline in 6MWD. Conclusions: These results suggest that patients with preoperative impairments in pulmonary function and muscle strength, and those who require prolonged chest tube drainage or develop POCs are likely to have impaired exercise capacity. Therefore, individual assessment and follow-up of patients with such factors is indicated.

Successful treatment based on molecular biological assessment of invasive anaplastic lymphoma kinase-positive inflammatory myofibroblastic tumor of the lung.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) of the lung is rare. This disease often shows neoplastic features with anaplastic lymphoma kinase positiveness as well as inflammatory features, such as steroid-responsive immunoglobulin G4 (IgG4)-related sclerosing disease. Since many cases have been reported as advanced, various treatment strategies should be considered based on clinical and biological features of each case. CASE PRESENTATION: We report a 49-year-old male with IMT, which seemed invading the left atrium from preoperative imaging modalities. Serological and pathological examinations from the biopsy specimen revealed high expression of anaplastic lymphoma kinase expression in the tumor. On the other hand, IgG4/IgG ration in the tumor was small, where a therapeutic effect of steroid was not expected, leading to surgical treatment rather than a steroid administration. The tumor was completely resected en bloc with the right lower lobe of the lung and a part of the left atrium. The postoperative course of the patient was uneventful. The patient has remained recurrence free over 5 years from the surgery. CONCLUSION: In this case, preoperative biological assessment prior to the treatment led to a good clinical course. We believe that molecular biological examination is important in the determination of treatment strategy for this rare disease as well as imaging modalities.

Ischaemic events are rare, and the prevalence of hypertension is not high in Japanese adults with haemophilia: First multicentre study in Asia.

INTRODUCTION: With the increasing life expectancy of patients with haemophilia (PWH), the number of PWH with age-related comorbidities, such as ischaemic events, is increasing. AIM: We conducted this multicentre observational study to identify the risk factors for major ischaemic events in PWH. METHODS: This study was the first multicentre observational study, conducted with the participation of five haemophilia treatment centres in Japan, conducted in ≥30-year-old adult PWH. The latest data recorded in the medical charts between 1 January and 31 December 2016 were reviewed. Healthcare data collected from the National Health and Nutrition Survey were used as the control data. RESULTS: Data of a total of 711 patients were collected. Only two PWH (0.3%) had a history of ischaemic events. Age-adjusted analysis indicated that the prevalence of hypertension defined as a blood pressure of 140/90 mm Hg or over was similar in the PWH to that in the males of the general population. However, when hypertension was defined more strictly (≥130/85 mm Hg), the prevalence was significantly lower in PWH than in the general male population. The hypertension in PWH was associated with the age, BMI, CKD, HIV infection and inhibitors. In particular, the odds ratio for the presence of inhibitors was high (odds ratio = 7.529). CONCLUSION: Whether the present results can be attributed to Japanese ethnicity or to the presence of haemophilia per se remains uncertain. We propose to initiate a prospective study for further investigation.

Correction: Regeneration of esophagus using a scaffold-free biomimetic structure created with bio-three-dimensional printing.

[This corrects the article DOI: 10.1371/journal.pone.0211339.].

Regeneration of esophagus using a scaffold-free biomimetic structure created with bio-three-dimensional printing.

