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Ge'ez has been used in Ethiopian churches for centuries to read and interpret the Bible. As a part of the liturgy and religious ceremonies, it is also utilized in prayer and chanting. Since the language is ancient, plenty of handwritten physical documents are generated. Recognizing handwritten Ge'ez numerals poses significant challenges due to variations in handwriting styles, incomplete or overlapping strokes, noise, and distortion. This study introduces an end-to-end approach for handwritten Ge'ez multiple numeral recognition employing deep neural networks. The proposed method streamlines recognition by eliminating manual feature extraction stages. To enable end-to-end training without explicit alignment, the model uses attention mechanisms and a connectionist temporal classification-based loss function. The proposed model is evaluated on 120,000 handwritten Ge'ez multiple numeral images, which is a syntactically generated dataset. The developed recognition model achieved a character error rate (CER) of 2.81% and a word error rate (WER) of 18.13%. These results highlight the effectiveness of the approach in accurately and reliably recognizing handwritten Ge'ez multiple numerals.

Despite the historical significance of the Ge’ez script, there is a notable scarcity of studies on Ge’ez digit recognition, compounded by the challenges posed by the absence of publicly accessible datasets. The complex structure of Ge’ez digits further complicates the recognition task. In response to this gap, our study addresses the development of a digit recognition model based on deep learning (DL) specifically tailored for printed Ge’ez digits, accompanied by the creation of a comprehensive study dataset. The proposed model architecture seamlessly integrates one input layer, six convolutional layers, and three Max-Pooling layers. To assess the model’s performance, we meticulously curated a Ge’ez digit dataset comprising 72,000 images, well-suited for DL applications using the ocropus-linegen model within OCRopus, a free document analysis tool. Leveraging cutting-edge DL algorithms, our proposed model demonstrates an impressive accuracy of 97.29%. This surpasses the performance of previous Ge’ez digit recognition models, marking a noteworthy advancement in this underexplored domain.

Amharic stands as the second most widely spoken Semitic language globally, trailing only Arabic. As a result, it is a highly resourceful language for hardcopy-document collection, and automatic recognition technology is required. Recognizing handwritten Amharic words is a difficult task because of factors such as variations in individual handwriting for the same words, connectivity of two words without spaces, similarities in the shapes of alphabet characters, and noise from scanned images. The Amharic alphabet has a vast character set that adapted most of its characters from the most popular script called Ethiopic script, formerly known as Ge’ez script, and added unique characters. Despite significant advancements in optical character recognition (OCR) research, Amharic script recognition has received less attention. This study employs a deep learning (DL) approach with additive attention to recurrent neural networks (RNN) to achieve precise recognition of handwritten Amharic words. Seven convolutional neural networks (CNN) and two RNN, using a connectionist temporal classification (CTC) strategy, make up this recognition model architecture, enabling efficient recognition through sequential feature extraction. The study addressed deep learning data insufficiency by using augmentation techniques to increase datasets. The study used an original dataset of 12,047 handwritten Amharic words and an augmented dataset of 22,00 images. The developed model achieved an average character error rate (CER) of 2.84% and an average word error rate (WER) of 9.75% for the testing dataset. These results are indeed promising, offering a glimpse into the potential of this attention-based approach for handwritten Amharic word recognition. This research represents a significant step toward bridging the gap in OCR technology for Amharic script and showcases the transformative capabilities of DL in pattern recognition.

Recognizing handwritten text is a challenging task, especially for scripts with numerous alphabets and symbols. The Ethiopic script has a vast character set and is used for historical documents in typewritten, handwritten, and hand-printed forms. However, despite its importance as an ancient script, optical character recognition research has not given enough attention to Ethiopic text recognition. In recent years, deep learning (DL) has emerged as a powerful technique for recognizing patterns. In this study, a DL approach is used to recognize historical Ethiopic handwritten texts. The recognition model employs an end-to-end strategy enabling sequential feature extraction and efficient recognition. An attention mechanism coupled with a connectionist temporal classification architecture is the core of this recognition model architecture. In addition, there are seven convolutional neural networks and two recurrent neural networks. We increase the training data using data augmentation techniques to address the data scarcity common in deep learning applications. The experiments include an original training dataset of 79,684 historical handwritten images and an augmented dataset of 10,000 images containing Ethiopic texts. The model used for recognition showed promising results. For “Test Set I” which had 6,150 samples, the character error rate (CER) was 17.95%, and for “Test Set II” which had 15,935 samples, the CER was 29.95%. These outcomes indicate that this approach has the potential to improve the recognition of historical handwritten Ethiopic text.

