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As food transits the gastrointestinal tract, food structures are disrupted and nutrients are absorbed across the gut barrier. In the past decade, great efforts have focused on the creation of a consensus gastrointestinal digestion protocol (i.e., INFOGEST method) to mimic digestion in the upper gut. However, to better determine the fate of food components, it is also critical to mimic food absorption in vitro . This is usually performed by treating polarized epithelial cells (i.e., differentiated Caco-2 monolayers) with food digesta. This food digesta contains digestive enzymes and bile salts, and if following the INFOGEST protocol, at concentrations that although physiologically relevant are harmful to cells. The lack of a harmonized protocol on how to prepare the food digesta samples for downstream Caco-2 studies creates challenges in comparing inter laboratory results. This article aims to critically review the current detoxification practices, highlight potential routes and their limitations, and recommend common approaches to ensure food digesta is biocompatible with Caco-2 monolayers. Our ultimate aim is to agree a harmonized consensus protocol or framework for in vitro studies focused on the absorption of food components across the intestinal barrier.

Key Clinical Message: Successful management of a rare case involving both dens evaginatus and dens invaginatus in the same tooth, monitored over a 24-month follow-up., Abstract: Dens invaginatus (DI) is a congenital dental anomaly characterized by the presence of a tooth that resembles a "tooth within a tooth." Conversely, dens evaginatus (DE) is a developmental anomaly distinguished by an additional tubercle or cusp on the tooth's crown. Both DI and DE can result in pulpal and periapical diseases in the affected tooth. This article presents a case of a healthy 14-year-old male with recurrent swelling under the chin and a wound with pus drainage on the right side of the submental area, associated with his left mandibular lateral incisor affected by both DI and DE. Clinical and radiographic examinations revealed that the tooth was necrotic and had a chronic apical abscess. Cone beam computed tomography (CBCT) confirmed Oehlers' type III DI and a talon cusp on the lingual surface of the same tooth. The patient underwent orthograde endodontic treatment. Passive ultrasonic activation of a 5.25% NaOCl solution and a mixture of Ca(OH) 2 and a 2% chlorhexidine solution were utilized to effectively clean and eliminate the persistent pus discharge. After the resolution of the patient's symptoms, the apical third of the root canal and the invaginated space were filled with a plug of mineral trioxide aggregate (MTA), while the remaining root canal was filled using a sealer-based obturation technique. A 24-month follow-up visit revealed complete bone regeneration in the previously affected periradicular tissues., Competing Interests: None., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: The association between endometriosis and the outcome of pregnancy is one of the interesting topics. Endometriosis-related pain is alleviated with pregnancy; however, it is known to cause adverse outcomes in pregnancy. The main cause is systemic chronic inflammation caused by higher levels of cytokines, growth factors, and angiogenesis factors., Objective: This study aimed to clarify the relationship between endometriosis, deep endometriosis, adenomyosis, surgical treatment, and poor maternal consequences., Materials and Methods: In this case-control study, data from 250 women who gave birth in Hazrat Rasoul Akram hospital, Tehran, Iran from February 2015 to December 2019 was extracted from the hospital information system in January 2020. Participants were divided into 2 groups: 125 women with endometriosis and 125 women without endometriosis. We looked at how endometriosis affected mothers and newborn babies. Data on pregnancy, delivery, and newborns of both groups was extracted., Results: The mean age of participants was 32.74 ± 4.10 and 31.7 ± 5.53 yr in endometriosis and control group, respectively. In terms of pregnancy complications, placenta previa, placenta accreta, placenta abruption, pre-eclampsia, gestational diabetes mellitus, and postpartum hemorrhage remarkably increased in the endometriosis group compared to the control group. Small for gestational age was significantly higher in rectal endometriosis than women without rectal endometriosis (p = 0.03). The neonatal intensive care unit admission rate was notably higher in infants of the endometriosis group compared to controls (40.7% vs. 24.8%, p = 0.009)., Conclusion: Our findings showed women with endometriosis are at a higher risk for important adverse maternal outcomes., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2024 Shahmoradi et al.)

Background: Various techniques have been proposed to predict and evaluate the timing and conditions of childbirth in pregnant women at different stages of pregnancy. Providing precise methods for forecasting childbirth status can reduce the burden on the healthcare system. This study aimed to evaluate the predictive value of transvaginal sonography of cervical length (CL) and cervical angle (CA) on full-term delivery outcomes., Methods: This cohort study analyzed 151 pregnant women between 37 and 42 weeks of gestational age who were treated at Rasoul Akram Hospital affiliated with Iran University of Medical Sciences from June 2023 to January 2024. All Participants received transvaginal examinations. This study evaluated the accuracy of CL and CA by transvaginal sonography in predicting outcomes like vaginal delivery, cesarean section, necessity for labor induction, and the rate of Premature Rupture of Membranes (PROM). The study used the Receiver Operating Characteristic (ROC) curve to determine the optimal cutoff for predicting birth outcomes., Results: The mean age of the pregnant women was 28.9 ± 4.22 years, while the average duration of pregnancy was 39.8 ± 2.11 weeks. Cesarean delivery was performed on 45 individuals (29.8%) and 106 (70.1%) underwent vaginal delivery. The mean CL overall stood at 21.2 ± 6.4 mm. PROM was observed in 41 cases (27.1%) among full-term pregnancies. A significant difference was noted in mean CL between the cesarean and vaginal delivery groups (24.2 ± 2.4 vs. 20.1 ± 2.1 mm, p  = 0.001). The predictive value of a CL measuring 21 mm for cesarean delivery was 72.2% sensitive and 79.1% specific. Similarly, a CL of 22 mm showed 66.6% sensitivity and 80.2% specificity for labor induction. Regarding PROM in full-term pregnancies, a CL assessment demonstrated 59.8% sensitivity and 69.1% specificity. Finally, a CA of 115.2° exhibited 70.3% sensitivity and 78.4% specificity in predicting vaginal delivery., Conclusion: The present study showed that evaluating CL and CA via transvaginal sonography demonstrated adequate diagnostic accuracy in predicting spontaneous birth, need for labor induction, cesarean delivery, and incidence of PROM in full-term pregnant women. This method is suggested to be an accurate and appropriate way to predict delivery results.