Various strategies have been attempted to replace esophageal defects with natural or artificial substitutes using tissue engineering. However, these methods have not yet reached clinical application because of the high risks related to their immunogenicity or insufficient biocompatibility. In this study, we developed a scaffold-free structure with a mixture of cell types using bio-three-dimensional (3D) printing technology and assessed its characteristics in vitro and in vivo after transplantation into rats. Normal human dermal fibroblasts, human esophageal smooth muscle cells, human bone marrow-derived mesenchymal stem cells, and human umbilical vein endothelial cells were purchased and used as a cell source. After the preparation of multicellular spheroids, esophageal-like tube structures were prepared by bio-3D printing. The structures were matured in a bioreactor and transplanted into 10-12-week-old F344 male rats as esophageal grafts under general anesthesia. Mechanical and histochemical assessment of the structures were performed. Among 4 types of structures evaluated, those with the larger proportion of mesenchymal stem cells tended to show greater strength and expansion on mechanical testing and highly expressed α-smooth muscle actin and vascular endothelial growth factor on immunohistochemistry. Therefore, the structure with the larger proportion of mesenchymal stem cells was selected for transplantation. The scaffold-free structures had sufficient strength for transplantation between the esophagus and stomach using silicon stents. The structures were maintained in vivo for 30 days after transplantation. Smooth muscle cells were maintained, and flat epithelium extended and covered the inner surface of the lumen. Food had also passed through the structure. These results suggested that the esophagus-like scaffold-free tubular structures created using bio-3D printing could hold promise as a substitute for the repair of esophageal defects.

Concurrent chemoradiotherapy using cisplatin and S-1, followed by surgery for stage II/IIIA non-small cell lung cancer.

OBJECTIVES: Because chemoradiotherapy using cisplatin and S-1, an oral fluoropyrimidine, is effective for unresectable non-small cell lung cancer (NSCLC), an induction setting was used in a multicenter phase II study (Clinical trial number: UMIN000008205). The correlations of relapse and clinicopathological factors were analyzed. METHODS: We defined locally advanced NSCLC as pathologically proven chest wall invasion or hilar and/or mediastinal lymph node metastases by endobronchial ultrasound-guided transbronchial needle aspiration. The patients received two courses of S-1 administration for 14 days and intravenous cisplatin injection on day 8. A total dose of 40 Gy radiotherapy was concurrently received. Surgical resection was performed after completion of the treatment. RESULTS: Of the 23 eligible patients, 18 had stage IIIA and 5 had stage IIB NSCLC. Twenty of the eligible patients (87.0%) completed the regimen. Six (26.1%) complete responses were identified and 12 cases (52.2%) were histopathologically downstaged by induction chemoradiotherapy (ICRT). The 3-year overall survival rate was 58.1% and relapse-free survival (RFS) rate was 52.0%, respectively. Among several clinicopathological parameters, univariate RFS analysis identified that only downstaging was significantly associated with longer RFS times (p = 0.003). The radiological response did not reflect pathological response. When the variables of preoperative pathologically proven N2 metastasis, pathological ICRT effectiveness, and downstaging were included in the Cox proportional hazard modes, only the parameter of downstaging displayed significant hazard ratio (hazard ratio 0.13, p = 0.010). CONCLUSION: This protocol is considered an option among preoperative therapies and has obvious benefits for pathologically downstaged cases. CLINICAL TRIAL NUMBER: UMIN000008205. TRIAL REGISTRATION DATE: June 19, 2012.

Replacement of Rat Tracheas by Layered, Trachea-Like, Scaffold-Free Structures of Human Cells Using a Bio-3D Printing System.

Current scaffold-based tissue engineering approaches are subject to several limitations, such as design inflexibility, poor cytocompatibility, toxicity, and post-transplant degradation. Thus, scaffold-free tissue-engineered structures can be a promising solution to overcome the issues associated with classical scaffold-based materials in clinical transplantation. The present study seeks to optimize the culture conditions and cell combinations used to generate scaffold-free structures using a Bio-3D printing system. Human cartilage cells, human fibroblasts, human umbilical vein endothelial cells, and human mesenchymal stem cells from bone marrow are aggregated into spheroids and placed into a Bio-3D printing system with dedicated needles positioned according to 3D configuration data, to develop scaffold-free trachea-like tubes. Culturing the Bio-3D-printed structures with proper flow of specific medium in a bioreactor facilitates the rearrangement and self-organization of cells, improving physical strength and tissue function. The Bio-3D-printed tissue forms small-diameter trachea-like tubes that are implanted into rats with the support of catheters. It is confirmed that the tubes are viable in vivo and that the tracheal epithelium and capillaries proliferate. This tissue-engineered, scaffold-free, tubular structure can represent a significant step toward clinical application of bioengineered organs.