Kidney transplant (KT) requires long-term glucocorticoid (GC) treatment against acute and/or chronic rejection. Glucocorticoid-induced osteoporosis (GIOP) is one of the major concerns in kidney transplant recipients (KTRs). Therefore, it is essential to accumulate GIOP data from paediatric KTRs to aid in their healthy growth. A serial observational study of bone strength was carried out in an 8-year-old girl with bilateral hypoplastic kidney who underwent ABO-compatible living-donor KT and GC treatment over 2 years. Bone strength was evaluated by bone mineral density (BMD) and serum bone turnover markers (BTMs), including serum alkaline phosphatase (S-ALP), serum tartrate-resistant acid phosphatase 5b (S-TRACP-5b), and serum undercarboxylated osteocalcin (S-ucOC). All the levels of BTMs and BMD from 1 M to 4 M remained lower than the levels at 0 months (0 M: baseline). After gradual reduction of GC dose (4 M-24 M), S-ALP levels increased from baseline and S-TRACP-5b levels remained lower than the baseline level, but BMD recovered to baseline and increased. The S-ucOC levels did not increase from baseline. The patient's height growth velocity SDS was +3.99 for 23 months, and no fracture occurred during this observation period. A consistent, predominantly formative state of bone, which maintained higher S-ALP levels and lower S-TRACP-5b levels compared to baseline, could contribute to increased BMD. In addition, no increase in S-ucOC levels from baseline could be associated with no deterioration of bone strength. This case suggests that measurement of BMD and, S-ALP, TRACP-5b and ucOC could be useful for evaluating the trend on bone strength in a paediatric KTR., (© 2024 Asian Pacific Society of Nephrology.)

In kidney transplant recipients (KTRs), viral infection can lead to antibody and/or T-cell mediated rejection, resulting in kidney transplant dysfunction. Therefore, it is critical to prevent infections. However, KTRs exhibit suboptimal responses to SARS-CoV-2 and/or influenza vaccines, partly due to immunosuppressant therapy. Inter- and intra-individual differences in the biological responses to vaccines may also affect patients' antibody production ability. This study included KTRs who received an messenger RNA SARS-CoV-2 vaccine (3 doses), and an inactivated quadrivalent influenza vaccine (1 or 2 doses). We measured the patients' total antibody titers against SARS-CoV-2 spike antigen, and hemagglutination inhibition (HI) titers against influenza A/H1N1, A/H3N2, B/Yamagata, and B/Victoria. Five patients were eligible for this study. Of these 5 KTRs, two produced anti-SARS-CoV-2 spike antibody titers to a seroprotective level, and also produced HI titers against A/H1N1 to a seroprotective level. Another 2 KTRs did not produce seroprotective anti-SARS-CoV-2 antibody titers, but produced seroprotective HI titers against A/H1N1. The remaining KTR produced a seroprotective anti-SARS-CoV-2 antibody titer, but did not produce a seroprotective HI titer against A/H1N1. The 2 KTRs who did not produce seroprotective anti-SARS-CoV-2 antibody titers following vaccination, later developed COVID-19, and this infection increased their titers over the seroprotective level. This study demonstrated that inter- and intra-individual differences in biological responses to vaccines should be considered in pediatric KTRs, in addition to immunosuppressant effects. Personalized regimens, such as augmented or booster doses of vaccines, could potentially improve the vaccination efficacy against SARS-CoV-2 and influenza., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The purpose of this study was to clarify the structural relationship of quality of life (QOL) in survivors of breast cancer, including difficulty in daily life and negative experiences in daily activities, as health-related indicators., Methods: Participants were survivors of breast cancer for more than 2 years after primary breast cancer surgery and belonged to self-help groups. The assessment used FACT-B (QOL), HADS (anxiety and depression), SOC (sense of coherence), WHODAS 2.0 (difficulties in daily life), and CAOD (negative experiences in daily activities). Bayesian structural equation modeling (BSEM) was performed to analyze the hypothesized model. If the causal model was significant, multiplication of the path coefficient from emotional distress (anxiety and depression) to QOL, and from SOC to emotional distress, was considered a direct effect on QOL, and from SOC to difficulty in daily life, from difficulty in daily life to negative experiences in daily activities, and from negative experiences in daily activities to anxiety and depression were considered indirect effects on QOL., Results: The participants comprised 73 survivors of breast cancer. The goodness of fit of the model in the BSEM was satisfactory. The direct effect was 0.274, and the indirect effect was 0.164., Conclusions: An additional finding of this study is that coping with difficulty in daily life and negative experiences in daily activities related to QOL may improve QOL.