Background: Many genitourinary tract disorders could be attributed partly to the microbiota. This study sought to conduct a systematic review of the role of the microbiota in urinary chronic pelvic pain syndrome (UCPPS)., Methods: We searched Embase, Scopus, Web of Science, and PubMed with no time, language, or study type restrictions until December 1, 2023. The JBI Appraisal Tool was used to assess the quality of the studies. Study selection followed the PRISMA statement. Studies addressing microbiome variations among patients suffering from interstitial cystitis/bladder pain syndrome (IC/BPS) or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and a control group were considered eligible., Results: A total of 21 studies (1 UCPPS, 12 IC/BPS, and 8 CP/CPPS) comprising 1125 patients were enrolled in our final data synthesis. It has been shown that the reduced diversity and discrepant composition of the gut microbiota may partly be attributed to the UCPPS pathogenesis. In terms of urine microbiota, some operational taxonomic units were shown to be elevated, while others became less abundant. Furthermore, various bacteria and fungi are linked to specific clinical features. Few investigations denied UCPPS as a dysbiotic condition., Conclusions: Urinary and intestinal microbiota appear to be linked with UCPPS, comprising IC/BPS and CP/CPPS. However, given the substantial disparity of published studies, a battery of prospective trials is required to corroborate these findings., (© 2024 Wiley Periodicals LLC.)

Arsenic with the scientific name AS is an element that exists everywhere. It is the fourth among the abundant elements in water, the twelfth in the human body, and the twentieth in the earth's crust. This element exists in sulfide, carbonate, and elemental forms. Different names of arsenic are known as white arsenic (As 2 O 3 ), yellow arsenic (As 2 S 3 ), and red arsenic (As 4 S 4 ). Nowadays, due to its unique properties, arsenic has received much attention from researchers for use in the synthesis of arsenic nanoparticles. According to various studies, arsenic nanoparticles are synthesized by various methods, including biological, physical, and chemical, and it has been shown that the synthetic method used is very important because it has a significant effect on their shape, size, and biological function. Arsenic nanoparticles are among the nanoparticles that have attracted the attention of researchers due to their particle potential as well as their anticancer, antitumor, cytotoxic, and antimicrobial applications. Therefore, the aim of this study is to investigate arsenic nanoparticles biosynthesized by different physical, biological, and chemical methods and their biomedical applications., (© 2024 Wiley Periodicals LLC.)

Background: Idiopathic intracranial hypertension (IIH) is a rare medical condition in children. Based on the different radiological findings reported in various studies in pediatric IIH, this study was conducted to determine the diagnostic value of MRI findings in diagnosing IIH in children., Methods: In this retrospective study, the medical records of all children aged 1 to 18 years who visited Ghaem Hospital in Mashhad, Iran, between 2012 and 2022 and were diagnosed with IIH were gathered. Forty-nine cases of children with IIH and 48 control cases of children with the first unprovoked seizure with no indications of increased intracranial pressure for comparison were selected. Patient demographic information and MRI findings were extracted. The comparison between different MRI findings in the case and control groups was conducted using statistical tests., Results: In the case group, the mean diameter of the subarachnoid space expansion around the optic nerve was 5.96 ± 1.21, compared to 4.79 ± 0.33 in the control group, with statistically significant difference (P < 0.001). All the patients with flattening of the posterior globe or transverse sinus stenosis were in the case group, and the frequency of these findings in the case group was significantly higher than in the control group (P < 0.001). The majority of patients (95.5%) classified under category 3 and 4 of empty sella were part of the case group, and the statistical test results indicated a significant difference between the two groups (P < 0.001). The optic nerve sheath diameter cut-off of 5.35 mm, when used for expansion of the subarachnoid space around the optic nerve, with a sensitivity of 82% and a specificity of 100% in diagnosing IIH., Conclusion: The most reliable diagnostic indicators for diagnosing IIH in children are perioptic subarachnoid space expansion with high sensitivity, and posterior globe flattening and transverse sinus stenosis with high specificity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To investigate the association between vitamin D3 level and oxidative stress biomarkers such as Heat Shock Protein 70 (HSP70), ferric reducing ability of plasma (FRAP), advanced oxidation protein products (AOPP) and advanced glycation end products (AGEs) in patients with Type 2 diabetes., Method: In this cross-sectional study, 54 patients including 32 females and 22 males with a mean age of 54.92 ± 11.37 years with T2D attending the diabetes clinic from 2021 to 2022 were included. According to the average level of vitamin D in this population (14.91), they were divided into two groups with vitamin D ≤15 ng/mL and vitamin D >15 ng/mL. Multivariate regression analysis was conducted to evaluate the relationship between vitamin D and AOPP, HSP and FRAP parameters. The correlation between vitamin D and other variables was evaluated via the Pearson correlation test., Result: Vitamin D level had a positive relation with FRAP (β = 0.32, p = 0.017) and HSP (β = 0.39, p = 0.003), but had a negative relation with AOPP (β = -0.30, p = 0.02). The level of 2hPP also had a negative relation with the level of vitamin D (β = -0.33, p = 0.03). There was not any relationship between the level of vitamin D and AGEs or other variables. After adjusting for multiple confounders for the multivariate regression model, HSP remained significant., Conclusion: This research indicates the relationship between vitamin D levels and oxidative stress biomarkers in patients with Type 2 diabetes., (© 2024 The Author(s). Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Key Clinical Message: Systemic Lupus Erythematosus (SLE) can have an insidious onset and a fatal prognosis in children. Patients presenting without typical signs of SLE should undergo further evaluation if they are not responding to the initial diagnosis and treatment. This is especially true for patients with rapidly progressing symptoms and deterioration in spite of treatment., Abstract: Pediatric Systemic Lupus Erythematosus is a chronic autoimmune disorder with various organ involvement pulmonary involvement in the course of this disorder is a rare yet potentially life-threatening complication. In this case report we highlight the findings of a 16-year-old girl acutely and initially presenting with cough and fever, eventually complicating to diffuse alveolar hemorrhage and gradual loss of consciousness. Although the patient was started on immunosuppressive treatment after the diagnosis of lupus, based on renal and hematological impairment, was made and initially responded, she eventually deteriorated., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Instrument fracture in the root canal system is an unpleasant incident that may occur during root canal treatment. Comprehensive cleaning of the root canal system is often impossible in the presence of a broken instrument. Therefore, it is often imperative to remove the broken fragment from the root canal system. To date, various methods have been proposed for the removal of broken instruments from the root canal system. However, no consensus has been reached on a safe technique with a high success rate for broken instrument removal. This case series reports six cases of successful removal of broken instruments using different methods including the ultrasonic, tube-and-glue, tube-and-wire, tube-and-internal shaft, and the forceps techniques and also provides a brief review of the relevant literature., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2024 Mohsen Aminsobhani et al.)