Balloon-Based Organ Retractor With Increased Safety and Reduced Invasiveness During Video-Assisted Thoracoscopic Surgery.

OBJECTIVES: In recent years, video-assisted thoracoscopic surgery (VATS) has increasingly become the preferred technique for thoracic surgery. However, the inherent characteristics of the lungs as large, soft, slippery, and delicate creates difficulties for pulmonary surgery. In this article, we outline the development and assessment of a balloon-based organ retractor for VATS via collaboration between medical and engineering personnel. METHODS: A dry lab trial and accompanying questionnaire assessment were performed by a group of thoracic surgeons. Objective pressure measurements were obtained, and animal experiment on pigs was performed. RESULTS: In the dry lab trial, use of the developed organ retractor required significantly less time and resulted in fewer difficulties than using a Cherry Dissector. The measured pressure per mm2 of the developed retractor was clearly lower than that for the Cherry Dissector. The questionnaire completed by the surgeons following the dry lab and animal experiments showed that most of the surgeons (7 surgeons out of 9) were satisfied with the quality of the balloon-based retractor based on a score of 3.13 ± 0.28 (mean ± standard deviation) out of 4.0. During the animal experiment, the balloon-based retractor provided stable and clear viewing with minimal need for adjustment. CONCLUSION: This balloon-based retractor could contribute to increased safety and less-invasive VATS.

Adenocarcinoma arising from an enteric cyst of the posterior mediastinum.

Mediastinal enteric cysts are rare congenital thoracic cysts. The majority of mediastinal enteric cysts occur in infants, while they are rare in adults. Although most of these cysts are benign, surgical resection is sometimes performed, and malignant changes found in enteric cysts are rare. A 52-year-old man was incidentally discovered to have a posterior mediastinal mass and we excised the mass thoracoscopically. Histopathological findings showed an enteric cyst with adenocarcinoma. Comparing the pathological and magnetic resonance imaging (MRI) findings, MRI would help to detect malignant changes in such cysts. Although malignant changes found in mediastinal enteric cysts are extremely rare, clinicians should always keep in mind that those cysts have malignant potential and careful evaluation of MRI would be a clue for surgical indication.

Three-dimensional (3D) bronchial tree model for bronchial resection with pulmonary segmentectomy.

There has been an increase in pulmonary segmentectomy procedures because of increased numbers of individuals with small lung cancer. However, it is difficult to identify the correct bronchus during surgery even with pre-operative three-dimensional (3D) computed tomography. We investigated using a 3D-printed model of the bronchi to prepare for bronchus resection during pulmonary segmentectomy. The model was useful to determine pre-operatively which bronchus should be transected, and being composed of a soft material it could be mobilized similarly to the actual bronchus during surgery. This simulation can increase surgeons' confidence to identify the correct bronchus during pulmonary segmentectomy.

Initial experience with a 3D printed model for preoperative simulation of the Nuss procedure for pectus excavatum.

The incidence of pectus excavatum has been estimated to be between 0.1% and 0.8% though a large autopsy series reports. After publication of the Nuss procedure for pectus excavatum, it became widely accepted. However, there are still some complications, such as over-correction and recurrence. To reduce differences in the procedure due to surgeons' experience level, preoperative simulation may be useful. Thus, we performed simulated surgery using a specific patient's three-dimensional (3D) chest wall model made by a 3D printer before operation. A 13-year-old male patient with a severe deformity of the chest underwent the Nuss procedure. As in the simulation, bars were inserted into the 5th and 7th intercostal spaces (ICS), leading to improvement of the chest wall. This simulation can increase surgeons' confidence to improve the deformity by determination of the number and insertion sites of bars.