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Resolving protein-protein interactions (PPIs) inside biomolecular condensates is crucial for elucidating their functions and regulation mechanisms. The transient nature of condensates and the multiple localizations of clients, however, have rendered it challenging to determine compartment-specific PPIs. Here we developed a condensation-enhanced, spatially directed, metabolic incorporation-assisted photocrosslinking strategy-termed DenseMAP-for spatiotemporally resolved dissection of the direct protein interactome within condensates. By leveraging our condensation-enhanced photocrosslinker and the spatially directed biotin tagging, DenseMAP enabled stress-granule-specific interactome mapping of the N 6 -methyladenosine readers YTHDF1 and YTHDF2, and uncovered the functional role of phosphorylation on the SARS-CoV-2 nucleocapsid protein in regulating virus replication. Further applying DenseMAP for direct interactome mapping of the subcompartmental scaffold protein NPM1 deciphered nucleolar granular component proteome, and unveiled the critical role of SUMOylation in controlling nucleolar proteome homeostasis. DenseMAP provides a platform technology for analysing functional PPI networks within subcellular and subcompartmental condensates under diverse physiological and/or pathological settings., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Many studies have examined the effectiveness of lifestyle modifications such as exercise, diet, weight loss, and stress reduction in controlling hypertension in elderly individuals, and several meta-analyses have reported that both aerobic and resistance exercise can reduce blood pressure in this population. In addition, the higher sensitivity to sodium in elderly individuals highlights the importance of restricting salt intake for blood pressure control. Low-sodium salt or potassium supplementation can help with blood pressure control in elderly individuals with hypertension. Several clinical trials have shown that both the Dietary Approaches to Stop Hypertension (DASH) and a Mediterranean diet pattern are effective in reducing blood pressure in older hypertensive patients. Although moderate alcohol consumption does not appear to negatively impact blood pressure control in older adults, blood pressure increases along with heavy alcohol intake. Some studies have indicated that coffee intake increases blood pressure in elderly hypertensive subjects, especially for those who consume more than 3 cups a day. Clinical studies have shown that weight loss through exercise and diet control is beneficial for controlling hypertension in elderly individuals. Anxiety, depression and insomnia also appear to have an impact on elderly hypertension. In this review, we discuss the effectiveness of lifestyle modifications and non-pharmacological management of these factors and their impact on hypertension in elderly individuals, and how to effectively implement them in real-world settings., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated in vitro, in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate T cells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond., Competing Interests: Declaration of interests P.R.C., F.L., J. Lin, and H. Zhang are listed as inventors on a patent application (PCT/CN2021/130337) filed on this work through Peking University., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To evaluate whether co-treatment of repeated GnRHa triggers with GnRH antagonist protocols can improve the clinical outcomes in in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) procedures., Methods: In this retrospective study, 712 Chinese Han women aged 20-42 undergoing autologous IVF/ICSI-ET with a flexible GnRH antagonist protocol were analyzed. The 735 cycles were split into the single (n = 238) and the repeated (n = 497) GnRHa groups. In the single GnRHa group, 0.2 mg of triptorelin was given for oocyte maturation, whereas in the repeated GnRHa group, two doses of 0.2 mg were administered 12 h apart. PSM design was used for a fair comparison. The main study outcomes included the clinical pregnancy rate (CPR), live birth rate (LBR), good-quality embryo rate, and fertilization rate. Multivariate logistic regression analyses were used to identify all potential factors affecting clinical outcomes., Results: Post-PSM, analysis of 159 cycles per group showed the repeated GnRHa group outperforming the single GnRHa group in IVF fertilization rates (71.5% vs. 67.7%, P < 0.05) and good-quality embryo rate (47.1% vs. 43.7%, P < 0.05). Furthermore, the repeated GnRHa group achieved higher CPR (72.6% vs. 53.4%, P < 0.05) and LBR (59.7% vs. 43.8%, P < 0.05) in FET cycles. Multivariate logistic regression indicated a significant negative correlation between the use of a single GnRHa trigger and both clinical pregnancy (OR = 0.382, P < 0.05) and live birth (OR = 0.518, P < 0.05)., Conclusion: Our study reported that individuals who received a repeated GnRHa trigger exhibited higher CPR and LBR during FET cycles compared to those who received a single dose GnRHa trigger., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Traumatic optic neuropathy (TON) is a rare complication of facial trauma that results in vision loss. Clinical diagnosis of TON is based on a history of head trauma and an ophthalmic examination; however, the risk factors for TON and the ideal treatment strategy remain undetermined. This study aimed to identify predictive risk factors for TON and evaluate the effectiveness of current treatments with respect to visual outcomes in patients with TON., Methods: This study retrospectively enrolled patients with periorbital facial bone fracture between 2008 and 2019. Initial facial bone computed tomography, ophthalmic exam results, initial Glasgow Coma Scale, and Injury Severity Score were recorded. This study classified patients into 4 intervention groups (i.e., medication, surgery, combination therapy, and observation) to compare the outcome of visual acuity., Results: This study enrolled 1168 patients with facial bone fractures, 93 (7.96%) of whom were diagnosed as having TON. Independent risk factors for TON included optic canal fracture, medial orbital wall fracture, retrobulbar hematoma, and head Abbreviated Injury Scale ≥4. Patients with TON who initially presented with no light perception tended to have poor final visual acuity (VA) outcomes. The results indicated no significant difference in VA improvement among patients receiving observation, megadose corticosteroid therapy, surgical decompression, or combined steroid therapy and decompression., Conclusion: Clinicians can achieve early prediction of TON in patients with an initial unconscious state and the identified risk factors. The results indicated that the conservative observation yielded noninferior VA outcomes in patients with TON compared with those receiving medication or surgical treatment., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Arteriovenous malformations (AVMs) are uncommon cerebral lesions that can cause significant neurological complications. Surgical resection is the gold standard for treatment, but endovascular embolization and stereotactic radiosurgery (SRS) are viable alternatives., Objective: To compare the outcomes of endovascular embolization versus SRS in the treatment of AVMs with Spetzler-Martin grades I-III., Methods: This study combined retrospective data from 10 academic institutions in North America and Europe. Patients aged 1 to 90 years who underwent endovascular embolization or SRS for AVMs with Spetzler-Martin grades I-III between January 2010 and December 2023 were included., Results: The study included 244 patients, including 84 who had endovascular embolization and 160 who had SRS. Before propensity score matching (PSM), complete obliteration at the last follow-up was achieved in 74.5% of the SRS group compared with 57.8% of the embolization group (OR=0.47; 95% CI 0.26 to 0.48; P=0.01). After propensity score matching, SRS still achieved significantly higher occlusion rates at last follow-up (78.9% vs 55.3%; OR=0.32; 95% CI 0.12 to 0.90; P=0.03).Hemorrhagic complications were higher in the embolization group than in the SRS group, although this difference did not reach statistical significance after PSM (13.2% vs 2.6%; OR=5.6; 95% CI 0.62 to 50.47; P=0.12). Similarly, re-treatment rate was higher in the embolization group (10.5% vs 5.3%; OR=2.11; 95% CI 0.36 to 12.31; P=0.40) compared with the SRS group., Conclusion: Our findings indicate that SRS has a significantly higher obliteration rate at last follow-up compared with endovascular embolization. Also, SRS has a higher tendency for fewer hemorrhagic complications and lower re-treatment rate. Further prospective studies are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Genetic modification of genes such as recombination activating gene 2 (RAG2) or interleukin-2 receptor-γ (IL2RG) results in pigs exhibiting severe combined immunodeficiency (SCID). Pigs presenting a SCID phenotype are important animal models that can be used to establish xenografts and to study immune system development and various immune-related pathologies. However, due to their immunocompromised nature, SCID pigs have shortened lifespans and are notoriously difficult to maintain. The failure-to-thrive phenotype makes the establishment of a breeding population of RAG2/IL2RG double-knockout pigs virtually impossible. Here, to overcome this limitation, we investigated whether reconstituting the immune system of SCID piglets with a fetal bone allograft would extend their lifespan. Following intramuscular transplantation, allografts gave rise to lymphocytes expressing T cell (CD3, CD4 and CD8), B cell (CD79α) and natural killer cell (CD335) lineage markers, which were detected in circulation as well in the spleen, liver, bone marrow and thymic tissues. The presence of lymphocytes indicates broad engraftment of donor cells in the recipient SCID pigs. Unlike unreconstituted SCID pigs, the engrafted animals thrived and reached puberty under standard housing conditions. This study demonstrates a novel method to extend the survival of SCID pigs, which may improve the availability and use of SCID pigs as a biomedical animal model., (© 2024. The Author(s).)

