Soft Bioelectronics Using Nanomaterials and Nanostructures for Neuroengineering.

The identification of neural networks for large areas and the regulation of neuronal activity at the single-neuron scale have garnered considerable attention in neuroscience. In addition, detecting biochemical molecules and electrically, optically, and chemically controlling neural functions are key research issues. However, conventional rigid and bulky bioelectronics face challenges for neural applications, including mechanical mismatch, unsatisfactory signal-to-noise ratio, and poor integration of multifunctional components, thereby degrading the sensing and modulation performance, long-term stability and biocompatibility, and diagnosis and therapy efficacy. Implantable bioelectronics have been developed to be mechanically compatible with the brain environment by adopting advanced geometric designs and utilizing intrinsically stretchable materials, but such advances have not been able to address all of the aforementioned challenges.Recently, the exploration of nanomaterial synthesis and nanoscale fabrication strategies has facilitated the design of unconventional soft bioelectronics with mechanical properties similar to those of neural tissues and submicrometer-scale resolution comparable to typical neuron sizes. The introduction of nanotechnology has provided bioelectronics with improved spatial resolution, selectivity, single neuron targeting, and even multifunctionality. As a result, this state-of-the-art nanotechnology has been integrated with bioelectronics in two main types, i.e., bioelectronics integrated with synthesized nanomaterials and bioelectronics with nanoscale structures. The functional nanomaterials can be synthesized and assembled to compose bioelectronics, allowing easy customization of their functionality to meet specific requirements. The unique nanoscale structures implemented with the bioelectronics could maximize the performance in terms of sensing and stimulation. Such soft nanobioelectronics have demonstrated their applicability for neuronal recording and modulation over a long period at the intracellular level and incorporation of multiple functions, such as electrical, optical, and chemical sensing and stimulation functions.In this Account, we will discuss the technical pathways in soft bioelectronics integrated with nanomaterials and implementing nanostructures for application to neuroengineering. We traced the historical development of bioelectronics from rigid and bulky structures to soft and deformable devices to conform to neuroengineering requirements. Recent approaches that introduced nanotechnology into neural devices enhanced the spatiotemporal resolution and endowed various device functions. These soft nanobioelectronic technologies are discussed in two categories: bioelectronics with synthesized nanomaterials and bioelectronics with nanoscale structures. We describe nanomaterial-integrated soft bioelectronics exhibiting various functionalities and modalities depending on the integrated nanomaterials. Meanwhile, soft bioelectronics with nanoscale structures are explained with their superior resolution and unique administration methods. We also exemplified the neural sensing and stimulation applications of soft nanobioelectronics across various modalities, showcasing their clinical applications in the treatment of neurological diseases, such as brain tumors, epilepsy, and Parkinson's disease. Finally, we discussed the challenges and direction of next-generation technologies.

Disentangling sex-dependent effects of APOE on diverse trajectories of cognitive decline in Alzheimer's disease.

Current diagnostic systems for Alzheimer's disease (AD) rely upon clinical signs and symptoms, despite the fact that the multiplicity of clinical symptoms renders various neuropsychological assessments inadequate to reflect the underlying pathophysiological mechanisms. Since putative neuroimaging biomarkers play a crucial role in understanding the etiology of AD, we sought to stratify the diverse relationships between AD biomarkers and cognitive decline in the aging population and uncover risk factors contributing to the diversities in AD. To do so, we capitalized on a large amount of neuroimaging data from the ADNI study to examine the inflection points along the dynamic relationship between cognitive decline trajectories and whole-brain neuroimaging biomarkers, using a state-of-the-art statistical model of change point detection. Our findings indicated that the temporal relationship between AD biomarkers and cognitive decline may differ depending on the synergistic effect of genetic risk and biological sex. Specifically, tauopathy-PET biomarkers exhibit a more dynamic and age-dependent association with Mini-Mental State Examination scores (p<0.05), with inflection points at 72, 78, and 83 years old, compared with amyloid-PET and neurodegeneration (cortical thickness from MRI) biomarkers. In the landscape of health disparities in AD, our analysis indicated that biological sex moderates the rate of cognitive decline associated with APOE4 genotype. Meanwhile, we found that higher education levels may moderate the effect of APOE4, acting as a marker of cognitive reserve.

Screening mammography performance according to breast density: a comparison between radiologists versus standalone intelligence detection.

