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A goal of regenerative medicine is to use induced pluripotent stem cells to generate an autologous graft for transplantation. This study tests the feasibility of the approach to treat age-related macular degeneration. Age-related macular degeneration (AMD) is one of the most prevalent retinal diseases that threaten vision in older populations in developed countries. 1 – 4 Neovascular (also called “wet”) AMD is more prevalent than atrophic (or “dry”) AMD in Japan 5 and is associated with the ectopic development of a choroidal neovascular membrane in the subretinal space of the center of the retina (the macula). Physical disruption and functional impairment of the retinal pigment epithelium (RPE), a monolayer sheet of cells that supports the overlying photoreceptors and underlying choroidal vasculature, occur in the course of wet AMD. 6 Current treatments of AMD that involve the . . .

Induced differentiation is one of the most experience- and skill-dependent experimental processes in regenerative medicine, and establishing optimal conditions often takes years. We developed a robotic AI system with a batch Bayesian optimization algorithm that autonomously induces the differentiation of induced pluripotent stem cell-derived retinal pigment epithelial (iPSC-RPE) cells. From 200 million possible parameter combinations, the system performed cell culture in 143 different conditions in 111 days, resulting in 88% better iPSC-RPE production than that obtained by the pre-optimized culture in terms of the pigmentation scores. Our work demonstrates that the use of autonomous robotic AI systems drastically accelerates systematic and unbiased exploration of experimental search space, suggesting immense use in medicine and research.

Immune attacks are key issues for cell transplantation. To assess the safety and the immune reactions after iPS cells-derived retinal pigment epithelium (iPS-RPE) transplantation, we transplanted HLA homozygote iPS-RPE cells established at an iPS bank in HLA-matched patients with exudative age-related macular degeneration. In addition, local steroids without immunosuppressive medications were administered. We monitored immune rejections by routine ocular examinations as well as by lymphocytes-graft cells immune reaction (LGIR) tests using graft RPE and the patient’s blood cells. In all five of the cases that underwent iPS-RPE transplantation, the presence of graft cells was indicated by clumps or an area of increased pigmentation at 6 months, which became stable with no further abnormal growth in the graft during the 1-year observation period. Adverse events observed included corneal erosion, epiretinal membrane, retinal edema due to epiretinal membrane, elevated intraocular pressure, endophthalmitis, and mild immune rejection in the eye. In the one case exhibiting positive LGIR tests along with a slight fluid recurrence, we administrated local steroid therapy that subsequently resolved the suspected immune attacks. Although the cell delivery strategy must be further optimized, the present results suggest that it is possible to achieve stable survival and safety of iPS-RPE cell transplantation for a year.

ABSTRACT Induced differentiation is one of the most experience- and skill-dependent processes in regenerative medicine, and establishing optimal conditions often takes years (an inordinate amount of time). Here, we developed a robotic-AI system that autonomously induces the differentiation of iPS cell-derived RPE (iPSC-RPE) cells. The system performed 216 forty-day cell culture experiments, with a total experimentation time of 8,640 days. The search for optimal differentiation conditions was accelerated using a novel batch Bayesian optimization technique with local penalization, compressing the search time to 185 days, with a cumulative robot operating time of 995 h. From 200 million possible parameter combinations, the system optimized the iPSC-RPE production conditions to yield improved pigmented scores that were up to 88% higher than the scores obtained with the pre-optimized conditions. Transferring tacit knowledge and skills often constitutes a serious obstacle when transposing basic cell experimental research from the laboratory to the medical forefront or for scaling to mass production. Our work demonstrates that autonomous robotic-AI systems can be effectively utilized for the systematic exploration of experimental conditions independently from the tacit knowledge of skilled professionals. This option guarantees immense use in future research. Competing Interest Statement G.N.K., T.K., M.K., K.M., and T.N. are employees, executives, or stakeholders of Robotic Biology Institute Inc., which may benefit financially from the increased scientific use of LabDroid Maholo. T.T., C.T.W., T.H., S.H., T.S., Y.O., and K.T. are employees, shareholders, or stakeholders of Epistra Inc., which may benefit financially from the increased scientific use of developed software. All other authors declare no competing interests. Footnotes * ↵✉ Contact authors