Objective: Nordalbergin is a coumarin extracted from Dalbergia sissoo DC. To date, the biological effects of nordalbergin have not been well investigated. To investigate the anti-inflammatory responses and the anti-oxidant abilities of nordalbergin using lipopolysaccharide (LPS)-activated macrophages and LPS-induced sepsis mouse model., Materials and Methods: Production of nitrite oxide (NO), prostaglandin E2 (PGE 2 ), pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β), reactive oxygen species (ROS), tissue damage and serum inflammatory markers, and the activation of the NLRP3 inflammasome were examined., Results: Our results indicated that nordalbergin reduced the production of NO and pro-inflammatory cytokines in vitro and ex vivo. Nordalbergin also suppressed iNOS and cyclooxygenase-2 expressions, decreased NF-κB activity, and attenuated MAPKs signaling pathway activation by decreasing JNK and p38 phosphorylation by LPS-activated J774A.1 macrophages. Notably, nordalbergin diminished NLRP3 inflammasome activation via repressing the maturation of IL-1β and caspase-1 and suppressing ROS production by LPS/ATP- and LPS/nigericin-activated J774A.1 macrophages. Furthermore, nordalbergin exhibited protective effects against the infiltration of inflammatory cells and also inhibited the levels of organ damage markers (AST, ALT, BUN) by LPS-challenged mice., Conclusion: Nordalbergin possesses anti-inflammatory effects in macrophage-mediated innate immune responses, alleviates ROS production, decreases NLRP3 activation, and exhibits protective effects against LPS-induced tissue damage in mice., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

As technology advances rapidly, a diverse array of Internet of Things (IoT) devices finds widespread application across numerous fields. The intelligent nature of these devices not only gives people more convenience, but also introduces new challenges especially in security when transmitting data in fog-based cloud environments. In fog computing environments, data need to be transmitted across multiple devices, increasing the risk of data being intercepted or tampered with during transmission. To securely share cloud ciphertexts, an alleged proxy re-encryption approach is a commonly adopted solution. Without decrypting the original ciphertext, such a mechanism permits a ciphertext intended for user A to be easily converted into the one intended for user B. However, to revoke the decryption privilege of data users usually relies on the system authority to maintain a user revocation list which inevitably increases the storage space. In this research, the authors come up with a fog-based proxy re-encryption system with revocable identity. Without maintaining the traditional user revocation list, the proposed scheme introduces a time-updated key mechanism. The time-update key could be viewed as a partial private key and should be renewed with different time periods. A revoked user is unable to obtain the renewed time-update key and hence cannot share or decrypt cloud ciphertexts. We formally demonstrate that the introduced scheme satisfies the security of indistinguishability against adaptively chosen identity and chosen plaintext attacks (IND-PrID-CPA) assuming the hardness of the Decisional Bilinear Diffie-Hellman (DBDH) problem in the random oracle model. Furthermore, compared with similar systems, the proposed one also has lower computational complexity as a whole.

Background: Patients with cleft lip and palate anomalies suffer from associated negative psychosocial effects despite undergoing reconstructive surgeries. Discrimination from others may be a contributing factor. We aim to understand whether people react differently to cleft and non-cleft subjects in questions regarding aesthetic appraisal and interpersonal impressions, as well as whether diverging opinions exist between people of different backgrounds., Materials and Methods: Using the 3dMD system, three-dimensional craniofacial images of cleft (n = 20) and non-cleft (n = 5) pediatric individuals were obtained and used to create a Likert scale-based questionnaire. Participants from three different backgrounds, including adolescent peers, adult laypersons, and plastic surgeons, were recruited to complete the assessment. The resulting data were transferred to a bar graph and analyzed with the item response theory-graded response model to estimate the latent traits and capability of each subject., Results: Non-cleft images obtained more positive responses than cleft images in questions of both aesthetic appraisal and interpersonal impressions. However, some of the cleft images were rated similarly, or even superior, to non-cleft images in questions regarding interpersonal impressions. Surgeons showed the greatest latent capability in differentiating between cleft and non-cleft images, followed by adult laypersons, and then adolescent peers., Conclusions: Despite cleft patients experiencing drastic improvements in appearance post-repair, all subject groups responded differently to questions concerning aesthetic and social impressions of pediatric cleft and non-cleft images. Plastic surgeons were more critical than others. These findings may offer further insight to clinicians, educators, and caregivers into the social challenges faced by cleft individuals., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Glucosamine (GlcN) is one of the dietary supplements used in the treatment of osteoarthritis. Endogenously, GlcN is synthesized from glucose through the hexosamine pathway. In addition to ameliorating arthritis, several biological functions of GlcN have been reported, including insulin resistance in skeletal muscle. However, the regulatory role of GlcN in skeletal muscle development is not clear. We therefore investigated the effect of GlcN on myoblast proliferation, differentiation, and myotube development and their underlying mechanisms in C2C12 cells. Myoblast proliferation was measured by MTT assay. The expressions of MyoD, myogenin (MyoG), and myosin heavy chain (MyHC) were identified as determinants of myoblast differentiation. Expressions of atrogin-1 and muscle RING-finger protein-1 (MuRF-1) were identified as markers of myotube atrophy. The results show that treatment with GlcN significantly reduced myoblast proliferation and phosphorylation of Stat3 and S6K. These findings suggest that GlcN can inhibit growth of myoblasts through inhibiting phosphorylation of Stat3 and S6K. In addition, GlcN significantly suppressed the expression of MyoD, MyoG, and MyHC, as well as myotube formation. Pretreatment of C2C12 myoblast cells with ER stress inhibitors significantly blocked GlcN-inhibited MyHC expression and myotube formation. It can be concluded that GlcN suppressed myogenic differentiation via a pathway that involved ER stress. Moreover, GlcN decreased myotube diameter and expression of MyHC, as well as increased MuRF-1 in C2C12 myotubes. Meanwhile, GlcN also reduced the expressions of phosphorylated Akt and mTOR were stimulated after GlcN treatment in C2C12 myotubes. Thus, GlcN induced skeletal muscle atrophy by inhibiting the protein synthesis pathway. Chronic GlcN infusion also caused skeletal muscle atrophy in mice. In conclusion, GlcN regulated important stages of skeletal muscle development through different signaling pathways., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death worldwide and in Taiwan. It is highly prevalent and has a tremendous impact on global health. Therefore, the Taiwan Society of Cardiology developed these best-evidence preventive guidelines for decision-making in clinical practice involving aspects of primordial prevention including national policies, promotion of health education, primary prevention of clinical risk factors, and management and control of clinical risk factors. These guidelines cover the full spectrum of ASCVD, including chronic coronary syndrome, acute coronary syndrome, cerebrovascular disease, peripheral artery disease, and aortic aneurysm. In order to enhance medical education and health promotion not only for physicians but also for the general public, we propose a slogan (2H2L) for the primary prevention of ASCVD on the basis of the essential role of healthy dietary pattern and lifestyles: " Healthy Diet and Healthy Lifestyles to Help Your Life and Save Your Lives ". We also propose an acronym of the modifiable risk factors/enhancers and relevant strategies to facilitate memory: " ABC 2 D 2 EFG-I'M 2 ACE" : Adiposity, Blood pressure, Cholesterol and Cigarette smoking, Diabetes mellitus and Dietary pattern, Exercise, Frailty, Gout/hyperuricemia, Inflammation/infection, Metabolic syndrome and Metabolic dysfunction-associated fatty liver disease, Atmosphere (environment), Chronic kidney disease, and Easy life (sleep well and no stress). Some imaging studies can be risk enhancers. Some risk factors/clinical conditions are deemed to be preventable, and healthy dietary pattern, physical activity, and body weight control remain the cornerstone of the preventive strategy., Competing Interests: Ting-Hsing Chao has been on the speaker bureau for Astrazeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Novartis, Pfizer, Sanofi, Tanabe, and TSH biopharm. All other authors report no potential conflicts of interest in relation to these guidelines.