In the present study, an efficacious, safe, inexpensive and eco-friendly microextraction was provided by deep eutectic solvents based on dispersive liquid-liquid microextraction (DLLME - DES) followed by GFAAS. A series of DESs were synthesised using l -menthol as hydrogen bond acceptor (HBA) and carboxylic acids with 4, 6, 8 and 10 carbon atoms as hydrogen bond donors (HBD). The synthesised DESs were used as extractants of arsenic ions. Under optimised conditions, good linearity with coefficient of determination ( r 2 ) 0.992 and an acceptable linear range of 0.3-100 µg kg -1 was obtained. The limit of detection was 0.1 µg kg -1 (S/ N  = 3) for arsenite (As(III)) ions, and a high enrichment factor (EF = 200) was obtained. The enhancement factor and extraction recovery (ER%) of the method were 340 and 60%, respectively. RSDs including inter- and intra-day ranged from 3.2% to 5.8% in three examined concentrations. After a specific digestion, the capability of the synthesised DES in the extraction of As(III) from rice was tested. Total inorganic arsenic was separated similarly after reduction of arsenate (As(V)) to As(III), and As(V) concentration was calculated by difference. Using a second digestion method, total arsenic concentration (sum of organic and inorganic arsenic) in the samples was determined.

Competing Interests: The authors report no conflicts of interest.

Celiac disease (CD) is a chronic autoimmune enteropathy and multifactorial disease caused by inappropriate immune responses to gluten in the small intestine. Weight loss, anemia, osteoporosis, arthritis, and hepatitis are among the extraintestinal manifestations of active CD. Currently, a strict lifelong gluten-free diet (GFD) is the only safe, effective, and available treatment. Despite the social burden, high expenses, and challenges of following a GFD, 2 to 5 percent of patients do not demonstrate clinical or pathophysiological improvement. Therefore, we need novel and alternative therapeutic approaches for patients. Innovative approaches encompass a broad spectrum of strategies, including enzymatic degradation of gluten, inhibition of intestinal permeability, modulation of the immune response, inhibition of the transglutaminase 2 (TG2) enzyme, blocking antigen presentation by HLA-DQ2/8, and induction of tolerance. Hence, this review is focused on comprehensive therapeutic strategies ranging from dietary approaches to novel methods such as antigen-based immunotherapy, cell and gene therapy, and the usage of nanoparticles for CD treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Since the beginning of the 21st century, competency-based education has been proposed as an approach to education in many disciplines including the medical sciences and it has become a dominant approach in many countries. We aimed to explore the lived experiences of general medical students about developing competencies in the academic curriculum., Methods: We conducted a phenomenology method to study lived experiences of general medical students through selecting participants via a purposeful sampling strategy. Snowballing and maximum variation samplings were also applied to recruit additional participants. The study was conducted at a Medical School in Iran. Three successive phases of qualitative data analysis, namely, data reduction by coding, data structuring by categorization, and data interpretation by discussion were applied to analyze the interviews., Results: The results of the research showed that students' lived experiences fall under 4 main themes with 9 subthemes. The main themes show that (1) the compartmentalized curriculum in basic courses is experienced as the missing parts in a puzzle, (2) the physiopathology curriculum is experienced as swimming on land, (3) the externship is experienced as touring a mysterious land, (4) the internship is experienced as unleashed arrows., Discussion: Our findings reveal that despite the changes already made in the curriculum, its compartmentalization is still a main obstacle to achieving competency-based medical education. A strict requirement for leaving the discipline-based curriculum behind is to use an integrated approach, in which basic science courses are connected with clinical cases, and physiopathology courses are connected with externships and internships., (Copyright © 2024 Karami, Hashemi and Van Merrienboer.)

The search for new sources of fortified components from low-cost and sustainable sources has become a trend in the last decade. Food byproducts containing valuable bioactive compounds such as dietary fiber, protein, and phytochemicals are being used as substrates for obtaining beneficial components that can promote health. Extrusion is an efficient technology for converting food by-products into nutrient-rich food ingredients. The objective of this work was to optimize the extrusion process to obtain the best combination of moisture content (14, 18 and 22%) and screw speed (SS) (120,150 and180 rpm), apple pomace (AP): semi-defatted sesame cake (SDSC) blends (25:75, 50:50 and 75:25 w/w) to fabricate textured functional ingredients (TFI) with high values of expansion ratio (ER), water absorption index (WAI), brightness level, total phenolic compounds (TPC) and antioxidant activity (AA) and lower hardness based on a central composite design. The optimal treatment was determined at 176 rpm SS, 18% moisture content and a ratio of (75:25) AP: SDSC. The desirability value has indicated an appropriate match between the predicted and the observed response. TFI exhibited higher soluble dietary fiber fraction (WAI) values and lower plate count values during 30 days of storage compared to the unprocessed by-product, suggesting that TFI could be successfully used for the manufacture of innovative, high quality products such as porridge, beverages, cookies, soups and others that could provide health benefits based on the values obtained., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elnaz milani reports financial support was provided by Academic Center for Education Culture and Research. Elnaz Mialni reports a relationship with Elnaz Milani that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Comprehensive palliative care for patients with heart failure can be developed by educating cardiac nurses. The current study aimed to design a heart failure palliative care educational program for nurses., Materials and Methods: This study was carried out using the multi-method approach based on two out of four steps of Uys educational program development at Dr. Chamran Hospital, Isfahan, in 2020-2021. In step 1, educational needs were collected through literature review, interviews with 15 patients and 10 nurses, examination of patients' documents and medical records, and observation. Then, in step 2, the importance and necessity of teaching the proposed topics and the teaching and evaluation method of the items were assessed through two rounds of delphi technique (15 expert panel members). Eventually, the educational program was finalized., Results: In step 1, the educational needs of nurses were identified in 6 general fields and 26 general learning topics. In step 2, educational needs [specialized knowledge (55% necessity and 55% importance) and social support (33% necessity and 33% importance)], teaching methods (role-playing, experiential learning, and journal club), and evaluation method (the information analysis method) were removed due to a lack of consensus (11%). Finally, the main parts of the program, including the program mission and vision, general learning topics, general goals, objectives, teaching strategies, and evaluation strategies, were compiled., Conclusions: This program provides nurses with up-to-date information on various aspects of the physical, psychological, social, spiritual, and educational needs of heart failure patients and ensures the provision of better services to them., Competing Interests: Nothing to declare., (Copyright: © 2024 Iranian Journal of Nursing and Midwifery Research.)