Background: Early decompressive surgery within 24 hours improves the functional outcome of patients with traumatic spinal cord injury; however, little is known about the effect of early surgery for spontaneous spinal epidural hematoma (SSEH). In this study, we aimed to investigate the effectiveness of ultraearly hematoma evacuation (<12 hours) for SSEH., Methods: Patients with SSEH treated with surgical hematoma evacuation at our institution between January 2000 and July 2021 were retrospectively analyzed. Neurologic function was evaluated using the American Spinal Injury Association Impairment Scale (AIS). AIS grades A-C were defined as severe, and grades D and E as mild. AIS grades D and E at the final follow-up were considered favorable outcomes. Preoperative status and postoperative treatment results were compared between patients who had hematoma evacuation within 12 hours of onset and those who underwent surgery after 12 hours., Results: Twenty-five consecutive patients were included in the analysis. Preoperatively, 23 patients (92.0%) had severe AIS. Fourteen (56.0%) patients underwent early surgery. At the final follow-up, 21 patients (84.0%) achieved favorable outcomes. Patients treated with ultraearly surgery had significantly better outcomes (100% vs. 63.6%, P = 0.03). Additionally, the time from onset to surgery was significantly shorter in patients with AIS improvement by 2 or more grades than that in patients with AIS improvement of 1 or less (median 8 hours vs. 14 hours, P = 0.0001)., Conclusions: Ultraearly surgery within 12 hours for SSEH was associated with better functional outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Diarrheal illnesses are a long-standing public health problem in developing countries due to numerous sanitation issues and a lack of safe drinking water. Floods exacerbate public health issues by spreading water-borne infectious diseases such as diarrhea through the destruction of sanitation facilities and contamination of drinking water. There has been a shortage of studies regarding the magnitude of diarrheal disease in flood-prone areas. Therefore, this research aimed to evaluate the prevalence of diarrheal disease and its predictors among under-five children living in flood-prone localities in the south Gondar zone of Northwest Ethiopia., Method: A community-based cross-sectional research was carried out in flood-prone villages of the Fogera and Libokemkem districts from March 17 to March 30, 2021. Purposive and systematic sampling techniques were used to select six kebeles and 717 study units, respectively. Structured and pretested questionnaires were used to collect the data. A multivariable analysis was performed to determine the predictors of diarrheal disease, with P -value <0.05 used as the cut-off point to declare the association., Result: The prevalence of a diarrheal disease among under-five children was 29.0%. The regular cleaning of the compound [AOR: 2.13; 95% CI (1.25, 3.62)], source of drinking water [AOR: 2.36; 95% CI: (1.26, 4.41)], animal access to water storage site [AOR: 3.04; 95% CI: (1.76, 5.24)], vector around food storage sites [AOR: 9.13; 95% CI: (4.06, 20.52)], use of leftover food [AOR: 4.31; 95% CI: (2.64, 7.04)], and fecal contamination of water [AOR: 12.56; 95% CI: (6.83, 23.20)] remained to have a significant association with diarrheal diseases., Conclusion: The present study found that the prevalence of the diarrheal disease among under-five children was high. Routine compound cleaning, the source of drinking water, animal access to a water storage site, vectors near food storage sites, consumption of leftover food, and fecal contamination of water were significant predictors of diarrheal disease. Therefore, it is advised to provide improved water sources, encourage routine cleaning of the living area, and offer health education about water, hygiene, and sanitation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Birhan, Bitew, Dagne, Amare, Azanaw, Genet, Engdaw, Tesfaye, Yirdaw and Maru.)

We report the discovery of two compounds, TKD150 and TKD152, that promote the aggregation of α-synuclein (aSN) using a real-time quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C-H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TKD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PA86, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of α-synucleinopathy-related diseases., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Gaucher disease (GD), the most common lysosomal storage disorders, is caused by GBA gene mutations resulting in glycosphingolipids accumulations in various tissues, such as the brain. While suppressing glycosphingolipid accumulation is the central strategy for treating peripheral symptoms of GD, there is no effective treatment for the central nervous system symptoms. As glycosphingolipid biosynthesis starts from ceramide glycosylation by glucosylceramide synthase (GCS), inhibiting GCS in the brain is a promising strategy for neurological GD. Herein, we discovered T-036, a potent and brain-penetrant GCS inhibitor with a unique chemical structure and binding property. T-036 does not harbor an aliphatic amine moiety and has a noncompetitive inhibition mode to the substrates, unlike other known inhibitors. T-036 exhibited sufficient exposure and a significant reduction of glucosylsphingolipids in the plasma and brain of the GD mouse model. Therefore, T-036 could be a promising lead molecule for treating central nervous system symptoms of GD., (© 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