Diagnosing and differentiating spinal vascular pathologic conditions is challenging. Small structures, lengthy imaging examinations, and overlapping imaging features increase the difficulty. Yet, subtle findings and helpful protocols can narrow the differential diagnosis. The authors aim to help radiologists make accurate and timely diagnoses of spinal vascular pathologic conditions in and around the spinal cord by highlighting spinal vascular anatomy, imaging findings, and three broad categories of abnormalities: infarcts, anomalies, and tumors. © RSNA, 2024.

In genetic studies of cerebrovascular diseases, the optimal vessels to use as controls remain unclear. Our goal is to compare the transcriptomic profiles among 3 different types of control vessels: superficial temporal artery (STA), middle cerebral arteries (MCA), and arteries from the circle of Willis obtained from autopsies (AU). We examined the transcriptomic profiles of STA, MCA, and AU using RNAseq. We also investigated the effects of using these control groups on the results of the comparisons between aneurysms and the control arteries. Our study showed that when comparing pathological cerebral arteries to control groups, all control groups presented similar responses in the activation of immunological processes, the regulation of intracellular signaling pathways, and extracellular matrix productions, despite their intrinsic biological differences. When compared to STA, AU exhibited upregulation of stress and apoptosis genes, whereas MCA showed upregulation of genes associated with tRNA/rRNA processing. Moreover, our results suggest that the matched case-control study design, which involves control STA samples collected from the same subjects of matched aneurysm samples in our study, can improve the identification of non-inherited disease-associated genes. Given the challenges associated with obtaining fresh intracranial arteries from healthy individuals, our study suggests that using MCA, AU, or paired STA samples as controls are feasible strategies for future large-scale studies investigating cerebral vasculopathies. However, the intrinsic differences of each type of control should be taken into consideration when interpreting the results. With the limitations of each control type, it may be most optimal to use multiple tissues as controls., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H 2 S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H 2 S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism., (© 2024. The Author(s).)

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to understand the detailed cellular and molecular mechanisms involved, which will enable the development of safer and more effective treatment options. Endothelial cells (ECs), the cells that line the vascular lumen, are integral to the pathogenesis of bAVMs. Understanding the fundamental role of ECs in pathological conditions is crucial to unraveling bAVM pathophysiology. This review focuses on the current knowledge of bAVM-relevant signaling pathways and dysfunctions in ECs, particularly the endothelial-to-mesenchymal transition (EndMT).

Gac fruit ( Momordica cochinchinensis Spreng.) is a prominent source of carotenoids, renowned for its exceptional concentration of these compounds. This study focuses on optimizing the extraction of active components from the aril of gac fruit by evaluating the effects of extraction temperature, solid-liquid ratio, and extraction time. The primary objective is to maximize the yield of gac oil while assessing its antioxidant capacity. To analyze the kinetics of the solid-liquid extraction process, both first-order and second-order kinetic models were employed, with the second-order model providing the best fit for the experimental data. In addition, the potential of gac fruit peel as a precursor for biochar production was investigated through carbonization. The resultant biochars were evaluated for their efficacy in adsorbing crystal violet (CV) dye from aqueous solutions. The adsorption efficiency of the biochars was found to be dependent on the carbonization temperature, with the highest efficiency observed for BCMC550 (91.72%), followed by BCM450 (81.35%), BCMC350 (78.35%), and BCMC250 (54.43%). The adsorption isotherm data conformed well to the Langmuir isotherm model, indicating monolayer adsorption behavior. Moreover, the adsorption kinetics were best described by the pseudo-second-order model. These findings underscore the potential of gac fruit and its byproducts for diverse industrial and environmental applications, highlighting the dual benefits of optimizing gac oil extraction and utilizing the peel for effective dye removal.

Background: Clear aligner therapy has an aesthetic advantage over fixed appliance therapy. However, to our knowledge, no study has objectively compared patient orthodontic and aesthetic outcomes between clear aligner and fixed appliance therapies administered after orthognathic surgery (OGS)., Methods: This study included patients with no history of congenital craniofacial deformities who underwent surgery-first OGS and received clear aligner or fixed appliance therapy. The patients' grades on the Dental Health Component (DHC) and Aesthetic Component of the Index of Orthodontic Treatment Need and scores on the Peer Assessment Rating (PAR) index were calculated before OGS (T0), after OGS (T1), and after orthodontic therapy (T2)., Results: This study included 33 patients (clear aligner therapy, n = 19; fixed appliance therapy, n = 14). No considerable between-group differences were noted in the DHC and AC grades at T0, T1, or T2. Furthermore, percentage of reduction in the PAR index score was more significant in the clear aligner group (74.4%) than in the fixed appliance group (63.2%) from T0 to T1 ( P = 0.035); however, no between-group differences were noted from T1 to T2 or from T0 to T2. Both groups exhibited substantially improved DHC grades, Aesthetic Component grades, and PAR index scores at T1 and T2., Conclusions: Patient outcomes were similar between the clear aligner and fixed appliance groups after orthodontic therapy. However, the former group exhibited more favorable immediate results after OGS than did the latter group. Thus, as an adjunct therapy for patients with malocclusion, clear aligner therapy may be more effective than fixed appliance therapy., Clinical Question/level of Evidence: Therapeutic, II., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: The association between patient age and cerebral arterial vasospasm (CVS) and delayed cerebral ischemia (DCI) risk following aneurysmal subarachnoid hemorrhage (aSAH) remains unclear. This study aims to assess the role of age on aSAH-related complications., Methods: Single-center retrospective study comprising aSAH patients treated between January 2009 and March 2023. Age was analyzed as continuous and categorical variables (<60 yrs vs. ≥60 yrs and by decade). Outcomes of interest included radiographic CVS, DCI, cerebral infarction, in-hospital mortality, length-of-stay (LOS), ventriculoperitoneal shunt placement, and modified Rankin Scale (mRS) scores at discharge and 3-month follow-up., Results: Nine hundred and twenty-five aSAH patients were included. Most (n = 598; 64.6%) were <60 yrs old (46 ± 9.1 yrs). CVS likelihood was lower in the older cohort (aOR = 0.56 [0.38-0.82]). Patients ≥60 yrs had higher mortality rates (aOR = 2.24 [1.12-4.47]) and worse mRS scores at discharge (aOR = 2.66 [1.91-3.72]) and 3-month follow-up (aOR = 2.19 [1.44-3.32]). Advanced age did not have a significant effect on DCI or cerebral infarction risk. Higher in-hospital mortality was documented with increasing age (P < 0.001). A significant interaction between CVS and age for the outcome of DCI was documented, with a stronger positive effect on poor outcomes (i.e., higher odds of DCI) among patients aged <60 years compared to those aged ≥60., Conclusions: There is an inverse relationship between patient age and CVS incidence following aSAH. Nonetheless, patients ≥60 yrs had comparable DCI rates, higher in-hospital mortality, and worse functional outcomes than their younger counterparts. Routine screening and reliance on radiographic CVS as primary marker for aSAH-related complications should be reconsidered, particularly in older patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To discover effective photosensitizers for photodynamic therapy (PDT), a series of new meso -tetraphenyltetrabenzoporphyrin ( m -Ph 4 TBP) derivatives were designed, prepared, and characterized. All m -Ph 4 TBPs own two characteristic absorption bands in the range of 450-500 and 600-700 nm and have the ability to generate singlet oxygen upon photoexcitation. Most of the m -Ph 4 TBPs demonstrated high photoactivity, among which compounds I 4 , I 6 , I 12 , and I 13 induced apoptosis and also exhibited excellent photodynamic activities in vivo . Nonetheless, the liver organs of the I 4 and I 6 -PDT groups showed clear calcifications, whereas the liver tissues of the other PDT groups showed no calcification. It was indicated that compared to phenolic m -Ph 4 TBPs, glycol m -Ph 4 TBPs exhibited superior biological safety in mice. According to comprehensive evaluations, m -Ph 4 TBP I 12 displayed excellent photodynamic antitumor efficacy and biological safety and can be regarded as a promising antitumor drug candidate., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Effective antitumor immunity hinges on the specific engagement between tumor and cytotoxic immune cells, especially cytotoxic T cells. Although investigating these intercellular interactions is crucial for characterizing immune responses and guiding immunotherapeutic applications, direct and quantitative detection of tumor-T cell interactions within a live-cell context remains challenging. We herein report a photocatalytic live-cell interaction labeling strategy (CAT-Cell) relying on the bioorthogonal decaging of quinone methide moieties for sensitive and selective investigation and quantification of tumor-T cell interactions. By developing quinone methide-derived probes optimized for capturing cell-cell interactions (CCIs), we demonstrated the capacity of CAT-Cell for detecting CCIs directed by various types of receptor-ligand pairs (e.g., CD40-CD40L, TCR-pMHC) and further quantified the strengths of tumor-T cell interactions that are crucial for evaluating the antitumor immune responses. We further applied CAT-Cell for ex vivo quantification of tumor-specific T cell interactions on splenocyte and solid tumor samples from mouse models. Finally, the broad compatibility and utility of CAT-Cell were demonstrated by integrating it with the antigen-specific targeting system as well as for tumor-natural killer cell interaction detection. By leveraging the bioorthogonal photocatalytic decaging chemistry on quinone methide, CAT-Cell provides a sensitive, tunable, universal, and noninvasive toolbox for unraveling and quantifying the crucial but delicate tumor-immune interactions under live-cell settings.