Purpose: SLC4A10 encodes a plasma membrane-bound transporter, which mediates Na + -dependent HCO 3 - import, thus mediating net acid extrusion. Slc4a10 knockout mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness., Methods: Utilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modeling were performed to study the possible functional consequences of the variant alleles., Results: The families harbor 8 segregating ultra-rare biallelic SLC4A10 variants (7 missense and 1 splicing). Phenotypically, patients present with global developmental delay/intellectual disability and central hypotonia, accompanied by variable speech delay, microcephaly, cerebellar ataxia, facial dysmorphism, and infrequently, epilepsy. Neuroimaging features range from some non-specific to distinct neuroradiological findings, including slit ventricles and a peculiar form of bilateral curvilinear nodular heterotopia. In silico analyses showed 6 of 7 missense variants affect evolutionarily conserved residues. Functional analyses supported the pathogenicity of 4 of 7 missense variants., Conclusion: We provide evidence that pathogenic biallelic SLC4A10 variants can lead to neurodevelopmental disorders characterized by variable abnormalities of the central nervous system, including altered brain ventricles, thus resembling several features observed in knockout mice., Competing Interests: Conflict of Interest James R. Lupski owns stock in 23andMe and is a paid consultant for Genome International. Rhonda E. Schnur is an employee of GeneDx, LLC. The other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

In September 2022, the Public Health Agency of Sweden observed an increase in domestic Salmonella Typhimurium cases through the Swedish electronic notification system, and an outbreak strain was identified with whole genome sequencing. Overall, 109 cases with symptom onset between 17 September and 24 November 2022 were reported from 20 of 21 Swedish regions. The median age of cases was 52 years (range 4-87 years) and 62% were female. A case-control study found cases to be associated with consumption of rocket salad (adjusted odds ratio (aOR) = 4.9; 95% confidence interval (CI): 2.4-10, p value < 0.001) and bagged mixed salad (aOR = 4.0; 95% CI: 1.9-8.1, p value < 0.001). Trace-back, supported by Finnish authorities who identified the Swedish outbreak strain in a Finnish cluster during the same time period, identified rocket salad, cultivated, pre-washed and pre-packed in Sweden as the likely source of the outbreak. No microbiological analyses of rocket salad were performed. Our investigation indicates that bagged leafy greens such as rocket salad, regardless of pre-washing procedures in the production chain, may contain Salmonella and cause outbreaks, posing a health risk to consumers. We emphasise the need for primary producers of leafy greens to identify possible contamination points to prevent outbreaks.

Echinococcus granulosus sensu lato (E. granulosus s.l.) is a zoonotic parasite, causing cystic echinococcosis in humans. In the present study, prevalence and genotypes of E. granulosus s.l. was assessed in stools collected from 244 dogs including 138 stray and 106 domestic animals using high resolution melting curve (HRM) method. Initially, to detect taeniid eggs in feces, all samples were examined using the formalin-ether techniques. Genomic DNA was extracted from the positive samples and E. granulosus s.l. was differentiated from other Taeniidae parasites using SSU-rDNA gene and E. granulosus s.l. was analyzed for genotyping using HRM based on the cox1 gene. In total, 12.7% (31/244) of the samples were positive for Taeniidae eggs. In addition, among the positive samples, 77.4% (24/31) were positive for E. granulosus s.l.. In details, 11.3% (12/106) of the domestic dogs and 8.7% (12/138) of the stray dogs were positive for E. granulosus s.l.. The results of HRM analysis showed that all E. granulosus s.l. isolates were G1 strain. Findings of the present study indicated a considerable prevalence of E. granulosus G1 among dogs in the northeast of Iran and imply a serious risk of transmitting to humans and livestock., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests related to this research., (Copyright © 2023. Published by Elsevier B.V.)

Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM&#95;032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function., (© 2023. The Author(s).)

Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation and promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks to the necessity of providing a sufficient number of MSCs to achieve clinically efficient outcomes, prolonged in vitro cultivation is indisputable. However, either following long-term in vitro expansion or aging in elderly individuals, MSCs face cellular senescence. Senescent MSCs undergo an impairment in their function and therapeutic capacities and secrete degenerative factors which negatively affect young MSCs. To this end, designing novel investigations to further elucidate cellular senescence and to pave the way toward finding new strategies to reverse senescence is highly demanded. In this review, we will concisely discuss current progress on the detailed mechanisms of MSC senescence and various inflicted changes following aging in MSC. We will also shed light on the examined strategies underlying monitoring and reversing senescence in MSCs to bypass the comprised therapeutic efficacy of the senescent MSCs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Wilson's disease is a complicated medical condition caused by the accumulation of copper, mostly in the liver and brain. The genetic basis of Wilson's disease is attributed to the presence of pathogenic variants in the ATP7B copper-transporting gene, which prevents the excretion of copper through the biliary tract. To date, ATP7B remains the only identified gene that has been linked to the development of this disease. Our understanding of the disease has been associated with the identification of particular disease-causing variants that present specific impairments in copper transporters. It is crucial to identify the most frequent variant in terms of ethnicity to facilitate testing of its functionality. This study represents the initial comprehensive analysis of ATP7B variants, providing insights into the extensive range of disease-causing mutations. Here, we describe the 1275 distinct ATP7B variants documented so far, with particular emphasis on their regional and ethnic prevalence. The H1069Q missense variant is the most frequently reported in Europe, Northern America, and North Africa, whereas the R778L, C271*, and M645R variants are the most prevalent in the East Asian, Middle Eastern-South Asian, and South American populations, respectively. Acquiring such knowledge would facilitate the implementation of a selective mutation screening approach, targeting the most predominant variant identified within a specific ethnic group or geographic region for better diagnosis of the disease., Competing Interests: All authors declare no competing interests., (© 2023 The Authors.)