The hERG channel is a voltage-gated potassium channel involved in cardiac repolarization. Off-target hERG inhibition by drugs has become a critical issue in the pharmaceutical industry. The three-dimensional structure of the hERG channel was recently reported at 3.8-Å resolution using cryogenic electron microscopy (cryo-EM). However, the drug inhibition mechanism remains unclear because of the scarce structural information regarding the drug- and potassium-bound hERG channels. In this study, we obtained the cryo-EM density map of potassium-bound hERG channel complexed with astemizole, a well-known hERG inhibitor that increases risk of potentially fatal arrhythmia, at 3.5-Å resolution. The structure suggested that astemizole inhibits potassium conduction by binding directly below the selectivity filter. Furthermore, we propose a possible binding model of astemizole to the hERG channel and provide insights into the unusual sensitivity of hERG to several drugs., Competing Interests: Declaration of interests H.O. and T. Maru are employees of Axcelead Drug Discovery Partners, Inc. R.I. is an employee of Daiichi Sankyo RD Novare Co., Ltd. K.Y. and S.I. are employees of Takeda Pharmaceutical Co., Ltd., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: Glucocorticoids (GC) are essential medicines for idiopathic steroid-sensitive nephrotic syndrome (ISSNS) and IgA nephropathy (IgAN), with good clinical results. However, they cause bone fragility. The aim of this study was to elucidate GC effects on bone strength assessed as bone mineral density (BMD) and bone quality, using bone turnover markers (BTM), in children with ISSNS or IgAN., Methods: Eleven children with ISSNS and 13 with IgAN were included. All the patients received GC treatment according to each protocol. The BMD and BTM-serum alkaline phosphatase (S-ALP), tartrate-resistant acid phosphatase 5b (S-TRACP-5b), and undercarboxylated osteocalcin (S-ucOC)-were measured from the initiation of steroid treatment (STx) to the end of STx in both groups., Results: In ISSNS, S-ALP and S-ucOC levels were decreased significantly at 1 month. BMD and S-TRACP-5b levels showed no significant change through this observation period. In IgAN, BMD and S-ALP levels were decreased significantly at 1 and 3 months, respectively, and recovered to baseline at 10 months after the initiation of GC dosage reduction. S-TRACP-5b levels were decreased significantly at 3 months and remained lower than at baseline through the observation period. In both groups, S-ucOC levels did not directly reflect bone strength., Conclusion: This study clarified the following three points regarding GC effects on bone strength in children with ISSNS or IgAN: first, S-ALP is a more sensitive bone quality marker than S-TRACP-5b; second, BMD loss was observed only when both S-ALP and S-TRACP-5b levels decreased, and third, S-ucOC levels do not directly reflect bone strength., (© 2020 Asian Pacific Society of Nephrology.)

In individuals treated with immunosuppressive therapies, the varicella-zoster virus (VZV) infection can become disseminated and lead to a life-threatening condition. There is currently no established treatment strategy for this life-threatening condition. Here, we describe a case where plasma exchange (PE) with a high dose of acyclovir (ACV) ameliorated the severe effects, including VZV-hemophagocytic lymphohistiocytosis (VZV-HLH) and disseminated intravascular coagulation (DIC), in a 9-year-old girl with steroid-dependent nephrotic syndrome. This 9-year-old girl experienced frequent relapse steroid-dependent nephrotic syndrome. She had been treated with steroids, tacrolimus, mizoribine, and rituximab. She had not previously received a varicella vaccine. She was admitted with only one vesicular rash. At admission, a serum test revealed 1.6 × 10 6 copies/mL of VZV DNA. The patient rapidly developed VZV-HLH and DIC. A combination of a high dose of ACV, immunoglobulin, and steroid pulse therapy could not improve these severe complications. Therefore, PE was applied. PE with a high dose of ACV successfully reduced serum VZV DNA from 7.5 × 10 6 to 2.8 × 10 4 copies/mL. This reduction in the VZV DNA copy number suggested that the combination of PE and a high dose of ACV was effective in treating a disseminated VZV infection. To the best of our knowledge, this is the first report showing that PE with a high dose of ACV ameliorated the severe complications of disseminated VZV by reducing the VZV DNA copy number.