CRISPR-Cas technology has transformed our ability to introduce targeted modifications, allowing unconventional animal models such as pigs to model human diseases and improve its value for food production. The main concern with using the technology is the possibility of introducing unwanted modifications in the genome. In this study, we illustrate a pipeline to comprehensively identify off-targeting events on a global scale in the genome of three different gene-edited pig models. Whole genome sequencing paired with an off-targeting prediction software tool filtered off-targeting events amongst natural variations present in gene-edited pigs. This pipeline confirmed two known off-targeting events in IGH knockout pigs, AR and RBFOX1 , and identified other presumably off-targeted loci. Independent validation of the off-targeting events using other gene-edited DNA confirmed two novel off-targeting events in RAG2/IL2RG knockout pig models. This unique strategy offers a novel tool to detect off-targeting events in genetically heterogeneous species after genome editing.

Background: Computer-assisted surgical simulation (CASS) allows more precise orthognathic surgery. However, few studies have evaluated associations between CASS-designed bilateral sagittal split osteotomy (SSO) and bone contact surface in class II mandibular asymmetry. This study aims to evaluate the effects of using computer-assisted simulation and design modification of SSO to improve bony contact in skeletal class II asymmetry., Methods: This retrospective analysis reviewed 28 patients with class II asymmetry who underwent orthognathic surgery, including 15 with modified SSO (group CS) and 13 with conventional SSO (group C). Modified SSO was designed under CASS. Operative characteristics, postoperative outcomes, and complications were collected and compared between the two groups., Results: Bony contact was found at the distal end of the proximal segment in all group CS patients, while bone gap was noted in all group C patients ( P < 0.05). Moreover, bone graft was used in four group C patients but was not used in all cases in group CS patients ( P < 0.05). A trend toward lower operative time or perioperative bleeding was noted in group CS, but without statistical significance. After 1-year follow-up, inferior alveolar nerve disturbances were noted in two group CS patients and one group C patient. Palpable bone gap with uneven jaw line was noted in two group C patients 1 year after surgery and one patient received fat graft treatment., Conclusion: The simulation-based SSO modification provides appropriate contact surface and eliminates the bone gap between proximal and distal segments in class II asymmetry., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: Patients with aneurysmal subarachnoid hemorrhage (aSAH) who survive the rupture are at risk for delayed neurologic deficits and cerebral infarction. The ideal method(s) of surveillance for cerebral vasospasm, and the link between radiographic vasospasm and delayed neurologic deficits, remain controversial. We instituted a postbleed day 7 angiography protocol with the stated goals of identification of vasospasm, improving neurologic outcomes, and possibly lowering cost of care., Methods: We conducted a quality improvement project in which we retrospectively analyzed consecutive cases of aSAH from a single institution over a 5-year period. Patients were excluded if they did not receive treatment for their aneurysm or were < 18 years of age. We analyzed demographic and outcome information for patients managed by protocolled angiography versus those who were managed by as-needed endovascular rescue therapy. Statistical tests were performed comparing means and proportions in both cohorts, as appropriate., Results: In total, 223 patients were identified who met inclusion criteria. In total, 157 patients were identified in the protocolled day 7 angiography group, and 66 were in the nonprotocolled angiography group. Demographics were similar between the day 7 angiogram and medical management cohorts, except for a higher mean age among the latter group (p = 0.016). The protocolled angiography group underwent a significantly greater number of angiograms (p < 0.001) and had a significantly higher cost of hospitalization ($240,327 vs. $205,719, p = 0.03), with no significant difference in rate of cerebral infarction, length of intensive care unit stay, length of hospital stay, discharge location, or discharge modified Rankin Score., Conclusions: This cohort comparison analysis draws into question the practice of protocolized cerebral angiography in patients with aSAH., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Ischemic and hemorrhagic stroke incidence tends to be higher among minority racial and ethnic groups. The effect of race and ethnicity following an aneurysmal subarachnoid hemorrhage (aSAH) remains poorly understood. Thus, we aimed to explore the association between race and ethnicity and aSAH outcomes., Methods: Single-center retrospective review of patients with aSAH from January 2009 to March 2023. Primary outcome was in-hospital mortality. Secondary outcomes included delayed cerebral ischemia, cerebral infarction, radiographic and symptomatic vasospasm, pulmonary complications, epileptic seizures, external ventricular drain placement, and modified Rankin Scale score at discharge and 3-month follow-up. Associations between race and ethnicity and outcomes were assessed using binary and ordinal regression models, with multivariable models adjusted for significant covariates., Results: A total of 1325 patients with subarachnoid hemorrhage presented to our center. Among them, 443 cases were excluded, and data from 882 patients with radiographically confirmed aSAH were analyzed. Distribution by race and ethnicity was 40.8% (n=360) White, 31.4% (n=277) Hispanic, 22.1% (n=195) Black, and 5.7% (n=50) Asian. Based on Hunt-Hess and modified Fisher grade, aSAH severity was similar among groups ( P =0.269 and P =0.469, respectively). In-hospital mortality rates were highest for Asian (14.0%) and Hispanic (11.2%) patients; however, after adjusting for patient sex, age, health insurance, smoking history, alcohol and substance abuse, and aneurysm treatment, the overall likelihood was comparable to White patients. Hispanic patients had higher risks of developing cerebral infarction (adjusted odds ratio, 2.17 [1.20-3.91]) and symptomatic vasospasm (adjusted odds ratio, 1.64 [1.05-2.56]) than White patients and significantly worse discharge modified Rankin Scale scores (adjusted odds ratio, 1.44 [1.05-1.99]). Non-White patients also demonstrated a lower likelihood of 0 to 2 discharge modified Rankin Scale scores (adjusted odds ratio, 0.71 [0.50-0.98]). No significant interactions between race and ethnicity and age or sex were found for in-hospital mortality and functional outcomes., Conclusions: Our study identified significant differences in cerebral infarction and symptomatic vasospasm risk between Hispanic and White patients following aSAH. A higher likelihood of worse functional outcomes at discharge was found among non-White patients. These findings emphasize the need to better understand predisposing risk factors that may influence aSAH outcomes. Efforts toward risk stratification and patient-centered management should be pursued., Competing Interests: Disclosures Dr Becerril-Gaitan receives research funding through the National Institutes of Health (NIH; 1U01NS102289 and 1UF1NS120871). Dr Chen receives research funding through NIH (1U01NS102289 and 1UF1NS120871). The other authors report no conflicts.