BACKGROUND: Artificial intelligence (AI) algorithms for the independent assessment of screening mammograms have not been well established in a large screening cohort of Asian women. We compared the performance of screening digital mammography considering breast density, between radiologists and AI standalone detection among Korean women. METHODS: We retrospectively included 89,855 Korean women who underwent their initial screening digital mammography from 2009 to 2020. Breast cancer within 12 months of the screening mammography was the reference standard, according to the National Cancer Registry. Lunit software was used to determine the probability of malignancy scores, with a cutoff of 10% for breast cancer detection. The AI's performance was compared with that of the final Breast Imaging Reporting and Data System category, as recorded by breast radiologists. Breast density was classified into four categories (A-D) based on the radiologist and AI-based assessments. The performance metrics (cancer detection rate [CDR], sensitivity, specificity, positive predictive value [PPV], recall rate, and area under the receiver operating characteristic curve [AUC]) were compared across breast density categories. RESULTS: Mean participant age was 43.5 ± 8.7 years; 143 breast cancer cases were identified within 12 months. The CDRs (1.1/1000 examination) and sensitivity values showed no significant differences between radiologist and AI-based results (69.9% [95% confidence interval [CI], 61.7-77.3] vs. 67.1% [95% CI, 58.8-74.8]). However, the AI algorithm showed better specificity (93.0% [95% CI, 92.9-93.2] vs. 77.6% [95% CI, 61.7-77.9]), PPV (1.5% [95% CI, 1.2-1.9] vs. 0.5% [95% CI, 0.4-0.6]), recall rate (7.1% [95% CI, 6.9-7.2] vs. 22.5% [95% CI, 22.2-22.7]), and AUC values (0.8 [95% CI, 0.76-0.84] vs. 0.74 [95% CI, 0.7-0.78]) (all P < 0.05). Radiologist and AI-based results showed the best performance in the non-dense category; the CDR and sensitivity were higher for radiologists in the heterogeneously dense category (P = 0.059). However, the specificity, PPV, and recall rate consistently favored AI-based results across all categories, including the extremely dense category. CONCLUSIONS: AI-based software showed slightly lower sensitivity, although the difference was not statistically significant. However, it outperformed radiologists in recall rate, specificity, PPV, and AUC, with disparities most prominent in extremely dense breast tissue.

Lugol's Solution Reduces Positive Margins and Residual Disease After the Large Loop Excision of Transformation Zone.

OBJECTIVE: This study aimed to examine whether the intraoperative use of Lugol's solution reduces the proportion of positive resection margins (RMs) using the data of women who underwent large loop excision of the transformation zone (LLETZ). MATERIALS AND METHODS: A total of 1,751 consecutive women with cervical intraepithelial neoplasia (CIN) who underwent LLETZ with or without Lugol's solution were retrospectively retrieved from each database of 3 university hospitals in South Korea. Outcomes included positive RMs and residual disease pathologically confirmed within 6 months after LLETZ. RESULTS: Positive RMs were noted in 345 cases (19.7%). Among 1,507 women followed up, residual disease was diagnosed in 100 cases (6.6%) (69/308 cases with positive RMs; 31/1,199 cases with negative RMs). The Lugol's solution group was less likely to have positive RMs (11.8% vs 25.5%, p < .01), to require additional surgical intervention (5.4% vs 10.2%, p < .01), and to have residual disease (4.9% vs 8.0%, p = .02). On multiple logistic regression analysis, Lugol's solution reduced the proportion of positive RMs (adjusted odds ratio [aOR], 0.31). Age (50 years or older; aOR, 1.64), preconization cervical cytology (aOR, 1.53), high-risk human papillomavirus (aOR, 1.75), and CIN 2 or 3 (aOR, 2.65) were independent risk factors for margin positivity ( p < .01 for all except high-risk human papillomavirus of p = .05). CONCLUSIONS: Lugol's solution optimizes CIN treatment by reducing the proportion of positive RMs and residual disease after LLETZ.

Potential Molecular Markers Related to Lymph Node Metastasis and Stalk Resection Margins in Pedunculated T1 Colorectal Cancers Using Digital Spatial Profiling: A Pilot Study with a Small Case Series.