Background: Recent developments regarding the contribution of microRNAs to tumor angiogenesis and the oncogenic effects of microRNAs point to their potential role in breast cancer angiogenesis. Tumor-derived exosomes are considered a rich source of microRNAs that can regulate the function of other cells in the tumor microenvironment, including vascular endothelial cells. This study analyzes the effect of tamoxifen chemotherapy on the expression of a key microRNA, miR-329, and introduces a regulatory link between this microRNA and the KDM1A gene associated with the vascular endothelial growth factor (VEGF) messaging pathway., Materials and Methods: MCF-7 breast cancer cells were purchased and cultured in a complete culture medium. These cells were treated with tamoxifen and then their exosomes were extracted from the culture medium. The RNAs of the exosomes were isolated and the expression of miR-329, VEGF, and KDM1A genes in the exosomes was investigated using the real-time polymerase chain reaction (PCR) method., Results: The results of this study showed that tamoxifen treatment increased the expression of miR-329 in exosomes derived from MCF-7 cancer cells. The expression of KDM1A and VEGF genes in drug-treated cell exosomes is downregulated., Conclusion: The results of this experiment demonstrated that the treatment of breast cancer cells with tamoxifen reduces the expression of VEGF and KDM1A by increasing miR-329. The treatment therefore reduces angiogenesis, and thus its anti-tumor effects are applied.

Background: NBIA (neurodegeneration with brain iron accumulation) is a diverse collection of neurodegenerative illnesses defined by iron accumulation in the basal ganglia. The fatty acid hydroxylase-associated neurodegeneration, or FAHN, is one of the uncommon subtypes of NBIAs, associated with inherited autosomal recessive mutations in gene coding the membrane-bound fatty acid 2 hydroxylase (FA2H) enzyme., Cases: Here, we report two cases with FAHN from two unrelated families from Iran confirmed by whole exome sequencing., Conclusion: FAHN is an uncommon variant of NBIA that may manifest as spastic paraparesis without signs of iron buildup on brain imaging. As a result, it should be taken into account while making a differential diagnosis of the hereditary spastic paraplegia (HSP) syndrome, especially in individuals who lack iron deposits., (© 2023. Fondazione Società Italiana di Neurologia.)

Objectives: The increase in the number of jurisdictions legalising medical assistance in dying (MAiD) has contributed to a growth in the number of family and friends who may face unique elements of grief and bereavement. The aim of this study was to review the literature of grief and bereavement of family and friends following MAiD, and to summarise findings for the development of community resources and programming., Methods: We performed a scoping review with workshop consultation of stakeholders. Six electronic databases and the grey literature were searched for qualitative, quantitative and review articles. Content-analytical techniques and multidisciplinary discussions led to the development of concepts and a conceptual framework., Results: Twenty-eight articles met the inclusion criteria. We identified five concepts that impact the grief and bereavement of family/friends: relationships between family/friends and the patient as well as healthcare providers; aspects of MAiD grief which can include secrecy and/or anticipatory grief; preparations which may include family/friends and should be centralised and harmonised; end of life as an opportunity for ceremony; and the aftereffects during which mental health outcomes are studied., Conclusion: This multidisciplinary scoping review incorporates stakeholder consultation to find that support is needed to address the complicated and changing emotions of family/friends before, during and after a MAiD death. Furthermore, additional societal normalisation of MAiD is necessary to reduce secrecy and stigma and improve the accessibility of resources for family/friends., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship., Methods: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity., Results: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy., Conclusions: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders"., (© 2023. The Author(s).)

The effectiveness of lifestyle interventions in reducing caloric intake and increasing physical activity for preventing Type 2 Diabetes (T2D) has been previously demonstrated. The use of modern technologies can potentially further improve the success of these interventions, promote metabolic health, and prevent T2D at scale. To test this concept, we built a remote program that uses continuous glucose monitoring (CGM) and wearables to make lifestyle recommendations that improve health. We enrolled 2,217 participants with varying degrees of glucose levels (normal range, and prediabetes and T2D ranges), using continuous glucose monitoring (CGM) over 28 days to capture glucose patterns. Participants logged food intake, physical activity, and body weight via a smartphone app that integrated wearables data and provided daily insights, including overlaying glucose patterns with activity and food intake, macronutrient breakdown, glycemic index (GI), glycemic load (GL), and activity measures. The app furthermore provided personalized recommendations based on users' preferences, goals, and observed glycemic patterns. Users could interact with the app for an additional 2 months without CGM. Here we report significant improvements in hyperglycemia, glucose variability, and hypoglycemia, particularly in those who were not diabetic at baseline. Body weight decreased in all groups, especially those who were overweight or obese. Healthy eating habits improved significantly, with reduced daily caloric intake and carbohydrate-to-calorie ratio and increased intake of protein, fiber, and healthy fats relative to calories. These findings suggest that lifestyle recommendations, in addition to behavior logging and CGM data integration within a mobile app, can enhance the metabolic health of both nondiabetic and T2D individuals, leading to healthier lifestyle choices. This technology can be a valuable tool for T2D prevention and treatment., (© 2023. The Author(s).)

Objective: This study aimed to investigate the validity of simulation-based assessment of robotic-assisted cardiac surgery skills using a wet lab model, focusing on the use of a time-based score (TBS) and modified Global Evaluative Assessment of Robotic Skills (mGEARS) score., Methods: We tested 3 wet lab tasks (atrial closure, mitral annular stitches, and internal thoracic artery [ITA] dissection) with both experienced robotic cardiac surgeons and novices from multiple European centers. The tasks were assessed using 2 tools: TBS and mGEARS score. Reliability, internal consistency, and the ability to discriminate between different levels of competence were evaluated., Results: The results demonstrated a high internal consistency for all 3 tasks using mGEARS assessment tool. The mGEARS score and TBS could reliably discriminate between different levels of competence for the atrial closure and mitral stitches tasks but not for the ITA harvesting task. A generalizability study also revealed that it was feasible to assess competency of the atrial closure and mitral stitches tasks using mGEARS but not the ITA dissection task. Pass/fail scores were established for each task using both TBS and mGEARS assessment tools., Conclusions: The study provides sufficient evidence for using TBS and mGEARS scores in evaluating robotic-assisted cardiac surgery skills in wet lab settings for intracardiac tasks. Combining both assessment tools enhances the evaluation of proficiency in robotic cardiac surgery, paving the way for standardized, evidence-based preclinical training and credentialing., Clinical Trial Registry Number: NCT05043064., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 The Author(s).)