Ultrasensitive protein identification is of paramount importance in basic research and clinical diagnostics but remains extremely challenging. A key bottleneck in preventing single-molecule protein sequencing is that, unlike the revolutionary nucleic acid sequencing methods that rely on the polymerase chain reaction (PCR) to amplify DNA and RNA molecules, protein molecules cannot be directly amplified. Decoding the proteins via amplification of certain fingerprints rather than the intact protein sequence thus represents an appealing alternative choice to address this formidable challenge. Herein, we report a proof-of-concept method that relies on residue-resolved DNA barcoding and composition code counting for amplifiable protein fingerprinting (AmproCode). In AmproCode, selective types of residues on peptides or proteins are chemically labeled with a DNA barcode, which can be amplified and quantified via quantitative PCR. The operation generates a relative ratio as the residue-resolved 'composition code' for each target protein that can be utilized as the fingerprint to determine its identity from the proteome database. We developed a database searching algorithm and applied it to assess the coverage of the whole proteome and secretome via computational simulations, proving the theoretical feasibility of AmproCode. We then designed the residue-specific DNA barcoding and amplification workflow, and identified different synthetic model peptides found in the secretome at as low as the fmol/L level for demonstration. These results build the foundation for an unprecedented amplifiable protein fingerprinting method. We believe that, in the future, AmproCode could ultimately realize single-molecule amplifiable identification of trace complex samples without further purification, and it may open a new avenue in the development of next-generation protein sequencing techniques., (© The Author(s) 2024. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

The prevalence of obesity and morbid obesity in Taiwan has risen sharply in recent decades, as in other parts of the world, necessitating urgent action to prevent and curb its detrimental effects. Asian populations are susceptible to the repercussions of obesity at a lower body weight. A higher BMI is associated with more frequent outpatient visits, in-hospital admissions, higher medical costs, and a lower quality of life. However, effective weight management approaches are unlikely to be maintained in the long term without assimilation into daily lifestyle practices. This qualitative study, based on semi-structured interviews with 14 doctors, dieticians, and nurses who work to control the weight of people with obesity, explored and identified multilevel barriers in the context of daily life to improve the efficacy and execution of weight management strategies. They considered diets, physical activity, and sleep as key weight management activities. The cultural and psychosocial aspects of daily life were observed to have an impact upon weight management, particularly family conflicts due to cultural dynamics and socially and culturally reinforced food practices. To improve population weight, less-recognised aspects need to be addressed alongside the inclusion of mental health specialists in weight management protocols and policy interventions to minimise obesogenic practices and create environments conducive to weight management.

Introduction: Free flap transfer for head and neck defects has gained worldwide acceptance. Because flap failure is a devastating outcome, studies have attempted to identify risk factors-including renal failure. We sought to determine whether end-stage renal disease (ESRD) patients undergoing dialysis are at increased risk of flap failure following microsurgical head and neck reconstruction., Patients and Methods: The study's participants were patients who underwent free flap reconstruction in the head and neck region at Hualien Tzu Chi Hospital between January 2010 and December 2019. We used the National Health Insurance "Specific Diagnosis and Treatment Code" to identify patients undergoing dialysis; these patients comprised the dialysis group, whose members were matched to a non-dialysis group for age and gender. The dependent variables were flap survival rate, take-back rate, and flap failure risk between the dialysis and non-dialysis groups., Results: We included 154 patients in the dialysis (n = 14) and non-dialysis (n = 140) groups. The groups were similar in terms of age and most comorbidities, except diabetes mellitus, hypertension, and coronary artery disease, which were more prevalent in the dialysis group. The dialysis and non-dialysis groups had similar flap survival rates (100% vs. 92.9%; p = .600). Twenty-three patients underwent take-back surgery, most in the non-dialysis group (14.3% vs. 15.0%; p = 1.000). Patients in the dialysis group were more likely to have prolonged intensive care unit stays; however, dialysis alone did not predict flap failure (OR: 0.83; p = .864)., Conclusion: This study found no significant differences in free flap survival and take-back rates between patients with and without dialysis. Dialysis did not increase the risk of flap failure following microsurgical head and neck reconstruction in this study; however, prospective, randomized controlled trials are needed., (© 2024 Wiley Periodicals LLC.)

Background: Septated chronic subdural hematomas (cSDH) have high rates of recurrence despite surgical evacuation. Middle meningeal artery embolization (MMAE) has emerged as a promising adjuvant for secondary prevention, yet its efficacy remains ill-defined., Methods: This is a retrospective review of septated cSDH cases treated at our institution. The surgery-only group was derived from cases performed before 2018, and the surgery+MMAE group was derived from cases performed 2018 or later. The primary outcome was reoperation rate. Secondary outcomes were recurrence, change in hematoma thickness, and midline shift., Results: A total of 34 cSDHs in 28 patients (surgery+MMAE) and 95 cSDHs in 83 patients (surgery-only) met the inclusion criteria. No significant difference in baseline characteristics between groups was identified. The reoperation rate was significantly higher in the surgery-only group (n = 16, 16.8%) compared with the surgery+MMAE cohort (n = 0, 0.0%) (p=0.006). A reduced incidence of recurrence (p=0.011) was also seen in the surgery+MMAE group., Conclusions: MMAE for septated cSDH was found to be highly effective in preventing recurrence and reoperation. MMAE is an adjunct to surgical evacuation may be of particular benefit in this patient cohort., Competing Interests: Declaration of Competing Interest The authors have no financial interest in items described in this submissionon., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cellular context is crucial for understanding the complex and dynamic kinase functions in health and disease. Systematic dissection of kinase-mediated cellular processes requires rapid and precise stimulation ('pulse') of a kinase of interest, as well as global and in-depth characterization ('chase') of the perturbed proteome under living conditions. Here we developed an optogenetic 'pulse-chase' strategy, termed decaging kinase coupled proteomics (DeKinomics), for proteome-wide profiling of kinase-driven phosphorylation at second-timescale in living cells. We took advantage of the 'gain-of-function' feature of DeKinomics to identify direct kinase substrates and further portrayed the global phosphorylation of understudied receptor tyrosine kinases under native cellular settings. DeKinomics offered a general activation-based strategy to study kinase functions with high specificity and temporal resolution under living conditions., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The present study evaluated the three-dimensional changes of the pharyngeal airway after orthognathic surgery (OGS) in patients with unilateral and bilateral clefts, and in unilateral cleft patients with and without pharyngeal flap (PF)., Methods: Forty-five patients with unilateral or bilateral clefts undergoing OGS were enrolled. Cone-beam computed tomographic images were obtained before and after OGS. We measured the pharyngeal airway volumes, minimal cross-sectional area, and the horizontal displacement of facial landmarks., Results: The patients with bilateral cleft exhibited smaller initial velopharyngeal volume (unilateral, 8623 mm 3 ; bilateral, 7781 mm 3 ; P = 0.211), whereas the velopharyngeal volume increased significantly with a median of 744 mm 3 after OGS ( P = 0.031). The median horizontal displacement of A point was 2.9 and 2.6 mm among the patients with unilateral and bilateral clefts, respectively ( P = 0.276), and the median horizontal displacement of B point was -2.9 and -3.3 mm among patients with unilateral and bilateral clefts, respectively ( P = 0.618). The unilateral cleft patients with PF exhibited lower initial velopharyngeal volume (patients with a history of PF surgery, 7582 mm 3 ; patients without a history of PF surgery, 8756 mm 3 ; P = 0.129) and a lower increase in velopharyngeal volume (patients with a history of PF surgery, 437 mm 3 ; patients without a history of PF surgery, 627 mm 3 ; P = 0.739) after OGS., Conclusions: Midface hypoplasia and the decrease in the velopharyngeal volume were more prominent among the bilateral cleft patients and the unilateral cleft patients with PF. After OGS, the velopharyngeal volume increased considerably among the bilateral cleft patients, but no considerable differences were noted among the unilateral cleft patients with PF., Clinical Question/level of Evidence: Risk, II., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Objective: To identify risk factors associated with adverse airway events (AAEs) in primary oral cancer patients undergoing tumor ablation followed by free tissue transfer without prophylactic tracheostomy., Methods: We retrospectively collected primary oral cancer patients who underwent tumor ablation surgery following free-tissue transfer without prophylactic tracheostomy during February 2017 to June 2019 in Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan. 379 patients were included. Data were analysed from 2020 to 2021. Demographics, comorbidities, intraoperative variables and postoperative respiration profile were obtained from the medical record. Main outcome was postoperative AAEs, including requirement of endotracheal intubation after extubation and tracheostomy after prolonged intubation., Results: Of the 379 patients, postoperative AAEs happened in 29 patients (7.6 %). In reintubation group, patients were older with more diabetes mellitus, hypertension and cerebrovascular disease. These patients had lower preoperative hemoglobin, creatinine, and albumin level with more intraoperative blood transfusion. In postoperative respiration profile, rapid shallow breathing index (RSBI) and PaO2/FiO2 (PF) ratio were poorer. On multivariate analysis, patient's age, tumor location, and cross-midline segmental mandibulectomy and a lower PF ratio were independent risk factors for postoperative AAEs., Conclusions: In head and neck cancer patients that underwent tumor ablation followed by free tissue transfer without prophylactic tracheostomy, patient's age, tumor location, cross-midline segmental mandibulectomy and P/F ratio are associated with postoperative AAEs., 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. Published by Elsevier B.V.)