There is a debate regarding the prediction of lymph node metastasis (LNM) in pedunculated T1 colorectal cancer (CRC). In this study with four cases of pedunculated T1 CRCs, we aimed to investigate gene expression variations based on the distance from the Haggitt line (HL) and identify potential molecular risk factors for LNM. By leveraging the Cancer Transcriptome Atlas and digital spatial profiling technology, we meticulously analyzed discrete regions, including the head, HL, proximal stalk region (300-1000 µm from HL), and distal stalk region (1500-2000 µm from HL) to identify spatially sequential molecular changes. Our findings showed significant overall gene expression variations among the head, proximal stalk, and distal stalk regions of pedunculated T1 CRCs compared to the control adenoma. Compared to LNM-negative T1 CRCs, LNM-positive T1 CRC showed that the expression of genes involved in immune-related pathways such as B2M, HLA-B, and HLA-E were significantly downregulated in the distal stalk region compared to the proximal stalk region. In summary, our results may tentatively suggest considering endoscopic resection of the stalk with a minimum 2000 µm margin from the HL, taking into account the gene expression alterations related to immune-related pathways. However, we acknowledge the limitations of this pilot study, notably the small case series, which may restrict the depth of interpretation. Further validation is imperative to substantiate these findings.

Substrate-binding loop interactions with pseudouridine trigger conformational changes that promote catalytic efficiency of pseudouridine kinase PUKI.

Pseudouridine, one major RNA modification, is catabolized into uracil and ribose-5'-phosphate by two sequential enzymatic reactions. In the first step, pseudouridine kinase (PUKI) phosphorylates pseudouridine to pseudouridine 5'-monophosphate. High-fidelity catalysis of pseudouridine by PUKI prevents possible disturbance of in vivo pyrimidine homeostasis. However, the molecular basis of how PUKI selectively phosphorylates pseudouridine over uridine with >100-fold greater efficiency despite minor differences in their Km values has not been elucidated. To investigate this selectivity, in this study we determined the structures of PUKI from Escherichia coli strain B (EcPUKI) in various ligation states. The structure of EcPUKI was determined to be similar to PUKI from Arabidopsis thaliana, including an α/ß core domain and ß-stranded small domain, with dimerization occurring via the ß-stranded small domain. In a binary complex, we show that Ser30 in the substrate-binding loop of the small domain mediates interactions with the hallmark N1 atom of pseudouridine nucleobase, causing conformational changes in its quaternary structure. Kinetic and fluorescence spectroscopic analyses also showed that the Ser30-mediated interaction is a prerequisite for conformational changes and subsequent catalysis by EcPUKI. Furthermore, S30A mutation or EcPUKI complexed with other nucleosides homologous to pseudouridine but lacking the pseudouridine-specific N1 atom did not induce such conformational changes, demonstrating the catalytic significance of the proposed Ser30-mediated interaction. These analyses provide structural and functional evidence for a pseudouridine-dependent conformational change of EcPUKI and its functional linkage to catalysis.

Novel Single-Particle Analytical Technique for Inhalable Airborne Microplastic Particles by the Combined Use of Fluorescence Microscopy, Raman Microspectrometry, and SEM/EDX.

This study presents a novel and efficient method for analyzing inhalable airborne microplastics (AMPs) in ambient PM10 aerosols. Although many studies have been conducted on MPs in a variety of environments, the physicochemical characteristics of AMPs of inhalable size (<10 µm) in ambient PM10 are poorly understood because of the lack of suitable analytical methods. The method employed in this study combines fluorescence microscopy, Raman microspectrometry (RMS), and scanning electron microscopy/energy-dispersive X-ray spectrometry (SEM/EDX) for an efficient and reliable investigation of inhalable AMPs, which constitute a small portion of ambient PM10 aerosol particles. Fluorescence microscopy and staining are used to select particles with high MP potential from ambient urban PM10 aerosols. The combination of RMS and SEM/EDX then allows for a detailed characterization of these particles on a single-particle basis. The results of the study show that ∼0.008% of the particles collected using a PM10 sampler had high MP potential, corresponding to ∼800 particles/m3. Among the stained particles of <10 µm, 27% were determined to be plastic, while the remaining 73% were found to be from tire/road wear. The number of inhalable AMPs was estimated to be 192 (±127) particles/m3. This study provides an important insight into the characteristics of inhalable AMPs in ambient PM10 aerosols that are particularly critical in respect of human health and climate change. The authors highlight that the use of a single fluorescence staining method can overestimate the number of inhalable AMPs in ambient air by including tire/road wear particles. To the best of their knowledge, this is the first study to demonstrate the morphological and spectroscopic characteristics of the same individual inhalable AMPs.