Mesenchymal stem cells (MSCs), as self-renewing multipotent stromal cells, have been considered promising agents for cancer treatment. A large number of studies have demonstrated the valuable properties of MSC-based treatment, such as low immunogenicity and intrinsic tumor-trophic migratory properties. To enhance the potency of MSCs for therapeutic purposes, equipping MSCs with targeted delivery functions using genetic engineering is highly beneficial. Genetically engineered MSCs can express tumor suppressor agents such as pro-apoptotic, anti-proliferative, anti-angiogenic factors and act as ideal delivery vehicles. MSCs can also be loaded with nanoparticle drugs for increased efficacy and externally moderated targeting. Moreover, exosomes secreted by MSCs have important physiological properties, so they can contribute to intercellular communication and transfer cargo into targeted tumor cells. The precise role of genetically modified MSCs in tumor environments is still up for debate, but the beginning of clinical trials has been confirmed by promising results from preclinical investigations of MSC-based gene therapy for a wide range of malignancies. This review highlights the advanced techniques of engineering/nano-engineering and MSC-derived exosomes in tumor-targeted therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Delivery systems designed through protein stabilized emulsions are promising for incorporating carotenoids in different products. Nevertheless, the versatility in structures of such systems raises questions regarding the effect of the bioactive compound localization on their bio-efficacy, in particular for double emulsions. In this context, the aims of this study were to determine the impact of the localization of lutein in different water/oil/water double emulsions versus a single oil/water emulsion on the stability and in vitro bioaccessibility of lutein, a lipophilic carotenoid. The inner aqueous phase, which contained whey protein isolate (WPI) nanoparticles obtained by desolvation, was emulsified in sunflower oil stabilized by polyglycerol polyricinoleate (PGPR). The primary emulsion was then emulsified in a continuous aqueous phase containing whey protein isolate (WPI) and xanthan gum, the latter to increase the viscosity of the outer phase and delay creaming. Lutein was incorporated using different strategies: (1) lutein entrapped by WPI nanoparticles within the inner water phase of a double emulsion (W-L/O/W); (2) lutein incorporated into the oil phase of the double emulsion (W/O-L/W); (3) lutein incorporated in the oil phase of a single emulsion (O-L/W). All systems contained similar whey protein concentrations, as well as all other stabilizers. W-L/O/W sample showed the lowest lutein stability against light exposure during storage, and the highest lutein bioaccessibility after in vitro digestion, for freshly made samples. Furthermore, the in vitro bioaccessibility of lutein incorporated into the single emulsion was considerably lower than those observed for the double emulsions. The results reinforce the importance of designing appropriate structures for delivering improved stability and bioaccessibility of bioactive compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan-based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre-HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes., Methods: Seventy-three pediatric patients receiving this management between 2015 and 2022 were included., Results: Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p = .034) and slowed lymphocyte engraftment (r = .290; p = .030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not to increase risk of acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p = .021 and p = .014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR = .204, p = .022)., Conclusion: The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group,  level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Major histocompatibility complex Class I (MHC-I) molecules bind to peptides derived from intracellular antigens and present them on the surface of cells, allowing the immune system (T cells) to detect them. Elucidating the process of this presentation is essential for regulation and potential manipulation of the cellular immune system. Predicting whether a given peptide binds to an MHC molecule is an important step in the above process and has motivated the introduction of many computational approaches to address this problem. NetMHCPan, a pan-specific model for predicting binding of peptides to any MHC molecule, is one of the most widely used methods which focuses on solving this binary classification problem using shallow neural networks. The recent successful results of Deep Learning (DL) methods, especially Natural Language Processing (NLP-based) pretrained models in various applications, including protein structure determination, motivated us to explore their use in this problem. Specifically, we consider the application of deep learning models pretrained on large datasets of protein sequences to predict MHC Class I-peptide binding. Using the standard performance metrics in this area, and the same training and test sets, we show that our models outperform NetMHCpan4.1, currently considered as the-state-of-the-art., 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., (Copyright © 2023 Hashemi, Hao, Ignatov, Paschalidis, Vakili, Vajda and Kozakov.)

Background: The increasing use of robot-assisted surgery (RAS) has led to the need for new methods of assessing whether new surgeons are qualified to perform RAS, without the resource-demanding process of having expert surgeons do the assessment. Computer-based automation and artificial intelligence (AI) are seen as promising alternatives to expert-based surgical assessment. However, no standard protocols or methods for preparing data and implementing AI are available for clinicians. This may be among the reasons for the impediment to the use of AI in the clinical setting., Method: We tested our method on porcine models with both the da Vinci Si and the da Vinci Xi. We sought to capture raw video data from the surgical robots and 3D movement data from the surgeons and prepared the data for the use in AI by a structured guide to acquire and prepare video data using the following steps: 'Capturing image data from the surgical robot', 'Extracting event data', 'Capturing movement data of the surgeon', 'Annotation of image data'., Results: 15 participant (11 novices and 4 experienced) performed 10 different intraabdominal RAS procedures. Using this method we captured 188 videos (94 from the surgical robot, and 94 corresponding movement videos of the surgeons' arms and hands). Event data, movement data, and labels were extracted from the raw material and prepared for use in AI., Conclusion: With our described methods, we could collect, prepare, and annotate images, events, and motion data from surgical robotic systems in preparation for its use in AI., (© 2023. The Author(s).)

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability., Methods: By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro., Results: In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well., Conclusion: By identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders., Competing Interests: Conflict of Interest Jeffrey B. Ratliff serves on the editorial board for the journal Neurology and has received consulting fees from Supernus Pharmaceuticals. All other authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Cerium(IV) ammonium nitrate (CAN) has been extensively used as a sacrificial oxidant to study water-oxidation catalysts (WOCs). Although nickel hydroxide has been extensively investigated as WOCs, the water-oxidation reaction (WOR) and mechanistic studies in the presence of CAN and nickel hydroxide were rarely performed. Herein, using in situ Raman spectroscopy, in situ X-ray absorption spectroscopy, and in situ electron paramagnetic resonance spectroscopy, WOR in the presence of CAN and β-Ni(OH) 2 was investigated. The proposed WOR mechanism involves the oxidation of β-Ni(OH) 2 by CAN, leading to the formation of γ-NiO(OH). γ-NiO(OH), in the presence of acidic conditions, evolves oxygen and is reduced to Ni(II). In other words, the role of β-Ni(OH) 2 is the storage of four oxidizing equivalents by CAN, and then a four-electron reaction could result in a WOR with low activation energy. β-Ni(OH) 2 in CAN at concentrations of 0.10 M shows WOR with a maximum turnover frequency and a turnover number (for 1000 s) of 5.5 × 10 -5 /s and 2.0 × 10 -2 mol (O 2 )/mol(Ni), respectively. In contrast to β-Ni(OH) 2 , Ni(OH 2 ) 6 2+ (aq) could not be oxidized to γ-NiO(OH). Indeed, Ni(OH 2 ) 6 2+ (aq) is the decomposition product of β-Ni(OH) 2 /CAN.