Tryptophan (Trp) plays a critical role in the regulation of protein structure, interactions and functions through its π system and indole N-H group. A generalizable method for blocking and rescuing Trp interactions would enable the gain-of-function manipulation of various Trp-containing proteins in vivo, but generating such a platform remains challenging. Here we develop a genetically encoded N 1 -vinyl-caged Trp capable of rapid and bioorthogonal decaging through an optimized inverse electron-demand Diels-Alder reaction, allowing site-specific activation of Trp on a protein of interest in living cells. This chemical activation of a genetically encoded caged-tryptophan (Trp-CAGE) strategy enables precise activation of the Trp of interest underlying diverse important molecular interactions. We demonstrate the utility of Trp-CAGE across various protein families, such as catalase-peroxidases and kinases, as translation initiators and posttranslational modification readers, allowing the modulation of epigenetic signalling in a temporally controlled manner. Coupled with computer-aided prediction, our strategy paves the way for bioorthogonal Trp activation on more than 28,000 candidate proteins within their native cellular settings., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Transcatheter aortic valve replacement (TAVR) is a well-established procedure using a catheter-introduced valve prosthesis for patients with severe aortic stenosis (AS). This retrospective study investigated sex-related differences in pre- and post-TAVR clinical and hemodynamic outcomes and analyzed data of the first 100 cases at Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUH) between December 2013 and December 2021. Baseline characteristics, procedural outcomes, mortality rates, and echocardiographic parameters were analyzed and compared between sexes. Among the 100 patients, male (46%) and female (54%) were of similar age (mean age, male 86.0 years vs. female 84.5 years) and of the same severity of AS (mean pressure gradient, male 47.5 mmHg vs. female 45.7 mmHg) at the time receiving the TAVR procedure. Women had smaller aortic valve areas calculated by continuity equation (0.8 ± 0.3 cm 2 vs. 0.7 ± 0.2 cm 2 , p < 0.001). In addition, women had better left ventricle ejection fraction (59.6 ± 14.0% vs. men 54.7 ± 17.2%, p < 0.01). In the post-TAVR follow-up, regression of left ventricle mass and dimension was better in women than in men. None of the patient died within 30 days after the procedure, and women tended to have a more favorable survival than men (2-year mortality and overall mortality rate in 8.3 year, women 9.1% and 22.2% vs. men 22.2% and 34.8%; p = 0.6385 and 0.1277, respectively). In conclusion, the sex-based difference in post-TAVR regression of LV remodeling suggests a need for sex-based evaluation for patients with severe AS and their post TAVR follow-up., (© 2024 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

In situ profiling of subcellular proteomics in primary living systems, such as native tissues or clinic samples, is crucial for understanding life processes and diseases, yet challenging due to methodological obstacles. Here we report CAT-S, a bioorthogonal photocatalytic chemistry-enabled proximity labeling method, that expands proximity labeling to a wide range of primary living samples for in situ profiling of mitochondrial proteomes. Powered by our thioQM labeling warhead development and targeted bioorthogonal photocatalytic chemistry, CAT-S enables the labeling of mitochondrial proteins in living cells with high efficiency and specificity. We apply CAT-S to diverse cell cultures, dissociated mouse tissues as well as primary T cells from human blood, portraying the native-state mitochondrial proteomic characteristics, and unveiled hidden mitochondrial proteins (PTPN1, SLC35A4 uORF, and TRABD). Furthermore, CAT-S allows quantification of proteomic perturbations on dysfunctional tissues, exampled by diabetic mouse kidneys, revealing the alterations of lipid metabolism that may drive disease progression. Given the advantages of non-genetic operation, generality, and spatiotemporal resolution, CAT-S may open exciting avenues for subcellular proteomic investigations of primary samples that are otherwise inaccessible., (© 2024. The Author(s).)

Background: Recruitment of participants is the greatest risk to completion of most clinical trials, with 20-40% of trials failing to reach the targeted enrollment. This is particularly true of trials of central nervous system (CNS) therapies such as intervention for chronic stroke. The PISCES III trial was an invasive trial of stereotactically guided intracerebral injection of CTX0E03, a fetal derived neural stem cell line, in patients with chronic disability due to ischemic stroke. We report on the experience using a novel hybrid recruitment approach of a patient-facing portal to self-identify and perform an initial screen for general trial eligibility (tier 1), followed by phone screening and medical records review (tier 2) prior to a final in-person visit to confirm eligibility and consent., Methods: Two tiers of screening were established: an initial screen of general eligibility using a patient-facing web portal (tier 1), followed by a more detailed screen that included phone survey and medical record review (tier 2). If potential participants passed the tier 2 screen, they were referred directly to visit 1 at a study site, where final in-person screening and consent were performed. Rates of screening were tracked during the period of trial recruitment and sources of referrals were noted., Results: The approach to screening and recruitment resulted in 6125 tier 1 screens, leading to 1121 referrals to tier 2. The tier 2 screening resulted in 224 medical record requests and identification of 86 qualifying participants for referral to sites. The study attained a viable recruitment rate of 6 enrolled per month prior to being disrupted by COVID 19., Conclusions: A tiered approach to eligibility screening using a hybrid of web-based portals to self-identify and screen for general eligibility followed by a more detailed phone and medical record review allowed the study to use fewer sites and reduce cost. Despite the difficult and narrow population of patients suffering moderate chronic disability from stroke, this strategy produced a viable recruitment rate for this invasive study of intracranially injected neural stem cells., Trial Registration: ClinicalTrials.gov Identifier: NCT03629275., (© 2024. The Author(s).)