Biofunctional Inorganic Layered Double Hydroxide Nanohybrid Enhances Immunotherapeutic Effect on Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is a widespread, recurrent, and chronic inflammatory skin condition that imposes a major burden on patients. Conventional treatments, such as corticosteroids, are associated with various side effects, underscoring the need for innovative therapeutic approaches. In this study, the possibility of using indole-3-acetic acid-loaded layered double hydroxides (IAA-LDHs) is evaluated as a novel treatment for AD. IAA is an auxin-class plant hormone with antioxidant and anti-inflammatory effects. Following the synthesis of IAA-LDH nanohybrids, their ability to induce M2-like macrophage polarization in macrophages obtained from mouse bone marrow is assessed. The antioxidant activity of IAA-LDH is quantified by assessing the decrease in intracellular reactive oxygen species levels. The anti-inflammatory and anti-atopic characteristics of IAA-LDH are evaluated in a mouse model of AD by examining the cutaneous tissues, immunological organs, and cells. The findings suggest that IAA-LDH has great therapeutic potential as a candidate for AD treatment based on its in vitro and in vivo modulation of AD immunology, enhancement of macrophage polarization, and antioxidant activity. This inorganic drug delivery technology represents a promising new avenue for the development of safe and effective AD treatments.

Alcohol consumption and the risk of new-onset uterine leiomyomas: a nationwide population-based study in 2.5 million Korean women aged 20 to 39 years.

BACKGROUND: Uterine leiomyomas are the most common benign tumors in women of childbearing age. Although there are several studies reporting the positive association of drinking alcohol with the incidence of uterine leiomyomas, studies targeting Korean women are lacking. OBJECTIVE: This study aimed to investigate the association between alcohol consumption and the risk of new-onset uterine leiomyomas in Korean women of early reproductive-age. STUDY DESIGN: This was a retrospective nationwide population-based cohort study using the Korean National Health Insurance Service database. Participants comprised 2,512,384 asymptomatic Korean women aged 20 to 39 years who underwent a national health examination from 2009 to 2012. The follow-up period was from the date of the first national health examination to the date of diagnosis of new-onset uterine leiomyomas or December 2018 if no uterine leiomyomas were detected. The diagnosis of uterine leiomyomas required 2 outpatient records within a year or 1 inpatient record of International Classification of Diseases, Tenth Revision (ICD-10) codes of uterine leiomyomas (D25) in the Korean National Health Insurance Service. Exclusion criteria were previously diagnosed uterine leiomyomas during the screening period (January 2002 to the date of first health examination) or uterine leiomyoma diagnosis within 1 year of baseline examination. The associations of alcohol consumption, amount drunk per drinking session, and sustained drinking over time with the risk of new-onset uterine leiomyomas were investigated. RESULTS: Approximately 6.1% of women aged 20 to 39 years were diagnosed with uterine leiomyomas after an average of 4.3 years. Alcohol consumption was associated with an increased incidence of new-onset uterine leiomyomas of 12% to 16% (hazard ratio, 1.12; 95% confidence interval, 1.11-1.14 for mild-to-moderate drinkers; hazard ratio, 1.16; 95% confidence interval, 1.12-1.20 for heavy drinkers). Drinking ≥1 days per week was associated with increased risk of uterine leiomyomas (hazard ratio, 1.11; 95% confidence interval, 1.10-1.12 for drinking 1 day per week; hazard ratio, 1.15; 95% confidence interval, 1.12-1.17 for drinking ≥3 days per week), and the association increased proportionately to the amount of alcohol consumed per drinking session (hazard ratio, 1.17; 95% confidence interval, 1.15-1.19 for ≥7 glasses per drinking session). Women who also reported alcohol consumption in the questionnaire administered 2 years later (sustained drinkers) exhibited a 20% increased risk of new-onset uterine leiomyomas (hazard ratio, 1.20; 95% confidence interval, 1.17-1.22) compared with women who answered that they did not drink alcohol at both times (sustained nondrinkers). In women who discontinued drinking, the risk was 3% (hazard ratio, 1.03; 95% confidence interval, 1.01-1.06), whereas in women who became drinkers, the risk was 14% (hazard ratio, 1.14; 95% confidence interval, 1.11-1.16). CONCLUSION: Having an alcohol drinking habit, the amount of alcohol consumed per drinking session, and sustained drinking over 2 years were significantly associated with the risk of new-onset uterine leiomyomas. Avoiding or discontinuing drinking could lower the risk of new-onset uterine leiomyomas in early reproductive-age women.