The voltage-gated sodium channel, Na v 1.1, is predominantly expressed in parvalbumin-positive fast spiking interneurons and has been genetically linked to Dravet syndrome. Starting from a high throughput screening hit isoxazole derivative 5, modifications of 5 via combinations of IonWorks and Q-patch assays successfully identified the nicotinamide derivative 4. Its increasing decay time constant (tau) of Na v 1.1 currents at 0.03 μM along with significant selectivity against Na v 1.2, Na v 1.5, and Na v 1.6 and acceptable brain exposure in mice was observed. Compound 4 is a promising Na v 1.1 activator that can be used to analyze pathophysiological functions of the Na v 1.1 channel towards treating various central nervous system diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Affinity maturation is one of the cardinal strategies for improving antibody function using in vitro evolutionary methods; one such well-established method is phage display. To minimise gene deletion, we previously developed an open sandwich (OS) method wherein selection was performed using only phage-displaying VH fragments after mixing with soluble VL fragments. The decrease in anti-EGFR antibody 528 affinity through humanization was successfully recovered by selecting VH mutants using this OS method. However, the affinity was not similar to that of parental 528. For further affinity maturation, we aimed to isolate VL mutants that act in synergy with VH mutants. However, the OS method could not be applied for selecting VL fragments because the preparation of soluble VH fragments was hampered by their instability and insolubility. Therefore, we initially designed a modified OS method based on domain-swapping of VH fragments, from added soluble Fv fragments to phage-displaying VL fragments. Using this novel Fv-added OS selection method, we successfully isolated VL mutants, and one of the Fv comprising VH and VL mutants showed affinity almost equivalent to that of parental 528. This method is applicable for engineering other VL fragments for affinity maturation.

We herein describe a case of somatostatinoma coexisting with a gastrointestinal stromal tumor (GIST) in the duodenum of an 81-year-old woman with Von Recklinghausen's disease (VRD) and common bile duct stone who presented with diarrhea of three months in duration. Gastroduodenoscopy revealed an ulcer on the second part of the duodenum. A 2.1-cm enhancing tumor was observed to extend from the ulcer on an abdominal computed tomography scan. Subtotal stomach-preserving pancreaticoduodenectomy revealed a somatostatinoma on the papilla of the vater and duodenal GIST. There have been only eight reports on VRD associated with ampullary somatostatinoma and GIST. An awareness of this possibility in patients with gastrointestinal lesions is necessary for proper treatment and patient management.

Elucidating the detailed mechanism of activation of membrane protein receptors and their ligand binding is essential for structure-based drug design. Membrane protein crystal structure analysis successfully aids in understanding these fundamental molecular interactions. However, protein crystal structure analysis of the G-protein-coupled receptor (GPCR) remains challenging, even for the class of GPCRs which have been included in the majority of structure analysis reports among membrane proteins, due to the substantial instability of these receptors when extracted from lipid bilayer membranes. It is known that increased thermostability tends to decrease conformational flexibility, which contributes to the generation of diffraction quality crystals. However, this is still not straightforward, and significant effort is required to identify thermostabilized mutants that are optimal for crystallography. To address this issue, a versatile screening platform based on a label-free ligand binding assay combined with transient overexpression in virus-like particles was developed. This platform was used to generate thermostabilized GPR40 [also known as free fatty acid receptor 1 (FFAR1)] for fasiglifam (TAK-875). This demonstrated that the thermostabilized mutant GPR40 (L42A/F88A/G103A/Y202F) was successfully used for crystal structure analysis.

We showed previously that humanization of 528, a murine anti-epidermal growth factor receptor (EGFR) antibody, causes reduced affinity for its target. Here, to improve the affinity of the humanized antibody for use in cancer immunotherapy, we constructed phage display libraries focused on the complementarity-determining regions (CDRs) of the antibody and carried out affinity selection. Two-step selections using libraries constructed in a stepwise manner enabled a 32-fold affinity enhancement of humanized 528 (h528). Thermodynamic analysis of the interactions between the variable domain fragment of h528 (h528Fv) mutants and the soluble extracellular domain of EGFR indicated that the h528Fv mutants obtained from the first selection showed a large increase in negative enthalpy change due to binding, resulting in affinity enhancement. Furthermore, mutants from the second selection showed a decrease in entropy loss, which led to further affinity maturation. These results suggest that a single mutation in the heavy chain variable domain (i.e. Tyr(52) to Trp) enthalpically contributed for overcoming the energetic barrier to the antigen-antibody interaction, which was a major hurdle for the in vitro affinity maturation of h528. We reported previously that the humanized bispecific diabody hEx3 Db, which targets EGFR and CD3, shows strong anti-tumor activity. hEx3 Db mutants, in which the variable domains of h528 were replaced with those of the affinity-enhanced mutants, were prepared and characterized. In a growth inhibition assay of tumor cells, the hEx3 Db mutants showed stronger anti-tumor activity than that of hEx3 Db, suggesting that affinity enhancement of h528Fv enhances the anti-tumor activity of the bispecific diabody.