Objective: We examined the relationship between factors of middle ear conditions and the outcome of ossiculoplasty in chronic otitis media (COM) by measuring the improvement in the air-bone gap (ABG) and air conduction threshold (TAC). Methods: This retrospective study analyzed 76 patients (77 ears) who underwent ossiculoplasty from among 520 COM patients who underwent tympanoplasty based on the maximum preservation of the original ossicles. The reconstructed ossicular chain was performed by preserving or utilizing the remaining malleus in all cases with the presence of the malleus manubrium. Patients with eardrum adhesion, cholesteatoma, and cholesterol granuloma were defined as having a compromised middle ear condition (Group A), and those without as having an uncompromised middle ear condition (Group B). In each group, pure-tone audiometry was performed preoperatively and postoperatively, and improvements in the ABG and TAC were compared. The effects of the types of tympanoplasty and the method of ossiculoplasty (columella versus incus interposition) on postoperative ABG and TAC were also compared. Results: The postoperative ABG improvement in Group B was significantly higher than that in Group A [β = 7.31, 95% confidence interval (CI) = 1.93-12.69, P  < .05]. Type III minor columella tympanoplasty yielded significantly better results than type III major and type Vb tympanoplasty (β = 11.42, 95% CI = 5.16-17.68, P  < .01). There were no significant differences in the postoperative ABG or TAC between the reconstruction groups with and without preservation of malleus. Conclusions: Our results indicate that complex cases compromised by adhesions, cholesteatoma, and cholesterol granuloma have worse outcomes regarding hearing improvement and success rates, while those with intact stapes suprastructure have better outcomes. Malleus was maximally preserved in the patients of this study; however, this showed no significant prognostic benefit in hearing., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Early clinical trials validating endovascular therapy (EVT) for emergent large vessel occlusion (ELVO) ischemic stroke in the anterior circulation initially focused on patients with small or absent completed infarctions (ischemic cores) to maximize the probability of detecting a clinically meaningful and statistically significant benefit of EVT. Subsequently, real-world experience suggested that patients with large core ischemic strokes (LCS) at presentation may also benefit from EVT. Several large, retrospective, and prospective randomized clinical trials have recently been published that further validate this approach. These guidelines aim to provide an update for endovascular treatment of LCS., Methods: A structured literature review of LCS studies available since 2019 and grading the strength and quality of the evidence was performed. Recommendations were made based on these new data by consensus of the authors, with additional input from the full SNIS Standards and Guidelines Committee and the SNIS Board of Directors., Results: The management of ELVO strokes with large ischemic cores continues to evolve. The expert panel agreed on several recommendations: Recommendation 1: In patients with anterior circulation ELVO who present within 24 hours of last known normal with large infarct core (70-149 mL or ASPECTS 3-5) and meet other criteria of RESCUE-Japan LIMIT, SELECT2, ANGEL-ASPECT, TESLA, TENSION, or LASTE trials, thrombectomy is indicated (Class I, Level A). Recommendations 2-7 flow directly from recommendation 1. Recommendation 2: EVT in patients with LCS aged 18-85 years is beneficial (Class I, Level A). Recommendation 3: EVT in patients with LCS >85 years of age may be beneficial (Class I, Level B-R). Recommendation 4: Patients with LCS and NIHSS score 6-30 benefit from EVT in LCS (Class I, Level A). Recommendation 5: Patients with LCS and NIHSS score <6 and >30 may benefit from EVT in LCS (Class IIa, Level A). Recommendation 6: Patients with LCS and low baseline mRS (0-1) benefit from EVT (Class I, Level A). Recommendation 7: Patients with LCS and time of last known well 0-24 hours benefit from EVT (Class I, Level A). Recommendation 8: It is recommended that patients with ELVO LCS who also meet the criteria for on-label or guideline-directed use of IV thrombolysis receive IV thrombolysis, irrespective of whether endovascular treatments are being considered (Class I, Level B-NR)., Conclusions: The indications for endovascular treatment of ELVO strokes continue to expand and now include patients with large ischemic cores on presentation. Further prospective randomized studies, including follow-up to assess the population-based efficacy of treating patients with LCS, are warranted., Competing Interests: Competing interests: The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health (“NIH”). SWH is an ex officio member of the SNIS Board of Directors. His research is supported by NIH (R01CA194533, R42CA265316, R01EB012031). He has consulting agreements with Medtronic, Imperative, and Cerenovus and an ownership interest in Filtro. His institution has contract and grant support from Siemens, Stryker Neurovascular, and Route 92. CMS has contract or research support from Penumbra, Medtronic, MIVI, Cerenovus, Stryker, Balt, and ownership interest in NTI. None of the other authors have relevant disclosures. JKB serves as a consultant for Stryker, Microvention, Cerenovus, Balt, Medtronic, Q’Apel Medical, Longeviti Neuro Solutions, and Siemens Healthineers. DR consults for Q’Apel, Penumbra, and Phenox. MRA is a member of the SNIS Board of Directors and a member of the editorial board for the JNIS. His research is supported by NIH (R21 DC016097-01A1, R56HL149124-01) and DOD (PR201091). He has consulting agreements with Medtronic, Stryker, Microvention, and VS3 Medical and ownership interest in VS3 Medical. His institution has contract and grant support from VS3 Medical., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tools predicting intracranial dural arteriovenous fistulas (dAVFs) treatment outcomes remain scarce. This study aimed to use a multicenter database comprising more than 1000 dAVFs to develop a practical scoring system that predicts treatment outcomes., Methods: Patients with angiographically confirmed dAVFs who underwent treatment within the Consortium for Dural Arteriovenous Fistula Outcomes Research-participating institutions were retrospectively reviewed. A subset comprising 80% of patients was randomly selected as training dataset, and the remaining 20% was used for validation. Univariable predictors of complete dAVF obliteration were entered into a stepwise multivariable regression model. The components of the proposed score (VEBAS) were weighted based on their ORs. Model performance was assessed using receiver operating curves (ROC) and areas under the ROC., Results: A total of 880 dAVF patients were included. Venous stenosis (presence vs absence), elderly age (<75 vs ≥75 years), Borden classification (I vs II-III), arterial feeders (single vs multiple), and past cranial surgery (presence vs absence) were independent predictors of obliteration and used to derive the VEBAS score. A significant increase in the likelihood of complete obliteration (OR=1.37 (1.27-1.48)) with each additional point in the overall patient score (range 0-12) was demonstrated. Within the validation dataset, the predicted probability of complete dAVF obliteration increased from 0% with a 0-3 score to 72-89% for patients scoring ≥8., Conclusion: The VEBAS score is a practical grading system that can guide patient counseling when considering dAVF intervention by predicting the likelihood of treatment success, with higher scores portending a greater likelihood of complete obliteration., Competing Interests: Competing interests: Dr. Kansagra is a consultant for Medtronic, Microvention, and Penumbra. Dr. Lanzino is a consultant for Superior Medical Editing. Dr. Kim is a MicroVention consultant, cofounder of SPI Surgical, and has NINDS grants. Dr. Levitt is a consultant for Medtronic and Minnetronix; he has NINDS, AHA, Stryker, and Medtronic grants and equity interest in Proprio. Dr. Gross is a MicroVention and Medtronic consultant. Dr. Derdeyn is a consultant for Penumbra, Genae, and Nono, and receives the support of non-study-related clinical or research efforts from Siemens Healthineers. Dr. Alaraj is a consultant for Cerenovus and Siemens, and has an NIH grant. Dr. Starke has consulting teaching agreements with Penumbra, Abbott, Medtronic, InNeruCo, and Cerenovus. Dr. Peterson is a consultant for Stryker, Penumbra, Medtronic, and Cerenovus, and has a stockholder in RIST Neurovascular. Dr. Samaniego is a MicroVention consultant. Dr. Piccirillo is a Bind-On-Demand insurance medical officer. Dr. Charbel is a Transonic consultant. Dr. Yavagal is a Medtronic, Cerenovus, Rapid Medical, and Neural Analytics consultant. The other authors have no personal, financial, or institutional interests to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The simplest and most abundant dicarbonyl in the atmosphere, glyoxal ((CHO) 2 ), and its geminal diols via stepwise hydration reactions, monohydrate (CHOCH(OH) 2 ) and dihydrate ((HC(OH) 2 ) 2 ), are proposed to be responsible for the generation of atmospheric acid and the increase in aerosol viscosity. In this work, the hydrates of glyoxal were prepared by dissolving glyoxal trimer dihydrate (C 6 H 10 O 8 ) in H 2 O and D 2 O and probed by infrared absorption spectrometry at varied temperatures. In glyoxal aqueous solution at a concentration of < 1 wt%, the monomeric dihydrate is predominant. Coupled with the predicted vibrational wavenumbers and the corresponding intensities using the B3LYP/aug-cc-pVTZ method, the intense IR bands at 1075 cm -1 and 1073 cm -1 are attributed to the C-O stretching modes of dihydrate and deuterium substituted dihydrate at the hydroxyl groups, denoted as d 4 -dihydrate ((HC(OD) 2 ) 2 ). Upon heating of the d 4 -dihydrate solution to cause dehydration, a new band generated at 1745 cm -1 was attributed to the C=O stretching mode of d 2 -monohydrate (CHOCH(OD) 2 ). Comparing the predicted wavenumbers of glyoxal monohydrate and the observed vibrational wavenumbers of the glycolaldehyde (HCOCH 2 OH), the wavenumber of the C=O stretching mode of monohydrate is reasonably presumed to be 1745 ± 5 cm -1 . These infrared characterizations of the glyoxal hydrates provide suitable detection windows for further investigating the roles of glyoxal and its hydrates in atmospheric and aerosol chemistry, as well as studying the relevant reaction kinetics., 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.)