Differentiation of autoimmune pancreatitis from pancreatic adenocarcinoma using CT characteristics: a systematic review and meta-analysis.

OBJECTIVES: To determine informational CT findings for distinguishing autoimmune pancreatitis (AIP) from pancreatic ductal adenocarcinoma (PDAC) and to review their diagnostic accuracy. METHODS: A systematic and detailed literature review was performed through PubMed, EMBASE, and the Cochrane library. Similar descriptors to embody the identical image finding were labeled as a single CT characteristic. We calculated the pooled diagnostic odds ratios (DORs) of each CT characteristic using a bivariate random-effects model. RESULTS: A total of 145 various descriptors from 15 studies (including 562 AIP and 869 PDAC patients) were categorized into 16 CT characteristics. According to the pooled DOR, 16 CT characteristics were classified into three groups (suggesting AIP, suggesting PDAC, and not informational). Seven characteristics suggesting AIP were diffuse pancreatic enlargement (DOR, 48), delayed homogeneous enhancement (DOR, 46), capsule-like rim (DOR, 34), multiple pancreatic masses (DOR, 16), renal involvement (DOR, 15), retroperitoneal fibrosis (DOR, 13), and bile duct involvement (DOR, 8). Delayed homogeneous enhancement showed a pooled sensitivity of 83% and specificity of 85%. The other six characteristics showed relatively low sensitivity (12-63%) but high specificity (93-99%). Four characteristics suggesting PDAC were discrete pancreatic mass (DOR, 23), pancreatic duct cutoff (DOR, 16), upstream main pancreatic duct dilatation (DOR, 8), and upstream parenchymal atrophy (DOR, 7). CONCLUSION: Eleven CT characteristics were informational to distinguish AIP from PDAC. Diffuse pancreatic enlargement, delayed homogeneous enhancement, and capsule-like rim suggested AIP with the highest DORs, whereas discrete pancreatic mass suggested PDAC. However, pooled sensitivities of informational CT characteristics were moderate. CLINICAL RELEVANCE STATEMENT: This meta-analysis underscores eleven distinctive CT characteristics that aid in differentiating autoimmune pancreatitis from pancreatic adenocarcinoma, potentially preventing misdiagnoses in patients presenting with focal/diffuse pancreatic enlargement. KEY POINTS: • Diffuse pancreatic enlargement (pooled diagnostic odds ratio [DOR], 48), delayed homogeneous enhancement (46), and capsule-like rim (34) were CT characteristics suggesting autoimmune pancreatitis. • The CT characteristics suggesting autoimmune pancreatitis, except delayed homogeneous enhancement, had a general tendency to show relatively low sensitivity (12-63%) but high specificity (93-99%). • Discrete pancreatic mass (pooled diagnostic odds ratio, 23) was the CT characteristic suggesting pancreatic ductal adenocarcinoma with the highest pooled DORs.

Effectiveness and complication rates of percutaneous transhepatic fluoroscopy-guided management of common bile duct stones: a single-arm meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis to determine the success and complication rate of percutaneous transhepatic fluoroscopy-guided management (PTFM) for the removal of common bile duct stones (CBDS). METHODS: A comprehensive literature search of multiple databases was conducted to identify original articles published between January 2010 and June 2022, reporting the success rate of PTFM for the removal of CBDS. A random-effect model was used to summarize the pooled rates of success and complications with 95% confidence intervals (CIs). RESULTS: Eighteen studies involving 2554 patients met the inclusion criteria and were included in the meta-analysis. Failed or infeasible endoscopic management was the most common indication of PTFM. The meta-analytic summary estimates of PTFM for the removal of CBDS were as follows: rate of overall stone clearance 97.1% (95% CI, 95.7-98.5%); stone clearance at first attempt 80.5% (95% CI, 72.3-88.6%); overall complications 13.8% (95% CI, 9.7-18.0%); major complications 2.8% (95% CI, 1.4-4.2%); and minor complications 9.3% (95% CI, 5.7-12.8%). Egger's tests showed the presence of publication bias with respect to the overall complications (p = 0.049). Transcholecystic management of CBDS had an 88.5% pooled rate for overall stone clearance (95% CI, 81.2-95.7%), with a 23.0% rate for complications (95% CI, 5.7-40.4%). CONCLUSION: The systematic review and meta-analysis answer the questions of the overall stone clearance, clearance at first attempt, and complication rate of PTFM by summarizing the available literature. Percutaneous management could be considered in cases with failed or infeasible endoscopic management of CBDS. CLINICAL RELEVANCE STATEMENT: This meta-analysis highlights the excellent stone clearance rate achieved through percutaneous transhepatic fluoroscopy-guided removal of common bile duct stones, potentially influencing clinical decision-making when endoscopic treatment is not feasible. KEY POINTS: • Percutaneous transhepatic fluoroscopy-guided management of common bile duct stones had a pooled rate of 97.1% for overall stone clearance and 80.5% for clearance at the first attempt. • Percutaneous transhepatic management of common bile duct stones had an overall complication rate of 13.8%, including a major complication rate of 2.8%. • Percutaneous transcholecystic management of common bile duct stones had an overall stone clearance rate of 88.5% and a complication rate of 23.0%.