BackgroundHuman papillomavirus (HPV) testing using self-collected vaginal samples and urine samples is convenient and effective for improving the screening rate. But, to serve as an alternative cervical cancer screening technique, such tests must offer sensitivity equivalent to the HPV testing of physician-collected cervical samples. To examine the effectiveness of HPV testing using self-collected samples and urine samples, we compared the results of HPV testing using these samples with those of HPV testing using physician-collected samples and cytological examinations.MethodsThe study population included 300 women (age: 20–50 years) with abnormal cervical cytology. The results of HPV testing using self-collected samples and urine samples and physician-collected samples and cervical cytology were compared.ResultsFor all HPV types, the κ-value was 0.773 for physician- and self-collected samples and 0.575 for physician-collected and urine samples. The κ-value for HPV type 16-positive samples was 0.988 for physician- and self-collected samples and 0.896 for physician-collected and urine samples. The κ-value for HPV type 18-positive samples was 0.856 for physician- and self-collected samples and 0.831 for physician-collected and urine samples. For other HPV types, the value was 0.809 for physician- and self-collected samples and 0.617 for physician-collected and urine samples.ConclusionsThe obtained results were consistent between physician- and self-collected samples as well as between physician-collected and urine samples. Considering that the agreement rate was particularly high for the high-risk HPV types 16 and 18, HPV testing using physician-collected samples, self-collected samples, and urine samples was equally effective for the types with high carcinogenicity.

Background One cause of the increase in cervical cancer rates in Japan is the long-term stagnation in the cervical cancer screening consultation rate. Therefore, improving the screening consultation rate is of urgent concern to reduce cervical cancer incidence. Self-collected human papilloma virus (HPV) tests have been successfully adopted in several countries, such as the Netherlands and Australia, as a measure of individuals who have not undergone cervical cancer screening in national programs. This study aimed to verify whether self-collected HPV tests presented an effective countermeasure for individuals who had not undergone the recommended cervical cancer screenings. Methods This study was conducted from December 2020 to September 2022 in Muroran City, Japan. The primary evaluated endpoint was the percentage of citizens who underwent cervical cancer screening at a hospital with positive self-collected HPV test results. The secondary endpoint was the percentage of included participants who were diagnosed with cervical intraepithelial neoplasia (CIN) or higher among those who visited a hospital and underwent cervical cancer screening. Results The included study participants were 7,653 individuals aged 20–50 years with no record of previous cervical cancer examination in the past 5 years. We mailed these participants information on self-administered HPV tests as an alternative screening procedure and sent the kit to 1,674 women who requested the test. Among them, 953 returned the kit. Among the 89 HPV-positive individuals (positive rate, 9.3%), 71 (79.8%) visited the designated hospital for an examination. A closer examination revealed that 13 women (18.3% of hospital visits) had a CIN finding of CIN2 or higher, among whom one each had cervical cancer and vulvar cancer, eight presented with CIN3, and three presented with CIN2; two cases of invasive gynecologic cancer were also identified. Conclusions We conclude that the self-collected HPV tests showed a certain efficacy as a measure of individuals who had not undergone the recommended cervical cancer screening. We devised ways to have the unexamined patients undergo HPV testing and ensure that HPV-positive individuals visited the hospital. Despite a few limitations, our findings suggest the effectiveness of this public health intervention.