Carbon dioxide (CO 2 ) is the node of alleviating global climate change and supporting living organisms on Earth. Currently, the warming climate and the growing population demand enhanced CO 2 fixation for a sustainable future, which stimulates innovations in biotechnology to tackle these challenges. To this endeavor, synthetic biology and metabolic engineering are enabling a promising approach to engineer synthetic carbon fixation in heterotrophic organisms combining the advantages of both autotrophs and heterotrophs. Here, we review the current advances in constructing synthetic CO 2 fixation pathways and discuss the underlying design principles with confronting challenges. Moreover, we highlight the application scenarios of these designs at different concentrations of CO 2 , and how sustainable bioproduction can be improved. We also foresee the future of engineering synthetic carbon fixation pathways for carbon recycling., 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.)

Biomolecule labeling in living systems is crucial for understanding biological processes and discovering therapeutic targets. A variety of labeling warheads have been developed for multiple biological applications, including proteomics, bioimaging, sequencing, and drug development. Quinone methides (QMs), a class of highly reactive Michael receptors, have recently emerged as prominent warheads for on-demand biomolecule labeling. Their highly flexible functionality and tunability allow for diverse biological applications, but remain poorly explored at present. In this regard, we designed, synthesized, and evaluated a series of new QM probes with a trifluoromethyl group at the benzyl position and substituents on the aromatic ring to manipulate their chemical properties for biomolecule labeling. The engineered QM warhead efficiently labeled proteins both in vitro and under living cell conditions, with significantly enhanced activity compared to previous QM warheads. We further analyzed the labeling efficacy with the assistance of density functional theory (DFT) calculations, which revealed that the QM generation process, rather than the reactivity of QM, contributes more predominantly to the labeling efficacy. Noteworthy, twelve nucleophilic residues on the BSA were labeled by the probe, including Cys, Asp, Glu, His, Lys, Asn, Gln, Arg, Ser, Thr, Trp and Tyr. Given their high efficiency and tunability, these new QM warheads may hold great promise for a broad range of applications, especially spatiotemporal proteomic profiling for in-depth biological studies., 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 Inc. All rights reserved.)

Background: The current fungal meningitis outbreak caused by contaminated epidural anesthesia with Fusarium solani among patients who underwent surgical procedures in Matamoros, Mexico remains a cause of concern. Its association with an increased susceptibility for cerebrovascular complications (CVC) has not been reported. This single-center study describes 3 patients with a unique pattern of CVC attributed to fungal meningitis., Methods: A retrospective case series of patients diagnosed with fungal meningitis following surgical procedures under contaminated epidural anesthesia who developed a unique pattern of CVC during their hospitalization., Results: Three female patients (mean age, 35 years) with CVC due to iatrogenic fungal meningitis were included. Positive Fungitell β-D-glucan assay in cerebrospinal fluid was documented in all cases, and F . solani was confirmed by polymerase chain reaction in case 3. All cases were complicated by severe vertebrobasilar circulation vasculopathy and arterial dissections with resultant subarachnoid hemorrhage and intraventricular hemorrhage, ultimately leading to patients' death., Conclusions: The death toll from the ongoing fungal meningitis outbreak keeps rising, underscoring the need for early recognition and aggressive treatment. We highlight the risk for vertebrobasilar circulation CVC among these patients. The angioinvasive nature of F . solani is yet to be clarified; however, a clear pattern has been observed. Public health awareness should be raised and a strong response should be pursued., Competing Interests: Disclosures Dr Choi reports stock options in ACASTI Pharm. Dr P.R. Chen reports grants from Stryker. The other authors report no conflicts.

Background: Presenilin 1 (PSEN1) is one of the genes linked to the prevalence of early onset Alzheimer's disease. In mice, inactivation of Psen1 leads to developmental defects, including vertebral malformation and neural development. However, little is known about the role of PSEN1 during the development in other species., Objective: To investigate the role of PSEN1 in vertebral development and the pathogenic mechanism of neurodegeneration using a pig model., Methods: CRISPR/Cas9 system was used to generate pigs with different mutations flanking exon 9 of PSEN1, including those with a deleted exon 9 (Δexon9). Vertebral malformations in PSEN1 mutant pigs were examined by X-ray, micro-CT and micro-MRI. Neuronal cells from the brains of PSEN1 mutant pigs were analyzed by immunoflourescence, followed by image analysis including morphometric evaluation via image J and 3D reconstruction., Results: Pigs with a PSEN1 null mutation (Δexon9-12) died shortly after birth and had significant axial skeletal defects, whereas pigs carrying at least one Δexon9 allele developed normally and remained healthy. Effects of the null mutation on abnormal skeletal development were also observed in fetuses at day 40 of gestation. Abnormal distribution of astrocytes and microglia in the brain was detected in two PSEN1 mutant pigs examined compared to age-matched control pigs. The founder pigs were bred to establish and age PSEN1ΔE9/+ pigs to study their relevance to clinical Alzheimer's diseases., Conclusions: PSEN1 has a critical role for normal vertebral development and PSEN1 mutant pigs serves as novel resources to study Alzheimer's disease.

Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current strategies often deliver either the prodrug or its complementary activator to the tumor with a monomechanism targeted mechanism, which cannot achieve the desired antitumor efficacy and safety profile. The orchestration of two distinct and orthogonal mechanisms should overcome the hierarchical heterogeneity of solid tumors to improve the delivery efficiency of both components simultaneously for bio-orthogonal prodrug therapies. We herein developed a dual-mechanism targeted bioorthogonal prodrug therapy by integrating two orthogonal, receptor-independent tumor-targeting strategies. We first employed the endogenous albumin transport system to generate the in situ albumin-bound, bioorthogonal-caged doxorubicin prodrug with extended plasma circulation and selective accumulation at the tumor site. We then employed enzyme-instructed self-assembly (EISA) to specifically enrich the bioorthogonal activators within tumor cells. As each targeted delivery mode induced an intrinsic pharmacokinetic profile, further optimization of the administration sequence according to their pharmacokinetics allowed the spatiotemporally controlled prodrug activation on-target and on-demand. Taken together, by orchestrating two discrete and receptor-independent targeting strategies, we developed an all-small-molecule based bioorthogonal prodrug system for dual-mechanism targeted anticancer therapies to maximize therapeutic efficacy and minimize adverse drug reactions for chemotherapeutic agents.

Background: Perampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER., Method: We analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups., Results: Overall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration., Conclusion: PER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Ltd.)