Applicable Forensic Biomarker for Drowning Diagnosis: Extracellular Signal-Regulated Kinase 2 (ERK2).

Drowning is a common cause of accidental death worldwide, and it continues to be a serious public health problem. However, diagnosing drowning is a challenging task in forensic investigation because it is difficult to prove actual drowning and other submerged deaths with the autopsy techniques that are currently in use. Here, we show biomarkers that may be helpful for the diagnosis of drowning. We divided the experimental animals into four groups (drowning, postmortem submersion, hypoxia, and control) to evaluate the expression patterns of extracellular signal-regulated kinase 1/2 (ERK1/2). On gene expression analysis, only ERK2 was found to be significantly increased in the drowning groups compared to the other cases. In the immunoblot analysis, phosphorylated ERK2 (p-ERK2) was found to be upregulated in the drowning groups. Immunohistochemical staining also showed that p-ERK in alveolar cells revealed a granular pattern in the drowning groups. However, the expression pattern of ERK2 over time after drowning differed between the freshwater and seawater drowning groups. Taken together, these results indicate that ERK2 may be useful for distinguishing between drowning and postmortem submersion if the postmortem interval (PMI) of drowning is short. Conversely, if the PMI is long from the time that death occurs until the discovery of dead bodies, it is possibly more helpful for identifying between freshwater and seawater drowning.

Risk of adverse obstetric outcomes in patients with a history of endometrial cancer: A nationwide population-based cohort study.

OBJECTIVE: To evaluate adverse obstetric outcomes in women with a history of endometrial cancer (EC). DESIGN: Population-based cohort study. SETTING: The Korean National Health Insurance (KNHI) claims database. POPULATION: Women who gave birth between 2009 and 2016, with a history of EC prior to pregnancy. METHODS: The KNHI database was used to compare obstetric outcomes of women with and without a history of EC, using the ICD-10 codes. Multivariable logistic regression models were used to determine the associations between a history of EC and adverse obstetric outcomes. MAIN OUTCOMES MEASURES: Adverse obstetric outcomes. RESULTS: Overall, 248 and 3 335 359 women with and without a history of EC, respectively, gave birth. When adjusted for age, primiparity and comorbidities, an increased risk of multiple gestations (odds ratio [OR] 4.925, 95% confidence interval [CI] 3.394-7.147), caesarean delivery (OR 2.005, 95% CI 1.535-2.62) and preterm birth (OR 1.941, 95% CI 1.107-3.404) was observed among women with a history of EC. We were unable to demonstrate significant differences in the risk of pre-eclampsia, gestational diabetes, vacuum delivery, placenta praevia, placenta accreta spectrum, placental abruption and postpartum haemorrhage between the groups. In the sensitivity analyses excluding multiple gestations, an increased risk of preterm birth was not observed among women with a history of EC (OR 1.276, 95% CI 0.565-2.881). CONCLUSIONS: There is no convincing evidence of an increased risk of adverse obstetric outcomes among women with a history of EC. Our findings would be useful in counselling of patients with EC who are undergoing fertility-sparing treatment.

The Swiss Kidney Stone Cohort: A Longitudinal, Multicentric, Observational Cohort to Study Course and Causes of Kidney Stone Disease in Switzerland.