Background: One of the challenges when transitioning from International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) to International Classification of Diseases, 11th Revision (ICD-11) is to ensure clinical coding accuracy., Objective: To determine the accuracy of clinical coding with ICD-11 in comparison with ICD-10 and identify causes of coding errors in real clinical coding environments., Method: The study was conducted prospectively in two general hospitals. Medical records of discharged inpatients were coded by hospital clinical coders with both ICD-11 and ICD-10 on different days. These medical records were recoded by five mentors. Codes assigned by mentors were used as the gold standard for the evaluation of accuracy., Results: The accuracy of ICD-10 and ICD-11 coding for 1578 and 2168 codes was evaluated. Coding accuracy was 89.1% and 74.2% for ICD-10 and ICD-11. In ICD-11, the lowest accuracy was observed in chapters 22 (injuries), 10 (ear) and 11 (circulatory) (51.1%, 53.8% and 62.7%, respectively). In both ICD-10 and ICD-11, the most important cause of the coding errors was clinical coders' mistakes (79.5% and 81.8% for ICD-10 and ICD-11, respectively)., Conclusion: Accuracy of clinical coding with ICD-11 was lower relative to ICD-10. Hence, it is essential to carry out initial preparations, particularly the training of clinical coders based on their needs, as well as the necessary interventions to enhance the documentation of medical records according to ICD-11 before or simultaneous with the country-wide implementation., Implications: Clinical coders need complete training, especially in using extension codes and post-coordination coding. Local ICD-11 guidelines based on the needs of local users and reporting policies should be developed. Furthermore, documentation guidelines based on ICD-11 requirements should be developed.

Background: Chinese hamster ovary (CHO) cells are the most predominantly utilized host for the production of monoclonal antibodies (mAbs) and other complex glycoproteins. A major challenge in the process of CHO cell culture is the occurrence of cell death following different stressful conditions, which hinders the production yield. Engineering genes involved in pathways related to cell death is a remarkable strategy to delay apoptosis, improve cell viability and enhance productivity. SIRT6 is a stress-responsive protein that regulates DNA repair, maintains genome integrity, and is critical for longevity and cell survival in organisms., Methods and Results: In this study, SIRT6 was stably overexpressed in CHO-K1 cells and the impact of its expression on apoptosis related gene expression profile, viability, apoptosis, and mAb productivity was investigated. While a significant increase was observed in Bcl-2 mRNA level, caspase-3 and Bax mRNA levels were decreased in the SIRT6 engineered cells compared to the parental CHO-K1 cells. Moreover, improved cell viability and decreased rate of apoptotic progression was observed in a SIRT6-derived clone in comparision to the CHO-K1 cells during 5 days of batch culture. anti-CD52 IgG1 mAb titers were improved up to 1.7- and 2.8-fold in SIRT6-derived clone during transient and stable expression, respectively., Conclusions: This study indicates the positive effects of SIRT6 overexpression on cell viability and anti-CD52 IgG1 mAb expression in CHO-K1 cells. Further studies are needed to examine the potential of SIRT6-engineered host cells for the production of recombinant biotherapeutics in industrial settings., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Liver fibrosis is a significant cause of morbidity and mortality without approved treatment. The therapeutic effects of Imatinib as a tyrosine kinase inhibitor on reversing liver fibrosis have already been shown. However, considering the conventional route of Imatinib administration, the amount of drug to be used is very high, and its side effects are raised. Therefore, we designed an efficient pH-sensitive polymer for the targeted delivery of Imatinib in treating a carbon tetrachloride (CCl4)-induced liver fibrosis. This nanotherapeutic system-based Vitamin A (VA)-modified Imatinib-loaded poly (lactic-co-glycolic acid)/Eudragit S100 (PLGA-ES100) has been successfully fabricated by adapting the solvent evaporation technique. The applying ES100 on the surface of our desired nanoparticles (NPs) protects drug release at the acidic pH of the gastric and guarantees the effective release of Imatinib at a higher pH of the intestine. Besides, VA-functionalized NPs could be an ideal efficient drug delivery system due to the high capacity of hepatic cell lines to absorb VA. For induction of liver fibrosis, CCL4 was intraperitoneally (IP) injected twice a week for six weeks in BALB/c mice. Oral administration of VA-targeted PLGA-ES100 NPs loaded with Rhodamine Red™ by live animal imaging showed a preferential accumulation of the selected NPs in the liver of mice. Besides, administrating targeted Imatinib-loaded NPs significantly decreased serum levels of ALT, and AST, and also reduced the expression of extracellular matrix components, including collagen I, collagen III, and α-SMA, considerably. Interestingly, histopathological evaluation of liver tissues through H&E and Masson's trichrome staining showed that oral administration of targeted Imatinib-loaded NPs reduced hepatic damage by enhancing hepatic structure condition. Also, the Sirius-red staining indicated a reduction in collagen expression during treatment with targeted NP containing Imatinib. The immunohistochemistry result on liver tissue shows a significant decrease in the expression of α-SMA in groups treated with targeted NP. In the meantime, administration of a very scarce dose of Imatinib via targeted NP caused a substantial decline in the expression of fibrosis marker genes (Collagen I, Collagen III, α-SMA). Our results confirmed that novel pH-sensitive VA-targeted PLGA-ES100 NPs could efficiently deliver Imatinib to the liver cells. Loading Imatinib in the PLGA-ES100/VA might overcome many challenges facing conventional Imatinib therapy, including gastrointestinal pH, the low concentration at the target region, and toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Alzheimer's disease, a progressive neurological condition, is associated with various internal and external risk factors in the disease's early stages. Early diagnosis of Alzheimer's disease is essential for treatment management. Circulating exosomal microRNAs could be a new class of valuable biomarkers for early Alzheimer's disease diagnosis. Different kinds of biosensors have been introduced in recent years for the detection of these valuable biomarkers. Isolation of the exosomes is a crucial step in the detection process which is traditionally carried out by multi-step ultrafiltration. Microfluidics has improved the efficiency and costs of exosome isolation by implementing various effects and forces on the nano and microparticles in the microchannels. This paper reviews recent advancements in detecting Alzheimer's disease related exosomal microRNAs based on methods such as electrochemical, fluorescent, and SPR. The presented devices' pros and cons and their efficiencies compared with the gold standard methods are reported. Moreover, the application of microfluidic devices to detect Alzheimer's disease related biomarkers is summarized and presented. Finally, some challenges with the performance of novel technologies for isolating and detecting exosomal microRNAs are addressed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Nurses play an important role in cancer prevention. However, studies conducted on nurses' roles, in the field of cancer prevention in Iran, are very limited. This study will identify the role of nurses and designs, implements, and evaluates a program to expand their role in the prevention of colorectal cancer (CRC)., Materials and Methods: This exploratory mixed-methods study will be performed using quantitative-qualitative methods in three consecutive stages. In the first phase, a qualitative study will be conducted to identify the potential and actual roles of nurses in Iran using in-depth semi-structured interviews. Participants will be selected by purposive and snowball sampling, followed by a literature review; the actual and potential roles of nurses at the primary, secondary, and tertiary levels of CRC prevention in Iran and around the world will be extracted. And the actual role is determined. In the second phase, the roles of nurses will be prioritized using the modified Delphi method, and the program will be designed. In the third phase, the part of the program will be implemented as a quasi-experimental intervention, and the effect of the intervention will be evaluated., Conclusion: Developing a program can provide some evidence for promoting nurses' position in cancer prevention. Moreover, it is expected that this program promotes knowledge and empowerment and the position of nurses to provide primary, secondary, and tertiary cancer prevention. The entry of nurses into the field of cancer prevention leads to better quality care and more cost-effectiveness., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Education and Health Promotion.)