PurposePre-operative prediction of histological response to neoadjuvant therapy aids decisions regarding surgical management of borderline resectable pancreatic cancer (BRPC). We elucidate correlation between pre-/post-treatment whole-tumor apparent diffusion coefficient (ADC) value and rate of tumor cell destruction. We newly verify whether post-treatment ADC value at the site of vascular contact predicts R0 resectability of BRPC.MethodsWe prospectively reviewed 28 patients with BRPC who underwent diffusion-weighted magnetic resonance imaging before neoadjuvant chemotherapy and surgery. Correlation between the percentage of tumor cell destruction and various parameters was analyzed. Strong parameters were assessed for their ability to predict therapeutic histological response and R0 resectability.ResultsPre-/post-treatment whole-tumor ADC value correlated with tumor cell destruction rate by all parameters (R = 0.630/0.714, P < 0.001/< 0.0001). The post-treatment cutoff value of ADC at the site of vascular contact for discriminating histological response of tumor destruction of ≤ 50% and tumor destruction of > 50% was determined at 1.42 × 10−3 mm2/s. It predicts R0 with 88% sensitivity, 50% specificity, and 61% accuracy. For histological response, the post-treatment whole-tumor ADC cutoff value for discriminating between tumor destruction of ≤ 50% and tumor destruction of > 50% was determined at 1.40 × 10−3 mm2/s. It predicts histological response with 100% sensitivity, 81% specificity, and 89% accuracy. It predicts R0 with 88% sensitivity, 70% specificity, and 75% accuracy.ConclusionsPost-treatment whole-tumor ADC value may be a predictor of R0 resectability in patients with BRPC. Tumor cell destruction rate is indicated by the difference between pre-/post-treatment ADC values. This difference is strongly affected by the pre-treatment ADC value. The cutoff value of ADC at the site of vascular contact could not discriminate R0 resectability.

Objective The impact of the coronavirus disease 2019 (COVID‐19) pandemic on epilepsy care across Japan was investigated by conducting a multicenter retrospective cohort study. Methods This study included monthly data on the frequency of (1) visits by outpatients with epilepsy, (2) outpatient electroencephalography (EEG) studies, (3) telemedicine for epilepsy, (4) admissions for epilepsy, (5) EEG monitoring, and (6) epilepsy surgery in epilepsy centers and clinics across Japan between January 2019 and December 2020. We defined the primary outcome as epilepsy center‐specific monthly data divided by the 12‐month average in 2019 for each facility. We determined whether the COVID‐19 pandemic‐related factors (such as year [2019 or 2020], COVID‐19 cases in each prefecture in the previous month, and a state of emergency) were independently associated with these outcomes. Results In 2020, the frequency of outpatient EEG studies (−10.7%, P < .001) and cases with telemedicine (+2608%, P = .031) were affected. The number of COVID‐19 cases was an independent associated factor for epilepsy admission (−3.75 × 10−3% per case, P < .001) and EEG monitoring (−3.81 × 10−3% per case, P = .004). Furthermore, a state of emergency was an independent factor associated with outpatient with epilepsy (−11.9%, P < .001), outpatient EEG (−32.3%, P < .001), telemedicine for epilepsy (+12,915%, P < .001), epilepsy admissions (−35.3%; P < .001), EEG monitoring (−24.7%: P < .001), and epilepsy surgery (−50.3%, P < .001). Significance We demonstrated the significant impact that the COVID‐19 pandemic had on epilepsy care. These results support those of previous studies and clarify the effect size of each pandemic‐related factor on epilepsy care.

We present long-term density trends of the Earth's upper atmosphere at altitudes between 71 and 116 km, based on atmospheric occultations of the Crab Nebula observed with X-ray astronomy satellites, ASCA, RXTE, Suzaku, NuSTAR, and Hitomi. The combination of the five satellites provides a time period of 28 yr from 1994 to 2022. To suppress seasonal and latitudinal variations, we concentrate on the data taken in autumn (49< doy <111) and spring (235< doy <297) in the northern hemisphere with latitudes of 0--40 degrees. With this constraint, local times are automatically limited either around noon or midnight. We obtain four sets (two seasons times two local times) of density trends at each altitude layer. We take into account variations due to a linear trend and the 11-yr solar cycle using linear regression techniques. Because we do not see significant differences among the four trends, we combine them to provide a single vertical profile of trend slopes. We find a negative density trend of roughly -5 %/decade at every altitude. This is in reasonable agreement with inferences from settling rate of the upper atmosphere. In the 100--110 km altitude, we found an exceptionally high density decline of about -12 %/decade. This peak may be the first observational evidence for strong cooling due to water vapor and ozone near 110 km, which was first identified in a numerical simulation by Akmaev et al. (2006). Further observations and numerical simulations with suitable input parameters are needed to establish this feature.