BACKGROUND: Kidney stone disease has a high prevalence worldwide of approximately 10% of the population and is characterized by a high recurrence rate. Kidney stone disease results from a combination of genetic, environmental, and lifestyle risk factors, and the dissection of these factors is complex. METHODS: The Swiss Kidney Stone Cohort (SKSC) is an investigator-initiated prospective, multicentric longitudinal, observational study in patients with kidney stones followed with regular visits over a period of 3 years after inclusion. Ongoing follow-ups by biannual telephone interviews will provide long-term outcome data. SKSC comprises 782 adult patients (age >18 years) with either recurrent stones or a single stone event with at least one risk factor for recurrence. In addition, a control cohort of 207 individuals without kidney stone history and absence of kidney stones on a low-dose CT scan at enrolment has also been recruited. SKSC includes extensive collections of clinical data, biochemical data in blood and 24-h urine samples, and genetic data. Biosamples are stored at a dedicated biobank. Information on diet and dietary habits was collected through food frequency questionnaires and standardized recall interviews by trained dieticians with the Globodiet software. CONCLUSION: SKSC provides a unique opportunity and resource to further study cause and course of kidney disease in a large population with data and samples collected of a homogeneous collective of patients throughout the whole Swiss population.

Optical Duality of Molybdenum Disulfide: Metal and Semiconductor.

The two different light-matter interactions between visible and infrared light are not switchable because control mechanisms have not been elucidated so far, which restricts the effective spectral range in light-sensing devices. In this study, modulation of the effective spectral range is demonstrated using the metal-insulator transition of MoS2. Nondegenerate MoS2 exhibits a photoconductive effect in detecting visible light. In contrast, degenerate MoS2 responds only to mid-infrared (not visible) light by displaying a photoinduced heating effect via free carrier absorption. Depending on the doping level, the optical behavior of MoS2 simulates the photoconductivity of either the semiconductor or the metal, further indicating that the optical metal-insulator transition is coherent with its electrical counterpart. The electrical switchability of MoS2 enables the development of an unprecedented and novel design optical sensor that can detect both visible and mid-IR (wavelength of 9.6 µm) ranges with a singular optoelectronic device.

Different miRNAs Related to FBXW7 Mutations or High Mitotic Indices Contribute to Rectal Neuroendocrine Tumors: A Pilot Study.

Recent studies suggest that miRNA may be involved in the development of rectal neuroendocrine tumors (NETs). We explored the frequency of clinicopathologically relevant mutations and miRNA expression in rectal NETs to examine molecular profiles related to prognosis and behavior. Twenty-four eligible specimens with endoscopically excised rectal NETs were selected. Next-generation sequencing and an miRNA expression assay were used to evaluate the expression profile relevant to common genetic mutations in rectal NETs. Kyoto Encyclopedia of Genes and Genomes analysis predicted that the possible target signaling pathways were correlated with dysregulated miRNAs. Nineteen rectal NETs harbored more than one mutation in the 24 cancer-related genes. Seven miRNAs (hsa-miR-769-5p, hsa-miR-221-3p, hsa-miR-34a-5p, hsa-miR-181c-5p, hsa-miR-1246, hsa-miR-324-5p, and hsa-miR-361-3p) were significantly down-regulated in tumors harboring the FBWX7 mutation. Unsupervised hierarchical clustering analysis showed that up-regulation of these seven miRNAs may result in high mitotic indices, indicating the role of miRNAs in tumor progression. Among the down-regulated miRNAs, hsa-miR-769-5p was strongly correlated with extracellular matrix-receptor interaction and lysine degradation. Among the clinicopathological factors, up-regulated hsa-miR-3934-5p was linked to an increased mitotic count. No change in miRNA expression was associated with a tumor size >1 cm, lymphovascular invasion, or Ki-67 index. In summary, we identified different miRNA signatures involved in FBXW7 mutations or high mitotic indices in rectal NETs, which may play a critical role in tumor behavior.

Medical Management of Dyslipidemia for Secondary Stroke Prevention: Narrative Review.

Dyslipidemia is a major risk factor for stroke, following hypertension, diabetes, and smoking, and is an important risk factor for the prevention and treatment of coronary artery disease and peripheral vascular disease, including stroke. Recent guidelines recommend considering low-density lipoprotein cholesterol (LDL-C)-lowering therapies, such as statins (preferably), ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to prevent the occurrence or recurrence of stroke, adhering to the "lower is better" approach. In this review, we examined the evidence supporting lipid-lowering medications like statins, ezetimibe, and PCSK9 inhibitors for secondary stroke prevention and dyslipidemia management in different stroke subtypes. Stroke guidelines advocate for administering the maximum tolerable dose of statins as the primary treatment and as soon as possible despite the potential for new-onset diabetes mellitus and possible muscle and liver toxicity due to their demonstrated benefits in secondary prevention of cardiovascular diseases and mortality reduction. When statin use is insufficient for LDL lowering, ezetimibe and PCSK9 inhibitors are recommended as complementary therapies. It is essential to establish lipid-lowering therapy goals based on the stroke subtype and the presence of comorbidities.