Developmental coordination disorder (DCD) remains largely underdiagnosed and masked by other co-occurring conditions. The aim of this study was to (1) provide the first review of research regarding auditory-motor timing and synchronization abilities in children with DCD and (2) examine whether reduced motor performance may be associated with difficulties in auditory perceptual timing. The scoping review was carried out across five major databases (MEDLINE, Embase, PsycINFO, CINAHL, and Scopus) in accordance with the PRISMA-ScR guidelines. Studies were screened by two independent reviewers against the inclusion criteria, without publication date restrictions. From an initial return of 1673 records, 16 articles were included in the final review and synthesized based on the timing modality studied (i.e., auditory-perceptual, motor, or auditory-motor). Results suggest that children with DCD have difficulties with rhythmic movements both with and without external auditory cues and further indicate that variability in and slowness of motor response are key characteristics of DCD, regardless of the experimental task. Importantly, our review highlights a significant gap in the literature regarding auditory perceptual abilities in DCD. In addition to testing auditory perception, future studies should compare the performance of children with DCD on paced and unpaced tasks to determine whether auditory stimuli contribute to a more or less stable performance. This knowledge may inform future therapeutic interventions.

Background: The number of available musculoskeletal tumor registries is relatively small. We developed a registry system focused on the clinical aspects of musculoskeletal tumors to improve quality of care indexes through the development of updated national protocols. In this study, we describe our protocol, challenges, and the data collected during the implementation of the registry system in a single-specialty orthopedic center in Iran., Methods: Three main malignant bone tumors, including osteosarcoma, Ewing sarcoma, and chondrosarcoma, were included in the registry. After establishing a steering committee, we defined the minimum data set based on a literature review and suggestions from an expert panel. Accordingly, the data collection forms and the web-based software were developed. The collected information was categorized into 9 classes, including demographics, socioeconomic data, signs and symptoms, past medical history, family history, laboratory tests, tumor characteristics, primary treatment, and follow-up. Data collection was performed both retrospectively and prospectively., Results: Until September 21, 2022, a total of 71 patients were registered (21 patients prospectively and 50 patients retrospectively) and consisted of 36 (50.7%) cases of osteosarcoma, 13 (18.3%) cases of Ewing sarcoma, and 22 (31%) cases of chondrosarcoma. The implementation of the registry demonstrated promising data regarding the tumor characteristics, delay patterns, and socioeconomic status of the patients., Conclusion: The main lessons learned were to develop a monitoring system to make sure that the new staff is adequately trained for the registration process as well as avoid the inclusion of time-consuming useless data in the minimum data set., Competing Interests: The authors declare that they have no competing interests., (© 2023 Iran University of Medical Sciences.)

Background: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the leading causes of hepatocellular carcinoma (HCC) worldwide. Limited data exist on surgical outcomes for NAFLD/NASH-related HCC compared with other HCC etiologies. We evaluated differences in clinicopathological characteristics and outcomes of patients undergoing surgical resection for NAFLD/NASH-associated HCC compared with other HCC etiologies., Methods: Demographic, clinicopathological features, and survival outcomes of patients with surgically resected HCC were collected. NAFLD activity score (NAS) and fibrosis score were assessed by focused pathologic review in a subset of patients., Results: Among 492 patients screened, 260 met eligibility (NAFLD/NASH [n = 110], and other etiologies [n = 150]). Median age at diagnosis was higher in the NAFLD/NASH HCC cohort compared with the other etiologies cohort (66.7 vs. 63.4 years, respectively, P = .005), with an increased percentage of female patients (36% vs. 18%, P = .001). NAFLD/NASH-related tumors were more commonly >5 cm (66.0% vs. 45%, P = .001). There were no significant differences in rates of lymphovascular or perineural invasion, histologic grade, or serum AFP levels. The NAFLD/NASH cohort had lower rates of background liver fibrosis, lower AST and ALT levels, and higher platelet counts (P < .01 for all). Median overall survival (OS) was numerically shorter in NAFLD/NASH vs other etiology groups, however, not statistically significant., Conclusions: Patients with NAFLD/NASH-related HCC more commonly lacked liver fibrosis and presented with larger HCCs compared with patients with HCC from other etiologies. No differences were seen in rates of other high-risk features or survival. With the caveat of sample size and retrospective analysis, this supports a similar decision-making approach regarding surgical resection for NAFLD/NASH and other etiology-related HCCs., (© The Author(s) 2023. Published by Oxford University Press.)