Usefulness of 3-Dimensional Computed Tomography Assessment of Femoral Tunnel after Anterior Cruciate Ligament Reconstruction.

Positioning of the femoral tunnel during anterior cruciate ligament (ACL) reconstruction is the most crucial factor for successful procedure. Owing to the inter-individual variability in the intra-articular anatomy, it can be challenging to obtain precise tunnel placement and ensure consistent results. Currently, the three-dimensional (3D) reconstruction of computed tomography (CT) scans is considered the best method for determining whether femoral tunnels are positioned correctly. Postoperative 3D-CT feedback can improve the accuracy of femoral tunnel placement. Precise tunnel formation obtained through feedback has a positive effect on graft maturation, graft failure, and clinical outcomes after surgery. However, even if femoral tunnel placement on 3D CT is appropriate, we should recognize that acute graft bending negatively affects surgical results. This review aimed to discuss the implementation of 3D-CT evaluation for predicting postoperative outcomes following ACL re-construction. Reviewing research that has performed 3D CT evaluations after ACL reconstruction can provide clinically significant evidence of the formation of ideal tunnels following anatomic ACL reconstruction.

Incidental Axillary Dose of Tomotherapy in Hypofractionated Whole Breast Radiotherapy for Early Breast Cancer: A Dosimetrical Analysis.

Background and Objectives: Intensity-modulated radiation therapy (IMRT) is becoming a more common method of performing whole breast irradiation (WBI) for early breast cancer. This study aimed to examine the incidental dose to the axillary region using tomotherapy, a unique form of IMRT. Patients and Methods: This study included 30 patients with early-stage breast cancer who underwent adjuvant WBI using TomoDirect IMRT. A hypofractionation scheme of 42.4 Gy delivered in 16 fractions was prescribed. The plan comprised of two parallel-opposed beams, along with two additional beams positioned anteriorly at gantry angles of 20° and 40° from the medial beam. The incidental dose received at axillary levels I, II, and III was evaluated using several dose-volume parameters. Results: The study participants had a median age of 51 years, and 60% had left-sided breast cancer. The mean dose of the axilla for levels I, II, and III were 15.5 ± 4.8 Gy, 14.9 ± 4.2 Gy, and 1.5 ± 1.6 Gy, respectively. Adequate coverage of the axilla, defined as V95%[%], was achieved for 4.7 ± 3.9%, 4.8 ± 3.7%, and 0 ± 0% for levels I, II, and III, respectively. The results were compared with those of previously published studies, and the axillary mean dose and V95%[%] of TomoDirect IMRT were low, comparable to other IMRT techniques, and lower than those of traditional tangential therapy. Conclusions: While incidental axillary radiation during WBI has been proposed to assist in regional disease control, the TomoDirect plan was demonstrated to decrease this dose, and a hypofractionation scheme would further lower its biological effectiveness. Future clinical studies should incorporate dosimetrical analysis of incidental axillary dose, in order to facilitate hypofractionated IMRT planning with risk-adjusted axilla coverage in early breast cancer.

Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma.

Chimeric Antigen Receptor (CAR) T cell immunotherapy is revolutionizing treatment for patients suffering from B-cell lymphoma (BL). However, the current method of CAR T cell production is complicated and expensive, requiring collection of patient blood to enrich the T cell population, ex vivo engineering/activation, and quality assessment before the patient can receive the treatment. Herein we leverage Spleen Selective ORgan Targeted (SORT) Lipid Nanoparticles (LNPs) to produce CAR T cells in situ and bypass the extensive and laborious process currently used. Optimized Spleen SORT LNPs containing 10 % 18 : 1 PA transfected CD3+, CD8+, and CD4+ T cells in wild-type mice. Spleen SORT LNPs delivered Cre recombinase mRNA and CAR encoding mRNA to T cells in reporter mice and in a lymphoreplete B cell lymphoma model (respectively) after intravenous injection without the need for active targeting ligands. Moreover, in situ CAR T cells increased the overall survival of mice with a less aggressive form of B cell lymphoma. In addition, in situ transfected CAR T cells reduced tumor metastasis to the liver by increasing tumor infiltrating lymphocytes. Overall, these results offer a promising alternative method for CAR T cell production with pre-clinical potential to treat hematological malignancies.